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"abstract": "Carotidynia is characterised by inflammation limited to the common carotid artery, which has been recognised as a distinct disease entity by advanced vascular imaging. Although most cases of carotidynia are idiopathic, we herein present a case of carotidynia after anticancer chemotherapy. A 64-year-old male patient received docetaxel followed by granulocyte-colony stimulating factor (G-CSF) for the treatment of lung squamous carcinoma. After the treatment, bilateral cervical pain developed. Vascular imaging, including magnetic resonance imaging, computed tomography and ultrasonography, showed characteristics specific for carotidynia. Although there was no strong confirmation using tests such as a challenge test, our observations suggest that docetaxel or G-CSF could be a causative drug triggering carotidynia.",
"affiliations": "Division of Respiratory Medicine, Nihon University School of Medicine, 30-1 Ohyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan. shayashi@med.nihon-u.ac.jp.",
"authors": "Hayashi|Shinichi|S|;Maruoka|Shuichiro|S|;Takahashi|Noriaki|N|;Hashimoto|Shu|S|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel",
"country": "Singapore",
"delete": false,
"doi": "10.11622/smedj.2014127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0037-5675",
"issue": "55(9)",
"journal": "Singapore medical journal",
"keywords": null,
"medline_ta": "Singapore Med J",
"mesh_terms": "D000970:Antineoplastic Agents; D017536:Carotid Artery, Common; D000077143:Docetaxel; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007249:Inflammation; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D043823:Taxoids; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "0404516",
"other_id": null,
"pages": "e142-4",
"pmc": null,
"pmid": "25273942",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7249508;8208434;20407388;11566713;21246181;15728007;22023945;20091034;19782860;3048700;19888788;14574303;6016255;18983217;14979299",
"title": "Carotidynia after anticancer chemotherapy.",
"title_normalized": "carotidynia after anticancer chemotherapy"
} | [
{
"companynumb": "JP-ACCORD-026500",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS"
},
"drugadd... |
{
"abstract": "Overuse or misuse of antibiotics is one reason for the emergence of antibiotic resistance. Here, we present four cases where antibiotics were started (or proposed) although they were not needed. The first case was asymptomatic bacteriuria where antibiotic therapy was initiated but then stopped after the case was referred to the infectious diseases (ID) service. The second case was a cholangiocarcinoma patient in whom four antibiotics were continued after completing the treatment for a remote infection. Hence, the ID team discontinued the unneeded therapy after considering that the inflammatory process was due to malignancy. The third case was a patient who was diagnosed with pneumonia in whom both antibiotics and an antiviral were initiated. However, antibiotic therapy was continued despite the lack of bacterial growth in the respiratory culture. Thus, it wasn't until the ID team evaluated the case and decided that the pneumonia was viral in nature that antibiotic therapy was discontinued. The last case was for a patient who presented with dry cough presumed to be a pneumonia and was about to be started on antibiotics. The ID team noticed the patient had a history of decompensated congestive heart failure causing the cough. Antibiotics were not initiated when lack of clinical findings suggestive of pneumonia was also confirmed. These cases represent an example of daily occurrences of antibiotics overuse. Healthcare providers are encouraged to augment their knowledge regarding the safe and judicious use of antibiotics, as well as consulting an ID expert if doubts concerning the necessity of antibiotics arise.",
"affiliations": "PharmD, BCPS, Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, 7027 Abdullah Al-Sulaiman Road, Jeddah 22254-2265, Saudi Arabia.;PharmD, Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, 7027 Abdullah Al-Sulaiman Road, Jeddah 22254-2265, Saudi Arabia.;PharmD, Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, 7027 Abdullah Al-Sulaiman Road, Jeddah 22254-2265, Saudi Arabia.;PharmD, Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, 7027 Abdullah Al-Sulaiman Road, Jeddah 22254-2265, Saudi Arabia.;PharmD, Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, 7027 Abdullah Al-Sulaiman Road, Jeddah 22254-2265, Saudi Arabia.;PharmD, Pharmacy Practice Department, Faculty of Pharmacy, King Abdulaziz University, 7027 Abdullah Al-Sulaiman Road, Jeddah 22254-2265, Saudi Arabia.",
"authors": "Thabit|Abrar K|AK|;Turkistani|Shouq A|SA|;Alsubaie|Shahad A|SA|;Takroni|Enas A|EA|;Basaeed|Lamis F|LF|;Saadawi|Daleen W|DW|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.18683/germs.2020.1230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2248-2997",
"issue": "10(4)",
"journal": "Germs",
"keywords": "Antibiotics; infection; infectious diseases; stewardship",
"medline_ta": "Germs",
"mesh_terms": null,
"nlm_unique_id": "101596099",
"other_id": null,
"pages": "380-384",
"pmc": null,
"pmid": "33489953",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "32013238;17173212;29896067;27080992;32544153;33110790;15127367;25496207;32971291;28356901;32338547",
"title": "When antibiotics experts say no to antibiotics.",
"title_normalized": "when antibiotics experts say no to antibiotics"
} | [
{
"companynumb": "SA-ASTELLAS-2021US003886",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "Women with mechanical heart valves (MHV) requiring anticoagulation (AC) are at high risk for hemorrhagic complications. Despite guidelines to manage antenatal and peripartum AC, there are few evidence-based recommendations to guide the initiation of postpartum AC. We reviewed our institutional experience of pregnant women with MHV to lay the groundwork for recommendations of immediate postpartum AC therapy.\nThis descriptive retrospective cohort used ICD-9 and -10 codes to identify pregnant women with MHV on AC at the Yale-New Haven Hospital from 2007 to 2018. All identified patients were confirmed by chart review. Delivery hospitalization and the immediate postpartum AC management were reviewed. Maternal complications recorded were postpartum hemorrhage, transfusion, wound hematoma, intra-abdominal bleeding, stroke, valve thrombosis, and death. Further, immediate neonatal outcomes were detailed.\nForty-two pregnant women with nonnative heart valves were identified during the study period. From those pregnant women, nine had an MHV and were anticoagulated throughout gestation. Of 19 total pregnancies, 14 met the inclusion criteria. The median gestational age of the delivered pregnancies was early term (37w2d). Nine deliveries were via cesarean (64%). The median time to restart AC after birth was 6 hours. After six deliveries (43%), AC was initiated ≤6 hours postpartum. Hemorrhagic complications occurred in six cases (43%), including wound and intra-abdominal hematomas. Four cases (29%) required blood transfusion. No maternal strokes, thrombotic events, or deaths were recorded. Five (38.5%) neonates required admission to the neonatal intensive care unit.\nMHV in pregnancy was rare but was associated with significant maternal morbidity, particularly postpartum hemorrhagic complications. We noted significant variability in the timing of restarting postpartum AC and in the selected agents. Pooled institutional data and an interdisciplinary approach are recommended to minimize competing risks and sequelae of valve thrombosis and obstetrical hemorrhage and, thereby, to optimize maternal outcomes and develop evidence-based guidelines for postpartum AC management.",
"affiliations": "Department of Obstetrics, Gynecology and Reproductive Sciences, Section of Maternal-Fetal Medicine, Yale University School of Medicine, New Haven, CT, USA, roxanna.irani@ucsf.edu.;Department of Pediatrics, Section of Pediatric Cardiology, Adult Congenital Heart Program, Yale University School of Medicine, New Haven, CT, USA.;Department of Pediatrics, Section of Pediatric Cardiology, Adult Congenital Heart Program, Yale University School of Medicine, New Haven, CT, USA.;Department of Obstetrics, Gynecology and Reproductive Sciences, Section of Maternal-Fetal Medicine, Yale University School of Medicine, New Haven, CT, USA, roxanna.irani@ucsf.edu.;Department of Obstetrics, Gynecology and Reproductive Sciences, Section of Maternal-Fetal Medicine, Yale University School of Medicine, New Haven, CT, USA, roxanna.irani@ucsf.edu.;Department of Obstetrics, Gynecology and Reproductive Sciences, Section of Maternal-Fetal Medicine, Yale University School of Medicine, New Haven, CT, USA, roxanna.irani@ucsf.edu.",
"authors": "Irani|Roxanna A|RA|;Santa-Ines|Ann|A|;Elder|Robert W|RW|;Lipkind|Heather S|HS|;Paidas|Michael J|MJ|;Campbell|Katherine H|KH|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IJWH.S177547",
"fulltext": "\n==== Front\nInt J Womens HealthInt J Womens HealthInternational Journal of Women’s HealthInternational Journal of Women's Health1179-1411Dove Medical Press 10.2147/IJWH.S177547ijwh-10-663Original ResearchPostpartum anticoagulation in women with mechanical heart valves Irani Roxanna A 1*Santa-Ines Ann 2*Elder Robert W 2Lipkind Heather S 1Paidas Michael J 1Campbell Katherine H 1\n1 Department of Obstetrics, Gynecology and Reproductive Sciences, Section of Maternal-Fetal Medicine, Yale University School of Medicine, New Haven, CT, USA, roxanna.irani@ucsf.edu\n2 Department of Pediatrics, Section of Pediatric Cardiology, Adult Congenital Heart Program, Yale University School of Medicine, New Haven, CT, USACorrespondence: Roxanna A Irani, Department of Obstetrics, Gynecology and Reproductive Sciences, Section of Maternal-Fetal Medicine, University of California San Francisco, 550 16th Street, 7th Floor, San Francisco, CA 94143, USA, Tel +1 415 476 3156, Email roxanna.irani@ucsf.edu* These authors contributed equally to this work\n\n2018 25 10 2018 10 663 670 © 2018 Irani et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nWomen with mechanical heart valves (MHV) requiring anticoagulation (AC) are at high risk for hemorrhagic complications. Despite guidelines to manage antenatal and peripartum AC, there are few evidence-based recommendations to guide the initiation of postpartum AC. We reviewed our institutional experience of pregnant women with MHV to lay the groundwork for recommendations of immediate postpartum AC therapy.\n\nStudy design\nThis descriptive retrospective cohort used ICD-9 and -10 codes to identify pregnant women with MHV on AC at the Yale-New Haven Hospital from 2007 to 2018. All identified patients were confirmed by chart review. Delivery hospitalization and the immediate postpartum AC management were reviewed. Maternal complications recorded were postpartum hemorrhage, transfusion, wound hematoma, intra-abdominal bleeding, stroke, valve thrombosis, and death. Further, immediate neonatal outcomes were detailed.\n\nResults\nForty-two pregnant women with nonnative heart valves were identified during the study period. From those pregnant women, nine had an MHV and were anticoagulated throughout gestation. Of 19 total pregnancies, 14 met the inclusion criteria. The median gestational age of the delivered pregnancies was early term (37w2d). Nine deliveries were via cesarean (64%). The median time to restart AC after birth was 6 hours. After six deliveries (43%), AC was initiated ≤6 hours postpartum. Hemorrhagic complications occurred in six cases (43%), including wound and intra-abdominal hematomas. Four cases (29%) required blood transfusion. No maternal strokes, thrombotic events, or deaths were recorded. Five (38.5%) neonates required admission to the neonatal intensive care unit.\n\nConclusion\nMHV in pregnancy was rare but was associated with significant maternal morbidity, particularly postpartum hemorrhagic complications. We noted significant variability in the timing of restarting postpartum AC and in the selected agents. Pooled institutional data and an interdisciplinary approach are recommended to minimize competing risks and sequelae of valve thrombosis and obstetrical hemorrhage and, thereby, to optimize maternal outcomes and develop evidence-based guidelines for postpartum AC management.\n\nKeywords\npregnancyanticoagulationpostpartum hemorrhagemechanical heart valve\n==== Body\nPlain language summary\nWomen with mechanical heart valves are at increased risk for various complications during pregnancy and in the postpartum period. Consistent use of anticoagulation is required to reduce the risk of a blood clot forming on the mechanical valve – a life-threatening emergency. The mother’s anticoagulation is stopped during labor and delivery (or cesarean delivery) to reduce the risk of bleeding during childbirth. However, there is limited guidance on the best time to restart the anticoagulation after the birth of the baby. This study has revealed that there is a significant risk of bleeding complications in the postpartum period as well as wide variation on when the anticoagulation is restarted after delivery. Information obtained from this study will help provide guidance in developing a safer approach to start anticoagulants after childbirth. Initiation of anticoagulation after delivery should optimally minimize the risk of bleeding and the risk of blood clot formation.\n\nIntroduction\nOver the past several decades, the treatment of valvular heart disease has advanced, allowing many individuals with congenital or early acquired heart disease to go on to live full, healthy lives. As a result, women in the reproductive age with a mechanical heart valve (MHV) are increasingly pursuing pregnancy and require tight control of anticoagulation (AC) throughout gestation.1\n\nGiven the teratogenic risks of vitamin K antagonists (VKA) to the fetus,2 as well as the known thrombogenic and cardiovascular risks to the mother, women with MHVs were, in many cases, previously advised to avoid pregnancy; however, this is no longer the case. If a woman is in an otherwise well-controlled health state with appropriate cardiac function, the physiological changes of pregnancy are usually well tolerated, and AC therapy can be adjusted to minimize embryonic teratogenicity while decreasing maternal thrombogenic risk. Ideally, the pregnancy is planned after discussions with cardiologists and obstetricians, who can review maternal and fetal risks with the woman. Counseling a patient on AC options during the antepartum period requires a discussion of specific risks and benefits of various treatment options, followed by shared decision-making to determine the optimal treatment regimen. As most patients are maintained on VKA outside of pregnancy, fetal risks are critical to review in view of the dose-related response of VKA-mediated embryopathy.1,3,4 Despite recommendations for VKA to serve as the first-line antepartum treatment,5 low-molecular weight heparin (LMWH) – which does not cross the placenta and is safely used in pregnancy for other AC requirements – is increasingly identified by patients and providers as the antepartum treatment of choice despite concerns on increased maternal risk of valve thrombosis.6,7\n\nEven in experienced hands, the management of AC therapy for this high-risk patient population is a challenge. Most of the current obstetric literature focuses on antepartum AC, with guidance for transition to the intrapartum period and limited direction for the early postpartum period. The American College of Obstetrics and Gynecology recommends that AC can be reasonably resumed 4–6 hours after vaginal delivery, and 6–12 hours after a cesarean.8 However, these guidelines are directed toward women treated for thromboembolism in pregnancy and are not specific for women with MHV; of note, the optimal time to restart AC therapy in the postpartum period for women with MHV is unclear. This is, in part, due to limited investigation into the initiation of postpartum therapeutic AC in this patient population.9\n\nAlthough AC is required to prevent valve thrombosis and its sequelae, initiation of therapeutic postpartum AC in this patient population appears to be a particularly high-risk treatment. Vause et al recently reported a population-based descriptive study, which reported that women with MHV in the UK suffer from high rates of maternal mortality and morbidity.10 A large number of morbidities stemmed from hemorrhagic complications experienced in the postpartum period; however, there was no detailed description of postpartum AC management in this cohort.10,11\n\nThere are several important factors that need to be considered with regard to how to best to manage women with MHV during pregnancy; however, there is a paucity of investigation into how best to initiate early postpartum AC in this patient population. We sought to examine our institutional experience on early postpartum initiation of AC in women with MHV, with the hope of laying the groundwork for evidence-based guidelines for the resumption of postpartum AC in this high-risk population.\n\nMethods\nA descriptive retrospective analysis was conducted of pregnant women with MHV on AC therapy who delivered at a single institution. This study was approved by the Yale University Human Investigation Committee. Due to the retrospective nature of the study, individual patient consent was not required. The independent review board-approved study period spanned April 1, 2007 to February 1, 2018. The ICD, Ninth and Tenth Revisions, Clinical Modification (ICD-9-CM and ICD-10-CM) diagnosis and procedure codes for mechanical valve, mitral valve replacement, and aortic valve replacement, as well as primary or secondary diagnosis codes for pregnancy and various methods of delivery, were employed to identify patients. The electronic medical record database was implemented between 2011 and 2012; access to electronic records prior to that time was limited and, therefore, paper charts were reviewed.\n\nFor inclusion into the study, women had to have an MHV in place in the mitral or aortic position and been on AC therapy during the study period of the recorded pregnancy episode. Patients with bioprosthetic heart valves were excluded. Medical records were reviewed and verified to meet the inclusion criteria.\n\nOutcome variables included AC therapy prior to and during pregnancy, as well as prior to delivery, and was identified as VKA, LMWH, or heparin IV infusion. The AC method and timing, postdelivery, of medication reinitiation were recorded. The cohort of pregnancies was then divided into two groups: women who were restarted on AC 6 hours or less after delivery, and women who were reinitiated on AC more than 6 hours postpartum.8\n\nOther maternal outcomes recorded included primary and secondary postpartum hemorrhage, wound hematoma, intra-abdominal bleed, vaginal hematoma, need for reoperation or other intervention, valve thrombosis, known cardiac rhythm with management and complications, stroke, length of hospital stay, and maternal death. The timing and indication for delivery were identified.\n\nFetal and neonatal outcomes were recorded. They included intrauterine fetal growth restriction, intrauterine fetal demise, neonatal birthweight, Apgar scores at 1 and 5 minutes, and neonatal intensive care unit (ICU) admission.\n\nStatistical analysis\nFor descriptive analysis, continuous variables were reported as the mean with SD, median, and range. Categorical variables were reported as proportions.\n\nResults\nThe initial search identified 42 women with a nonnative heart valve who also had a pregnancy episode recorded during the 10-year study period at our institution. After a detailed chart review, nine women were confirmed to have an MHV that required AC during gestation. Other women were primarily excluded due to the temporality of their MHV placement and pregnancy timing – that is, the MVH was implanted after the index pregnancy. The nine women meeting inclusion criteria had 19 pregnancy episodes recorded (Figure 1). Demographics are delineated in Table 1. Of the women with an MHV on AC during gestation, 55.6% had a mechanical aortic valve and 44.4% had a mitral valve.\n\nAntepartum and intrapartum AC management\nOf the cohort of 19 pregnancies, five pregnancies did not meet the inclusion criteria and were excluded from the analysis; these included an ectopic pregnancy, a spontaneous abortion at 9 weeks of gestation, and three elective terminations, all of which were completed without operative or hemodynamic complications. The timing and type of AC resumption after their procedures were not specifically recorded.\n\nBefore pregnancy, the majority of women (88.9%) were therapeutically anticoagulated on warfarin, and one was on LMWH as she was attempting conception and desired to avoid warfarin-induced teratogenicity. During pregnancy, 88.9% of women who were on warfarin transitioned to LMWH early in the first trimester. One patient remained on VKA throughout gestation due to a known difficulty in achieving therapeutic AC on LMWH.\n\nIn late gestation, or during a planned admission immediately prior to delivery, the majority of patients (85.7%) were transitioned from LMWH to heparin. One patient remained on LMWH until 1 day prior to anticipated delivery. Another patient remained on warfarin during her delivery, as she presented in active labor without time to effectively transition to heparin infusion.\n\nDelivery timing and modes\nOf the delivered pregnancies (n=14), the mean gestational age of delivery was preterm at 35w2d (Table 2); however, the median was an early term at 37w2d (range 28w2d–39w1d). Nine deliveries were via cesarean (64.3%), two were vacuum-assisted vaginal (14.3%), and three were spontaneous vaginal (21.4%) births. Of the cesarean births, one was emergent due to placental abruption. An assisted second stage of delivery was planned in one case due to maternal cardiac status.\n\nThere were varying modes of analgesia utilized in the deliveries. In total, 21.4% of deliveries received pain control via regional spinal analgesia, 35.7% by epidural anesthesia, and 35.7% through general endotracheal anesthesia. One patient elected to have no medicinal intervention for pain during labor, unrelated to AC status.\n\nPostpartum AC management\nAll patients had AC resumption during their hospitalization for delivery. For the entire cohort of delivered pregnancies, the mean time to restart AC after birth was 10 hours (SD 8 hours, range 2–27 hours, median 6 hours; Table 3). Six deliveries (42.8%) were followed by resumption of some form of AC ≤6 hours postpartum (mean 5 hours, SD 2 hours, range 2–6 hours, median 6 hours). In these cases, two patients had mitral MHVs, and four had aortic MHVs. Five deliveries (35.7%) recorded resumption of AC therapy .6 hours postpartum (mean 16 hours, SD 7 hours, range 2–27 hours, median 16 hours). All five cases were in patients with an MHV in the mitral position. Three deliveries did not have the specific time to resumption of AC recorded (Figure 1 and Table 3). The anticoagulants employed postpartum were continuous IV heparin (79.6%), enoxaparin (14.3%), or warfarin (7.1%). There were no instances of combination therapy in the early postpartum period.\n\nPostpartum complications\nHemorrhagic complications occurred in six of 14 deliveries (42.8%, Table 3). Three (21.4%) of the cases were complicated by primary postpartum hemorrhage, and the other three (21.4%) were secondary postpartum hemorrhage. The average estimated blood loss at the time of delivery for all patients was 582±189 mL.\n\nSpecifically, an incisional wound hematoma developed in a patient restarted on enoxaparin 27 hours postoperatively. This was managed conservatively and did not require surgical intervention or debridement. An intra-abdominal hematoma occurred on postoperative day 3 in a woman transitioned to intravenous heparin 6 hours postoperatively. Due to hemodynamic instability, surgical intervention was required for clot evacuation and rapid control of active extravasation. Another intra-abdominal bleed occurred in a patient who was reheparinized 4 hours after her cesarean delivery and required embolization of an inferior epigastric artery. Four cases (28.6%) required postpartum transfusion of blood products (packed RBCs±fresh frozen plasma). The institutional massive transfusion protocol was not employed in any of the cases. In this series, no maternal valve thromboses, strokes, or deaths were recorded.\n\nThe mean total length of hospitalization for these patients was 8 days (SD 4 days, median 7 days, range 3–14 days), and the mean length of hospitalization postpartum was 5 days (SD 2 days, median 4 days, range 2–10 days).\n\nArrhythmia burden\nAt the start of their pregnancies, 57.1% of the cohort had normal sinus rhythm, none were identified as having atrial fibrillation, and 42.9% were reported as having some other type of rhythm abnormality (ventricular arrhythmia, ventricular tachycardia, complete heart block, etc.; Table 4). The majority of women (57.1%, n=8) were neither prescribed a medication for their rhythm control during gestation, nor did they have a pacemaker or implantable cardioverter defibrillator in place. In total, 35.7% (n=5) of the cohort was medicated antepartum for their arrhythmia and 14.3% (n=2) had a device in place (pacemaker or implantable cardioverter defibrillator).\n\nPeripartum rhythm complications did not occur in the majority of cases (78.6%). Three women (21.4%) were identified as having rhythm complications either antepartum or immediately postpartum. They included ventricular tachycardia requiring admission and additional medications in two cases and atrial flutter requiring cardioversion in another.\n\nFetal and newborn outcomes\nOf the 19 pregnancy episodes, there were 14 deliveries and 13 livebirths (Table 5). One case of intrapartum intrauterine fetal demise was identified. In this case, there was a known fetal genetic abnormality (Smith-Lemli-Optiz syndrome). The majority of the remaining live-born infants (92.8%) were appropriately sized for gestational age. There was one case of fetal growth restriction. No structural abnormalities were confirmed in all delivered neonates. Apgar scores of <7 were recorded in 38.5% of newborns at 1 minute, and 30.1% of newborns at 5 minutes; 38.5% of newborns required a neonatal ICU admission. There were no identified cases of fetal or neonatal hemorrhage.\n\nDiscussion\nThe presence of MHV during pregnancy is rare. However, in our series, these women demonstrate a high rate of clinically significant hemorrhagic complications in the immediate postpartum period, warranting evidence-based direction in the management of required therapeutic AC after delivery. The maternal outcomes reported here are consistent with those previously described, where at least 40% of women suffer some form of major maternal morbidity.10–12 However, in these prior reports, the postpartum AC strategies and timing of reinitiation of postpartum AC are only tangentially commented upon, with vague timelines of resumption of AC.\n\nSimilar to findings described by Vause et al and Sadler et al, we did not observe any standard approach to intrapartum AC.10–12 Women in our study were primarily on LMWH during pregnancy and then transitioned to heparin infusion for both intrapartum and immediate postpartum AC. This management is different from guidelines that recommend the use of VKA in the second and third trimesters of pregnancy.5 We recorded no maternal valve thrombosis, stroke, or death in this cohort of women mostly maintained on LMWH throughout gestation. This may be partly attributed to the use of a serial assessment of anti-Xa levels throughout gestation with subsequent LMWH dose adjustment as well as prompt restarting of maternal AC postpartum.6,7,13,14 However, the numbers in our cohort are limited.\n\nIn our series, the patterns of postpartum AC management – which we believe was critical to maternal postpartum outcomes – varied widely. The majority (79%) of postpartum patients were restarted on heparin infusion, which allows for hourly titration dictated by serial partial thromboplastin time levels as well as the ease of reversal in the setting of uncontrolled bleeding. The range of time from delivery to the resumption of therapeutic AC was quite broad, ranging between 2 and 27 hours. Approximately half of our patients were restarted before or at 6 hours postpartum. When we reviewed the specific adverse maternal postpartum outcomes, two women restarted AC at less 6 hours postpartum experienced significant intra-abdominal bleeding. Half of the ≤6-hour group and 60% of the .6-hour group suffered from obstetrical hemorrhage overall, although no statistical significance could be drawn between the groups, given the limited number of unique patients. Restarting AC ≤6 hour postdelivery did not increase the incidence of postpartum transfusion in this cohort. Taken together, all women with an MHV have a collective increased risk of major maternal morbidity postpartum, as well as preterm delivery with resultant NICU admission. In our series, there was no observed thrombogenic harm for the group of women who had AC restarted after 6 hours – but before 27 hours – postpartum.\n\nDue to the association between a fibrillation and valve thrombosis, we specifically looked at this parameter in order to assess if our patients were at increased risk of a thrombogenic event. Prepregnancy arrhythmias were noted in 43% of patients; however, none of them were diagnosed with atrial fibrillation. The majority of women had no peripartum rhythm complications (79%), whereas 21% suffered from a peripartum arrhythmia complication necessitating treatment (medical treatment, cardioversion). This observation underscores the need for close cardiac monitoring peripartum with a multidisciplinary team skilled in assessing and treating cardiovascular complications in this population.\n\nPast case series and meta-analyses in the literature have highlighted the maternal thrombogenic risks associated with various AC methods in pregnancy, which can be mitigated by the prompt resumption of therapeutic AC in the postpartum period according to published guidelines,8,15 and the need for nuanced decision-making with regard to AC choice as it relates to fetal effects.16 However, newer literature highlights maternal postpartum risks, especially hemorrhagic complications associated with therapeutic AC in the early postpartum period.10 The development of severe hemorrhagic complications may limit the use of AC, may increase the need for additional procedures to control bleeding and decrease mobility, and may prolong hospitalization, as reflected in our data where the median total hospitalization and postpartum lengths of stays were extended. All these factors are known to increase the risk of maternal thrombotic sequelae and should be considered.\n\nThe 2014 AHA/ACC Valvular Heart Disease Guidelines provide concise, although limited, recommendations for pregnant patients with an MHV in the antepartum period. However, these recommendations do not distinguish between MHV positions – that is, mitral vs aortic – and there are no obstetric-specific guidelines that outline optimal times for restarting postpartum AC.5,17 Antepartum, therapeutic AC with frequent monitoring is recommended with the addition of low-dose aspirin in the second and third trimesters. The preferred method of AC is VKA; however, due to the concern of embryopathy in patients requiring higher doses of VKA (>5 mg/day), the guidelines recommend the first-trimester use of subcutaneous LMWH at least twice daily or as continuous intravenous unfractionated heparin.\n\nWithin the field of cardiovascular surgery, there are no strict guidelines detailing initiation of postoperative AC management for MHV patients, regardless of reproductive status.5 Most cardiovascular surgeons and cardiologists managing AC evaluate each case and design an AC strategy based on the patient’s individual risks and needs. The position of the valve (the mitral being more thrombogenic than the aortic), arrhythmia burden, left ventricular function, and overall cardiovascular status are considered in AC planning. In consultation with cardiology and cardiovascular surgery, it seems prudent for the obstetric team to similarly individualize the care of each gravid MHV patient.\n\nThe number of pregnancies in women with mechanical valve replacement remains low; however, the development of improved cardiac therapies for children and young adults has resulted in a growing population of reproductive women with cardiovascular disease who desire pregnancy. Women with MHV are a high-risk cohort requiring special consideration; a single management algorithm cannot be applied to all. Prior to pregnancy, the ultimate decision to proceed with an MHV should be based on an interdisciplinary conversation between the patient, her cardiologists, and cardiothoracic surgeon, reflecting on the patient’s age, potential need or risk for reintervention, and reproductive and lifestyle preferences, while taking into account the risks related to lifelong AC requirements.\n\nMore nuanced recommendations with regard to optimal early postpartum AC for women with MHV are needed. These recommendations should not only take into consideration the mode of delivery and postpartum bleeding risk, but weigh factors such as valve location and type, cardiac function, and arrhythmia burden. Importantly, women with MHV in pregnancy should be managed by a coordinated maternal cardiac team that includes cardiologists, obstetricians, and anesthesiologists skilled at managing MHV in pregnancy. Knowledge of increased risk for bleeding complications should prompt close postpartum surveillance and management when reinitiating AC.\n\nAlthough the data collection spanned a 10-year period, given the rarity of mechanical valve usage in conjunction with parturition, our retrospective cohort is small. Additional limitations of the study include lack of management details for some pregnancies. This finding is attributed to the non-uniform methodology in recording the exact time that AC is reinitiated. The rarity of the event, coupled with the inconsistencies of documentation, highlights the need for a standard to collect information so that these women have clear plans to disseminate to their medical teams.\n\nIncorporating strategies from other surgical disciplines, pooling obstetric outcome data, and reviewing the practice patterns of referral institutions will be paramount to generate evidence-based guidelines for AC management in the critical immediate postpartum period in the at-risk group of gravid women with MHV. Initiation of AC after delivery should minimize competing risks and sequelae of valve thrombosis and obstetrical hemorrhage.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Flowchart of study population.\n\nNote: Three of the completed gestations did not have the time to anticoagulation resumption recorded after delivery.\n\nAbbreviations: D&C, dilation and curettage; SAB, spontaneous abortion (miscarriage).\n\nTable 1 Patient demographics (n=9 patients)\n\nPatient characteristic\t\t\nAge (years)\t\n Median\t25\t\n Range\t19–39\t\nRace (n)\t\n Caucasian\t4\t\n African American\t2\t\n Hispanic\t2\t\n Other\t1\t\nTobacco use (n)\t\n During pregnancy\t3\t\nBMI (kg/m2)\t\n Median\t27.0\t\n Range\t19.3–46.3\t\nValve location (n)\t\n Mitral\t4\t\n Aortic\t5\t\nGravidity/parity\t\n Median\t2/0\t\n Range\t4–1/1–0\t\nAntepartum AC (n)\t\n Warfarin PO\t1\t\n Heparin SC\t2\t\n Enoxaparin SC\t6\t\nAbbreviations: AC, anticoagulation; BMI, body mass index; PO, by mouth; SC, subcutaneous injection.\n\nTable 2 Maternal delivery outcomes (n=14 cases)\n\nMaternal delivery outcomes\tn (%) or median (range)\t\nGA (w/d) at delivery\t\n Mean\t35w2d\t\n Median\t37w2d (28w2d–39w1d)\t\nMode of delivery\t\n Vaginal\t3 (21.4)\t\n Vacuum-assisted\t2 (14.3)\t\n Cesarean\t9 (64.3)\t\nAnesthesia\t\n None\t1 (7.1)\t\n Spinal\t3 (21.4)\t\n Epidural\t5 (35.7)\t\n GETA\t5 (35.7)\t\nIntrapartum AC\t\n Warfarin PO\t1 (7.1)\t\n Heparin infusion\t12 (85.7)\t\n Enoxaparin SC\t1 (7.1)\t\nPostpartum AC\t\n Warfarin PO\t1 (7.1)\t\n Heparin infusion\t11 (79.6)\t\n Enoxaparin SC\t2 (14.3)\t\nAbbreviations: AC, anticoagulation; GA (w/d), gestational age in weeks and days; GETA, general endotracheal anesthesia; PO, by mouth; SC, subcutaneous injection.\n\nTable 3 Maternal outcomes. Selected maternal outcomes in the postpartum period were recorded (n=14 cases). There were no maternal deaths, CVA, or thrombosed valves noted during any of the delivery admissions. One patient suffered a CVA at 16 weeks of gestation but recovered by the time of delivery\n\nMaternal outcomes\tTime to anticoagulation postpartum\t\nAll deliveries (n=14) n (%), or median (range)\t≤6 hours (n=6) n (%), or median (range)\t>6 hours (n=5) n (%), or median (range)\t\nTime to AC resumption PP (n=11 recorded)\t\nMedian (hours)\t6 (2–27)\t6 (2–6)\t16 (7–27)\t\nPP hemorrhage\t6 (42.8)\t3 (50.0)\t3 (60.0)\t\nTransfusion\t4 (28.6)\t2 (33.3)\t2 (40.0)\t\nWound hematoma\t2 (14.3)\t0\t1 (20.0)\t\nIntra-abdominal bleed\t2 (14.3)\t2 (33.3)\t0\t\nVaginal hematoma\t0\t0\t0\t\nSurgical reintervention\t1 (7.1)\t1 (16.6)\t0\t\nVessel embolization\t1 (7.1)\t1 (16.6)\t0\t\nLength of stay, total hospitalization\t\n Median (days)\t7 (3–14)\t11 (6–14)\t4 (3–9)\t\nLength of stay, postpartum hospitalization\t\n Median (days)\t4 (2–10)\t5 (3–9)\t4 (2–7)\t\nValve thrombosis\t0\t0\t0\t\nStroke\t0\t0\t0\t\nDeath\t0\t0\t0\t\nAbbreviations: AC, anticoagulation; CVA, cerebrovascular accident; PP, postpartum.\n\nTable 4 Maternal rhythm complications (n=14 cases). Other forms of rhythms recorded were ventricular tachycardia and high-grade ventricular arrhythmias. Peripartum rhythm complications included atrial flutter requiring cardioversion and ventricular tachycardia\n\nMaternal cardiac status\tn (%)\t\nKnown rhythm\t\n NSR\t8 (57.1)\t\n Atrial fibrillation\t0\t\n Other\t6 (42.9)\t\nAntepartum management of cardiac rhythm\t\n Medication\t5 (35.7)\t\n ICD/PM\t2 (14.3)\t\n Observation/expectant\t8 (57.1)\t\nPeripartum rhythm complications\t\n Yes\t3 (21.4)\t\n No\t11 (78.6)\t\nAbbreviations: ICD, implantable cardioverter defibrillator; NSR, normal sinus rhythm; PM, pacemaker.\n\nTable 5 Fetal and neonatal outcomes (n=14 cases). Selected fetal and neonatal outcomes were recorded for the 14 continuing pregnancies\n\nFetal or neonatal outcome\tn (%)\t\nLive births\t13 (92.8)\t\nIntrauterine fetal demise\t1 (7.2)\t\nMedian birth weight\t3,020 g\t\nIntrauterine growth restriction\t1 (7.2)\t\nNICU admission\t5 (38.5)\t\nApgar ≤7 at 1 minute\t5 (38.5)\t\nApgar ≤7 at 5 minutes\t4 (30.1)\t\nAbbreviation: NICU, neonatal intensive care unit.\n==== Refs\nReferences\n1 Sillesen M Hjortdal V Vejlstrup N Sørensen K Pregnancy with prosthetic heart valves – 30 years’ nationwide experience in Denmark Eur J Cardiothorac Surg 2011 40 2 448 454 21277217 \n2 Iturbe-Alessio I Fonseca MC Mutchinik O Santos MA Zajarías A Salazar E Risks of anticoagulant therapy in pregnant women with artificial heart valves N Engl J Med 1986 315 22 1390 1393 3773964 \n3 Hung L Rahimtoola SH Prosthetic heart valves and pregnancy Circulation 2003 107 9 1240 1246 12628941 \n4 Elkayam U Singh H Irani A Akhter MW Anticoagulation in pregnant women with prosthetic heart valves J Cardiovasc Pharmacol Ther 2004 9 2 107 115 15309247 \n5 American College of CardiologyAmerican College of Cardiology/American Heart Association American Heart Association 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Thorac Cardiovasc Surg 2014 148 1 e1 e132 24939033 \n6 McLintock C McCowan LM North RA Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin BJOG 2009 116 12 1585 1592 19681850 \n7 Snape E Thachil J Clarke B Vause S Anti-Xa based dose changes during low molecular weight heparin anticoagulation for mechanical prosthetic heart valves during pregnancy J Obstet Gynaecol 2018 38 5 721 722 29436886 \n8 James A Committee on Practice Bulletins–Obstetrics Practice bulletin no. 123: thromboembolism in pregnancy Obstet Gynecol 2011 118 718 729 21860313 \n9 Freedman RA Bauer KA Neuberg DS Zwicker JI Timing of postpartum enoxaparin administration and severe postpartum hemorrhage Blood Coagul Fibrinolysis 2008 19 1 55 59 18180616 \n10 Vause S Clarke B Tower CL Hay C Knight M (on behalf of UKOSS). Pregnancy outcomes in women with mechanical prosthetic heart valves: a prospective descriptive population based study using the United Kingdom Obstetric Surveillance System (UKOSS) data collection system BJOG 2017 124 9 1411 1419 28019065 \n11 Vause S Clarke B Tower C Hay C Knight M Mechanical prosthetic heart valves (MPHV) in pregnancy are associated with a high risk of maternal and fetal morbidity and mortality Heart 2017 103 19 1557 \n12 Sadler L McCowan L White H Stewart A Bracken M North R Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves BJOG 2000 107 2 245 253 10688509 \n13 Fox NS Laughon SK Bender SD Saltzman DH Rebarber A Anti-factor Xa plasma levels in pregnant women receiving low molecular weight heparin thromboprophylaxis Obstet Gynecol 2008 112 4 884 889 18827132 \n14 Sephton V Farquharson RG Topping J A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy Obstet Gynecol 2003 101 6 1307 1311 12798541 \n15 European Society of Gynecology (ESG) Association for European Paediatric Cardiology (AEPC) German Society for Gender Medicine (DGesGM) ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC) Eur Heart J 2011 32 24 3147 3197 21873418 \n16 Steinberg ZL Dominguez-Islas CP Otto CM Stout KK Krieger EV Maternal and fetal outcomes of anticoagulation in pregnant women with mechanical heart valves J Am Coll Cardiol 2017 69 22 2681 2691 28571631 \n17 Nishimura RA Otto CM Bonow RO 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on clinical practice guidelines J Am Coll Cardiol 2017 70 2 252 289 28315732\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1411",
"issue": "10()",
"journal": "International journal of women's health",
"keywords": "anticoagulation; mechanical heart valve; postpartum hemorrhage; pregnancy",
"medline_ta": "Int J Womens Health",
"mesh_terms": null,
"nlm_unique_id": "101531698",
"other_id": null,
"pages": "663-670",
"pmc": null,
"pmid": "30498374",
"pubdate": "2018",
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"title": "Postpartum anticoagulation in women with mechanical heart valves.",
"title_normalized": "postpartum anticoagulation in women with mechanical heart valves"
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"abstract": "Adalimumab is commonly used to treat autoimmune diseases with few reported hematological adverse reactions. We herein describe the case of an 85-year-old Japanese man with plaque psoriasis who developed autoimmune hemolytic anemia (AIHA) after 3 years of adalimumab treatment. The patient suddenly developed hematuria and dyspnea on exertion while receiving adalimumab treatment. Laboratory data showed low hemoglobin levels and slightly increased reticulocyte counts, while direct and indirect antiglobulin tests were positive. The patient was diagnosed with AIHA which resolved after replacing the adalimumab treatment with prednisolone therapy. The findings from this case indicate that AIHA may be caused by long-term adalimumab treatment.",
"affiliations": "Nagano Chuo Hospital, Japan.",
"authors": "Harada|Yukinori|Y|;Yamamoto|Hiroaki|H|;Sato|Midori|M|;Kodaira|Mutsuki|M|;Kono|Tsunesuke|T|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D011239:Prednisolone; D000068879:Adalimumab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.3433",
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"issn_linking": "0918-2918",
"issue": "54(9)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000068879:Adalimumab; D000369:Aged, 80 and over; D000744:Anemia, Hemolytic, Autoimmune; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D003298:Coombs Test; D004417:Dyspnea; D006417:Hematuria; D006801:Humans; D008297:Male; D011239:Prednisolone; D011565:Psoriasis",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1103-4",
"pmc": null,
"pmid": "25948357",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autoimmune hemolytic anemia during adalimumab treatment for plaque psoriasis.",
"title_normalized": "autoimmune hemolytic anemia during adalimumab treatment for plaque psoriasis"
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"companynumb": "JP-ABBVIE-15P-087-1389196-00",
"fulfillexpeditecriteria": "1",
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"abstract": "BACKGROUND Novel Coronavirus 2019 (COVID-19) has been in the spotlight since the first cases were reported in December 2019. COVID-19 has been found to cause severe acute respiratory distress syndrome and, more uncommonly, subcutaneous emphysema and pneumomediastinum. We present a case series of 3 patients with COVID-19 infection managed in the Intensive Care Unit and found to have subcutaneous emphysema and pneumomediastinum on chest imaging. CASE REPORT We present a case series of 3 men, ages 36, 47, and 78 years, diagnosed with COVID-19 via RT-PCR, found to have severe acute respiratory distress syndrome, and managed in the Intensive Care Unit. Two patients described in this case series were mechanically ventilated on low positive end-expiratory pressures and developed subcutaneous emphysema and pneumomediastinum on chest imaging, and 1 patient developed subcutaneous emphysema prior to intubation. Each of these patients had a more eventful hospital course and worse outcomes than most COVID-19 infected patients. CONCLUSIONS Subcutaneous emphysema and pneumomediastinum in COVID-19 patients have been rarely reported and is poorly understood. In our institution, we have found the diagnosis of subcutaneous emphysema and pneumomediastinum in COVID-19 patients is associated with unfavorable outcomes and worse prognosis.",
"affiliations": "Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA.;Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA.;Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA.;Department of Pulmonology and Critical Care, Jersey Shore University Medical Center, Neptune, NJ, USA.;Department of Pulmonology and Critical Care, Jersey Shore University Medical Center, Neptune, NJ, USA.",
"authors": "Al-Azzawi|Mohammed|M|;Douedi|Steven|S|;Alshami|Abbas|A|;Al-Saoudi|Ghadier|G|;Mikhail|John|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.925557",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32703927\n10.12659/AJCR.925557\n925557\nArticles\nSpontaneous Subcutaneous Emphysema and Pneumomediastinum in COVID-19 Patients: An Indicator of Poor Prognosis?\nAl-Azzawi Mohammed ABEF1 Douedi Steven ABEF1 Alshami Abbas ABEF1 Al-Saoudi Ghadier ABF2 Mikhail John ABF2 \n1 Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, U.S.A.\n\n2 Department of Pulmonology and Critical Care, Jersey Shore University Medical Center, Neptune, NJ, U.S.A.\nCorresponding Author: Steven Douedi, e-mail: Steven.Douedi@hackensackmeridian.orgAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n24 7 2020 \n21 e925557-1 e925557-6\n29 4 2020 08 7 2020 15 7 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Case series\n\nPatients: Male, 36-year-old • Male, 47-year-old • Male, 78-year-old\n\nFinal Diagnosis: COVID-19 • pneumomediastinum • subcutaneous emphysema\n\nSymptoms: Respiratory distress • shortness of breath\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Critical Care Medicine • Pulmonology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nNovel Coronavirus 2019 (COVID-19) has been in the spotlight since the first cases were reported in December 2019. COVID-19 has been found to cause severe acute respiratory distress syndrome and, more uncommonly, subcutaneous emphysema and pneumomediastinum. We present a case series of 3 patients with COVID-19 infection managed in the Intensive Care Unit and found to have subcutaneous emphysema and pneumomediastinum on chest imaging.\n\nCase Reports:\nWe present a case series of 3 men, ages 36, 47, and 78 years, diagnosed with COVID-19 via RT-PCR, found to have severe acute respiratory distress syndrome, and managed in the Intensive Care Unit. Two patients described in this case series were mechanically ventilated on low positive end-expiratory pressures and developed subcutaneous emphysema and pneumomediastinum on chest imaging, and 1 patient developed subcutaneous emphysema prior to intubation. Each of these patients had a more eventful hospital course and worse outcomes than most COVID-19 infected patients.\n\nConclusions:\nSubcutaneous emphysema and pneumomediastinum in COVID-19 patients have been rarely reported and is poorly understood. In our institution, we have found the diagnosis of subcutaneous emphysema and pneumomediastinum in COVID-19 patients is associated with unfavorable outcomes and worse prognosis.\n\nMeSH Keywords:\nCoronavirusCOVID-19Pneumomediastinum, DiagnosticSubcutaneous Emphysema\n==== Body\nBackground\nNovel Coronavirus 2019 (COVID-19), also known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), causes severe pneumonia and acute respiratory distress syndrome (ARDS), with a high mortality rate [1]. Subcutaneous emphysema is not commonly seen in this infection and can be suggestive of more serious disease [2]. We present a cases series of patients diagnosed with COVID-19 and found to have sub-cutaneous emphysema and pneumomediastinum associated with a more complicated hospital course.\n\nCase Reports\nFirst case\nA 36-year-old man with a history of poorly controlled type 1 diabetes mellitus (hemoglobin A1c on admission 15.1%) presented to the Emergency Department complaining of worsening shortness of breath, fevers, and dry cough of 1-week duration. On examination, he was evidently short of breath but not using accessory muscles and was able to speak in full sentences. His laboratory tests on admission were significant for a C-reactive protein of 20.34 mg/dL (normal value: 0.0–0.74 mg/dL), D-dimer of 6298 ng/mL (normal value: <500 ng/mL), and procalcitonin level of 0.52 ng/mL (normal value: <0.05 ng/mL). His arterial blood gas showed a pH of 7.293, partial pressure of carbon dioxide (pCO2) of 18.8 mmHg, pO2 of 90.4 mmHg, and oxygen saturation of 94.3%. A chest X-ray was performed, showing bilateral ground-glass opacities and diffuse infiltrates worse at the bilateral lung bases, as well as evidence of subcutaneous emphysema (Figure 1). He was diagnosed with COVID-19 using reverse-transcriptase polymerase chain reaction (RTPCR) assay and was also found to have anion-gap metabolic acidosis due to diabetic ketoacidosis (blood glucose level on admission 410 mg/dL). He was started on insulin infusion and intravenous fluids for ketoacidosis. He was also started on azithromycin, vitamin C, zinc sulfate, and hydroxychloroquine for COVID-19.\n\nWhile in the Emergency Department, he became hypoxic with an oxygen saturation of 82% on room air and was placed on supplemental oxygen. His condition continued to worsen, and he was subsequently intubated and transferred to the Intensive Care Unit. On day 3, he remained in critical condition and was given 1 dose of tocilizumab. He was also started on high-dose solumedrol for a 7-day course. On day 5, a computed tomography (CT) scan of the chest was obtained, showing bilateral ground-glass opacities, pneumomediastinum, and moderatesized subcutaneous emphysema (Figure 2). His positive endexpiratory pressure (PEEP) was 6 cmH2O and peak pressure was 30. By day 7, his subcutaneous emphysema had improved, and on day 8 it was no longer present. Due to worsening and severe ARDS, the decision was made to place him in prone position for 18 hours a day. After minimal improvement and on high ventilator settings, on day 9 he began veno-venous extracorporeal membrane oxygenation at 3 liters per minute and pump speed of 4100 rpm. Despite aggressive management, his condition deteriorated, and he ultimately died due to his condition on day 15 of hospitalization.\n\nSecond Case\nA 47-year-old man with a past medical history of drug abuse (now on methadone) and alcohol abuse was admitted for acute hypoxic respiratory failure. At an urgent care center, he had tested positive for COVID-19 a few days prior to admission following complaints of shortness of breath and fevers for 1 week. His vitals on admission were blood pressure of 135/70 mmHg, temperature 100.9°F (38.2°C), heart rate of 110 beats per minute, oxygen saturation of 75% on room air, and respiratory rate of 28 breaths per minute. He was in mild-to-moderate distress on exam, his pulse O2 improved initially to the low 90s on 15 liters non-rebreather mask, then started declining, and he became hypoxic to the mid 80s on 60 liters and fraction of inspired oxygen (FiO2) of 100% via Optiflow machine. He was subsequently intubated for progressive hypoxemia, and his saturation dropped to the low 60s. His initial ventilator setting was 100% FiO2 and PEEP of 12 cmH2O. X-rays taken after intubation and on the next day showed the endotracheal tube was in place, with no subcutaneous emphysema or pneumomediastinum visible (Figure 3).\n\nHe had elevated inflammatory markers with ferritin 493 ng/mL, CRP 3.02 ng/mL, D-dimer 6867, and LDH 389 U/L and was started on a 5-day course of hydroxychloroquine, azithromycin, and zinc sulfate. His PaO2/FiO2 ratio (P/F ratio) was 85, so the decision was made to prone him for 18 hours and he received 1 dose of 8 mg/kg of tocilizumab. The following day, his P/F ratio improved to 207, so his ventilator setting was changed to 80% FiO2 and PEEP stayed at 12 cmH2O. On day 3, a chest X-ray showed a right subcutaneous emphysema and pneumomediastinum and his PEEP was subsequently decreased from 12 to 10 (Figure 3).\n\nOver the course of the next 2 days, his PEEP was weaned down to 8 cmH2O, and a chest X-ray on day 6 showed significant improvement of the subcutaneous emphysema. On day 8, the patient had a right spontaneous apical pneumothorax, for which a chest tube was placed. His respiratory status continued to improve, and he was ultimately extubated on day 13 and was transferred to the general medical floors for further management.\n\nThird case\nA 78-year-old man with a history of hypertension and hyper-lipidemia presented to our facility complaining of shortness of breath and confusion. In the Emergency Department, his vital signs were a temperature of 99°Ft, heart rate 126 beats per minute, blood pressure 126/72 mmHg, and oxygen saturation 89% on room air. He was intubated in the Emergency Department, and he tested positive for COVID-19 the following day. He was started on hydroxychloroquine, azithromycin, zinc sulfate, and vitamin C for a 5-day course. On day 3, his mean arterial pressure dropped to <60 mmHg, so he was started on norepinephrine infusion for hemodynamic stability. He remained on a FiO2 of 100% and PEEP of 5 cmH2O. A portable chest X-ray on day 5 showed subcutaneous emphysema and pneumomediastinum, which were not seen on the chest X-rays taken on day 1 and 3 (Figure 4). He remained in critical condition, eventually requiring the addition of 2 more vasopressors to maintain a mean arterial pressure of >60 mmHg. On day 8, the decision was made at the request of his family to withdraw care and pursue comfort measures, and the patient died.\n\nDiscussion\nSubcutaneous emphysema can be spontaneous, secondary to trauma or infection, or iatrogenic secondary to barotrauma or medical procedures [3]. Iatrogenic subcutaneous emphysema and pneumomediastinum, although rare, can occur following endotracheal intubation and is usually evident within 24 hours after intubation [4,5]. Mechanisms proposed to explain such complications include tracheal mucosal tear, over-inflation of the endotracheal tube cuff, and congenital dehiscence in the mucosa [6]. Barotrauma, another iatrogenic cause of subcutaneous emphysema in mechanically ventilated patients, has only been reported when plateau pressure exceeds 35 cmH2O [7]. Our patients did not develop subcutaneous emphysema within 24 hours of intubation and did not have plateau pressure above 35 cmH2O (Figures 5–7).\n\nSpontaneous subcutaneous emphysema and pneumomediastinum have been reported as uncommon clinical findings in COVID-19 patients [2,8,9], and it has been suspected to be the sequelae of alveolar membrane rupture secondary to direct infection of pneumocytes type I and II [8]. In general, sub-cutaneous emphysema causes mild symptoms and resolves on its own, but can be life-threatening if expanding into the chest wall, and can lead to worsening respiratory acidosis and failure [3,10].\n\nChu et al. reported that subcutaneous emphysema and pneumomediastinum can complicate severe acute respiratory syndrome (SARS), and that in this subset of patients, the development of these pathologies indicated worse disease and patients requiring more aggressive management [11]. The coincidence of also seeing this clinical manifestation in COVID-19 may indicate a similar viral pathogenesis [12]. Our 3 patients had unfavorable outcomes compared with patients with similar profiles in our institution, which may suggest that subcutaneous emphysema is a predictor of poor prognosis. However, larger case-controlled studies are needed to determine if a correlation between COVID-19 disease severity and subcutaneous emphysema and pneumomediastinum does in fact exist.\n\nConclusions\nSubcutaneous emphysema and pneumomediastinum can be a spontaneous condition seen in COVID-19 patients. In non-COVID-19 patients, it is commonly self-limited; however, COVID-19 patients with subcutaneous emphysema and pneumomediastinum seem to have more complicated hospital courses. Larger studies are warranted to investigate this possible correlation.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Chest X-ray of the first patient showing subcutaneous emphysema (denoted by arrows) prior to intubation.\n\nFigure 2. (A–D) Chest computed tomography of the first patient showing subcutaneous emphysema and pneumomediastinum (denoted by arrows).\n\nFigure 3. Chest X-rays of the second patient showing new-onset subcutaneous emphysema on day 3 (denoted by arrows).\n\nFigure 4. Chest X-rays of the third patient showing new-onset subcutaneous emphysema on day 5 (denoted by arrows).\n\nFigure 5. A graph showing the timeline of events and ventilator parameters for the first patient.\n\nFigure 6. A graph showing the timeline of events and ventilator parameters for the second patient.\n\nFigure 7. A graph showing the timeline of events and ventilator parameters for the third patient.\n==== Refs\nReferences:\n1. Zhai P Ding Y Wu X The epidemiology, diagnosis and treatment of COVID-19 Int J Antimicrob Agents 2020 55 5 105955 32234468 \n2. Zhou C Gao C Xie Y Xu M COVID-19 with spontaneous pneumomediastinum Lancet Infect Dis 2020 20 4 510 32164830 \n3. Aghajanzadeh M Dehnadi A Ebrahimi H Classification and management of subcutaneous emphysema: A 10-year experience Indian J Surg 2015 77 Suppl. 2 673 77 26730086 \n4. Pandey M Jain A Mehta A Sharma M Endotracheal intubation related massive subcutaneous emphysema and tension pneumomediastinum resulting in cardiac arrest J Postgrad Med 2003 49 2 188 89 12867707 \n5. Kaloud H Smolle-Juettner FM Prause G List WF Iatrogenic ruptures of the tracheobronchial tree Chest 1997 112 3 774 78 9315814 \n6. Jo YY Park WY Choi E Delayed detection of subcutaneous emphysema following routine endotracheal intubation – A case report Korean J Anesthesiol 2010 59 3 220 23 20877710 \n7. Boussarsar M Thierry G Jaber S Relationship between ventilatory settings and barotrauma in the acute respiratory distress syndrome Intensive Care Med 2002 28 4 406 13 11967593 \n8. Kolani S Houari N Haloua M Spontaneous pneumomediastinum occurring in the SARS-COV-2 infection IDCases 2020 21 e00806 \n9. Wang W Gao R Zheng Y Jiang L COVID-19 with spontaneous pneumothorax,pneumomediastinum and subcutaneous emphysema J Travel Med 2020 [Online ahead of print] \n10. Beck PL Heitman SJ Mody CH Simple construction of a subcutaneous catheter for treatment of severe subcutaneous emphysema Chest 2002 121 2 647 49 11834684 \n11. Chu CM Leung YY Hui JYH Spontaneous pneumomediastinum in patients with severe acute respiratory syndrome Eur Respir J 2004 23 6 802 4 15218989 \n12. Petrosillo N Viceconte G Ergonul O COVID-19, SARS and MERS: Are they closely related? Clin Microbiol Infect 2020 26 6 729 34 32234451\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D006801:Humans; D008297:Male; D008478:Mediastinal Emphysema; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D011379:Prognosis; D000086402:SARS-CoV-2; D013352:Subcutaneous Emphysema; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e925557",
"pmc": null,
"pmid": "32703927",
"pubdate": "2020-07-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12867707;26730086;11967593;20877710;11834684;32234468;32234451;32164830;32330274;15218989;32395425;9315814",
"title": "Spontaneous Subcutaneous Emphysema and Pneumomediastinum in COVID-19 Patients: An Indicator of Poor Prognosis?",
"title_normalized": "spontaneous subcutaneous emphysema and pneumomediastinum in covid 19 patients an indicator of poor prognosis"
} | [
{
"companynumb": "US-PFIZER INC-2020361094",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZINC SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "Tocilizumab, an anti-human interleukin 6 receptor (IL-6R) monoclonal antibody, is widely used to treat rheumatoid arthritis (RA) and is expected to exhibit clinical efficacy when used to treat other autoimmune diseases. However, a risk of opportunistic infection is occasionally recognized. A 54-year-old woman had received an oral corticosteroid and methotrexate to treat RA. Despite receiving these treatments, she received additional treatment with tocilizumab due to poor control of the disease activity. She presented at our hospital with a high fever and epigastralgia 19 days after receiving this treatment. A laboratory evaluation revealed liver injury and cytomegalovirus (CMV) viremia. Abdominal ultrasonography and computed tomography (CT) revealed hepatosplenomegaly, but no ascites. Upper gastrointestinal endoscopy revealed gastric erosions induced by CMV, which were confirmed immunohistochemically. Hence, we diagnosed the patient with CMV reactivation-induced acute hepatitis and gastric erosions under tocilizumab treatment. She received an anti-cytomegalovirus drug, ganciclovir, for 14 days due to her viremia and impaired general condition, which was suggestive of a severe infection. Her general condition subsequently improved, the liver function test results normalized, and the gastric erosions disappeared. In conclusion, although tocilizumab is very useful for treating certain autoimmune and inflammatory diseases, and will be prescribed more widely in the future, associated CMV infections must be closely monitored, as these can be lethal.",
"affiliations": "Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan.",
"authors": "Komura|Takuya|T|;Ohta|Hajime|H|;Nakai|Ryotaro|R|;Seishima|Jun|J|;Yamato|Masatoshi|M|;Miyazawa|Masaki|M|;Kaji|Kiichiro|K|;Marukawa|Yohei|Y|;Kagaya|Takashi|T|;Kitagawa|Kiyoki|K|;Kawashima|Atsuhiro|A|;Kaneko|Shuichi|S|;Unoura|Masashi|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab; D015774:Ganciclovir; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.5981",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(14)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid; D003586:Cytomegalovirus Infections; D005260:Female; D015774:Ganciclovir; D006505:Hepatitis; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D013276:Stomach Ulcer",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1923-7",
"pmc": null,
"pmid": "27432105",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus Reactivation Induced Acute Hepatitis and Gastric Erosions in a Patient with Rheumatoid Arthritis under Treatment with an Anti-IL-6 Receptor Antibody, Tocilizumab.",
"title_normalized": "cytomegalovirus reactivation induced acute hepatitis and gastric erosions in a patient with rheumatoid arthritis under treatment with an anti il 6 receptor antibody tocilizumab"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1033800",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPrimary angiitis of the CNS (PACNS) typically manifests with accumulating neurologic deficits from ischemic strokes. Intracerebral hemorrhage (ICH) is an uncommon complication. There is limited knowledge about the risk factors and features of hemorrhagic PACNS.\n\n\nMETHODS\nWe identified 49 patients (20 biopsy-proven) with PACNS diagnosed at our hospital from 1993 to 2015. We compared the features of hemorrhagic and nonhemorrhagic PACNS and analyzed the hemorrhagic PACNS cases in detail.\n\n\nRESULTS\nThe mean age was 51 ± 15 years; 13 patients were men. Five patients had ICH (mean age 52 ± 14 years; 4 men) including 4 where ICH was the first manifestation of PACNS. All ICH patients reported recent exposure to sympathomimetic drugs (e.g., diet pills, nasal decongestants). Patients with ICH had higher rates of headache (100% vs 43%, p = 0.022), especially thunderclap headache (60% vs 0%, p = 0.001), and eosinophilic vascular infiltrates on brain biopsy (50% vs 9%, p = 0.084). In all ICH patients, brain MRI showed lobar hemorrhages with concurrent punctate diffusion-restricted lesions, suggesting an acute inflammatory process. Four received a short course of immunosuppressive therapy. All patients showed complete clinical resolution or significant improvement within weeks.\n\n\nCONCLUSIONS\nIn this study, hemorrhagic PACNS was exclusively associated with sympathomimetic drug exposure. The high rate of thunderclap headache, lobar hemorrhages, and the self-limited clinical course suggests a shared mechanism between hemorrhagic PACNS and the reversible cerebral vasoconstriction syndrome (RCVS), a PACNS mimic. This RCVS-PACNS overlap syndrome may result from sympathomimetic drug-induced prolonged distal vasoconstriction, culminating in inflammation.",
"affiliations": "Massachusetts General Hospital and Harvard Medical School (MAT, MPF, ABS), Boston; Neurology Department (MAT), Hacettepe University Hospitals, Ankara, Turkey; Safar Center for Resuscitation (RMJ), University of Pittsburgh Medical Center, PA; and Government Medical College (JG), Kottayam, India.;Massachusetts General Hospital and Harvard Medical School (MAT, MPF, ABS), Boston; Neurology Department (MAT), Hacettepe University Hospitals, Ankara, Turkey; Safar Center for Resuscitation (RMJ), University of Pittsburgh Medical Center, PA; and Government Medical College (JG), Kottayam, India.;Massachusetts General Hospital and Harvard Medical School (MAT, MPF, ABS), Boston; Neurology Department (MAT), Hacettepe University Hospitals, Ankara, Turkey; Safar Center for Resuscitation (RMJ), University of Pittsburgh Medical Center, PA; and Government Medical College (JG), Kottayam, India.;Massachusetts General Hospital and Harvard Medical School (MAT, MPF, ABS), Boston; Neurology Department (MAT), Hacettepe University Hospitals, Ankara, Turkey; Safar Center for Resuscitation (RMJ), University of Pittsburgh Medical Center, PA; and Government Medical College (JG), Kottayam, India.;Massachusetts General Hospital and Harvard Medical School (MAT, MPF, ABS), Boston; Neurology Department (MAT), Hacettepe University Hospitals, Ankara, Turkey; Safar Center for Resuscitation (RMJ), University of Pittsburgh Medical Center, PA; and Government Medical College (JG), Kottayam, India.",
"authors": "Topcuoglu|Mehmet A|MA|;Jha|Ruchira M|RM|;George|Jacob|J|;Frosch|Matthew P|MP|;Singhal|Aneesh B|AB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/CPJ.0000000000000324",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2163-0402",
"issue": "7(1)",
"journal": "Neurology. Clinical practice",
"keywords": null,
"medline_ta": "Neurol Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101577149",
"other_id": null,
"pages": "26-34",
"pmc": null,
"pmid": "28243503",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "11117974;5000426;21601163;24782189;12791938;22038406;27272485;2956531;4394271;22995694;21864073;19132558;3275856;20884871;26020379;15659428;11781419;10671124;27043703;9214418;12372748;11295994;14675610;15605198;21482916;15383767;11117973",
"title": "Hemorrhagic primary CNS angiitis and vasoconstrictive drug exposure.",
"title_normalized": "hemorrhagic primary cns angiitis and vasoconstrictive drug exposure"
} | [
{
"companynumb": "US-ACELLA PHARMACEUTICALS, LLC-2023655",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3... |
{
"abstract": "BACKGROUND\nAlthough few studies have reported hyponatremia due to carbamazepine or oxcarbazepine in patients with epilepsy, no study has investigated cases of carbamazepine- or oxcarbazepine-induced hyponatremia or unsteady gait in patients with neuropathic pain. Herein, we report a case of oxcarbazepine-induced lower leg weakness in a patient with trigeminal neuralgia and summarize the diagnosis, treatment, and changes of clinical symptoms.\n\n\nMETHODS\nA 78-year-old male with a history of lumbar spinal stenosis was admitted to the hospital after he experienced lancinating pain around his right cheek, eyes, and lip, and was diagnosed with trigeminal neuralgia at the right maxillary and mandibular branch. He was prescribed oxcarbazepine (600 mg/d), milnacipran (25 mg/d), and oxycodone/naloxone (20 mg/10 mg/d) for four years. Four years later, the patient experienced symptoms associated with spinal stenosis, including pain in the lower extremities and unsteady gait. His serum sodium level was 127 mmol/L. Assuming oxcarbazepine to be the cause of the hyponatremia, oxcarbazepine administration was put on hold and the patient was switched to topiramate. At subsequent visit, the patient's serum sodium level had normalized to 143 mmol/L and his unsteady gait had improved.\n\n\nCONCLUSIONS\nOxcarbazepine-induced hyponatremia may cause lower extremity weakness and unsteady gait, which should be differentiated from those caused by spinal stenosis.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul 07061, South Korea.;Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam 13620, South Korea. hiitsme@hanmail.net.",
"authors": "Song|Hyun-Gul|HG|;Nahm|Francis Sahngun|FS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v8.i5.922",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2307-8960",
"issue": "8(5)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Drug-related side effects and adverse reactions; Hyponatremia; Oxcarbazepine; Spinal stenosis; Trigeminal neuralgia",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "922-927",
"pmc": null,
"pmid": "32190628",
"pubdate": "2020-03-06",
"publication_types": "D002363:Case Reports",
"references": "10824078;30178160;14640340;26336972;28542738;20881597;23225488;27333872;29631131;28375911;25031812;26975593",
"title": "Oxcarbazepine for trigeminal neuralgia may induce lower extremity weakness: A case report.",
"title_normalized": "oxcarbazepine for trigeminal neuralgia may induce lower extremity weakness a case report"
} | [
{
"companynumb": "KR-ALLERGAN-2014540US",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NALOXONE HYDROCHLORIDE\\OXYCODONE HYDROCHLORIDE"
},
... |
{
"abstract": "Despite recent advances in treatment with multidrug chemotherapy regimens, outcomes of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain very poor. Treatment with targeted therapies has shown marginal benefits due to intrinsic or acquired resistance. Actionable mutations, while detected infrequently in patients with PDAC, are becoming increasingly used in personalized medicine. Here, we describe an epidermal growth factor receptor (EGFR)-activating mutation (E746_T751>VP) to erlotinib, a first-generation tyrosine kinase inhibitor (TKI), in a patient with metastatic PDAC. After an initial partial response to erlotinib for 12 months, the patient's disease progressed with emergence of the EGFR A647T mutation. Certainly, the patient also progressed after switching therapy to a third-generation EGFR TKI (osimertinib). This case illustrates the posttreatment evolution of EGFR A647T-mediated resistance to the first- and third-generation TKIs. To our knowledge, this is the first case to report the aforementioned activating and resistance-mediated mutations. In summary, genomic analysis performed in this patient with PDAC on the tumor biopsy and peripheral blood provided tools to understand mechanisms of response and resistance to targeted therapy with EFGR TKIs.",
"affiliations": "Department of Oncologic Sciences, Mitchell Cancer Institute, The University of South Alabama, Mobile, Alabama, USA.;College of Allied Health Professions, The University of South Alabama, Mobile, Alabama, USA.;Division of Interventional Radiology, The University of South Alabama, Mobile, Alabama, USA.;Medical Oncology, Mitchell Cancer Institute, The University of South Alabama, Mobile, Alabama, USA.;Medical Oncology, Mitchell Cancer Institute, The University of South Alabama, Mobile, Alabama, USA.;Medical Oncology, Mitchell Cancer Institute, The University of South Alabama, Mobile, Alabama, USA.;Gynecology Oncology, Mitchell Cancer Institute, The University of South Alabama, Mobile, Alabama, USA.;Medical Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.;Division of Interventional Radiology, The University of South Alabama, Mobile, Alabama, USA.;Department of Oncologic Sciences, Mitchell Cancer Institute, The University of South Alabama, Mobile, Alabama, USA.;Division of Interventional Radiology, The University of South Alabama, Mobile, Alabama, USA.",
"authors": "Patel|Girijesh Kumar|GK|;Perry|Josiah B|JB|;Abdul-Rahim|Osama|O|;Frankel|Arthur E|AE|;Cameron|Daniel|D|;Taylor|William|W|;Rocconi|Rodney P|RP|;Abushahin|Laith|L|;Nelson|Cindy|C|;Singh|Ajay P|AP|;Khushman|Moh'd|M|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "India",
"delete": false,
"doi": "10.4103/jcrt.JCRT_729_18",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "16(4)",
"journal": "Journal of cancer research and therapeutics",
"keywords": "A647T; E746_T751>VP mutation; epidermal growth factor receptor; erlotinib; osimertinib; pancreatic ductal adenocarcinoma; resistance",
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000368:Aged; D021441:Carcinoma, Pancreatic Ductal; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms; D011379:Prognosis; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "950-954",
"pmc": null,
"pmid": "32930150",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Epidermal growth factor receptor-activating mutation(E746_T751>VP) in pancreatic ductal adenocarcinoma responds to erlotinib, followed by epidermal growth factor receptor resistance-mediating mutation (A647T): A case report and literature review.",
"title_normalized": "epidermal growth factor receptor activating mutation e746 t751 vp in pancreatic ductal adenocarcinoma responds to erlotinib followed by epidermal growth factor receptor resistance mediating mutation a647t a case report and literature review"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0127689",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Spigelian hernias are a rare lateral ventral abdominal hernia that carry a high risk of strangulation due to their smaller sizes, and require surgical intervention. In more complex cases involving an anticoagulated patient, perioperative management of anticoagulation must be monitored and reviewed to avoid potential pitfalls. We present an 81-year-old woman who presented with right groin pain, and was requiring warfarin anticoagulation due to her cardiac history. The spigelian hernia was diagnosed and reduced laparoscopically, and the defect was repaired and reinforced by mesh. However, the patient suffered from catastrophic complications postoperatively related to her anticoagulation management. Spigelian hernias require surgical interventions. However, in an anticoagulated patient with significant comorbidities, perioperative anticoagulation needs to be closely monitored to balance the risk of thromboembolic disease with acceptable postoperative bleeding risks.",
"affiliations": "ACT Health, Canberra, ACT, Australia.;NSW Health, North Sydney, New South Wales, Australia.;Department of General Surgery, Kalgoorlie Regional Hospital, Kalgoorlie, Western Australia, Australia.",
"authors": "Tan|Xiaotong Cheryl|XC|;Nalavenkata|Sunny|S|;Yunaev|Michael|M|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222468",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "drug therapy related to surgery; general surgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D003937:Diagnosis, Differential; D017984:Enoxaparin; D017809:Fatal Outcome; D005260:Female; D006406:Hematoma; D006555:Hernia, Ventral; D006801:Humans; D010535:Laparoscopy; D010146:Pain; D019106:Postoperative Hemorrhage; D013526:Surgical Mesh",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29237666",
"pubdate": "2017-12-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1442961;11967699;18704620;22606580;10794211;9566569;2683401;9154771;22315266;19762550;12413315;19547696;9358097",
"title": "Spigelian hernia and pitfalls of postoperative anticoagulation.",
"title_normalized": "spigelian hernia and pitfalls of postoperative anticoagulation"
} | [
{
"companynumb": "AU-FRESENIUS KABI-FK201801071",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "Central nervous system (CNS) involvement in systemic B-cell non-Hodgkin lymphoma (B-NHL) at diagnosis (sysCNS) is rare. We investigated the outcome of 21 patients with sysCNS, most commonly diffuse large B-cell lymphoma, treated with high dose methotrexate (HD-MTX) and R-CHOP. The median number of cycles of HD-MTX and R-CHOP was 4 (range 1-8) and 6 (range 0-8), respectively. Consolidative whole brain radiotherapy (WBRT) was given to 33% (7/21) patients. With a median follow-up of 44 months the 3-year progression free survival (PFS) and overall survival (OS) were 45% (95%CI 34-56%) and 49% (95%CI 38-60%), respectively. Over 90% of patients had an unfavorable international prognostic index score, reflected by treatment-related mortality of 19% (4/21) and relapse-related mortality of 28% (6/21). The outcome of these patients was, however, unexpectedly good when compared to secondary CNS relapses. Prospective studies are needed to define the optimal treatment for patients with sysCNS, but its rarity might be challenging.",
"affiliations": "a Department of Haematology , University Medical Centre Groningen, University of Groningen , Groningen , Netherlands.;b Department of Neurology , Canisius-Wilhelmina Hospital , Nijmegen , Netherlands.;c Department of Haematology , Erasmus MC Cancer Institute , Rotterdam , Netherlands.;d Department of Neurology , University Medical Centre Groningen, University of Groningen , Groningen , Netherlands.;e Department of Neurology , Erasmus MC , Rotterdam , Netherlands.;a Department of Haematology , University Medical Centre Groningen, University of Groningen , Groningen , Netherlands.",
"authors": "Nijland|Marcel|M|;Jansen|Anne|A|;Doorduijn|Jeanette K|JK|;Enting|Roelien H|RH|;Bromberg|Jacoline E C|JEC|;Kluin-Nelemans|Hanneke C|HC|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2017.1285026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "58(9)",
"journal": "Leukemia & lymphoma",
"keywords": "Aggressive B-cell lymphoma; R-CHOP; central nervous system; methotrexate; systemic",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D016371:Cranial Irradiation; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "28278731",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of initial parenchymal central nervous system involvement in systemic aggressive B-cell lymphoma.",
"title_normalized": "treatment of initial parenchymal central nervous system involvement in systemic aggressive b cell lymphoma"
} | [
{
"companynumb": "NL-JNJFOC-20170706992",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nto compare the efficacy and safety of Adalimumab(ADA) and Infliximab(IFX), in a large Romanian population and to identify predictors of response. Methods We performed a national retrospective cohort study including 265 patients (136 ADA, 129 IFX) between 2008-2014. Binary logistic regression was performed with the statistical program Minitab.\n\n\nRESULTS\nPatients were half women, with a median age of 36, a median disease duration of 2.5 years, 80% received Azathioprine. Mean therapy duration was 20 months in ADA group and 36 months in IFX group. Complete response to Adalimumab respectively Infliximab was recorded in 77%vs.65%, secondary loss of response in 18%vs.28%, statistically comparable. We failed to identify predictors of response. In 79.2%of patients with secondary loss of response to ADA, the dose was escalated, 12.5% were switched to Infliximab. In 70%of patients that lost response to IFX, the dose was increased, 30% were switched to Adalimumab.\n\n\nCONCLUSIONS\nAdalimumab and Infliximab have similar efficacy, with a complete response rate of~70%. In case of secondary loss of response to IFX, the best solution is to switch to ADA, with 83% response rate, while in case of secondary loss of response to ADA, increasing the dose leads to 84 % response rate.",
"affiliations": "Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;University of Medicine \"Victor Babes\", Clinic of Gastroenterology, Timisoara.;Clinic County Hospital \"Sf.Spiridon\", Gastroenterology and Hepatology, Iassy.;Regional Institute of Gastroenterology and Hepatology \"O.Fodor\", Gastroenterology and Hepatology, Cluj.;Regional Institute of Gastroenterology and Hepatology \"O.Fodor\", Gastroenterology and Hepatology, Cluj.;Clinic Universitary Emergency Hospital, Bucharest.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;Clinic County Hospital \"Sf.Spiridon\", Gastroenterology and Hepatology, Iassy.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.;Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest.",
"authors": "Preda|C|C|;Fulger|L|L|;Gheorghe|L|L|;Gheorghe|C|C|;Goldis|A|A|;Trifan|A|A|;Tantau|M|M|;Tantau|A|A|;Negreanu|L|L|;Manuc|M|M|;Cijevschi-Prelipcean|C|C|;Iacob|R|R|;Tieranu|C|C|;Meianu|C|C|;Diculescu|M|M|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.12865/CHSJ.42.02.01",
"fulltext": "\n==== Front\nCurr Health Sci JCurr Health Sci JCHSJCurrent Health Sciences Journal2067-06562069-4032Medical University Publishing House Craiova 2016.02.0110.12865/CHSJ.42.02.01Original PaperAdalimumab and Infliximab in Crohn’s disease - real life data from a national retrospective cohort study PREDA C. 1FULGER L. 1GHEORGHE L. 1GHEORGHE C. 1GOLDIS A. 2TRIFAN A. 3TANTAU M. 4TANTAU A. 4NEGREANU L. 5MANUC M. 1CIJEVSCHI-PRELIPCEAN C. 3IACOB R. 1TIERANU C. 1MEIANU C. 1DICULESCU M. 11 Clinic Fundeni Institute, Gastroenterology & Hepatology, Bucharest2 University of Medicine “Victor Babes”, Clinic of Gastroenterology, Timisoara3 Clinic County Hospital “Sf.Spiridon”, Gastroenterology and Hepatology, Iassy4 Regional Institute of Gastroenterology and Hepatology “O.Fodor”, Gastroenterology and Hepatology, Cluj5 Clinic Universitary Emergency Hospital, BucharestCorresponding Author: Preda Carmen- Monica\nGastroenterology&HepatologyClinic Fundeni InstituteSos. Fundeni 258, 22328Bucharestpreda_monicaa@yahoo.comApr-Jun 2016 28 6 2016 42 2 115 124 12 4 2016 16 6 2016 Copyright © 2016, Medical University Publishing House Craiova2016This is an open-access article distributed under the terms of a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License, which permits unrestricted use, adaptation, distribution and reproduction in any medium, non-commercially, provided the new creations are licensed under identical terms as the original work and the original work is properly cited.ABSTRACT: Aim: to compare the efficacy and safety of Adalimumab(ADA) and Infliximab(IFX), in a large Romanian population and to identify predictors of response. Methods We performed a national retrospective cohort study including 265 patients (136 ADA, 129 IFX) between 2008-2014. Binary logistic regression was performed with the statistical program Minitab. Results: Patients were half women, with a median age of 36, a median disease duration of 2.5 years, 80% received Azathioprine. Mean therapy duration was 20 months in ADA group and 36 months in IFX group. Complete response to Adalimumab respectively Infliximab was recorded in 77%vs.65%, secondary loss of response in 18%vs.28%, statistically comparable. We failed to identify predictors of response. In 79.2%of patients with secondary loss of response to ADA, the dose was escalated, 12.5% were switched to Infliximab. In 70%of patients that lost response to IFX, the dose was increased, 30% were switched to Adalimumab. Conclusions: Adalimumab and Infliximab have similar efficacy, with a complete response rate of~70%. In case of secondary loss of response to IFX, the best solution is to switch to ADA, with 83% response rate, while in case of secondary loss of response to ADA, increasing the dose leads to 84 % response rate.\n\nAdalimumabInfliximabCrohn's disease\n==== Body\nIntroduction\nCrohn's disease (CD) is a lifelong disease arising from an interaction between genetic and environmental factors, but predominantly observed in developed countries of the world. The precise etiology is unknown, therefore a causal therapy is not yet available. [1]\n\nRemission is widely accepted as a CDAI of less than 150 points and response is increasingly\ndefined as a decrease in CDAI by ≥100 points [1]. Relapse is a flare of symptoms in a patient with established CD who\nis in clinical remission (CDAI of more than 150 with an increase of more than 70\npoints) [1]\n\nPatients with Steroid-refractory disease are those who have active disease despite prednisolone of up to 0.75 mg/kg/day over a period of 4 weeks. Steroid-dependent disease is defined either in patients who are unable to reduce steroids below the equivalent of prednisolone 10 mg/day (or budesonide below 3 mg/day) after 3 months of starting steroids, without recurrent active disease, or in patients who have a relapse after 3 months of stopping steroids. [1]\n\nMucosal healing evaluated through endoscopy is a surrogate marker of sustained controlled Crohn's disease [3]\n\nInfliximab (IFX, Remicade®) a chimeric immunoglobulin G (IgG) human (75%)/murine (25%) mAb administered by intravenous infusion, is indicated for induction and maintenance of remission in adult and pediatric CD [4]. \n\nAdalimumab (ADA, Humira) is a self-injected, fully humanized recombinant mAb. This agent is indicated for induction and maintenance of remission in adult CD. IFX and ADA have high binding affinity for both soluble and transmembrane forms of TNF, blocking interaction of TNF with p55 and p75 cell surface TNF receptors and neutralizing its biologic activity [5, 6]. In Romania, the use of IFX for CD has an experience of more than a decade.\n\nData regarding IFX use in CD come from randomized trials: ACCENT (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) I and II established the use of IFX for active maintenance, and fistulizing CD [7,8,9].\n\nThe purpose of this study was to evaluate whether Infliximab and Adalimumab achieve expectations in clinical practice in Romania: a country in eastern Europe where the incidence and prevalence of Crohn’s disease is lower than in eastern Europe, and the proportion of moderate-severe cases is much lower [10, 11]. \n\nMaterial and methods\nA retrospective cohort study was performed, enrolling all patients with Crohn’s disease in Romania treated with Infliximab and with Adalimumab in a period of 5 years (august 2008-august 2013). All these patients were biological naïve. The data were collected from each patient’s files existing in the archive of the National Inssurance Agency. All subjects included signed an informed consent stating that their data can be used in scientific purposes and the study was approved by the Regional Ethical Comitee.\n\nAll patients that stopped therapy were questioned regarding the reasons for stopping therapy by- phone or mail or e-mail. \n\nAccording to Romanian guidelines, patients eligible for therapy with biologic agents are adults or children (6 to 17 years) with moderate-severe Crohn’s disease with inadequate treatment response or intolerance to standard therapy (corticosteroids, azathioprine/6-Mercaptopurine, Methotrexate) or cortico-dependent, those with fistulizing CD non-responsive to conventional therapy (presumed non-having abscesses).\n\nAll patients received induction therapy with Infliximab 5 mg/kg 0,2,6 weeks, followed by maintenance therapy: 5 mg/kg at 8 weeks. If the subject looses the response, the interval between the doses is shortened at 6 or 4 weeks, or the dose is doubled to 10 mg/kg at 4 weeks at the indication of his physician-gastroenterologist.\n\nPatients on adalimumab received two induction doses (160 mg or 80 mg and 80 or 40mg subcutaneously [sc]) at weeks 0 and 2, respectively and maintenance (40 mg sc every other week) therapy. At or after eight weeks, patients with flare or nonresponse would have their dosage increased to 40 mg sc weekly.\n\nTheir diagnosis was confirmed by clinical evaluation and a combination of endoscopic, histological, radiological, and/or biochemical investigations.Patients were classified according to Montréal phenotype classification [12].\n\nThe recorded informations were: type of disease, age, sex, time of disease prior to IFX or ADA therapy, and location of CD (terminal ileum and colon, colon only, or ileum/small bowel only). Smoking history was poorly recorded and therefore omitted. Laboratory data were recorded in three periods to assess changes: within 1 month prior to IFX therapy, at 6 weeks after the first infusion and then at 6 months in the maintenance period. \n\nRelevant therapeutic data before IFX were recorded: either no therapy, either prednisone, either azathioprine. Azathioprine (AZA) was used at the standard dose of 2-2.5 mg/kg/day. Information on the intake of medications other than IFX after the start of infusion was recorded inconsistently and was therefore omitted from analysis. However, previous surgical interventions and the presence of external fistulae were recorded, as well as side effects.\n\nWe didn't have data regarding therapeutic drug monitoring in monoclonal therapy (trough serum infliximab levels and antibodies toward infliximab).\n\nScreening for active infection and for latent tuberculosis (chest X-ray and cutaneous PPD test or Quantiferon) was performed in all patients before starting anti-TNF therapy.\n\nThe median length of follow-up was also defined by the median length of treatment. Duration of response was reflected by the period of time between the first dose (induction phase) and the last dose. Those patients continuing therapy were considered to be in remission by their physicians, so this is a marker of successful maintenance or failure to relapse. \n\nComplete response was defined as remission of the disease: CDAI< 150 points at the last evaluation, partial response is a decrease in CDAI of more than 70 points at 12 weeks after the first administration of ADA/IFX, but remission was not obtained. Non-response is defined as a decrease of CDAI of less than 70 points at 12 weeks after the first administration of ADA/IFX, obviously without remission.\n\nStatistical analysis: Statistical analysis was performed with Minitab statistical\nsoftware (version 17, Minitab Inc., State College, Pennsylvania, USA). Descriptive\nstatistic was used to summarize the data. Averages with standard deviation were\ncalculated for continuous data and percentages were calculated for categorical data.\nDemographic and baseline characteristics of the two groups (those who received\ninfliximab and those with adalimumab) were compared using the chi-square test or\nFisher's exact test for categorical variables and the t-Student two-tailed test\nfor continuous variables, which have a normal distribution. P value <0.05 was\nconsidered significant. The association between the demographic, clinical and\nlaboratory parameters and response to therapy were examined through binary logistic\nregression as we have a dichotomous response variable (response Yes or No). \n\nResults\n265 patients were included in the study: 129 on Infliximab (IFX group) and 136 on Adalimumab (ADA group). All these patients are biological naïve. Their demographic and clinical features are showed in 1.\n\nTable 1 Demographic and clinical features of patients with Crohn’s disease treated with biologicals\n\nGROUP\n\n\t \n\n\tADA\n\n\tIFX\n\n\tp-value\n\n\t\n \n\n\t \n\n\tNo.\n\n\t%\n\n\tNo.\n\n\t%\n\n\t \n\n\t\nNo.\n\n\tTOTAL\n\n\t136\n\n\t129\n\n\t \n\n\t\nAGE\n\n\tMean\n\n\t38.154\n\n\t35.225\n\n\t0.052\n\n\t\nStd. Dev.\n\n\t12.481\n\n\t11.948\n\n\t\nSEX\n\n\tM\n\n\t73\n\n\t53.68%\n\n\t61\n\n\t47.29%\n\n\t0.298\n\n\t\n \n\n\tF\n\n\t63\n\n\t46.32%\n\n\t68\n\n\t52.71%\n\n\t\nINITIAL </p>\n<p>CDAI\n\n\tMean\n\n\t260.336\n\n\t273.855\n\n\t0.2\n\n\t\nStd. Dev.\n\n\t105.31\n\n\t115.42\n\n\t\nINITIAL CRP\n\n\tMean\n\n\t25.858\n\n\t35.590\n\n\t0.447\n\n\t\nStd. Dev\n\n\t47.668\n\n\t53.093\n\n\t\nA subgroups\n\n\tA1\n\n\t3\n\n\t2.21%\n\n\t7\n\n\t5.43%\n\n\t0.084\n\n\t\nA2\n\n\t93\n\n\t68.38%\n\n\t97\n\n\t75.19%\n\n\t\nA3\n\n\t40\n\n\t29.41%\n\n\t25\n\n\t19.38%\n\n\t\nL subgroups\n\n\tL1\n\n\t30\n\n\t22.06%\n\n\t14\n\n\t10.85%\n\n\t0.013\n\n\t\nL2\n\n\t40\n\n\t29.41%\n\n\t56\n\n\t43.41%\n\n\t\nL3\n\n\t66\n\n\t48.53%\n\n\t59\n\n\t45.74%\n\n\t\nDisease behaviour\n\n\tB1\n\n\t83\n\n\t61.03%\n\n\t67\n\n\t51.94%\n\n\t0.001\n\n\t\nB2\n\n\t31\n\n\t22.79%\n\n\t18\n\n\t13.95%\n\n\t\nB3\n\n\t22\n\n\t16.18%\n\n\t44\n\n\t34.11%\n\n\t\nSurgery before biologics\n\n\tY\n\n\t28\n\n\t20.59%\n\n\t23\n\n\t17.83%\n\n\t0.569\n\n\t\nN\n\n\t108\n\n\t79.41%\n\n\t106\n\n\t82.17%\n\n\t\nDisease duration (years)\n\n\tMean\n\n\t3.174\n\n\t4.129\n\n\t0.037\n\n\t\nStd.Dev.\n\n\t4.106\n\n\t4.407\n\n\t\nAzathioprine concomitant with biologics\n\n\tY\n\n\t112\n\n\t82.35%\n\n\t96\n\n\t74.42%\n\n\t0.116\n\n\t\nN\n\n\t24\n\n\t17.65%\n\n\t33\n\n\t25.58%\n\n\t\nIntolerance to AZA\n\n\t24\n\n\t17.65%\n\n\t19\n\n\t14.73%\n\n\t0.632\n\n\t\nCorticoresistant</p>\n<p>/corticodependant\n\n\tCorticodep.\n\n\t118\n\n\t86.76%\n\n\t98\n\n\t75.97%\n\n\t0.042\n\n\t\nCorticores.\n\n\t18\n\n\t13.24%\n\n\t29\n\n\t22.48%\n\n\t\nNA\n\n\t0\n\n\t0%\n\n\t2\n\n\t1.55%\n\n\t\n\nAccording to the data presented in table 1, the two groups of patients are statistically comparable, except for: location (ileal location more frequent in ADA group), disease behaviour (fistulising disease more prevalent in IFX group), disease duration (which is one year longer among IFX treated subjects), corticoresistant cases (more prevalent in IFX group). These data suggest that patients included in the IFX group are more difficult to treat. Regarding all the other parameters, the two groups are similar: patients are young with a mean of age around 36 years, M:F ratio is about 1:1, with a CDAI mean 270 points (which indicates moderate severity of CD at the moment of biologic initiation) and a CRP mean 30 mg/dl at initiation, approximately three quarters of cases have CD diagnosis between 17-40 years, 20% suffered surgical resections before biologic therapy. The great majority of patients, around 80%, received Azathioprine before starting IFX/AZA, while rate of intolerance to AZA is quite high, around 15%.\n\nIn 2 type of response to biologic therapy and therapy duration are presented.\n\nTable 2 Duration of biologic therapy and type of response to therapy according to group of patients \n\nGROUP\n\n\t \n\n\tADA\n\n\tIFX\n\n\tp-value\n\n\t\n \n\n\t \n\n\tNo.\n\n\t%\n\n\tNo.\n\n\t%\n\n\t \n\n\t\nNo.\n\n\tTOTAL\n\n\t136\n\n\t129\n\n\t \n\n\t\nTherapy duration (months)\n\n\tMean\n\n\t19.78\n\n\t35.78\n\n\t0.00001\n\n\t\nStd. Dev.\n\n\t10.01\n\n\t19.54\n\n\t\nType of response\n\n\tComplete response\n\n\t104\n\n\t76.47%\n\n\t84\n\n\t65.1%\n\n\t0.96811\n\n\t\n \n\n\tSecondary loss of response\n\n\t24\n\n\t17.65%\n\n\t37\n\n\t28.7%\n\n\t\n \n\n\tPrimary non-response\n\n\t5\n\n\t3.68%\n\n\t3\n\n\t2.3%\n\n\t \n\n\t\n \n\n\tPartial response\n\n\t3\n\n\t2.21%\n\n\t2\n\n\t1.55%\n\n\t \n\n\t\nTime to loss of response (months)\n\n\tMean\n\n\t12.71\n\n\t15.52\n\n\t0.0734\n\n\t\nStd. Dev.\n\n\t9.28\n\n\t7.87\n\n\t \n\n\t\nDuration of therapy differs significantly between the two groups: patients in IFX group received this drug for approximately 3 years, while those in ADA group for about 1.5 years.\n\nResponse to therapy in both groups is comparable and excellent: about 70% of patients respond very well, are in remission, and continue therapy. Secondary loss of response is more frequent among patients treated with Infliximab, about 30%, but that may be explained by the longer duration of the therapy. Risk of non-response is very similar between IFX and ADA, about 3%, while partial response is very rare, about 2% of the patients.\n\nRegarding latent tuberculosis, 52 patients (20.4%) proved to have latent tuberculosis and received chemoprophylaxis with Isoniazid 300 mg per day for 9 months.\n\n6 patients out of 265 (2.26%) were HBs antigen positive and received Entecavir for prophylaxy of chronic hepatitis B reactivation. Only 2 people were diagnosed with chronic hepatitis C (0.7%).\n\nPredictive factors of loss of response to biologic therapy were analyzed: male gender, younger age at diagnosis, perianal disease, fistulising disease, ileocolonic location, azathioprine administration prior anti-TNF therapy, anemia, disease duration, severe disease at initiation. As we can see in 3 and 4, we failed to identify significant predictors of loss of response to Infliximab respectively Adalimumab.\n\nTable 3 Predictive factors for loss of response to Infliximab\n\nPredictive factor\n\n\tOdds ratio (95% CI)\n\n\tP-value\n\n\t\nMale gender\n\n\t1.0200 (0.4879, 2.1324)\n\n\t0.958\n\n\t\nYounger age at diagnostic\n\n\t0.6250 (0.0952, 4.2221)\n\n\t0.280\n\n\t\nSevere disease at initiation\n\n\t1.0021 (0.9988, 1.0054)\n\n\t0.216\n\n\t\nFistulising behaviour\n\n\t1.1330 (0.5044, 2.5452)\n\n\t0.953\n\n\t\nIleocolonic disease\n\n\t0.5000 (0.1376, 1.8168)\n\n\t0.689\n\n\t\nPerianal disease\n\n\t0.6389 (0.2332, 1.7506)\n\n\t0.372\n\n\t\nAzathioprine before anti-TNF\n\n\t1.7137 (0.6972, 4.2122)\n\n\t0.229\n\n\t\nAnemia\n\n\t1.8963 (0.8978, 4.0054)\n\n\t0.091\n\n\t\nLonger disease duration\n\n\t1.0441 (0.9585, 1.1373)\n\n\t0.326\n\n\t\nTable 4 Predictive factors for loss of response to Adalimumab\n\nPredictive factor\n\n\tOdds ratio (95% CI)\n\n\tP-value\n\n\t\nMale gender\n\n\t0.6365 (0.2788, 1.4530)\n\n\t0.282\n\n\t\nFistulising behaviour\n\n\t1.8482 (0.6151, 5.5533)\n\n\t0.287\n\n\t\nIleocolonic disease\n\n\t1.8214 (0.6774, 4.8978)\n\n\t0.455\n\n\t\nPerianal disease\n\n\t1.2667 (0.3761, 4.2661)\n\n\t0.707\n\n\t\nAzathioprine before anti-TNF\n\n\t1.0364 (0.3507, 3.0628)\n\n\t0.948\n\n\t\nAnemia\n\n\t2.1875 (0.9465, 5.0554)\n\n\t0.069\n\n\t\nLonger disease duration\n\n\t0.9990 (0.8967, 1.1129)\n\n\t0.985\n\n\t\n\n1 describes the rate of complete response in time for the two groups. There is a tendency towards maintaining a better response in time in patients treated with Adalimumab, but the p-value was not statistically significant (0.057).\n\nFigure 1 Rate of complete response in time in patients with Crohn's disease treated with Adalimumab/Infliximab\n\n2 is a flowchart that depicts the evolution of the 136 patients treated with Adalimumab.\n\nFigure 2 Outcome of patients with Crohn’s disease treated with Adalimumab\n\n\nWith most patients with secondary loss of response to Adalimumab (79.2%), the choice was to escaladate the dose, which reinduced response in 84.2%. In 12.5% the decision was to switch to Infliximab, but with a significantly lower rate of response of only 33%. 9 patients out of 104 recorded with complete response at their last check-up stopped Adalimumab, most of them for an unknown reason, one for tuberculous lymphadenitis, 2 were non-compliant and 2 reported adverse events (artralgia). \n\n3 describes the evolution of the 129 patients treated with Infliximab.\n\nFigure 3 Outcome of patients with Crohn’s disease treated with Infliximab \n\n\nOut of the 85 patients recorded with complete response on Infliximab, 14 stopped therapy, most of them [11] for unknown reason, while 3 were proven to be non-compliant. In most of the 37 patients that lost response to IFX, the physician decision was to increase the dose, in half of the cases by doubling the dose to 10 mg/kg body weight at 8 weeks, and in half by shortening the infusion interval to 4 or 6 weeks, which resulted in regaining response in approximately 40% of patients. Interestingly, if the physician decided the switch to Adalimumab, which was the case in 12/38 subjects, the result was even better, approx.83% regained response, which happened also in the situation of the 6/8 patients who did not respond to the increased dose of Infliximab.\n\nRegarding safety of biologic therapy: in the Adalimumab group no allergic reaction was reported, we found only one case of erythema at injection site, one patient with lymph nodes tuberculosis, one pustulous psoriasis, one febrile syndrome of unknown origin, 2 patients with artralgias. In the Infliximab group, 9 cases of allergic reactions were reported (7% prevalence), 3 of them severe, with anaphylaxia, and one case of psoriasis was reported, in a young male, 14 years. 2 deaths were reported in the Infliximab group, none directly related to the drug, one in a patient with severe disease, with no response to IFX, who underwent surgery (intestinal resection), and the cause of death were complications related to surgery. The other death was in a female who associated severe metabolic syndrome and suffered a stroke.\n\nDiscussions\nComplete response to both biologic agents was comparable (around 70%), and did not differ significantly between Adalimumab and Infliximab. Other authors report the same rate of complete response in cohort study [13]. Secondary loss of response was reported more often in patients treated with Infliximab (almost 30%) than in those who received ADA (approx.17%), but these findings are biased by longer duration of IFX therapy than of ADA therapy. The ACCENT and CHARM trials revealed that secondary loss of response may occur in 20-50% of the patients [5, 14] (e.g., ACCENT I: 28.5%, ACCENT II: 42%, CHARM: 27%). \n\nIn the literature only limited data are available on the frequency of dose intensification in ADA treated patients new to biological therapy. Authors report a percentage of loss of response to ADA among primary responders between 18% and 34% [15, 20, 21, 22, 23, 24]. According to a recent meta-analysis [15], predictors for loss of response or dose escalation were male gender, current/former smoker status, family history of IBD, isolated colonic disease, extra-intestinal manifestations, 80/40 mg induction therapy, longer disease duration, greater baseline CDAI, concomitant corticosteroid use, no deep remission at week 12. Our statistical analysis, performed trough binary logistic regression failed to identify predictors of secondary loss of response to Adalimumab though we studdied: severe activity of the disease at the initiation of ADA, perianal manifestations, extension of the disease, fistulising behaviour, concomitant Azathioprine therapy, disease duration, stricturising behaviour, CRP levels. This might be a consequence of a relative small study population (136 patients). Lopez Palacios et al found in their study published in 2008 that perianal fistulising disease has a poor response to Adalimumab [21]. In induction (CLASSIC I) and maintenance (CHARM, EXTEND) adalimumab trials in patients with Crohn’s disease, moderate CD patients had the highest clinical remission rate and largest treatment effect size, while moderate-CD/high-CRP patients had the most pronounced efficacy [25]. \n\nIn case of loss of response to ADA, our study demonstrates that dose escalation is the best option, which is similar to other data from the literature (20) \n\n One of the most important dilemmas in the treatment of IBD nowadays is the efficacy and safety of combined biological and immunosuppressive therapies. Most of the studies report that combined immunosuppressive therapy decrease the frequency of loss of response (9, 15). Some studies found a more favorable response to IFX in combination with immunosuppressant compared to IFX monotherapy [16, 17, 26]. \n\nHowever, in the studies of Kinney et al and Regueiro et al [18, 19], dose intensification was not affected by concomitant use of immunomodulator therapy. In our study, the use of concomitant immunomodulator therapy did not impact on the risk for loss of response to biologicals. This is why we consider that the effect of combined therapy immunosuppressive+ biologic is controversial.\n\nResponse to IFX in CD patients is excellent in our study: about 65% are in remission at three years, which is comparable with other data from the literature [26].\n\nWe did not find any predictive factors for loss of response to Infliximab though we studied: age at diagnosis, disease activity of the at the moment of starting IFX therapy, perianal manifestations, disease phenotype, and this might be also a consequence of a relative small sample size (129 patients). Other authors suggests that an inflammatory disease phenotype and male gender predicted sustained clinical benefit [26, 27].\n\n Sprakes et al in their cohort study reported that 4.8% patients discontinued infliximab therapy during induction due to intolerable adverse events, a higher proportion than in our study (2.3%). We found indeed a prevalence of allergic reaction of 7%, but two thirds of these reaction were managed by slowing the rate of infusion and anti-allergic therapy. We report 65.1% of 129 patients with sustained clinical benefit compared to 54.3% of the UK cohort study. 28.7% of our patients experienced secondary loss of response, a much higher proportion than in Sprakes study (18.1%), but this difference may be explained by the longer follow-up in our study: 35.8 months versus 17 months. Our patients were managed half with reduction of the interval between the infusions and half with doubling of the IFX dose at 8 weeks, similar with the english study. In our study, patients regained response in 40%, but in the cohort study of Sprakes et al, no patient regained response [26]. \n\nOne of the most important finding of our study is that patients who experience a secondary loss of response to Infliximab may be more successfully managed with switch to Adalimumab, this strategy leading to regaining response in almost 80% of them. We found no data in the literature for comparison.\n\n If we make a comparison between ADA and IFX in CD, these two biologics are equally effective in Crohn’s disease with a sustained long term efficacy rate of about 70%. We have to outline the fact that the two groups of patients are not statistically comparable: the main difference is in therapy duration, which is longer in patients treated with Infliximab (3 years compared to approx.1.5 years in those treated with ADA). Another difference is the disease duration, longer in the IFX group (4.13 years compared to 3.17 years). The percentage of corticoresistant cases is higher in the Infliximab patients (22%), while in ADA group is 13%. Fistulising disease is present in 34% of patients in the IFX group compared to 16% in the ADA group, while ileal disease is more prevalent in the ADA group (22 vs. 11%). These data suggests that patients that received Infliximab are more difficult to treat.\n\n In the study of Zorzi et al, that also compared ADA and IFX, most of clinical characteristics were similar between patients treated with infliximab vs. adalimumab, but the two study populations differed in terms of CD duration (longer in the adalimumab group), perianal disease (more prevalent in the infliximab group), proportion of corticoresistant patients (higher in the IFX group). Zorzi et al found that Infliximab and adalimumab showed a similar efficacy, and two predictors of steroid-free remission using anti-TNFs were identified: non-smokers and non stricturing non penetrating behaviour [28].\n\nIn a very large recently published retrospective cohort study by using U.S. Medicare data from 2006 through 2010, patients with CD were included, who were new users of infliximab (n=1459) or adalimumab (n=871). Some difference between the two groups were found: in the ADA group the 5-th decade of age was predominant, bowel resection was more prevalent in the IFX group (0.8% vs. 0.5%), steroids were more often recently used in the IFX group, but the authors demonstrated good balance among the treatment groups after stratifying on propensity score. The authors observed similar effectiveness of infliximab and adalimumab for CD on the basis of 3 clinically important outcome measures: persistence on therapy, rates of surgery, rates of hospitalization [29].\n\nAnother comparative study of Infliximab and Adalimumab in Crohn’s disease was performed by Kestens et al in carefully matched cohorts. They found no significant differences between treatment groups: at 1 and 2 years, 62% and 41% of those receiving ADA vs. 65 and 49% of those receiving IFX had responses, respectively. Combining IFX or ADA with immunomodulator therapy was associated with a higher clinical response than monotherapy, but this was only significant among patients who received IFX [30]. \n\n 59 out of 267 patients suffered resections (ileocolonic or ileal or colonic) before biologic therapy. The indication for surgery was complicated CD, such as small-bowel obstruction or abscess formation due to penetrating disease. 31 received ADA and 28 ADA. 68% achieved complete response, comparable to non-resected patients (74.5%). 9 of the 28 (32.1) resected patients treated with IFX suffered resection under biological treatment, compared to 4 of the 31 (12.9%) treated with ADA, but p-value was not statistically significant 0.075. 13 of 208 non-resected subjects suffered surgical interventions on biologic therapy (6%).\n\nThe strength of our cohort is that it is population-based, because it encompassed all Crohn's patients treated with monoclonals in Romania. An important limitation of this study, inherent to a retrospective study, is the potential underreporting of adverse events, smoking status, and non-uniformity in assessment of some outcome parameters.\n\n In conclusion, the present daily clinical practice series showed that Adalimumab and Infliximab are equally effective in Crohn’s disease, with a complete response rate of ~70%. This study failed to identify predictors of poor response to both biologics. In case of secondary loss of response to Adalimumab, the best option seem to be to escaladate the dose, which reinduced response in 84.2%, while switching to Infliximab results in a lower rate of response of only 33%. In reverse, patients who lost response to IFX seem to respond better if they were switched to ADA (complete response rate 83%) than if their dosage was increased (response in 42%).\n\nAbbreviations\nCDAI- \n\n- \n\nmAb- \n\nADA- Adalimumab \n\nTNF- \n\nAST- \n\nALT- Alanine Aminotransferase\n\n- \n\n- \n\n- \n\nData sharing statement\nThe original anonymous dataset is available on request from the corresponding author at preda_monicaa@yahoo.com\n\nAcknowledgments\nAuthor contributions: Carmen Monica Preda designed and carried out the study, drafted the manuscript and contributed by critical revision of the manuscript. Larisa Elena Fulger performed statistical analyses. Gheorghe Liana treated studied patients. Gheorghe Cristian treated studied patients. Goldis Adrian treated studied patients. Trifan Anca treated studied patients. Tantau Marcel treated studied patients and contributed by critical revision of the manuscript. Tantau Alina treated studied patients. Negreanu Lucian treated studied patients. Constantinescu Gabriel treated studied patients. Becheanu Gabriel performed statistical analyses and contributed by critical revision of the manuscript. Manuc Mircea treated studied patients. Cijevschi-Prelipcean Cristina treated studied patients. Iacob Razvan treated studied patients. Tieranu Cristian treated studied patients. Meianu Corina performed statistical analyses and contributed by critical revision of the manuscript. Diculescu M designed the study, treated studied patients and contributed by critical revision of the manuscript. All authors read and approved the final manuscript.\n\nInstitutional review board statement: The study was reviewed and approved by the The Ethical Comitee of the Romanian National Health Inssurance Agency.\n\nInformed consent statement: All subjects included signed an informed consent stating that their data can be used in scientific purposes \n\nConflict-of-interest statement: \n\nPreda Carmen Monica and Iacob Razvan received educational grants from Abbvie and MSD. Gheorghe Liana, Gheorghe Cristian, Goldis Adrian, Tantau Marcel, Tantau Alina, Negreanu Lucian, Cijevschi-Prelipcean Cristina, Diculescu Mircea received honoraria and educational grants from Abbvie and MSD. Trifan Anca and Manuc Mircea received honoraria and educational grants from Abbvie. \n\nABBREVIATIONS\nAbbreviationExpansionCDCrohn's disease\n\nCDAICrohn's disease activity index\n\nIFXInfliximab\n\nmAbmonoclonal antibody\n\nADAAdalimumab\n\nTNFTumor necrosis factor\n\nASTAspartate Aminotransferase\n\nALTAlanine Aminotransferase\n\nCRPC reactive protein\n\nAZAAzathioprine\n\nOROdds ratio\n==== Refs\nReferences\n1 Van Assche G Dignass A Panes J Beaugerie L Karagiannis J Allez M for the European Crohn's and Colitis Organisation (ECCO). The second European evidence-based consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis Journal of Crohn's and Colitis 2010 4 7 27 \n2 Sandborn WJ Feagan BG Hanauer SB Lochs H L�fberg R Modigliani R A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease Gastroenterology 2002 122 512 530 11832465 \n3 D'Haens G Baert F Van Assche G Caenepeel P Vergauwe P Tuynman H Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial Lancet 2008 371 660 667 18295023 \n4 Dignass A Van Assche G Lindsay JO L�mann M S�derholm J Colombel JF for the European Crohn's and Colitis Organisation (ECCO). The second European evidence-based consensus on the diagnosis and management of Crohn's disease: Current management Journal of Crohn's and Colitis 2010 4 28 62 \n5 Lichtenstein GR Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response Therap Adv Gastroenterol 2013 4 6 269 293 \n6 Gonz�lez-Lama Y Su�rez CJ Bl�zquez I Calvo M Matallana V Vera I Mucosal healing in Crohn�s disease: Relevance and controversies in real life clinical practice Rev Esp Enferm Dig (Madrid) 2014 7 106 459 466 \n7 Hanauer SB Feagan BF Lichtenstein GR Mayer LF Schreiber S Colombel JF Maintenance infliximab for Crohn�s disease: the ACCENT I randomized trial Lancet 2002 9317 359 1541 1549 12047962 \n8 Sands BE Anderson FH Bernstein CN Chey WY Feagan BG Fedorak RN Infliximab maintenance therapy for fistulizing Crohn�s disease N Engl J Med. 2004 9 350 876 885 14985485 \n9 Fasci Spurio F Aratari A Margagnoni G Doddato MT Papi C Early Treatment in Crohn's Disease: Do We Have Enough Evidence to Reverse the Therapeutic Pyramid? J Gastrointest Liver Dis 2012 1 21 67 73 \n10 Gheorghe C Pascu O Gheorghe L Iacob R Dumitru E Tantau M Epidemiology of inflammatory bowel disease in adults who refer to gastroenterology care in Romania: a multicentric study European J Gastroenterology Hepatology 2004 16 1153 1161 \n11 Vadan R Gheorghe L Gheorghe C Low prevalence and mild course of inflammatory bowel diseases in South Eastern Europe J Gastrointest Liver Dis 2009 18 385 385 \n12 Silverberg MS Satsangi J Ahmad T Arnott ID Bernstein CN Brant SR Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology Can J Gastroenterol 2005 Suppl A 19 5 36 \n13 Molnar T Farkas K Nyari T Zsepes Z Nagy F Wittmann T Frequency and predictors of loss of response to Infliximab or Adalimumab in Crohn�s disease after one-year treatment period- a single center experience J Gastrointest Liver Dis 2012 3 21 265 269 \n14 Colombel JF Sandborn WJ Rutgeerts P Enns R Hanauer SB Panaccione R Adalimumab for maintenance of clinical response and remission in patients with Crohn�s disease: the CHARM trial Gastroenterology 2007 132 52 65 17241859 \n15 Billioud V Sandborn WJ Peyrin-Biroulet L Loss of response and need for adalimumab dose intensification in Crohn�s disease: a systematic review Am J Gastroenterol 2011 106 674 684 21407178 \n16 Gisbert JP Panes J Loss of response and requirement of infliximab dose intensification in Crohn�s disease: a review Am J Gastroenterol 2009 104 760 767 19174781 \n17 Danese S Fiorino G Reinisch W Review article: Causative factors and the clinical management of patients with Crohn's disease who lose response to anti-TNF-a therapy Aliment Pharmacol Ther 2011 1 34 1 10 21539588 \n18 Kinney T Rawlins M Kozarek R France R Patterson D Immunomodulators and �on demand � therapy with infliximab in Crohn�s disease: clinical experience with 400 infusions Am J Gastroenterol 2003 98 608 612 12650795 \n19 Regueiro M Siemanowski B Kip KE Plevy S Infliximab dose intensication in Crohn�s disease Inflamm Bowel Dis 2007 13 1093 1099 17480021 \n20 Baert F Glorieus E Reenaers C D'Haens G Peeters H Franchimont D Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn's patients Journal of Crohn's and Colitis 2013 7 154 160 \n21 L�pez Palacios N Mendoza JL Taxonera C Lana R Fuentes Ferrer M D�az-Rubio M Adalimumab induction and maintaining therapy in Crohn�s disease: an open study Rev Esp Enferm Dig (Madrid) 2008 11 100 676 681 \n22 Navas-L�pez VM Blasco-Alonso J Gir�n-Fern�ndez-Crehuet F Serrano-Nieto M J Sierra-Salinas C Efficacy and safety of adalimumab in the treatment of Crohn�s disease in children Rev Esp Enferm Dig (Madrid) 2013 10 105 579 584 \n23 Barreiro-de-Acosta M Lorenzo A Dom�nguez-Mu�oz JE Efficacy of adalimumab for the treatment of extraintestinal manifestations of Crohn�s disease Rev Esp Enferm Dig (Madrid) 2012 9 104 468 472 \n24 Cordero Ruiz P Castro M�rquez C M�ndez Rufi�n V Castro Laria L Caunedo �lvarez A Romero V�zquez J Efficacy of adalimumab in patients with Crohn Rev Esp Enferm Dig (Madrid) 2011 6 103 294 298 \n25 Sandborn WJ Colombel JF Pan�s J Castillo M Robinson AM Zhou Q Exploring the use of adalimumab for patients with moderate Crohn's disease: Subanalyses from induction and maintenance trials Journal of Crohn's and Colitis 2013 7 958 967 \n26 Sprakes MB Ford AC Warren L Greer D Hamlin J Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: A large single centre experience Journal of Crohn's and Colitis 2012 6 143 153 \n27 G�mez Senent S Barreiro-de Acosta M Garc�a-S�nchez V Enterocutaneous fistulas and Crohn's disease: Clinical characteristics and response to treatment Rev Esp Enferm Dig (Madrid) 2013 1 105 3 6 \n28 Zorzi F Zuzzi S Onali S Calabrese E Condino G Petruzziello C Efficacy and safety of infliximab and adalimumab in Crohn�s disease: a single centre study Aliment Pharmacol Ther 2012 35 1397 1407 22519466 \n29 Osterman MT Haynes K Delzell E Zhang J Bewtra M Brensinger CM Comparative Effectiveness of Infliximab and Adalimumab for Crohn�s Disease Clin Gastroenterol Hepatol 2014 12 811 817 23811254 \n30 Kestens C van Oijen MG Mulder CL van Bodegraven AA Dijkstra G de Jong D Adalimumab and Infliximab are equally effective for Crohn�s disease in patients not previously treated with anti-Tumor Necrosis Factor-a agents Clin Gastroenterol Hepatol 2013 7 11 826 831 23376000\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "42(2)",
"journal": "Current health sciences journal",
"keywords": "Adalimumab; Crohn's disease; Infliximab",
"medline_ta": "Curr Health Sci J",
"mesh_terms": null,
"nlm_unique_id": "101597164",
"other_id": null,
"pages": "115-124",
"pmc": null,
"pmid": "30568821",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "11832465;12047962;12650795;14985485;15489575;16151544;17241859;17480021;18295023;19159170;19174781;19795039;21122488;21122489;21407178;21539588;22325168;22457862;22519466;22537637;23012667;23130854;23376000;23517933;23548004;23811254;23814608;24641454;25490165",
"title": "Adalimumab and Infliximab in Crohn's disease - real life data from a national retrospective cohort study.",
"title_normalized": "adalimumab and infliximab in crohn s disease real life data from a national retrospective cohort study"
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"abstract": "Clindamycin has high bioavailability together with good diffusion in bone tissue and could represent an alternative antibiotic compound for the treatment of bone and joint infections (BJIs). However, data regarding the efficacy and safety of clindamycin for BJIs are limited. A monocentric cohort study based on our medical dashboard, which prospectively recorded 28 characteristics for all hospitalized patients since July 2005, was performed. BJIs were selected, and then, all mono-microbial BJI managed with clindamycin-based therapy were included. Remission was defined as the absence of clinical and/or microbiological relapse after treatment. The duration of follow-up without relapse was determined retrospectively using computerized medical records. For 10 years, 196 BJIs, of which 80 (41%) were device-associated infections, were treated with clindamycin-based therapy. The bacterial causative agent was Staphylococcus aureus in 130 cases (66%), coagulase-negative staphylococci in 29 cases (15%), streptococci in 31 cases (16%) and other bacteria in 6 cases (3%). When used in combination therapy, clindamycin was mainly paired with fluoroquinolones (31%) or rifampin (27%). The mean duration of clindamycin treatment was 7.4 ± 3.2 weeks (range, 1-24). An AE was recorded for 9 (4.5%) patients. Remission was recorded for 111 (57%) patients, with a mean duration of clinical follow-up of 28 ± 24 months. Treatment failure occurred in 22 (11%) patients, 50 patients (25%) were lost to follow-up, and 8 (4%) required long-term suppressive therapy. Among the assessable patients, clindamycin-based therapy was efficient in 111/133 cases (83%) and thus represents a reliable and safe alternative treatment option.",
"affiliations": "Infectious Diseases Department, Nice Academic Hospital, Hôpital Archet 1, Infectiologie 151, CHU de Nice, Route de St Antoine de Ginestière, 06200, Nice, France. courjon.j@chu-nice.fr.;Infectious Diseases Department, Nice Academic Hospital, Hôpital Archet 1, Infectiologie 151, CHU de Nice, Route de St Antoine de Ginestière, 06200, Nice, France.;Infectious Diseases Department, Nice Academic Hospital, Hôpital Archet 1, Infectiologie 151, CHU de Nice, Route de St Antoine de Ginestière, 06200, Nice, France.;Infectious Diseases Department, Nice Academic Hospital, Hôpital Archet 1, Infectiologie 151, CHU de Nice, Route de St Antoine de Ginestière, 06200, Nice, France.;Infectious Diseases Department, Nice Academic Hospital, Hôpital Archet 1, Infectiologie 151, CHU de Nice, Route de St Antoine de Ginestière, 06200, Nice, France.",
"authors": "Courjon|J|J|http://orcid.org/0000-0002-0445-5104;Demonchy|E|E|;Cua|E|E|;Bernard|E|E|;Roger|P-M|PM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-017-3094-5",
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"issue": "36(12)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Bone and joint infections; Clindamycin; Efficacy; Staphylococcus; Streptococcus; Tolerance",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D002981:Clindamycin; D015331:Cohort Studies; D015897:Comorbidity; D019468:Disease Management; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010000:Osteitis; D016896:Treatment Outcome",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "2513-2518",
"pmc": null,
"pmid": "28884303",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "3701108;7019193;24962979;22114965;6211138;20012334;18718729;22738613;11871494;21916775;18818959;25837442;19841148;15276398;26229122;18707833;19938297;23877571;25936632;26584261",
"title": "Efficacy and safety of clindamycin-based treatment for bone and joint infections: a cohort study.",
"title_normalized": "efficacy and safety of clindamycin based treatment for bone and joint infections a cohort study"
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"companynumb": "FR-PFIZER INC-2017411936",
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"activesubstancename": "CLINDAMYCIN HYDROCHLORIDE"
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{
"abstract": "A 21-year-old nonobese woman developed headaches and papilledema while excessively using 3 topical preparations of vitamin A. Neuroimaging studies were unremarkable and opening pressure on lumbar puncture was 300 mm H2O with normal cerebrospinal fluid composition. After discontinuation of the topical vitamin A preparations, the symptoms and signs of increased intracranial pressure resolved. The association of intracranial hypertension and topical vitamin A application has only been reported once previously.",
"affiliations": "Department of Internal Medicine, King Saud University, Riyadh, Saudi Arabia.",
"authors": "Mohammad|Yousef M|YM|;Raslan|Ismail R|IR|;Al-Hussain|Fawaz A|FA|",
"chemical_list": "D014815:Vitamins; D014801:Vitamin A",
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000374",
"fulltext": null,
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"issue": "36(4)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D000287:Administration, Topical; D005260:Female; D006801:Humans; D007427:Intracranial Pressure; D010211:Papilledema; D011559:Pseudotumor Cerebri; D014801:Vitamin A; D014815:Vitamins; D055815:Young Adult",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "412-413",
"pmc": null,
"pmid": "27111091",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Idiopathic Intracranial Hypertension Induced by Topical Application of Vitamin A.",
"title_normalized": "idiopathic intracranial hypertension induced by topical application of vitamin a"
} | [
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"companynumb": "SA-BAUSCH-BL-2016-011390",
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"activesubstance": {
"activesubstancename": "TRETINOIN"
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{
"abstract": "Metformin is an antidiabetic drug; used to treat type II diabetes mellitus, metformin associated lactic acidosis has an incidence of 2-9 cases / 100,000 patients / year with high mortality (30%). We have had the case of a 75-year-old woman with metabolic acidosis as a result of metformin assumption, treated by renal replacement therapy (CRRT) with continuous veno-venous hemodiafiltration (CVVHDF).\n\n\nRESULTS\nafter a short treatment period there was a reduction in Lactates (from 16.8 mmol/L to 12.6 mmol/L) and a progressive improvement of acidosis. In 72 hours the recovery of diuresis and subsequent suspension of CRRT was achieved.\n\n\nCONCLUSIONS\nCRRT, in addition to ensuring support for renal failure and volume correction, allowed a rapid recovery from metformin-associated lactic acidosis.",
"affiliations": "Unit of Anesthesia and Intensive Care, ASST Valtellina e Alto Lario, Ospedale E. Morelli, Sondalo, Italy.;Unit of Anesthesia and Intensive Care, ASST Valtellina e Alto Lario, Ospedale E. Morelli, Sondalo, Italy.;Unit of Anesthesia and Intensive Care, ASST Valtellina e Alto Lario, Ospedale E. Morelli, Sondalo, Italy.;Unit of Anesthesia and Intensive Care, ASST Valtellina e Alto Lario, Ospedale E. Morelli, Sondalo, Italy.",
"authors": "Ferrario|Matteo|M|;Apicella|Antonio|A|;Della Morte|Mauro|M|;Beretta|Enrico|E|",
"chemical_list": "D000925:Anticoagulants; D007004:Hypoglycemic Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D000077559:Sodium Citrate; D005665:Furosemide; D017693:Sodium Bicarbonate; D008687:Metformin",
"country": "Italy",
"delete": false,
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"issue": "35(5)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": " lactic acidosis ; CRRT; CVVHDF; metformin",
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D000925:Anticoagulants; D001986:Bronchial Spasm; D003131:Combined Modality Therapy; D005260:Female; D005665:Furosemide; D017583:Hemodiafiltration; D006801:Humans; D007004:Hypoglycemic Agents; D007022:Hypotension; D008687:Metformin; D000077725:Piperacillin, Tazobactam Drug Combination; D017693:Sodium Bicarbonate; D000077559:Sodium Citrate",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30234235",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of severe metformin-associated lactic acidosis treated with CVVHDF and regional anticoagulation with sodium citrate.",
"title_normalized": "a case of severe metformin associated lactic acidosis treated with cvvhdf and regional anticoagulation with sodium citrate"
} | [
{
"companynumb": "IT-INVENTIA-000247",
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"drugadditional": null,
... |
{
"abstract": "Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG.",
"affiliations": "Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA. trent.hummel@cchmc.org.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Hematology/Oncology, Ann and Robert H Lurie Children's Hospital of Chicago, 225 E Chicago Ave, Box 30, Chicago, IL, 60611, USA.;Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.;Division of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Physical Medicine & Rehabilitation, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.;Division of Neurology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 7051, Cincinnati, OH, 45229, USA.",
"authors": "Hummel|Trent R|TR|;Salloum|Ralph|R|;Drissi|Rachid|R|;Kumar|Shiva|S|;Sobo|Matthew|M|;Goldman|Stewart|S|;Pai|Ahna|A|;Leach|James|J|;Lane|Adam|A|;Pruitt|David|D|;Sutton|Mary|M|;Chow|Lionel M|LM|;Grimme|Laurie|L|;Doughman|Renee|R|;Backus|Lori|L|;Miles|Lili|L|;Stevenson|Charles|C|;Fouladi|Maryam|M|;DeWire|Mariko|M|",
"chemical_list": "D000068258:Bevacizumab; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-015-2008-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "127(1)",
"journal": "Journal of neuro-oncology",
"keywords": "Bevacizumab; Children; Diffuse intrinsic pontine glioma; High-grade glioma",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D020295:Brain Stem Neoplasms; D002166:Camptothecin; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D000077146:Irinotecan; D008297:Male; D060787:Neoplasm Grading; D010865:Pilot Projects; D011379:Prognosis; D015996:Survival Rate; D000077204:Temozolomide; D055815:Young Adult",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "53-61",
"pmc": null,
"pmid": "26626490",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15949234;24552317;23329387;10533725;20479404;16118771;24050762;11034104;21297126;24104527;19114704;18202416;18772396;19636000;22286061;16525181;24612214;24552318;21339192;2550594;17618441;24477622;23425999;22748663;19720927;12242114;7799011;16510333;17643088;10416597;16315242;16212813;23666431;16301833;16685456;23249962;21764221;15758009",
"title": "A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas.",
"title_normalized": "a pilot study of bevacizumab based therapy in patients with newly diagnosed high grade gliomas and diffuse intrinsic pontine gliomas"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US02354",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
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... |
{
"abstract": "Gaucher disease (GD), a lysosomal storage disorder, may result in end-stage lung disease. We report successful bilateral lung transplantation in a 49-year-old woman with GD complicated by severe pulmonary hypertension and fibrotic changes in the lungs. Before receiving the lung transplant, the patient was undergoing both enzyme replacement therapy (imiglucerase) and triple pulmonary hypertension treatment (epoprostenol, bosentan, and sildenafil). She had a history of splenectomy, severe bone disease, and renal involvement, all of which were related to GD and considered as relative contraindications for a lung transplantation. In the literature, lung transplantation has been suggested for severe pulmonary involvement in GD but has been reported only once in a child. To our knowledge, until now, no successful procedure has been reported in adults, and no reports deal with the severe potential posttransplantation complications specifically related to GD.",
"affiliations": "Department of Respiratory Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.;Department of Respiratory Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Clinical Pathology, Maasstad Hospital, Rotterdam, The Netherlands.;Department of Respiratory Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.;Department of Respiratory Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: p.vanhal@zzv.nl.",
"authors": "de Boer|Geertje M|GM|;van Dussen|Laura|L|;van den Toorn|Leon M|LM|;den Bakker|Michael A|MA|;Hoek|Rogier A S|RA|;Hesselink|Dennis A|DA|;Hollak|Carla E M|CE|;van Hal|Peter Th W|PT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "149(1)",
"journal": "Chest",
"keywords": "Gaucher disease; adult; complications; lung transplantation",
"medline_ta": "Chest",
"mesh_terms": "D005260:Female; D005776:Gaucher Disease; D006801:Humans; D016040:Lung Transplantation; D008875:Middle Aged; D018579:Patient Selection; D011658:Pulmonary Fibrosis",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e1-5",
"pmc": null,
"pmid": "26757299",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lung Transplantation in Gaucher Disease: A Learning Lesson in Trying to Avoid Both Scylla and Charybdis.",
"title_normalized": "lung transplantation in gaucher disease a learning lesson in trying to avoid both scylla and charybdis"
} | [
{
"companynumb": "NL-ACCORD-038827",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": null,
"druga... |
{
"abstract": "Pneumosinus Dilatans Frontalis (PDF) is a rare pathologic condition characterized by expansion and hyper aeration of the frontal sinuses. This abnormality has been described in otolaryngology, ophthalmology, neurology, and radiology journals, while only a few autopsy studies are reported in the English literature. The etiology of this condition remains unclear, although multiple theories have been proposed. Clinically, PDF is often an asymptomatic condition, but it can lead to significant bone deformation with esthetic complaints, and even severe associated neurological deficits. In the following case report, a 20-year-old Caucasian male committed suicide by asphyxia due to plastic bag suffocation combined with a vitiated atmosphere as a consequence of helium inhalation. At postmortem an abnormal expansion of the frontal sinuses was detected, involving the frontal bone just above the orbits. The defect showed a multiloculated appearance in the sinus cavities. An incidental diagnosis of PDF was made. A description of the findings and a hypothesis of the clinical relevance of PDF in the reported case are presented.",
"affiliations": "Department of Pathology, State University of New York - Upstate Medical University, 750 E Adams St, Syracuse, NY, 13210, USA. gittol@upstate.edu.;Department of Pathology, State University of New York - Upstate Medical University, 750 E Adams St, Syracuse, NY, 13210, USA.",
"authors": "Gitto|Lorenzo|L|http://orcid.org/0000-0002-1435-1819;Serinelli|Serenella|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12024-019-00120-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-769X",
"issue": "15(4)",
"journal": "Forensic science, medicine, and pathology",
"keywords": "Autopsy; Forensics; Pathology; Pneumosinus Dilatans frontalis; Sinuses",
"medline_ta": "Forensic Sci Med Pathol",
"mesh_terms": "D004108:Dilatation, Pathologic; D005626:Frontal Sinus; D006801:Humans; D033162:Incidental Findings; D008297:Male; D000081013:Suicide, Completed; D055815:Young Adult",
"nlm_unique_id": "101236111",
"other_id": null,
"pages": "646-648",
"pmc": null,
"pmid": "31161429",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15109127;22338242;17760490;24972755;24561372;17580810;24162268;23978497;28315298",
"title": "Pneumosinus Dilatans frontalis: a case of incidental autopsy diagnosis.",
"title_normalized": "pneumosinus dilatans frontalis a case of incidental autopsy diagnosis"
} | [
{
"companynumb": "US-ALSI-201900261",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HELIUM"
},
"drugadditional": null,
"drugad... |
{
"abstract": "The paper presents an analysis of fungemia cases which were caused by C. parapsilosis in a cancer center within 10 years, with the aim to compare risk factors and the outcome with fungemias caused by C. albicans and other non-albicans Candida spp. fungemias. Before 1990 (1988-1989) in our institutes C. parapsilosis fungemias were not observed at all. During 1990-1997, the proportion of C. parapsilosis among fungemias increased, in 1990-1993 from 0% to 7.1% in 1996-1997 to 14.2-15%. It represents 25% out of non-albicans Candida spp. fungemias and 7.9% out of all fungemias and is the third commonest pathogen after C. albicans (50.5%) and C. krusei (9.9%). Two from eight (25%) C. parapsilosis fungemias were breakthroughs, one appeared during prophylaxis with ketoconazol and one with fluconazol. Considering the proportion of C. parapsilosis among blood cultures, 13 of 170 blood cultures contained C. parapsilosis (6.6% among all yeasts from blood cultures). C. parapsilosis was the second commonest fungal organism isolated from blood cultures (after C. albicans) in our cancer center. Infected vascular catheters were surprisingly not the major risk factor: central venous catheters were documented as a source in two cases only. The commonest risk factors were similar to those occurring with other fungemias--such as preceding antimicrobial therapy (62.5%), neutropenia (50%) and prior prophylaxis with azoles.",
"affiliations": "Department of Medicine, School of Public Health, University of Trnava, Slovakia.",
"authors": "Krcméry|V|V|;Spánik|S|S|;Grausová|S|S|;Trupl|J|J|;Krupová|I|I|;Roidová|A|A|;Sálek|T|T|;Sufliarsky|J|J|;Mardiak|J|J|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole",
"country": "Slovakia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2685",
"issue": "45(5)",
"journal": "Neoplasma",
"keywords": null,
"medline_ta": "Neoplasma",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D002175:Candida; D002176:Candida albicans; D002177:Candidiasis; D002648:Child; D005260:Female; D015725:Fluconazole; D016469:Fungemia; D006801:Humans; D015994:Incidence; D008297:Male; D008826:Microbial Sensitivity Tests; D009369:Neoplasms; D012307:Risk Factors",
"nlm_unique_id": "0377266",
"other_id": null,
"pages": "336-42",
"pmc": null,
"pmid": "9921924",
"pubdate": "1998",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Candida parapsilosis fungemia in cancer patients--incidence, risk factors and outcome.",
"title_normalized": "candida parapsilosis fungemia in cancer patients incidence risk factors and outcome"
} | [
{
"companynumb": "SK-PFIZER INC-2020221341",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Extrapulmonary neuroendocrine carcinoma (NEC) is a rare disease, and there is no standard chemotherapy. A 73-year-old man was diagnosed with advanced gastric NEC. He received chemotherapy of irinotecan plus cisplatin, and amrubicin monotherapy. After failure of second-line chemotherapy, he received ramucirumab plus paclitaxel; this treatment was chosen because vascular endothelial growth factor 2 was strongly expressed in the tumor endothelial cells. After two cycles, his NEC had markedly reduced in size, and he continued with this treatment for over eight months. In this case, the combination of an anti-angiogenic inhibitor and a cytotoxic agent was highly effective for gastric NEC.",
"affiliations": "Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Japan.",
"authors": "Matsubara|Yuki|Y|;Ando|Takayuki|T|;Hosokawa|Ayumu|A|;Mihara|Hiroshi|H|;Takagi|Hiroaki|H|;Nakata|Naokatsu|N|;Yoshita|Hiroki|H|;Nanjo|Sohachi|S|;Kajiura|Shinya|S|;Fujinami|Haruka|H|;Sugiyama|Toshiro|T|",
"chemical_list": "D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077146:Irinotecan; C055866:amrubicin; C543333:ramucirumab; D017239:Paclitaxel; D002945:Cisplatin; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9369-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2915152310.2169/internalmedicine.9369-17Case ReportNeuroendocrine Carcinoma of the Stomach: A Response to Combination Chemotherapy Consisting of Ramucirumab Plus Paclitaxel Matsubara Yuki 1Ando Takayuki 1Hosokawa Ayumu 1Mihara Hiroshi 1Takagi Hiroaki 1Nakata Naokatsu 1Yoshita Hiroki 1Nanjo Sohachi 1Kajiura Shinya 1Fujinami Haruka 1Sugiyama Toshiro 1\n1 Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, JapanCorrespondence to Dr. Takayuki Ando, takayuki@med.u-toyama.ac.jp\n\n20 11 2017 1 3 2018 57 5 671 675 19 4 2017 14 6 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Extrapulmonary neuroendocrine carcinoma (NEC) is a rare disease, and there is no standard chemotherapy. A 73-year-old man was diagnosed with advanced gastric NEC. He received chemotherapy of irinotecan plus cisplatin, and amrubicin monotherapy. After failure of second-line chemotherapy, he received ramucirumab plus paclitaxel; this treatment was chosen because vascular endothelial growth factor 2 was strongly expressed in the tumor endothelial cells. After two cycles, his NEC had markedly reduced in size, and he continued with this treatment for over eight months. In this case, the combination of an anti-angiogenic inhibitor and a cytotoxic agent was highly effective for gastric NEC. \n\npaclitaxelramucirumabneuroendocrine carcinomachemotherapyVEGFR2\n==== Body\nIntroduction\nNeuroendocrine carcinoma (NEC) is a subgroup of neuroendocrine neoplasms (NENs) in the stomach. It exhibits high proliferative activity and vascularity as well as aggressive clinical behavior and has a poor prognosis. Platinum-based combination chemotherapy has been commonly used as a first-line treatment for NEC, and the efficacy of etoposide plus cisplatin versus irinotecan plus cisplatin has been compared in a phase III study for advanced gastrointestinal, hepatobiliary, or pancreatic NEC (1). However, no standard chemotherapy has been established for implementation following first-line treatment. Combination therapy of temozolomide plus capecitabine, amurubicin monotherapy, S-1, and retreatment with cisplatin plus etoposide have been reported, although the efficacy of these regimens is poor (2, 3).\n\nWe herein report a case of gastric NEC for which ramucirumab plus paclitaxel, an anti-angiogenic inhibitor, was highly effective in the third-line setting. In addition, we analyzed the human epidermal growth factor 2 (HER2) and vascular endothelial growth factor 2 (VEGFR2) protein expression in the patient's tumor to determine the optimum salvage chemotherapy strategy.\n\nCase Report\nA 73-year-old man was referred to our institution in June 2015 with complaints of anorexia and abdominal pain. A physical examination revealed a mass in the right upper quadrant. Blood tests failed to show leukocytosis or anemia, and the results of liver and renal function tests were within normal limits. The serum levels of neuro-specific enolase (NSE) and pro-gastrin-releasing peptide (proGRP), which are tumor markers for small cell lung cancer (SCLC), were 19.1 ng/mL (normal ＜16.3 ng/mL) and 39.4 pg/mL (normal ＜81.0 pg/mL), respectively. Upper gastrointestinal endoscopy revealed an irregularly and deeply ulcerated tumor in the posterior wall of the antral region of the stomach (Fig. 1a). Whole-body computed tomography (CT) revealed a gastric tumor and bulky lymph nodes with liver metastases (Fig. 1b). A histopathological examination of biopsy specimens showed cells with well-visible nucleoli arranged in sheets. Immunohistochemically, the cancer cells demonstrated positive staining for synaptophysin, a diagnostic marker of NENs. Based on these findings as well as the high Ki-67 labeling index (＞90%), a pathological diagnosis of gastric NEC was made (Fig. 2). The clinical disease stage was T4bN2M1, stage IV according to the tumor-node-metastasis staging system of the International Union Against Cancer.\n\nFigure 1. Endoscopic and abdominal computed tomography (CT) findings. (a) Esophagogastroduodenoscopy revealed an irregularly and deeply ulcerated tumor in the posterior wall of the antral region of the stomach. (b) CT scan showing the gastric tumor with bulky lymph nodes and liver metastases.\n\nFigure 2. Histopathological findings of tumor biopsy specimens. (a) Hematoxylin and Eosin staining showing hyperchromatic and well-visible nucleoli. (b) and (c) immunohistochemistry. Cancer cells demonstrated positive staining for synaptophysin (b) with a high Ki-67 labeling index (c).\n\nChemotherapy was considered as a treatment strategy, and its response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1, while its toxicity was evaluated according to the National Cancer Institute-Common Toxicity Criteria, version 4.0. The patient received irinotecan plus cisplatin treatment from August 2015 in accordance with the standard treatment for SCLC (4). He received 60 mg/m2 of irinotecan on day 1 and 60 mg/m2 of cisplatin on days 1, 8, and 15 every 4 weeks. Two weeks later, his abdominal pain had almost disappeared, and the best response was stable disease during four cycles of chemotherapy. However, CT showed enlarged lymph node metastasis, and disease progression was evident four months after the induction of first-line chemotherapy. We then started amrubicin monotherapy as a second-line treatment from January 2016. The patient received 40 mg/m2 of amrubicin for 3 days every 3 weeks. The best response was stable disease during eight cycles of amrubicin monotherapy. However, a new metastatic lesion was identified in the liver 6 months after commencing second-line chemotherapy, and the serum levels of NSE had increased to 56.9 ng/mL.\n\nAt this point, no further optimal chemotherapy options were available for this patient. In July 2016, following amrubicin monotherapy, the patient's performance status was 0, and his complete blood count (CBC) was not abnormal. A biochemical examination revealed high levels of lactate dehydrogenase (LDH) (372 U/L), alkaline phosphatase (ALP) (621 U/L), and γGTP (259 U/L). A discussion was held with the patient about empirical treatment according to gastric adenocarcinoma (3), although a histological evaluation by a repeated endoscopic biopsy did not concur with adenocarcinoma. We also analyzed the HER2 and VEGFR2 protein expression using biopsy specimens of gastric NEC for further treatment. The HER2 expression was negative in cancer cells, while VEGFR2 was strongly expressed in tumor endothelial cells compared with non-cancerous gastric mucosa (Fig. 3) and negative in cancer cells.\n\nFigure 3. Protein expression of vascular endothelial growth factor 2 (VEGFR2). (a) and (b) Immunohistochemical staining showed strong expression of VEGFR2 in tumor endothelial cells (a) compared with non-cancerous gastric mucosa (b).\n\nWe ultimately decided to initiate combination chemotherapy of ramucirumab plus paclitaxel as a third-line treatment, which is a standard treatment in the salvage setting for gastric adenocarcinoma (5). The patient was enthusiastic to receive this treatment, and its use was approved by our institution. Ramucirumab (8 mg/kg) and paclitaxel (80 mg/m2) were administered by intravenous infusion on days 1 and 15, and paclitaxel (80 mg/m2) alone was administered by intravenous infusion on day 8 of a 28-day cycle. After two cycles of combination chemotherapy, the liver and lymph node metastases had reduced markedly in CT scans and become partially hypoattenuated (Fig. 4). The patient's response to this treatment was evaluated as a partial response, and the serum levels of NSE had decreased. Endoscopically, we also found that the cancerous ulcer had reduced in size. The patient received this treatment for nine cycles, and the progression-free survival was 248 days after the induction of third-line treatment. In terms of adverse events, the patient experienced grade 1 hand-foot syndrome and malaise.\n\nFigure 4. Computed tomography (CT) and endoscopic findings before and after treatment with ramucirumab and paclitaxel. (a) and (c) Before third-line treatment. (b) and (d) After two cycles, CT showed that the size of the liver metastases had markedly decreased, with partial hypo-attenuation (a, b). Endoscopic findings also showed that the gastric NEC had responded to this treatment. NEC: neuroendocrine carcinoma\n\nDiscussion\nCombination chemotherapy of irinotecan plus cisplatin or etoposide plus cisplatin is most commonly selected for advanced NEC, based on the clinical and pathological similarities between extrapulmonary NEC and SCLC (6). However, the molecular features of extrapulmonary NEC are largely unknown. In cases of gastric NEC, an adenocarcinoma component is frequently seen in the superficial region, and this suggests that the cell clone of NEC originates from the stem cells of adenocarcinoma (7). Therefore, it may be necessary to select chemotherapy regimens based on the biological characteristics of the tumor. We experienced a patient with gastric NEC who responded to chemotherapy involving ramucirumab and paclitaxel as a third-line regimen; tests also showed that the endothelial VEGFR2 expression in this patient's tumor was high. To our knowledge, this is the first report to show that the combination treatment of an anti-angiogenic inhibitor and a cytotoxic agent is highly effective for NEC.\n\nAngiogenesis, defined as the formation of new blood vessels, plays an important role in physiological and pathological processes and is regulated by a number of molecules, including VEGF, fibroblastic growth factor, and hypoxia-inducible factor 1. Ramucirumab is a human IgG1 monoclonal antibody that binds to VEGFR2 on blood vessel endothelial cells, thereby inhibiting VEGF ligand binding and receptor signaling. The efficacy of ramucirumab monotherapy has been confirmed in patients with advanced gastric or gastroesophageal junctional adenocarcinoma who experienced disease progression following first-line fluoropyrimidine or platinum-containing chemotherapy [median survival: 5.2 vs. 3.8 months for ramucirumab and placebo, respectively: hazard ratio (HR), 0.776; 95% confidential interval (CI), 0.603-0.998, p=0.0047] (8). In the present study, biomarker analyses revealed that high endothelial VEGFR2 expression was associated with a non-significant prognostic trend toward a shorter progression-free survival, and the benefit of ramucirumab has been shown to be more pronounced in patients with a high VEGFR2 expression (9). Recently, the combination of ramucirumab plus paclitaxel was shown to significantly increase the OS compared with placebo plus paclitaxel (median survival: 9.6 vs. 7.4 months; hazard HR, 0.807; 95% CI, 0.678-0.962, p=0.017) (5). NENs are well known to be highly vascular neoplasms, and the immunohistochemical analyses of vasohibin-1, CD31, and endogolin have shown that pancreatic NECs exhibit higher angiogenic activity in endothelial cells than grade 1 or 2 pancreatic NETs (10). In our case, the protein expression of VEGFR2 in the patient's vascular tumor was high, which might be one of the reasons for the high activity of ramucirumab and paclitaxel against gastric NEC.\n\nA tumor's response to chemotherapy with anti-angiogenic inhibitor is characteristic (11). The optimum morphological response to bevacizumab, a monoclonal antibody against VEGF, has been shown to result in homogeneous morphology and hypo-attenuation with a sharply defined tumor-normal liver interface (12). It has been reported that the optimum morphological response was observed in 47% of patients treated with bevacizumab and 12% treated without bevacizumab and was associated with a pathological response and the OS in patients with colorectal liver metastases (12). In patients with hepatocellular carcinoma treated with sorafenib, evidence of greater benefit has been shown via the assessment of treatment efficacy using the modified RECIST criteria, which take tumor vascularity into account, than using the original RECIST criteria (13). In our case, the morphological response was only partially detected in the metastatic lesion, so we cannot report that the response was typical of ramucirumab. The likely explanation is that paclitaxel was also effective for this tumor, as it has been proven to be an active agent in clinical trials for SCLC as well as gastric adenocarcinoma (14).\n\nIn conclusion, we experienced a case wherein gastric NEC responded to the combination chemotherapy of ramucirumab plus paclitaxel in a salvage setting. Anti-angiogenic inhibitors might be effective for NEC, which has high angiogenic activity.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Ikeda M , Okuyama H , Takahashi H , et al \nChemotherapy for advanced poorly differentiated pancreatic neuroendocrine carcinoma . J Hepatobiliary Pancreat Sci \n22 : 623 -627 , 2015 .25755102 \n2. Ando T , Hosokawa A , Yoshita H , et al \nAmrubicin monotherapy for patients with platinum-refractory gastroenteropancreatic neuroendocrine carcinoma . Gastroenterol Res Pract \n2015 : 425876 , 2015 .26199623 \n3. Yamaguchi T , Machida N , Morizane C , et al \nMulticenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system . Cancer Sci \n105 : 1176 -1181 , 2014 .24975505 \n4. Noda K , Nishiwaki Y , Kawahara M , et al \nIrinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer . N Engl J Med \n346 : 85 -91 , 2002 .11784874 \n5. Wilke H , Muro K , Van Cutsem E , et al \nRamucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial . Lancet Oncol \n15 : 1224 -1235 , 2014 .25240821 \n6. Fazio N , Spada F , Giovannini M \nChemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view . Cancer Treat Rev \n39 : 270 -274 , 2013 .22819619 \n7. Yamasaki Y , Nasu J , Miura K , et al \nIntramucosal gastric mixed adenoneuroendocrine carcinoma completely resected with endoscopic submucosal dissection . Intern Med \n54 : 917 -920 , 2015 .25876572 \n8. Fuchs CS , Tomasek J , Yong CJ , et al \nRamucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial . Lancet \n383 : 31 -39 , 2014 .24094768 \n9. Fuchs CS , Tabernero J , Tomasek J , et al \nBiomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab . Br J Cancer \n115 : 974 -982 , 2016 .27623234 \n10. Yazdani S , Kasajima A , Tamaki K , et al \nAngiogenesis and vascular maturation in neuroendocrine tumors . Hum Pathol \n45 : 866 -874 , 2014 .24656098 \n11. Chun YS , Vauthey JN , Boonsirikamchai P , et al \nAssociation of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases . JAMA \n302 : 2338 -2344 , 2009 .19952320 \n12. Yoshita H , Hosokawa A , Ueda A , et al \nPredictive value of optimal morphologic response to first-line chemotherapy in patients with colorectal liver metastases . Digestion \n89 : 43 -48 , 2014 .24458112 \n13. Edeline J , Boucher E , Rolland Y , et al \nComparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma . Cancer \n118 : 147 -156 , 2012 .21713764 \n14. Ettinger DS , Finkelstein DM , Sarma RP , Johnson DH \nPhase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group study . J Clin Oncol \n13 : 1430 -1435 , 1995 .7751889\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(5)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "VEGFR2; chemotherapy; neuroendocrine carcinoma; paclitaxel; ramucirumab",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D018278:Carcinoma, Neuroendocrine; D002945:Cisplatin; D006801:Humans; D000077146:Irinotecan; D008297:Male; D017239:Paclitaxel; D013274:Stomach Neoplasms",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "671-675",
"pmc": null,
"pmid": "29151523",
"pubdate": "2018-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7751889;27623234;24094768;25240821;11784874;24975505;22819619;25755102;19952320;25876572;24458112;24656098;21713764;26199623",
"title": "Neuroendocrine Carcinoma of the Stomach: A Response to Combination Chemotherapy Consisting of Ramucirumab Plus Paclitaxel.",
"title_normalized": "neuroendocrine carcinoma of the stomach a response to combination chemotherapy consisting of ramucirumab plus paclitaxel"
} | [
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"abstract": "A 62-year-old woman with advanced cancer was admitted to the hospital experiencing inadequate pain control. Underdosing of opiates resulted from the persistent and inappropriate labeling of her behavior as drug-seeking, and the medical staff expressed discomfort about the administration of high doses of opiates. Palliative care personnel achieved better symptom control by the use of more confident and more liberal opiate dosing. The patient's quality of life improved immensely without adverse effects. We investigated reasons that account for the widespread practice of opiate underdosing. These include biases such as opiophobia--often unspoken and sometimes unrecognized. We share these insights to enhance the practice of others.",
"affiliations": null,
"authors": "Varilla|Vincent|V|;Schneiderman|Henry|H|;Keefe|Sue|S|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-6178",
"issue": "79(9)",
"journal": "Connecticut medicine",
"keywords": null,
"medline_ta": "Conn Med",
"mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D008875:Middle Aged; D010148:Pain, Intractable; D010166:Palliative Care; D011788:Quality of Life; D013125:Spinal Neoplasms",
"nlm_unique_id": "0372745",
"other_id": null,
"pages": "521-4",
"pmc": null,
"pmid": "26630702",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "No Ceiling Dose: Effective Pain Control with Extraordinary Opiate Dosing in Cancer.",
"title_normalized": "no ceiling dose effective pain control with extraordinary opiate dosing in cancer"
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"companynumb": "US-BAUSCH-BL-2016-002864",
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"abstract": "BACKGROUND\nThe development of secondary soft tissue sarcomas after chemo-radiotherapy is a rare and little known event, but its frequency is increasing.\n\n\nMETHODS\nWe report two cases of secondary soft tissue sarcomas. The first is the case of a 51-year-old woman treated for Hodgkin's disease with chemotherapy and radiotherapy 15 years before she developed a high-grade malignant pleural sarcoma. The patient had no history of asbestos exposure. The second is the case of a 64-year-old woman with a giant cell malignant histiocytoma secondary to colorectal cancer treated with surgery and radiotherapy nine years before. The patients were not eligible for surgery or radiotherapy. Both were treated with chemotherapy (ifosfamide and epirubicin) without any relevant secondary effects; however, the response to therapy was poor.\n\n\nCONCLUSIONS\nThe causes of secondary malignancies are multifactorial, but radiation therapy and chemotherapy are certainly implicated in the development of post-therapy neoplasms that are difficult to treat.",
"affiliations": "Cure Palliative-Oncologia, Ospedale S Giovanni Battista, Gattinara, Italy. c.saggia@inwind.it",
"authors": "Saggia|Chiara|C|;Forti|Giorgio|G|;Biaggi|Gabriele|G|;Lattuada|Sara|S|;Santagostino|Alberto|A|;Angeli|Giovanni|G|;Pollo|Maria Cristina|MC|;Negru|Maria Emanuela|ME|;Alabiso|Oscar|O|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "90(6)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms; D005260:Female; D054747:Histiocytic Sarcoma; D006689:Hodgkin Disease; D006801:Humans; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced; D016609:Neoplasms, Second Primary; D010997:Pleural Neoplasms; D018714:Radiotherapy, Adjuvant; D012509:Sarcoma",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "622-4",
"pmc": null,
"pmid": "15762368",
"pubdate": "2004",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of secondary soft tissue sarcomas after radiotherapy and radiochemotherapy.",
"title_normalized": "two cases of secondary soft tissue sarcomas after radiotherapy and radiochemotherapy"
} | [
{
"companynumb": "IT-PFIZER INC-2020381025",
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"occurcountry": "IT",
"patient": {
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"actiondrug": "5",
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"activesubstancename": "EPIRUBICIN HYDROCHLORIDE"
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{
"abstract": "BACKGROUND\nContinuous subcutaneous infusion (CSCI) via ambulatory infusion pump (AIP) is a valuable method of pain control in palliative care. When using CSCI, low-dose methadone as add-on to other opioids might be an option in complex pain situations. This study aimed to investigate the effects, and adverse effects, of CSCI for pain control in dying patients, with particular interest in methadone use.\n\n\nMETHODS\nThis was an observational cohort study. Imminently dying patients with pain, admitted to specialized palliative inpatient wards and introduced on CSCI, were monitored daily by staff for symptoms (Integrated Palliative Care Outcome Scale - IPOS), sedation (Richmond Agitation and Sedation Scale - RASS), performance status (Eastern Cooperative Oncology Group - ECOG) and delirium (Confusion Assessment Method - CAM).\n\n\nRESULTS\nNinety-three patients with a median survival of 4 days were included. Of the 47 patients who survived ≥3 days, the proportion of patients with severe/overwhelming pain decreased from 45 to 19% (p < 0.001) after starting CSCI, with only a moderate increase in morphine equivalent daily dose of opioids (MEDD). Alertness was marginally decreased (1 point on the 10-point RASS scale, p = 0.001), whereas performance status and prevalence of delirium, regardless of age, remained unchanged. Both patients with methadone as add-on (MET, n = 13) and patients with only other opioids (NMET, n = 34), improved in pain control (p < 0.05 and 0.001, respectively), despite that MET patients had higher pain scores at baseline (p < 0.05) and were on a higher MEDD (240 mg vs.133 mg). No serious adverse effects demanding treatment stop were reported.\n\n\nCONCLUSIONS\nCSCI via AIP is an effective way to reduce pain in dying patients without increased adverse effects. Add-on methadone may be beneficial in patients with severe complex pain.",
"affiliations": "Department of Oncology Pathology, Karolinska Institutet, Stockholm, Sweden. per.furst@ki.se.;Department of Oncology Pathology, Karolinska Institutet, Stockholm, Sweden.;Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.;Department of Oncology Pathology, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Fürst|Per|P|http://orcid.org/0000-0001-5363-833X;Lundström|Staffan|S|;Klepstad|Pål|P|;Strang|Peter|P|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.1186/s12904-020-00681-3",
"fulltext": "\n==== Front\nBMC Palliat Care\nBMC Palliat Care\nBMC Palliative Care\n1472-684X BioMed Central London \n\n681\n10.1186/s12904-020-00681-3\nResearch Article\nContinuous subcutaneous infusion for pain control in dying patients: experiences from a tertiary palliative care center\nhttp://orcid.org/0000-0001-5363-833XFürst Per per.furst@ki.se 12 Lundström Staffan 12 Klepstad Pål 345 Strang Peter 12 1 grid.4714.60000 0004 1937 0626Department of Oncology Pathology, Karolinska Institutet, Stockholm, Sweden \n2 grid.4714.60000 0004 1937 0626Palliative Medicine, Stockholms Sjukhem Foundation, Stockholm, Sweden \n3 grid.5947.f0000 0001 1516 2393Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway \n4 grid.5947.f0000 0001 1516 2393European Palliative Research Centre, Department of Clinical and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway \n5 grid.52522.320000 0004 0627 3560Department of Anesthesiology and Intensive Care medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway \n10 11 2020 \n10 11 2020 \n2020 \n19 17219 7 2020 5 11 2020 © The Author(s) 2020Open 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.Background\nContinuous subcutaneous infusion (CSCI) via ambulatory infusion pump (AIP) is a valuable method of pain control in palliative care. When using CSCI, low-dose methadone as add-on to other opioids might be an option in complex pain situations. This study aimed to investigate the effects, and adverse effects, of CSCI for pain control in dying patients, with particular interest in methadone use.\n\nMethods\nThis was an observational cohort study. Imminently dying patients with pain, admitted to specialized palliative inpatient wards and introduced on CSCI, were monitored daily by staff for symptoms (Integrated Palliative Care Outcome Scale - IPOS), sedation (Richmond Agitation and Sedation Scale – RASS), performance status (Eastern Cooperative Oncology Group - ECOG) and delirium (Confusion Assessment Method - CAM).\n\nResults\nNinety-three patients with a median survival of 4 days were included. Of the 47 patients who survived ≥3 days, the proportion of patients with severe/overwhelming pain decreased from 45 to 19% (p < 0.001) after starting CSCI, with only a moderate increase in morphine equivalent daily dose of opioids (MEDD). Alertness was marginally decreased (1 point on the 10-point RASS scale, p = 0.001), whereas performance status and prevalence of delirium, regardless of age, remained unchanged.\n\nBoth patients with methadone as add-on (MET, n = 13) and patients with only other opioids (NMET, n = 34), improved in pain control (p < 0.05 and 0.001, respectively), despite that MET patients had higher pain scores at baseline (p < 0.05) and were on a higher MEDD (240 mg vs.133 mg). No serious adverse effects demanding treatment stop were reported.\n\nConclusions\nCSCI via AIP is an effective way to reduce pain in dying patients without increased adverse effects. Add-on methadone may be beneficial in patients with severe complex pain.\n\nKeywords\nCancerMethadoneOpioidsPainSubcutaneousInfusionStockholms Sjukhem Foundationissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPain is a common clinical problem in palliative care [1]. Eighty percent of patients with advanced cancer and 67% of patients with cardiovascular disease or chronic obstructive pulmonary disease will experience moderate to severe pain at the end of their lives [2]. A better understanding of pain mechanisms has improved pain therapy in recent years [3]. Especially, cancer patients in palliative care are adequately treated with low or moderate doses of opioids and only about 10 % need daily morphine doses over 600 mg [4]. However, with progressive deterioration at the end of life, continuous subcutaneous infusions (CSCI) become increasingly important to continue pain control in the dying [5]. The use of an ambulatory infusion pump (AIP), a small, portable pump that delivers medication via a thin subcutaneous catheter, has several advantages for pain control: It ensures a steady infusion of drugs, with reliable absorption if inserted in unaffected tissue, and allows combinations of drugs to be administered parenterally in a manner that is more convenient than repeated and painful injections. Thus, there is no need for an intravenous access [6, 7]. However, despite encouraging data in palliative care in earlier phases, there is a lack of prospective studies on the use of CSCI in the imminently dying.\n\nLow-dose add-on peroral methadone in combination with other opioids for pain is proposed to be a useful alternative to methadone therapy for better pain control at the end of life [8–12]. The addition of methadone is reported to improve pain relief in complex pain situations but, so far, only peroral or intermittent parenteral administration of low-dose add-on methadone has been studied, routes that are often not feasible in the imminently dying patient [13–15]. Alternative routes of methadone administration are therefore needed and there is a need for further exploration of the effects, and possible adverse effects, of CSCI in this patient group [13, 14].\n\nWhereas patient-reported outcomes are encouraged, this is not possible in imminently dying patients, as the majority of them are not able to complete a questionnaire for obvious reasons, such as, terminal delirium, extreme tiredness or lowered level of consciousness. For this reason, very few studies on symptoms and symptom control have been performed in the very last days of life, a period which is important both for the patient and for their families. A way to overcome this problem is to use validated instruments allowing proxy measures, e.g. assessments made by staff.\n\nThe primary aim of the study was to report the effects on pain intensity and occurrence of adverse effects, e.g. sedation, confusion, and respiratory depression, when prescribing an AIP for CSCI in imminently dying patients. A secondary aim was to specifically study the effects of the addition of low-dose methadone to a CSCI comprising another opioid in this patient group.\n\nMethods\nThe methods and results sections are reported, when applicable, based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria [16].\n\nStudy design\nAt the specialized palliative care in-patient unit at Stockholm Sjukhem Foundation, we conducted an observational cohort study in patients who were prescribed CSCI via AIP for symptom management during the last days of life. Patients were included from February 1, 2019 to January 22, 2020 and followed up daily, with the last follow-up on January 28, 2020.\n\nPopulation\nAll Swedish-speaking patients over the age of 18 years who were neither sedated nor unconscious and who, during daytime (7 am – 8 pm) as part of their regular care, were prescribed a CSCI of drugs were asked to participate in the study. Inclusions were not possible during other hours due to limited available resources for performing the inclusion procedure.\n\nDefinition of total cohort and main study group\nThe total cohort consisted of all patients that were included. The main study group consisted of those patients from the main study group, who had pain at inclusion and who survived for three days or more.\n\nVariables\nFor every patient, baseline data on age, sex, indication for CSCI, prevalence, intensity and type of pain were registered. Daily registrations covered the previous 24 h and included medications, site of SC infusion, skin irritation around the SC needle, and other symptoms including patient anxiety, alertness, performance status and occurrence of confusion.\n\nData sources and rating scales\nAs the patients were in an acute dying phase with rapid deterioration from day to day, the study applied exclusively instruments allowing proxy measures (staff measures). The daily assessments were performed by the registered nurse responsible for the patients’ care on that day and could thus be performed by various individuals from day to day. The proxy version of the Integrated Palliative Care Outcome Scale (IPOS) was used to assess the patient’s symptoms and relatives’ concerns [17]. The IPOS-variables pain and anxiety were reported on an ordinal scale estimating how much the patient was affected, ranging from 0 (not at all) to 4 (overwhelmingly/worst pain imaginable) and these numerical estimates were then used to calculate the pain and anxiety levels. The Richmond Agitation and Sedation Scale (RASS) was used to indicate the level of patient alertness (+ 4 combative via 0 alert and calm to − 5 unarousable) [18, 19]. Performance status was assessed according to the Eastern Cooperative Oncology Group (ECOG/WHO) performance status (0 fully active to 5 dead) and the Confusion Assessment Method (CAM) instrument was used for assessing delirium in a Yes/No format [20, 21].\n\nStudy size\nThis is a descriptive study, and no sample size calculation was performed.\n\nStatistical methods and missing data\nDescriptive statistics are presented with both means and medians as appropriate. T-tests were used to compare age and survival, and, for other variables, the following non-parametric tests were applied: chi-square test to compare proportions, Mann–Whitney U test to compare independent groups and Wilcoxon signed-rank test to compare dependent groups.\n\nFrom initiation of CSCI until day 3, there were missing data on an average of 5 patients per day of the total study cohort, though in no case for more than one consecutive day. For missing data, the last observation carried forward was used. Analysis was performed using SPSS Version 26.\n\nEthical approval (2018/2103–31/1) was obtained from the Regional Ethical Review Board (Stockholm, Sweden) and all participants consented to inclusion in the study.\n\nResults\nDuring the study period, 321 patients were prescribed CSCI and a total of 93 were included in the study intended to be followed prospectively. Of those not included, 88% were assessed as too ill to give formal consent and 12% abstained (Fig. 1). Mean age of the included patients was 76.3 years (median 77 years), 57% were women, (Table 1). Indications for CSCI were: inability to swallow due to deterioration of general condition in 49 (53%) patients, uncontrolled pain with oral pain medication in 27 (29%) patients, bowel obstruction in 6 (6%) patients and unspecified reasons in 11 (12%) patients. On day 0 (initiation of CSCI), the mean pain score was 2.2 (median 2), with 5 (5%) patients rating no pain (Table 2). Two thirds of the reported pain mechanisms were combined nociceptive and neuropathic. For other characteristics, see Table 1.\nFig. 1 Flow chart of patient selection\n\nTable 1 Patient characteristics and pain mechanisms on the day of CSCI initiation\n\n\tTotal cohort\tMain study group, ≥ 3 days of survival\t\nTotal\tMethadone in CSCI\tNo methadone in CSCI\t\n\tn = 93\tn = 47\tn = 13\tn = 34\t\nFemales\nn (%)\t53 (57)\t25 (53)\t5 (38)\t19 (56)\t\nAge\nyears\t\n mean (SD)\t76.3 (10.6)\t75.6 (12.1)\t68.7 (11.7)\t78.2 (11.5)*\t\n median (IQR)\t77 (12)\t76 (16)\t71 (14.5)\t77.5 (16.3)\t\nSurvival\ndays\t\n mean (SD)a\t8 (10)\t9 (9)\t13 (8)\t8 (10)*\t\n median (IQR)\t4 (5)\t5 (9)\t14 (14)\t4 (5)\t\nMidazolam\t\n used midazolam n (%)\t63 (68)\t30 (64)\t7 (54)\t23 (68)\t\nDose, mg/24 h\t\n mean (SD)\t8.0 (11)\t7.1 (9)\t18.8 (11.2)\t8.7 (7.4)\t\n median (IQR)\t5 (10)\t5 (10)\t20 (25)\t6.3 (5)\t\n range (mg)\t0–50\t0–37.5\t2.5–31\t2.5–37.5\t\nPerformance status\t\n mean (SD)\t3.4 (0.9)\t3.3 (1)\t3.4 (0.9)\t3.5 (0.5)\t\n median (IQR)\t4 (1)\t4 (IQR 1)\t4 (1)\t4 (1)\t\nReported pain mechanism\nn (%)\t71 (76)\t37 (80)\t10 (77)\t25 (53)\t\n Mixed nociceptive and neuropathic pain\t47 (66)\t26 (70)\t6 (60)\t18 (72)\t\n Nociceptive pain\t19 (27)\t6 (16)\t2 (20)\t4 (16)\t\n Neuropathic pain\t5 (7)\t5 (14)\t2 (20)\t3 (12)\t\nMalignant diagnoses\nn (%)\t\n Gastrointestinal (other than pancreas)\t25 (27)\t12 (26)\t3 (23)\t9 (26)\t\n Lung\t19 (21)\t11 (23)\t5 (38)\t6 (18)\t\n Urogenital (other than prostate)\t11 (12)\t6 (13)\t2 (15)\t4 (12)\t\n Pancreas\t7 (8)\t2 (4)\t\t2 (6)\t\n Breast\t7 (8)\t3 (6)\t\t3 (9)\t\n Hematological\t5 (5)\t3 (6)\t1 (8)\t2 (6)\t\n Prostate\t2 (2)\t1 (2)\t\t1 (3)\t\n Head and neck\t2 (2)\t1 (2)\t\t1 (3)\t\n Skin\t1 (1)\t1 (2)\t1 (8)\t\t\n Other/unknown origin\t6 (6)\t3 (6)\t1 (8)\t2 (6)\t\nNon-malignant diagnoses\nn (%)\t\n lung fibrosis\t2 (2)\t2 (4)\t\t2 (6)\t\n COPD\t2 (2)\t\t\t\t\n Heart failure\t2 (2)\t\t\t\t\n Renal failure\t1 (1)\t1 (2)\t\t1 (3)\t\n Stroke\t1 (1)\t1 (2)\t\t1 (3)\t\naAfter exclusion of one outlier with 125 days of survival\n\nSignificance of difference between the subgroups of the main study group that were prescribed methadone in CSCI (n = 13) and those who were not (n = 34):*p < 0.05\n\nThis table shows the basic characteristics of the groups analyzed in the study on the day when the continuous subcutaneous infusion was started. The total cohort was all 93 patients who received continuous subcutaneous infusion (CSCI) and were included. The main study group consisted of the 47 patients who survived at least 3 days. Of these, 13 patients were prescribed methadone in CSCI and 34 were not.\n\n(n number of patients, SD standard deviation, IQR inter quartile range)\n\nTable 2 Pain and opioid doses\n\n\tTotal cohort\tMain study group, ≥ 3 days of survival\t\nTotal\tMethadone in CSCI\tNo methadone in CSCI\t\n\tn = 93\tn = 47 (13 + 34)\tn = 13\tn = 34\t\n\tDay 0\tDay 0\tDay 3\tDay 0\tDay 3\tDay 0\tDay 3\t\nLevel of pain\n(0–4)a\t\n Mean (SD)\t2.2 (1.1)\t2.2 (1.2)\t1.5 (1.2)***\t2.9 (1.0)\t2.1 (1.3)*\t2.0 (1.1)\t1.2 (1.1)***\t\n Median (IQR)\t2 (2)\t2 (2)\t2 (2)\t3 (1)\t2 (2)\t2 (2)\t1 (1)\t\n Severe to overwhelming pain (scores 3–4) n (%)\t39 (42)\t21 (45)\t9 (19)***\t10 (77)\t6 (46)*\t11 (32)\t3 (9)***\t\nMEDDb\nof opioids,\nmg\t\n Mean (SD)\t179 (175)\t184 (181)\t205 (182)*\t306 (257)\t354 (225)\t133 (108)\t142 (116)*\t\n Median (IQR)\t120 (169)\t123 (151)\t150 (210)\t240 (310)\t300 (193)\t113 (120)\t105 (125)\t\n Range\t22.5–1020\t22.5–1020\t30–870\t22.5–1020\t75–870\t30–435\t30–563\t\nMethadone,\nmg\t\n Mean (SD)\t5.5 (4.6)\t–\t–\t7.5 (4.8)\t7.7 (4.5)\t–\t–\t\n Median (IQR)\t5 (7.5)\t–\t–\t5 (5)\t5 (5)\t–\t–\t\n Range\t0–20\t–\t–\t2.5–20\t5–20\t–\t–\t\naOrdinal scale from 0 (not at all affected by pain) to 4 (overwhelmingly)\n\nbTotal morphine equivalent (oral) daily doses\n\nSignificance of difference from day 0 to day 3:*p < 0.05; ** p < 0.01; ***p ≤ 0.001. The comparisons are made for the main study group (n = 47), for the MET group (n = 13) and the NMET group (n = 34), respectively\n\nThe table refers partly to the situation at the day for start of the continuous subcutaneous infusion (CSCI), and partly 3 days later. It is divided into the different groups analyzed in the study, i.e. the total cohort which is all 93 patients who received CSCI from day 0 and the 47 patients who survived at least 3 days and who make up the main study group. The 13 patients in the main study group who were prescribed methadone in CSCI are the MET group and the 34 who were not prescribed methadone are the NMET group. The table shows levels of pain at the different times, and also the doses of opioids that the patients were prescribed, including methadone.\n\n(n number of patients, SD standard deviation, IQR inter quartile range)\n\n\n\nThree patients, one of whom received methadone, experienced local erythema which disappeared within one day after changing the injection site. In all three cases, the needle had been in place for at least 5 days.\n\nPatients with 3 days or more of survival time\nTo enable the study of the effects and adverse effects of opioids over time, patients with no pain and with a survival of less than 3 days, as well as patients who also received additional palliative sedation, were excluded from further analyses, leaving 47 patients in the main study group. This group included patients receiving midazolam prescribed for anxiety, but not for sedation. The median survival in this cohort was 5 days (mean 9). For further characteristics, see Table 1.\n\nAdjuvant analgesics and opioids\nThirty-three patients (70%) used peroral non-opioids and/or adjuvant analgesics on the day of initiation of CSCI (mean 1.7 adjuvants), including corticosteroids, paracetamol (acetaminophen), NSAIDs, antidepressants and gabapentinoids. The following opioids (oral or parenteral) were used in the main study group until the switch to CSCI: Oxycodone in 61% of the cases, morphine in 23%, fentanyl patches in 14% and hydromorphone in 2% of the cases. All oral opioids were discontinued upon conversion to CSCI. The total mean morphine equivalent daily dose (MEDD) via CSCI at baseline was 184 mg. In eight cases, only opioids were used in the AIP, in 17 cases the opioids were combined with one additional drug, in 16 cases with two others and in six cases with three other drugs. For specific details on CSCIs containing methadone, see Table 3.\nTable 3 Continuous Subcutaneous Infusions for the MET group\n\nAge-group\tPatient\tMalignancy\tMax Methadone dose/24 h. in CSCI (mg)\tLocal toxicity\tRegular opioid in CSCI\tOther drugs in CSCI\t\n40–49\t1\tLiver\t20\tno\tmorphine\tmidazolam, haloperidol\t\n\t4\tThyroid\t10\tno\thydromorphone\tmidazolam, hyoscine butylbromide, metoclopramide\t\n60–69\t2\tAbdominal\t5\tno\toxycodone\thyoscine butylbromide\t\n\t6\tLung\t5\tno\toxycodone\tmidazolam, hyoscine butylbromide, haloperidol\t\n\t7\tLung\t10\tno\thydromorphone\tmidazolam, metoclopramide\t\n\t13\tLung\t5\tno\thydromorphone\tmidazolam, hyoscine butylbromide, haloperidol\t\n70–79\t5\tB-cell lymfoma\t7.5\tyes\toxycodone\tmidazolam\t\n\t8\tBladder\t5\tno\toxycodone\t\t\n\t9\tBladder\t20\tno\thydromorphone\tmidazolam, haloperidol\t\n\t10\tLung\t10\tno\thydromorphone\tmidazolam, haloperidol\t\n\t11\tLung\t5\tno\thydromorphone\tmidazolam, haloperidol\t\n80–89\t3\tColon\t5\tno\toxycodone\t\t\n\t12\tMerkel cell\t10\tno\toxycodone\tmidazolam, haloperidol\t\nThis table describes the characteristics of the 13 patients who were prescribed methadone in continuous subcutaneous infusion (CSCI), the MET group. By local toxicity is meant whether or not skin erythema occurred.\n\n\n\nPain and other symptoms from day 0 to day 3\nPain\nThe proportion of patients severely or overwhelmingly affected by pain decreased from 45 to 19% (p < 0.001) and the mean pain score from 2.2 (median 2) to 1.5 (median 2) on the five-point pain IPOS scale, (Table 2).\n\nAlertness\nThe mean level of alertness went from − 0.2 to − 1.2, i.e. 1 point on a 10-point scale (p = 0.001), (Table 4). During the same period, doses of midazolam (median 7.5 to 9.4 mg, p = 0.31) and performance status did not change significantly.\nTable 4 Adverse effects\n\n\tTotal cohort\tMain study group, ≥ 3 days of survival\t\nTotal\tMethadone in CSCI\tNo methadone in CSCI\t\n\tn = 93\tn = 47\tn = 13\tn = 34\t\n\tDay 0\tDay 0\tDay 3\tDay 0\tDay 3\tDay 0\tDay 3\t\nAlertnessa\t\n Mean (SD)\t−0.5 (1.2)\t−0.2 (1)\t−1.2 (1,7)***\t0.4 (0.9)\t−0.9 (1.7)*\t− 0.4 (1)\t−1.3 (1.7)*\t\n Median (IQR)\t0 (1)\t0 (2)\t−1 (2)\t0 (1)\t0 (2)\t−0.5 (1)\t−1 (2)\t\nDeliriumb\t\n Prevalence n (%)\t27 (29)\t14 (30)\t15 (32)\t4 (31)\t5 (39)\t10 (29)\t10 (29)\t\n Prev. < 75 years\t12 (32)\t7 (33)\t9 (43)\t4 (31)\t5 (39)\t8 (32)\t7 (28)\t\n Prev. ≥ 75 years\t15 (27)\t7 (27)\t6 (23)\t3 (30)\t2 (20)\t12 (27)\t4 (9)\t\nAnxiety\nc\t\n median (IQR)\t3 (1)\t3 (1)\t2 (2)\t3 (1)\t2 (1.8)\t3 (1.5)\t2 (2)\t\naOrdinal scale from + 4 (combative) to −5 (unarousable)\n\nbPrevalence of confusion/delirium (Yes/No)\n\ncOrdinal scale from 0 (not at all) to 4 (always)\n\nSignificance of differences from day 0 to day 3:*p < 0.05; ***p ≤ 0.001\n\nIn this table, the status of all 93 patients regarding alertness, prevalence of delirium and anxiety on the day of initiation, day 0, of continuous subcutaneous infusion (CSCI) is reported under total cohort. The main study group is the 47 patients who survived at least 3 days. The changes from day 0 to day 3 in adverse effects is shown for the total group and also for the 13 patients who received methadone in CSCI and the 34 patients who did not.\n\n(n number of patients, SD standard deviation, IQR inter quartile range)\n\n\n\nDelirium\nDelirium was seen in 30% of the patients at day 0 and did not change significantly over time (day 0 vs. day 3). Neither were there differences between patients under or above 75 years of age, (Table 4).\n\nAnxiety\nAt baseline, 52% of the patients were reported to be anxious most of the time or always. On day 3 however, this proportion was significantly lower, 26% (p = 0.04), (Table 4).\n\nPatients receiving methadone\nThirteen patients received low-dose methadone added to the continuous infusion (MET). The median time of survival from initiation of CSCI was 14 days for the MET group compared with 4 days for the group of patients whose CSCIs contained no methadone (NMET), respectively (p = 0.044), (Table 1). Of the 13 patients in the MET group, 10 were prescribed methadone for the first time on day 0 and the other 3 were previously on peroral methadone due to previous, insufficient pain control. After 3 days, the dose was unchanged in 72%, increased in 18% and decreased in 10% of the cases. The most common starting dose of SC methadone was 5 mg per 24 h (55%), (Table 2). All the patients used methadone until the CSCI was ended, in all cases due to death.\n\nOpioids\nAt baseline, the MEDD of opioids via CSCI for MET (median 240 mg) was almost twice the dose for NMET (median 133 mg), (p = 0.004). From days 0 to 3 there was an increase in opioid doses for NMET (p = 0.02).\n\nPain and other symptoms from day 0 to day 3\nPain\nOn day 0, MET compared with NMET patients had more severe pain (p = 0.02) and a higher proportion of severe/overwhelming pain, 77% vs. 32% (p = 0.009), (Table 2). On day 3, pain scores were significantly reduced for both MET and NMET patients (p = 0.04 and p = 0.001, respectively) and the proportion of severe pain was lower, (Table 2).\n\nAlertness\nMET started at a slightly higher alertness level than NMET (p = 0.02). The levels dropped from 0.4 to − 0.9 (median 0 to 0; p = 0.02) and from − 0.4 to − 1.3 (median − 0.5 to − 1; p = 0.02), respectively, (Table 4).\n\nThere were no significant differences between MET and NMET over time regarding doses of midazolam (p = 0.054), performance status, anxiety, or prevalence of delirium, (Table 1 and Table 4).\n\nSerious adverse effects\nOne MET patient had a respiratory ratio lower than eight breaths per minute on days three and four. No interventions were needed, and from day five he had normal respiratory ratios until death on day nine.\n\nDiscussion\nIn this study on symptom relief during the very last days of life, we report that the use of AIP for CSCI for pain control in dying patients contributed to improved analgesia with no clinically significant change in adverse effects. In addition, CSCI with low-dose methadone in combination with other regular opioids was prescribed at the individual physician’s discretion and resulted in improved analgesia for patients with the most severe pain.\n\nSeveral studies and guidelines report on the treatment of severe pain in patients in palliative care in less advanced stages [3, 22–24]. However, few studies investigate pain and symptom management in the imminently dying, due to the well-known problems related to symptom assessment [25, 26]. The short median survival time of four days confirms that the patients in this study were at the very end of life. In this setting, the most common reason for initiating CSCI was general deterioration causing impaired oral intake. Another major reason was to provide better pain relief by converting to parenteral drug delivery and, when judged necessary, by adding parenteral methadone. The need for better pain relief may be due to mixed nociceptive and neuropathic pain in two thirds of the patients in this study, a combination of pain mechanisms often difficult to treat [14].\n\nSignificant reduction in pain was seen for the entire group of patients who received CSCI with opioids for pain and who could be followed for at least three days. This was regardless of whether the pain was measured as the proportion of patients with severe pain or as the median and average pain scores based on the Likert scale for pain in the IPOS [17]. Advantages in CSCI administration of opioids in relation to pain control include a more stable serum concentration of the drug with avoidance of end-of-dose interval breakthrough pain and less adverse effects occurring at high peak concentrations following intermittent injections which allows a more adequate opioid dose titration [6, 27, 28]. In the imminently dying patients a rotation from oral intake to parenteral routes might be especially beneficial, as the oral route, including swallowing and absorption, might be unreliable in the last days and hours of life.\n\nIn this study, it was not recorded whether the same opioid was used when switching to CSCI or whether an alternative opioid was used. There may exist a cross-tolerance between opioids, meaning that a different opioid has a better analgesic effect than expected from equianalgesic tables [29]. However, a review by Schuster et al. 2018 confirmed the stated findings in the Cochrane review from 2004, that although widely practiced, robust evidence for the benefit of opioid rotation is still lacking [30, 31].\n\nPatients who required the addition of methadone for analgesia had higher pain scores and opioid doses at initiation of CSCI. Thus, the use the co-prescription of low-dose methadone with another opioid for CSCI via AIP was mainly initiated in patients with complex pain of high intensity, in order to improve pain control without large dose escalations of the regular opioid. This is in line with the study by Mercadante et al., that described how addition of methadone to another opioid in patients with cancer pain may reduce the need for opioid dose escalation [32]. As shown in this study, the apparent beneficial analgesic effect adding of low-dose methadone to another opioid for administration by CSCI is promising and reflects observations reported for oral administration [8–12].\n\nThere was a statistically significant decrease in alertness (p < 0.001). However, the clinical impact is probably minor as the change was 1.0 in a 10-grade scale, i.e. a 10 % deterioration, in acutely dying patients. Besides this, there were neither any increase in intensity of other adverse symptoms nor any serious adverse effects that demanded specific interventions. Moreover, we observed no significant differences over time or between MET and NMET regarding performance status, anxiety levels or doses of the anxiolytic midazolam. These observations agree with the general observation that adverse effects such as sedation, constipation, and respiratory depression are associated with the pharmacology of opioids as a class, and similar reactions are expected regardless of route [28].\n\nNotably, those in the subgroup MET had higher total opioid doses, still they survived marginally longer. The MET group’s longer survival from introduction to death may possibly be explained by their more complex pain situation, possibly resulting in an earlier introduction of CSCI.\n\nParticularly interesting is that the prevalence of delirium in the main study group did not change over time and did not differ between patients younger or older than 75 years of age. To the best of our knowledge, differences in adverse effects following introduction of CSCI for pain in different age groups has not been described before, but our findings are consistent with previous studies indicating that a steady infusion of subcutaneous drugs may be better tolerated [6, 33].\n\nProblems with local skin irritation at the site of CSCI has been associated with methadone but are reported to resolve with site rotation [15, 34–36]. In our prospective study, only low-doses of methadone were infused and we found only three cases of skin irritation, two in the NMET group and one in the MET group. The needle had been in the same place for at least five days which, therefore, may be as likely an explanation for the dermal erythema as the drugs in the CSCI. We therefore suggest that the risk of skin irritation should not be considered a major limiting factor for the use of methadone in CSCI.\n\nThere was a significant difference in mean age between the MET group, 68 years, and the NMET group, 78 years, (p < 0.05). We described a similar difference in a study from 2020 on a different sample [13]. To the best of our knowledge this has not been studied before and we do not know the underlying reason.\n\nWe do recognize some limitations of the study. First, as accounted for in the methods section, all patients receiving a CSCI were not included, usually due to illness and of ability to provide informed consent, as well as some patients refraining from participation. Second, as methadone, according to clinical guidelines, was mainly prescribed to patients with the most severe pain, the MET and NMET groups differed significantly at baseline as regards pain intensity and MEDD. Still, such comparisons of subgroups are of interest, as they reflect a clinical reality. Comparable control groups are difficult to achieve in a population of dying patients in need of parenteral drug administration, and randomization with control groups is seldom possible, for ethical reasons. Third, due to the severe illnesses of the patients, observer ratings had to be used. By definition, observer assessment may not directly reflect the patient’s experiences, meanwhile, they allow studies in the last days and hours of life, on an important patient group that is often excluded from studies. The assessments were based on subjective judgements by the registered nurses who performed the registrations. Consequently, the assessments came to a certain extent to depend on each individual’s level of knowledge, skills, and personal attitudes. Finally, this is a single-center study reflecting the experiences at one particular setting.\n\nStrengths include the prospective design until death and the use of validated instruments for symptom assessments. Another strength is that the proxy assessments were performed by trained personnel, which may have contributed to improved assessments of adverse effects [37].\n\nConclusions\nRegardless of age, CSCI via AIP for pain seems effective in reducing pain in dying patients without any substantial increase of adverse effects such as delirium or respiratory depression. An addition of low-dose methadone may be beneficial for CSCIs for patients with severe cancer pain at the end of life. The effectiveness of low-dose methadone in combination with the patient’s regular opioid needs further investigation, preferably with a randomized controlled trial.\n\nAbbreviations\nCSCIContinuous subcutaneous infusion\n\nAIPAmbulatory infusion pump\n\nCAMConfusion Assessment Method\n\nECOGEastern Cooperative Oncology Group\n\nhrs.Hours\n\nIPOSIntegrated Palliative Care Outcome Scale\n\nIQRInter quartile range\n\nMEDDMorphine equivalent daily dose of opioids\n\nMETPatients with methadone as add-on\n\nmgMilligrams\n\nnNumber\n\nNMETPatients on opioids other than methadone only\n\nNSAIDNon-steroidal anti-inflammatory drug\n\nRASSRichmond Agitation and Sedation Scale\n\nSCSubcutaneous\n\nSDStandard deviation\n\nSTROBEStrengthening the Reporting of Observational Studies in Epidemiology\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors would like to thank all the staff working in the palliative departments at Stockholm Sjukhem for their valuable participation with the data collection and Sara Runesdotter for her help with the statistics. David Boniface is acknowledged for linguistic revision.\n\nAuthors’ contributions\nAll authors (PF, SL, PK, PS) contributed to the design of the work or data collection, analysis, and interpretation of data; participated in revision; gave the final approval of the version to be published; and agreed to be responsible for the work. The authors read and approved the final manuscript.\n\nFunding\nThis work was supported by the Stockholm Sjukhem Foundation. The funding body did not participate in any part of the study (neither in the design, collection of data, analysis, interpretation nor in writing of the manuscript). Open Access funding provided by Karolinska Institute.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nEthical approval (2018/2103–31/1) was obtained from the Regional Ethical Review Board (Stockholm, Sweden) and all participants consented to inclusion in the study. The ethics permit referred to written consent, with or without assistance, depending on the situation. Therefore, each individual patient who was able to sign the consent did so himself and in cases where the general condition caused physical difficulties in writing (because of frailty caused by the dying process), the consent was filled in, with the patient’s approval, together with the patient.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. van den Beuken-van Everdingen MH Hochstenbach LM Joosten EA Tjan-Heijnen VC Janssen DJ Update on Prevalence of Pain in Patients With Cancer: Systematic Review and Meta-Analysis J Pain Symptom Manag 2016 51 6 1070 1090 10.1016/j.jpainsymman.2015.12.340 \n2. WHO, Palliative Care. https://www.who.int/news-room/fact-sheets/detail/palliative-care. Last accessed July 7, 2020.\n3. 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Last accessed July 7, 2020.\n8. Wallace E Ridley J Bryson J Mak E Zimmermann C Addition of methadone to another opioid in the management of moderate to severe cancer pain: a case series J Palliat Med 2013 16 3 305 309 10.1089/jpm.2012.0335 23391350 \n9. Salpeter SR Buckley JS Bruera E The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia J Palliat Med 2013 16 6 616 622 10.1089/jpm.2012.0612 23556990 \n10. Salpeter SR Buckley JS Buckley NS Bruera E The use of very-low-dose methadone and haloperidol for pain control in the hospital setting: a preliminary report J Palliat Med 2015 18 2 114 119 10.1089/jpm.2014.0266 25494475 \n11. Courtemanche F Dao D Gagne F Tremblay L Neron A Methadone as a Coanalgesic for palliative care Cancer patients J Palliat Med 2016 19 9 972 978 10.1089/jpm.2015.0525 27399839 \n12. Furst P Lundstrom S Klepstad P Runesdotter S Strang P Improved pain control in terminally ill Cancer patients by introducing low-dose Oral methadone in addition to ongoing opioid treatment J Palliat Med 2018 21 2 177 181 10.1089/jpm.2017.0157 28792784 \n13. Furst P Lundstrom S Klepstad P Strang P The use of low-dose methadone as add-on to regular opioid therapy in Cancer-related pain at end of life: a National Swedish Survey in specialized palliative care J Palliat Med 2020 23 2 226 232 10.1089/jpm.2019.0253 31436477 \n14. Furst P Lundstrom S Strang P Methadone in Swedish specialized palliative care-is it the magic bullet in complex cancer-related pain? PLoS One 2020 15 4 e0230845 10.1371/journal.pone.0230845 32275723 \n15. Shaiova L Berger A Blinderman CD Bruera E Davis MP Derby S Inturrisi C Kalman J Mehta D Pappagallo M Consensus guideline on parenteral methadone use in pain and palliative care Palliat Support Care 2008 6 2 165 176 10.1017/S1478951508000254 18501052 \n16. Vandenbroucke JP von Elm E Altman DG Gotzsche PC Mulrow CD Pocock SJ Poole C Schlesselman JJ Egger M Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration Epidemiology (Cambridge, Mass) 2007 18 6 805 835 10.1097/EDE.0b013e3181577511 \n17. Schildmann EK Groeneveld EI Denzel J Brown A Bernhardt F Bailey K Guo P Ramsenthaler C Lovell N Higginson IJ Discovering the hidden benefits of cognitive interviewing in two languages: the first phase of a validation study of the integrated palliative care outcome scale Palliat Med 2016 30 6 599 610 10.1177/0269216315608348 26415736 \n18. Sessler CN Gosnell MS Grap MJ Brophy GM O'Neal PV Keane KA Tesoro EP Elswick RK The Richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients Am J Respir Crit Care Med 2002 166 10 1338 1344 10.1164/rccm.2107138 12421743 \n19. Arevalo JJ Brinkkemper T van der Heide A Rietjens JA Ribbe M Deliens L Loer SA Zuurmond WW Perez RS Palliative sedation: reliability and validity of sedation scales J Pain Symptom Manag 2012 44 5 704 714 10.1016/j.jpainsymman.2011.11.010 \n20. Oken MM Creech RH Tormey DC Horton J Davis TE McFadden ET Carbone PP Toxicity and response criteria of the eastern cooperative oncology group Am J Clin Oncol 1982 5 6 649 655 10.1097/00000421-198212000-00014 7165009 \n21. Grover S Kate N Assessment scales for delirium: a review World J Psychiatry 2012 2 4 58 70 10.5498/wjp.v2.i4.58 24175169 \n22. Kongsgaard U, Kaasa S, Dale O, Ottesen S, Nordøy T, Hessling SE, von Hofacker S, Bruland Ø S, Lyngstadaas A: NIPH Systematic Reviews: Executive Summaries. In: Palliative Treatment of Cancer-Related Pain. edn. Oslo, Norway: Knowledge Centre for the Health Services at The Norwegian Institute of Public Health (NIPH); 2005.\n23. Edler-Buggy S Birtwistle J ElMokhallalati Y Kindl K Good P Bennett MI Regular dosing compared with as-needed dosing of opioids for management of chronic cancer pain: systematic review and meta-analysis Pain 2020 161 4 703 712 10.1097/j.pain.0000000000001755 31770157 \n24. Wiffen PJ Wee B Derry S Bell RF Moore RA Opioids for cancer pain - an overview of Cochrane reviews Cochrane Database Syst Rev 2017 7 Cd012592 28683172 \n25. Parsons HA Shukkoor A Quan H Delgado-Guay MO Palmer JL Fainsinger R Bruera E Intermittent subcutaneous opioids for the management of cancer pain J Palliat Med 2008 11 10 1319 1324 10.1089/jpm.2008.0155 19115891 \n26. Jordhoy MS Kaasa S Fayers P Ovreness T Underland G Ahlner-Elmqvist M Challenges in palliative care research; recruitment, attrition and compliance: experience from a randomized controlled trial Palliat Med 1999 13 4 299 310 10.1191/026921699668963873 10659099 \n27. Cools HJ Berkhout AM De Bock GH Subcutaneous morphine infusion by syringe driver for terminally ill patients Age Ageing 1996 25 3 206 208 10.1093/ageing/25.3.206 8670553 \n28. Anderson SL Shreve ST Continuous subcutaneous infusion of opiates at end-of-life Ann Pharmacother 2004 38 6 1015 1023 10.1345/aph.1D395 15122000 \n29. McPherson ML Why equianalgesic tables are only part of the answer to equianalgesia Ann Palliat Med 2020 9 2 537 541 10.21037/apm.2020.03.05 32233628 \n30. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev. 2004;(3):Cd004847.\n31. Schuster M Bayer O Heid F Laufenberg-Feldmann R Opioid Rotation in Cancer Pain Treatment A Systematic Review Deutsches Arzteblatt Int 2018 115 9 135 \n32. Mercadante S Villari P Ferrera P Casuccio A Addition of a second opioid may improve opioid response in cancer pain: preliminary data Support Care Cancer 2004 12 11 762 766 10.1007/s00520-004-0650-1 15206014 \n33. Radbruch L Trottenberg P Elsner F Kaasa S Caraceni A Systematic review of the role of alternative application routes for opioid treatment for moderate to severe cancer pain: an EPCRC opioid guidelines project Palliat Med 2011 25 5 578 596 10.1177/0269216310383739 21708861 \n34. Bruera E Fainsinger R Moore M Thibault R Spoldi E Ventafridda V Local toxicity with subcutaneous methadone. Experience of two centers Pain 1991 45 2 141 143 10.1016/0304-3959(91)90179-2 1876420 \n35. Mathew P Storey P Subcutaneous methadone in terminally ill patients: manageable local toxicity J Pain Symptom Manag 1999 18 1 49 52 10.1016/S0885-3924(99)00020-2 \n36. Centeno C Vara F Intermittent subcutaneous methadone administration in the management of cancer pain J Pain Palliat Care Pharmacother 2005 19 2 7 12 10.1080/J354v19n02_03 \n37. Zalon ML Nurses' assessment of postoperative patients' pain Pain 1993 54 3 329 334 10.1016/0304-3959(93)90033-L 8233548\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1472-684X",
"issue": "19(1)",
"journal": "BMC palliative care",
"keywords": "Cancer; Infusion; Methadone; Opioids; Pain; Subcutaneous",
"medline_ta": "BMC Palliat Care",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D000072716:Cancer Pain; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D055104:Infusions, Subcutaneous; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D010166:Palliative Care; D018709:Statistics, Nonparametric",
"nlm_unique_id": "101088685",
"other_id": null,
"pages": "172",
"pmc": null,
"pmid": "33172459",
"pubdate": "2020-11-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "27112310;18049195;27399839;32233628;29650892;15266542;23391350;23556990;25715160;31436477;31770157;18501052;25494475;28792784;24175169;7165009;16218160;29563006;28683172;22300860;8670553;32275723;10439572;1876420;15122000;10659099;22819440;8233548;15206014;21708861;26415736;19115891;12421743;16061456",
"title": "Continuous subcutaneous infusion for pain control in dying patients: experiences from a tertiary palliative care center.",
"title_normalized": "continuous subcutaneous infusion for pain control in dying patients experiences from a tertiary palliative care center"
} | [
{
"companynumb": "SE-MYLANLABS-2021M1009123",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Neuroleptic malignant syndrome (NMS) is a potentially life-threatening idiosyncratic reaction generally associated with neuroleptics. NMS is characterized by hyperthermia, extrapyramidal symptoms, elevated creatinine kinase (CK), altered mental state, leukocytosis, and problems with vegetative functions. Due to its lower affinity for dopaminergic receptors and higher affinity for serotonin receptors, olanzapine-associated atypical NMS were less common than typical neuroleptics. Here we report a case of NMS induced by sudden discontinuation and reinstitution of olanzapine in a patient with schizophrenia during perioperative period of lung resection, drawing attention to adverse events occurring with reinstitution of atypical neuroleptics in high-risk patients.",
"affiliations": "Department of Intensive Care Unit, Huashan Hospital Affiliated to Fudan University Shanghai, China.;Department of Mood Disorder, Shanghai Mental Health Center Shanghai, China.;Department of Thoracic Surgery, Huashan Hospital Affiliated to Fudan University Shanghai, China.;Department of Thoracic Surgery, Huashan Hospital Affiliated to Fudan University Shanghai, China.",
"authors": "Zhao|Zhiyong|Z|;Zhang|Hua|H|;Wang|Shaohua|S|;Chen|Xiaofeng|X|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1940-5901",
"issue": "8(7)",
"journal": "International journal of clinical and experimental medicine",
"keywords": "Neuroleptic malignant syndrome; atypical neuroleptics; perioperative period",
"medline_ta": "Int J Clin Exp Med",
"mesh_terms": null,
"nlm_unique_id": "101471010",
"other_id": null,
"pages": "11639-41",
"pmc": null,
"pmid": "26379999",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "21120111;2863986;3497368;2572206;17263746;3664920;17541044;22506626;10029891;23543750;9006400;10375159",
"title": "Sudden discontinuation and reinstitution of olanzapine-associated atypical neuroleptic malignant syndrome in a patient undergoing lung surgery.",
"title_normalized": "sudden discontinuation and reinstitution of olanzapine associated atypical neuroleptic malignant syndrome in a patient undergoing lung surgery"
} | [
{
"companynumb": "CN-DRREDDYS-USA/CHN/15/0053314",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of neuropsychiatric systemic lupus erythematosus successfully treated with mycophenolate mofetil (MMF). The patient was a 40-year-old female who maintained with 7 mg of prednisolone plus 100 mg of azathioprine (AZ) per day. According to transient ischemic attack that occurred repeatedly and an elevated level of interleukin-6 (IL-6) in spinal fluid, she was diagnosed as having neuropsychiatric systemic lupus erythematosus (NPSLE). Initial increase in doses of prednisolone and AZ to 20 mg and 150 mg per day, respectively, was ineffective. After switching from AZ to MMF, her symptoms of NPSLE completely resolved with marked improvement of the IL-6 level in her spinal fluid, suggesting that MMF was effective.",
"affiliations": "Division of Rheumatology, Matsuyama Red Cross Hospital, Japan.",
"authors": "Higashioka|Kazuhiko|K|;Yoshida|Kenji|K|;Oryoji|Kensuke|K|;Kamada|Kazuo|K|;Mizuki|Shinichi|S|;Tsukamoto|Hiroshi|H|;Yokota|Eisuke|E|;Akashi|Koichi|K|",
"chemical_list": "C508600:IL6 protein, human; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.4582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D002546:Ischemic Attack, Transient; D020945:Lupus Vasculitis, Central Nervous System; D009173:Mycophenolic Acid; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2255-9",
"pmc": null,
"pmid": "26328657",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Lupus Cerebrovascular Disease with Mycophenolate Mofetil.",
"title_normalized": "successful treatment of lupus cerebrovascular disease with mycophenolate mofetil"
} | [
{
"companynumb": "PHHY2015JP114298",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nUnexpected clinical laboratory concentrations often need to be investigated before they are acted upon in a clinical setting. Therapeutic drug monitoring (TDM) frequently involves drugs with narrow therapeutic windows and can be harmful to the patient if changes are made based on erroneous serum drug concentrations. Too little of the drug will result in ineffective therapy and too much of the drug can cause life threatening toxicities. There are many factors that can result in unexpected serum drug concentrations including differences in analytical methods being used, diet, timing of blood draw, genotype and compliance. All these factors should all be considered before deciding if changes should be made in a patient's therapeutic course.\n\n\nMETHODS\nWe determined the cause of 2 patient's unexpected TDM concentrations for sirolimus and tacrolimus. Using this approach in 2 patient cases, we describe how co-treatment and uncommon genotypes result in unexpected drug concentrations.\n\n\nCONCLUSIONS\nBoth cases involved unexpected drug values. In the first case, the cause was revealed to be a drug that was added to the patient's treatment regimen (posaconazole) that inhibits CYP3A4 which is responsible for sirolimus metabolism. In the second case, the patient was revealed to have an uncommon genotype for CYP3A5, causing higher metabolism and lower serum tacrolimus concentrations than the general population.",
"affiliations": "University of Louisville, Department of Pathology and Laboratory Medicine, United States.;University of Louisville Hospital, Medical Oncology and Hematology, United States.;University of Louisville, Department of Pathology and Laboratory Medicine, United States. Electronic address: sjortani@louisville.edu.",
"authors": "Millner|Lori|L|;Rodriguez|Cesar|C|;Jortani|Saeed A|SA|",
"chemical_list": "D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus; D016559:Tacrolimus",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-8981",
"issue": "450()",
"journal": "Clinica chimica acta; international journal of clinical chemistry",
"keywords": "Immunosuppressant; Pharmacogenetics; Sirolimus; Tacrolimus",
"medline_ta": "Clin Chim Acta",
"mesh_terms": "D000328:Adult; D051544:Cytochrome P-450 CYP3A; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D010597:Pharmacogenetics; D057285:Precision Medicine; D020123:Sirolimus; D016559:Tacrolimus",
"nlm_unique_id": "1302422",
"other_id": null,
"pages": "15-8",
"pmc": null,
"pmid": "26232156",
"pubdate": "2015-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A clinical approach to solving discrepancies in therapeutic drug monitoring results for patients on sirolimus or tacrolimus: Towards personalized medicine, immunosuppression and pharmacogenomics.",
"title_normalized": "a clinical approach to solving discrepancies in therapeutic drug monitoring results for patients on sirolimus or tacrolimus towards personalized medicine immunosuppression and pharmacogenomics"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0055298",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study is to report a case of C. difficile bacteremia in a Crohn's disease patient and to review the literature on previously reported cases.\n\n\nMETHODS\nSearches of MEDLINE and PubMed databases were made.\n\n\nRESULTS\nWe report the first case of C. difficile bacteremia in a Crohn's disease patient. There are 15 other reported cases of C. difficile bacteremia reported in the literature. We found that the majority of patients (10 of 15 patients) had polymicrobial bacteremia and that the overall mortality rate is significant, with 6 of 15 reported patients dying.\n\n\nCONCLUSIONS\nIn conclusion, we find that C. difficile bacteremia is associated with a significant mortality rate and it would seem prudent to consider aggressive antibiotic therapy.",
"affiliations": "Gastroenterology Fellow, Lankenau Hospital, 252 Lankenau Medical Bldg. East, 100 E Lancaster Ave., Wynnewood, PA 19096.",
"authors": "Daruwala|Cherag|C|;Mercogliano|Giancarlo|G|;Newman|Gary|G|;Ingerman|Mark J|MJ|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.4137/ccrep.s2204",
"fulltext": "\n==== Front\nClin Med Case RepClin Med Case RepClinical Medicine. Case Reports1178-6450Libertas Academica ccrep-2-2009-005Case ReportBacteremia Due to Clostridium Difficile: Case Report and Review of the Literature Daruwala Cherag 1Mercogliano Giancarlo 2Newman Gary 2Ingerman Mark J. 31 Gastroenterology Fellow, Lankenau Hospital, 252 Lankenau Medical Bldg. East, 100 E Lancaster Ave., Wynnewood, PA 19096.2 Gastroenterology Medical Staff, Lankenau Hospital, 252 Lankenau Medical Bldg. East, 100 E Lancaster Ave., Wynnewood, PA 19096.3 Infectious Diseases Medical Staff, Lankenau Hospital, 164 Lankenau Medical Bldg. East, 100 E Lancaster Ave., Wynnewood, PA 19096.Correspondence: Cherag Daruwala, MD, Gastroenterology Fellow, Lankenau Hospital, 252 Lankenau Medical Bldg. East, 100 E Lancaster Ave., Wynnewood, PA 19096. Tel: 610-645-2785; Fax: 610-896-5207; Email: cherag78@gmail.com2009 17 2 2009 2 5 9 © 2009 by the authors2009This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).Objective\nThe purpose of this study is to report a case of C. difficile bacteremia in a Crohn’s disease patient and to review the literature on previously reported cases.\n\nMethods\nSearches of MEDLINE and PubMed databases were made.\n\nResults\nWe report the first case of C. difficile bacteremia in a Crohn’s disease patient. There are 15 other reported cases of C. difficile bacteremia reported in the literature. We found that the majority of patients (10 of 15 patients) had polymicrobial bacteremia and that the overall mortality rate is significant, with 6 of 15 reported patients dying.\n\nConclusion\nIn conclusion, we find that C. difficile bacteremia is associated with a significant mortality rate and it would seem prudent to consider aggressive antibiotic therapy.\n\nClostridium difficileCrohn’s diseasebacteremia\n==== Body\nIntroduction\nClostridium difficile is the primary cause of pseudomembranous colitis and a major cause of antibiotic-associated diarrhea.1 In the original report of C. difficile published in 1935 the bacterium was named “the difficult clostridium” because early attempts at isolation were unsuccessful and it grew slowly in culture.3\n\nC. difficile produces an enterotoxin (toxin A) and a cytotoxin (toxin B). Toxin A has been shown to be the cause of diarrhea and pseudomembranous colitis.4\n\nC. difficile has rarely been reported to cause extraintestinal disease.1 The role of toxins A and B in extracolonic manifestations of C. difficile remains unclear. We report a case of C. difficile bacteremia in a Crohn’s disease patient and review the literature on previously reported cases.\n\nMethods\nA review of the published literature on C. difficile bacteremia was done using MEDLINE and PubMed databases. Searches were conducted to find articles from 1966–2008. Medical subject headings used to search the databases included C. difficile, including subheadings of bacteremia, extraintestinal disease and Crohn’s disease, as well as a keyword search using “C. difficile bacteremia.” Titles and abstracts of potentially relevant articles were reviewed by a single author.\n\nCase Report\nWe describe the case of a 50-year-old white male with small bowel Crohn’s disease initially admitted with nausea and abdominal distention secondary to a small bowel obstruction. The patient has a 30 year history of Crohn’s disease involving the jejunum and terminal ileum with multiple proximal small bowel strictures. He has had an appendectomy and back surgery in the past but was never treated surgically for his Crohn’s disease. He was on maintenance therapy with Azulfidine and Azathioprine. The patient was started on Infliximab in November 2005 after multiple admissions for small bowel obstruction. The patient was changed to Adalimumab in May 2007 for patient convenience and difficulty related to obtaining regular intravenous access. He denied any recent antibiotic use.\n\nComputerized tomography scanning on admission demonstrated a small bowel obstruction with thickened and edematous small bowel in the right lower quadrant 8–10 cm from the ileocecal valve with a small amount of ascites and no evidence of abscess. A nasogastric tube was placed for decompression and the patient was placed on solumedrol 20 mg intravenous (iv) every eight hours along with aggressive iv hydration and pain management with hydromorphone. The patient initially improved on hospital day number one. On the morning of hospital day number 2, the patient was reported to be febrile to 39.4 ºC and tachycardic. The patient was complaining of increased pain and on exam had significantly increased tenderness with absent bowel sounds. At that time, the blood culture drawn on admission was reported as growing Escherichia coli, Enterococcus fecalis and Klebsiella oxytoca. The patient was started on intravenous antibiotics (ampicillin/sulbactam and gentamicin) and taken for an emergent laparotomy. He was found to have a perforation with a free abdominal abscess and a partial small bowel obstruction of the jejunum. The patient underwent a small bowel resection with jejunojejunal anastamosis and a right hemicolectomy with ileocolonic anastamosis and ileostomy. The pathology revealed a T4N1 poorly differentiated adenocarcinoma of the jejunum. The patient did well clinically post-op however a routine blood culture drawn for fever on post-op day number one grew Clostridium difficile. The patient denied significant diarrhea. Subsequent stool studies sent for Clostridium difficile toxins A/B were negative. At that time, the patient had received four days of antibiotics. The patient was maintained on pipercillin-tazobactam. All other follow-op blood cultures were unremarkable. The patient received a total of 21 days of intravenous antibiotics (6 days of ampicillin/sulbactam and gentamicin followed by 15 days of pipercillin-tazobactam). The remainder of his post-op course was unremarkable and he made a full recovery.\n\nDiscussion\nWe report the first case of C. difficile bacteremia in a Crohn’s disease patient. There are 15 other reported cases of C. difficile bacteremia reported in the literature that are summarized in Table 1. The prevailing theory regarding the pathophysiology of C. difficile bacteremia is that the colonic wall inflammation associated with pseudomembranous colitis permits transient bacteremia to develop.\n\nThe overall mortality rate is significant, with 6 of 15 reported patients dying. In terms of the demographics, 11 of the 15 patients were male and the age range was from neonate to age 69. A high proportion (4 of the 15 patients) had an underlying malignancy. Unfortunately, C. difficile stool toxin was sent in only 7 of the patients. The stool toxin was positive in 5 out of the 7 patients. C. difficile Associated Diarrhea (CDAD) was reported in 6 out of the 7 patients. Two out of the 5 patients with positive stool toxin died. The majority of patients (10 of 15 patients) had polymicrobial bacteremia. Four of the reported cases occurred postoperatively.\n\nRecent antibiotic use was found to be a significant risk factor. Antibiotic use leads to an alteration of the intestinal microflora, leading to overgrowth of endogenous C. difficile or allowing colonization by nosocomial C. difficile. Only 12 of the case reports comment on antibiotic exposure (9 of 12 patients had antibiotic exposure). Cephalosporins were the most common class of antibiotics that these patients were exposed to.\n\nInformation on therapy is available on 11 of the patients. The activity of various drugs against C. difficile according to the Manual of Clinical Microbiology is summarized in Table 2. Among the cases reviewed, 4 were treated with metronidazole (2 of which died). The specification of oral versus intravenous therapy was incomplete. It is important to note that the two patients who died were both neutropenic leukemic patients. There were 7 patients that were treated (at least in part) with vancomycin and they all survived except one. Two of these patients were treated exclusively with oral vancomycin and they both survived. One of the patients was treated only with intravenous vancomycin and survived. There was also one patient treated with both oral and intravenous vancomycin who survived. The remaining three patients were treated with a regimen that included other antibiotics. In our case, the patient was successfully treated with pipercillin-tazobactam.\n\nC. difficile is a ubiquitous organism that can be found in the environment and exposure to the organism is common. It has been estimated that 15%–25% of adults become colonized after admission to the hospital.16 There is also growing literature to support a strong link between inflammatory bowel disease and C. difficile infection. Previous studies have demonstrated that 5%–20% of patients admitted with an IBD flare will have C. difficile infection.16 The growing literature support for the link between IBD flares and C. difficile infection along with the significant mortality associated with C. difficile bacteremia highlight the importance of this topic.\n\nIn conclusion, we find that C. difficile bacteremia is associated with a significant mortality rate. C. difficile Associated Diarrhea (CDAD) was reported in 6 out of the 15 patients. Not surprisingly, the majority of patients had recent antibiotic exposure. We found a high proportion of patients were male. We also found that the majority of patients had a polymicrobial bacteremia. Therefore, it is unclear if C. difficile is the primary pathogen. In terms of treatment, it would seem prudent to consider aggressive antibiotic therapy given the high mortality rate.\n\nNo Financial Disclosure\n\nBacteremia Due to Clostridium difficile: Case Report and Review of the Literature. The authors report no conflicts of interest.\n\nTable 1 Previous Reported Cases of Clostridium difficile Bacteremia.\n\nReference\tSex/Age\tClinical presentation\tStool C. difficile\tOther organisms isoloated\tAntibiotic exposure\tTreatment\tOutcome\t\n#5\tM/5\tURI\tNR\tNone\tNR\tNR\tNR\t\n#6\tM/68\tCirrhotic admitted with bacteremia, ascites, and spleenic abscess\tNR\tNone\tNone\tPenicillin G\tDied\t\n#7\tM/neonate\tNecrotic small bowel with peritonitis and bacteremia\tNR\tStaphylococcus epidermedis (likely procedural contaminant)\tAmpicillin and kanamycin\tSurgery, ampicillin and kanamycin\tDied\t\n#8\tM/65\tToe gangrene with septicemia\tNegative\tBacteroides fragilis\tCefuroxime\tOral vancomycin\tSurvived\t\n#9\tF/35\tAML patient admitted with neurtopenic fever/sepsis\tPositive\tBacteroides sp, group D steptococci\tCefotaxime + Gentamicin\tMetronidazole (iv)\nOral vancomycin\tDied\t\n#9\tF/69\tALL patient admitted with neutropenic fever/sepsis\tPositive\tBacteroides sp, Escherichia coli\tMetronidazole\nAmpicillin\nCloxacillin\nCotrimazole\nGentamicin\tMetronidazole\tDied\t\n#10\tM/62\tSplenic abscess with bacteremia\tNR\tPseudomonnas paucimobilis (spleen only)\tPipercillin\nNetilmycin\tMetronidazole\nCefoxitin\tSurvived\t\n#11\tM/39\tOropharyngeal cancer patient admitted with mandible radionecrosis\tPositive\tEscherichia coli\nEnterococcus fecalis\nBacteroides vulgatos\tNone\tMetronidazole (iv)\nVancomycin(iv)\nPefloxacin\tSurvived\t\n#1\tF/85\tNosocomial C. diff. colitis complicated by bacteremia\tPositive\tEnterococcus fecalis\tTicacillin/Clavulanic acid\tVancomycin(iv)\nGentamcin\tSurvived\t\n#12\tM/17\tDuchenne musculai dystrophy patient admitted with partial small bowel obstructionr\tNR\tCandida Parapsilosis\tNR\tNR\tSurvived\t\n#12\tF/33\tCervical cancer patient admitted with pelvic abscess and rectovaginal fistula after radiation\tNR\tClostridium cadaveris\nBacteroides melaninogenicus\tNR\tNR\tDied\t\n#12\tM/77\tPerforated sigmoid diverticulum\tNR\tEubacterium lentum\tNR\tNR\tDied\t\n#13\tM/3\tTonsilitis followed by pericarditis and diarrhea\tNR\tNone\tAmoxicillin/Clavulonic acid, Cefixime\tVancomycin (iv)\nSurvived\t\t\n#14\tM/18\tAbdominal pain and diarrhea after course of antibiotics for exudative sore throat\tPositive\tNone\tErythromycin\tOral Vancomycin\tSurvived\t\n#14\tM/78\tAdmitted after trauma, treatment for aspiration pneumonia complicated by C. difficile bacteremia\tNegative\tNone\tCefuroxime\nAmikacin\tVancomycin (oral and iv)\tSurvived\t\nNotes: URI, upper respiratory infection; NR, not reported; AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; IV, intravenous.\n\nTable 2 Activity of various drugs against C. difficile.\n\nAntimicrobial agent\tCLSI MIC breakpoint (μg/ml)\tC. difficile % susceptibility\t\n\n\t\nSusceptible\tIntermediate\t\nAmpicillin\t0.5\t1\t26%\t\nAmoxicillin-clavulanate\t4/2\t8/4\t100%\t\nPipercillin-tazobactam\t32/4\t64/4\t100%\t\nTicarcillin\t32\t64\t100%\t\nClindamycin\t2\t4\t56%\t\nVancomycin\t8\t16\t100%\t\nImipenem\t4\t8\t94%\t\nLinezolid\t2\t4\t91%\t\nMetronidazole\t8\t16\t100%\t\nTrimethoprim-sulfamethoxazole\t32\t64\t26%\t\nTrovfloxacin\t2\t4\t86%\t\nClinical and Laboratory Standards Institute (CLSI) approved method M11-A6(50a); data from Wadsworth Anaerobic Bacteriology. Johnson EA, Summanon P, Finegold SM. Manual of Clinical Microbiology, 9th ed. 2007; 904–905.\n==== Refs\nReferences\n1 Feldman R Kallich M Weinstein M Bacteremia Due to Clostridium difficile : Case Report and Review of Extrintestinal C. difficile infections Clinical Infectious Disease 1995 20 1560 2 \n2 Jacobs A Barnard K Fishel R Gradon J Extracolonic Manifestations of Clostridium difficile Infections Medicine 2001 80 88 101 11307591 \n3 Hall IC O’Toole E Intestinal Flora in Newborn Infants with a description of a new pathogenic anaerobe, Bacillus difficilus Am J Dis Child 1935 49 390 402 \n4 Johnson S Gerding DN Janoff EN Systemic and Mucosal Antibody Responses to Toxin A in patients infected with C. difficile J Infect Dis 1992 166 1287 94 1431247 \n5 Smith LD King EO Occurrence of Clostridium difficile infections of man J Bacteriology 1962 84 65 7 \n6 Saginur R Fogel R Begin L Spleenic Abscess due to Clostridium difficile J infect Dis 1983 147 1105 6854068 \n7 Genta VM Gilligan PH McCarthy LR Clostridium difficile peritonitis in a neonate Arch Pathol Lab Med 1984 108 82 3 6546347 \n8 Spencer RC Courtney SP Nichol CD Polymicrobial Septicemia due to Clostridium difficile and Bacteroides fragilis BMJ 1984 289 531 2 6432176 \n9 Rampling A Warren RE Bevan PC Hoggarth CE Swirsky D Hayhoe FG Clostridium difficile in haematological Malignancy J Clin Pathol 1985 38 445 51 3857233 \n10 Studemeister AE Beilke MA Kirmani N Splenic Abscess due to Clostridium difficile and Pseudomonnas paucimobilis Am J Gastroenterol 1987 82 389 90 3565349 \n11 Gerard M Defresne N Van der Auwera P Meunier F Polymicrobial Septicemia with Clostridium difficile in acute diverticulitis Eur J Clin Microbiol Infect Dis 1989 300 02 2497002 \n12 Wolf LE Sherwood GL Granowitz EV Extraintestinal Clostridium difficile : 10 Years Experience at a tertiary-care Hospital Mayo Clin Proc 1998 73 943 47 9787741 \n13 Cid A Juncal AR Aguilera A Regueiro BJ Clostridium difficile bacteremia in an immunocompetent child [letter] J Clin Microbiol 1998 36 1167 68 9542965 \n14 Byl B Jacobs F Struelens MJ Thys JP Extraintestinal Clostridium difficile infections Clin Infect Dis 1996 22 712 8729213 \n15 Johnson EA Summanon P Finegold SM Manual of Clinical Microbilogy 2007 9th ed 904 5 \n16 Michelassi F Taschieri A Tonelli F An international, multicenter, prospective, observational study of the side-to-side isoperistaltic strictureplasty in Crohn’s disease Dis Col Rectum 2007 50 277 84\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1178-6450",
"issue": "2()",
"journal": "Clinical medicine. Case reports",
"keywords": "Clostridium difficile; Crohn’s disease; bacteremia",
"medline_ta": "Clin Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101515695",
"other_id": null,
"pages": "5-9",
"pmc": null,
"pmid": "24179365",
"pubdate": "2009",
"publication_types": "D002363:Case Reports",
"references": "8729213;17245614;9787741;3857233;7548512;6432176;2497002;13914327;1431247;11307591;6546347;9542965;6854068;3565349",
"title": "Bacteremia due to clostridium difficile: case report and review of the literature.",
"title_normalized": "bacteremia due to clostridium difficile case report and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-2017185823",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"drug... |
{
"abstract": "Japanese encephalitis (JE) virus is estimated to result in 3500-50,000 clinical cases every year, with mortality rates of up to 20-50% and a high percentage of neurological sequelae in survivors. Vaccination is the single most important measure in preventing this disease. Inactivated Vero cell culture-derived JE vaccines have not been linked to any fatalities, and few serious adverse events after vaccination have been reported. Here, we report a case of sudden death in which a 10-year-old boy experienced cardiopulmonary arrest 5 min after receiving a Japanese encephalitis vaccination. He had been receiving psychotropic drugs for the treatment of pervasive developmental disorders. Postmortem examinations were nonspecific, and no signs of dermatologic or mucosal lesions or an elevation of the serum tryptase level, which are characteristic of anaphylaxis, were observed. A toxicological examination revealed that the blood concentrations of the orally administered psychotropic drugs were within the therapeutic ranges. The patient was considered to have died of an arrhythmia that was not directly associated with the vaccination.",
"affiliations": "Department of Legal Medicine, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan. Electronic address: bunaiy@gifu-u.ac.jp.;Department of Legal Medicine and Bioethics, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan.;Department of Legal Medicine, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan.;Department of Legal Medicine, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan.;Department of Legal Medicine, University of Toyama, School of Medicine, Toyama 930-0194, Japan.;Department of Pediatrics, Shimane University, School of Medicine, Izumo 693-8501, Japan.",
"authors": "Bunai|Yasuo|Y|;Ishii|Akira|A|;Akaza|Kayoko|K|;Nagai|Atsushi|A|;Nishida|Naoki|N|;Yamaguchi|Seiji|S|",
"chemical_list": "D022321:Japanese Encephalitis Vaccines; D011619:Psychotropic Drugs; C116917:acylcarnitine; D002097:C-Reactive Protein; D002331:Carnitine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6223",
"issue": "17(4)",
"journal": "Legal medicine (Tokyo, Japan)",
"keywords": "Adverse effects; Fatal arrhythmia; Japanese encephalitis vaccine; Psychotropic drugs; Sudden death; Vasovagal syncope",
"medline_ta": "Leg Med (Tokyo)",
"mesh_terms": "D000707:Anaphylaxis; D001145:Arrhythmias, Cardiac; D001344:Autopsy; D002097:C-Reactive Protein; D002331:Carnitine; D002423:Cause of Death; D002648:Child; D003645:Death, Sudden; D004672:Encephalitis, Japanese; D017809:Fatal Outcome; D006323:Heart Arrest; D006801:Humans; D022321:Japanese Encephalitis Vaccines; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D011619:Psychotropic Drugs; D053719:Tandem Mass Spectrometry; D035501:Uncertainty",
"nlm_unique_id": "100889186",
"other_id": null,
"pages": "279-82",
"pmc": null,
"pmid": "25819538",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of sudden death after Japanese encephalitis vaccination.",
"title_normalized": "a case of sudden death after japanese encephalitis vaccination"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2015-02348",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PIMOZIDE"
},
"drugadditional"... |
{
"abstract": "A case of severe action myoclonus after pulmonary arrest is described. Although there was benefit from oral pharmacotherapy, action myoclonus remained disabling. A favorable response to baclofen during an intrathecal trial led to eventual placement of an intrathecal baclofen pump. The present case illustrates the potential utility of intrathecal baclofen for treating this condition.\n\n\n\nV.",
"affiliations": "VA Medical Center, 178 Smyth Road, Manchester, NH 03104.;VA Medical Center, 178 Smyth Road, Manchester, NH 03104.",
"authors": "Whitlock|James A|JA|;Dumigan|Ryan W|RW|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.pmrj.2017.12.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1934-1482",
"issue": "10(8)",
"journal": "PM & R : the journal of injury, function, and rehabilitation",
"keywords": null,
"medline_ta": "PM R",
"mesh_terms": "D001418:Baclofen; D020520:Brain Infarction; D006323:Heart Arrest; D006801:Humans; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central; D009207:Myoclonus",
"nlm_unique_id": "101491319",
"other_id": null,
"pages": "870-872",
"pmc": null,
"pmid": "29366919",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of Postanoxic Action Myoclonus With Intrathecal Baclofen: A Case Report.",
"title_normalized": "treatment of postanoxic action myoclonus with intrathecal baclofen a case report"
} | [
{
"companynumb": "US-APOTEX-2018AP019174",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZONISAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (n = 20), teriparatide (n = 8), zoledronate (n = 8) or teriparatide/denosumab combination (n = 3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response.",
"affiliations": "Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece. Electronic address: a.anastasilakis@gmail.com.;First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Department of Endocrinology and Diabetes and Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece.;Laboratory for the Research of Musculoskeletal System \"Th. Garofalidis\", Medical School, National and Kapodistrian University of Athens, KAT Hospital, Athens, Greece.;Endocrinology Unit, 1st Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Laboratory for the Research of Musculoskeletal System \"Th. Garofalidis\", Medical School, National and Kapodistrian University of Athens, KAT Hospital, Athens, Greece.",
"authors": "Anastasilakis|Athanasios D|AD|;Polyzos|Stergios A|SA|;Makras|Polyzois|P|;Trovas|Georgios|G|;Yavropoulou|Maria P|MP|;Tournis|Symeon|S|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019379:Teriparatide; D000069448:Denosumab; D000077211:Zoledronic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jocd.2021.01.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1094-6950",
"issue": "24(4)",
"journal": "Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry",
"keywords": "Denosumab; discontinuation; fracture; osteoporosis; rebound; turnover",
"medline_ta": "J Clin Densitom",
"mesh_terms": "D015519:Bone Density; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005260:Female; D006115:Greece; D006801:Humans; D015663:Osteoporosis, Postmenopausal; D058866:Osteoporotic Fractures; D017698:Postmenopause; D012189:Retrospective Studies; D019379:Teriparatide; D000077211:Zoledronic Acid",
"nlm_unique_id": "9808212",
"other_id": null,
"pages": "591-596",
"pmc": null,
"pmid": "33541775",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Efficacy of Antiosteoporotic Medications in Patients With Rebound-Associated Fractures After Denosumab Discontinuation.",
"title_normalized": "efficacy of antiosteoporotic medications in patients with rebound associated fractures after denosumab discontinuation"
} | [
{
"companynumb": "GR-PFIZER INC-202101653295",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "Meningitis is a very uncommon complication of spinal anesthesia, and drug-induced aseptic meningitis (DIAM) is even rarer. We present two cases of DIAM following spinal anesthesia with bupivacaine and ropivacaine, respectively. The patients presented shortly after the procedure with typical meningitis symptoms. Since CSF (cerebrospinal fluid) analysis could not initially exclude bacterial meningitis, they were started on empirical antibiotics. CSF was subsequently found to be negative for viruses and bacteria in both cases, and antibiotics were promptly stopped. Both patients improved rapidly and without neurological sequelae. While it remains a diagnosis of exclusion, it is important to be aware of DIAM as recognition of the condition can lead to shorter admission times and avoid unnecessary use of antibiotics.\nA diagnosis of DIAM should be considered when a patient who recently underwent spinal anesthesia is admitted with symptoms and CSF compatible with meningitis.Clinical and laboratory findings (including CSF analysis) cannot distinguish between bacterial meningitis and DIAM.A negative CSF culture and rapid recovery confirm the diagnosis and stopping antibiotics at this point is effective.",
"affiliations": "Serviço de Medicina IV, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Serviço de Medicina IV, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, EPE Clínica Universitária de Pediatria, Faculdade de Medicina, Universidade de Lisboa. Lisboa, Portugal.;Serviço de Medicina IV, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Serviço de Medicina IV, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Serviço de Medicina IV, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.",
"authors": "Oliveira|Ricardo Paquete|RP|;Teixeira|Mafalda|M|;Cochito|Sofia|S|;Furtado|Ana|A|;Grima|Bruno|B|;Alves|José Delgado|JD|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2019_001334",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0013341334-1-10727-1-10-20191220ArticlesDrug-Induced Aseptic Meningitis Following Spinal Anesthesia Oliveira Ricardo Paquete 1Teixeira Mafalda 1Cochito Sofia 2Furtado Ana 1Grima Bruno 1Alves José Delgado 1\n1 Serviço de Medicina IV, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal\n2 Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, EPE Clínica Universitária de Pediatria, Faculdade de Medicina, Universidade de Lisboa. Lisboa, Portugal2020 31 12 2019 7 1 00133415 10 2019 23 10 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseMeningitis is a very uncommon complication of spinal anesthesia, and drug-induced aseptic meningitis (DIAM) is even rarer. We present two cases of DIAM following spinal anesthesia with bupivacaine and ropivacaine, respectively. The patients presented shortly after the procedure with typical meningitis symptoms. Since CSF (cerebrospinal fluid) analysis could not initially exclude bacterial meningitis, they were started on empirical antibiotics. CSF was subsequently found to be negative for viruses and bacteria in both cases, and antibiotics were promptly stopped. Both patients improved rapidly and without neurological sequelae. While it remains a diagnosis of exclusion, it is important to be aware of DIAM as recognition of the condition can lead to shorter admission times and avoid unnecessary use of antibiotics.\n\nLEARNING POINTS\nA diagnosis of DIAM should be considered when a patient who recently underwent spinal anesthesia is admitted with symptoms and CSF compatible with meningitis.\n\nClinical and laboratory findings (including CSF analysis) cannot distinguish between bacterial meningitis and DIAM.\n\nA negative CSF culture and rapid recovery confirm the diagnosis and stopping antibiotics at this point is effective.\n\nAseptic meningitisdrug-induced aseptic meningitisropivacainebupivacaine\n==== Body\nCASE 1\nA healthy 44-year-old woman was submitted to ankle arthroplasty under spinal anesthesia (bupivacaine and sufentanyl). There were no breaches in the aseptic precautions, and no anesthetic or surgical complications, and the patient was discharged. One day later she developed an occipital headache with sono and photophobia, vomiting and fever (38ºC). On admission, both physical and neurological examinations were normal, except for neck stiffness.\n\nLaboratory tests were remarkable only for leukocytosis (17900/mm3) and elevated C-reactive protein (CRP) (9.9 mg/dL). A brain computerized tomography (CT) scan was normal. CSF examination showed increased cell count (1116/mm3 with polymorphonuclear predominance) and hyperproteinorrachia (236 mg/dL) with hypoglycorrhachia (32 mg/dL).\n\nPrior to the microbiology results, a provisional diagnosis of bacterial meningitis was made and the patient was started on empirical antibiotherapy (ceftriaxone and vancomycin). Subsequently, blood, CSF and urine cultures revealed no bacteria and CSF virus panel (Polymerase chain reaction [PCR] for varicella-voster, herpes simplex, Ebstein-Barr and cytomegalovirus) was negative.\n\nThere was a rapid and complete clinical improvement in 48 hours. Antibiotics were stopped in less than 72h. The patient was discharged without neurological deficits on day 6.\n\nCASE 2\nA 34-year-old woman was admitted five days after giving birth through vaginal delivery under spinal anesthesia (ropivacaine and fentanyl). She complained of intense low back pain, bifrontal headache and low-grade fever starting on delivery day. On admission she had fever (38.6ºC), neck stiffness and Kernig’s sign. The rest of the neurological examination was normal. Observation by the gynecology department showed no signs of postpartum complications.\n\nLaboratory tests were normal apart from leukocytosis (13500/mm3; 85% neutrophils) and elevated CRP (7.4 mg/dL). CSF examination, performed after a traumatic first attempt, showed bloody fluid (invalidating the cell count), hyperproteinorrachia (104.6 mg/dL) and normal glucose (42 mg/dL), with a negative virus PCR panel. Brain CT scan was normal.\n\nPrior to the culture results, the patient was treated empirically for infectious meningitis with IV ceftriaxone, vancomycin and acyclovir.\n\nThe patient showed a rapid clinical recovery (in 48 hours). The lab inflammatory markers steadily decreased back to normal. Acyclovir was stopped by day 3 (after a negative CSF virus panel) and antibiotics were stopped by day 5 (after negative blood and CSF cultures). Indeed, on day 3, CSF analysis was repeated and showed 579/mm3 cells (with polymorphonuclear predominance), 154 mg/dL total protein and 47 mg/dL glucose. Microbiology exams were also negative. The patient was discharged asymptomatic on day 7.\n\nDISCUSSION\nMeningitis following spinal anesthesia is an extremely rare event (incidence <0.01%)[1] with potentially serious complications. As with meningitis in the general population, causes can be broadly divided into bacterial and aseptic types, the latter comprising infection by other microorganisms (viruses and some intracellular bateria), meningeal involvement in systemic diseases (autoimmune and neoplastic), and drug-induced forms. Two mechanisms have been proposed for DIAM: direct chemical irritation of the meninges as a result of intrathecal administration of the drug (anesthetics and chemotherapy); systemic immunological hypersensitivity (nonsteroidal antiinflammatory drugs, intravenous immunoglobulin and antibiotics)[2].\n\nIt is important to distinguish DIAM from bacterial meningitis, as the latter can lead to neurological sequelae and is a potentially life-threatening condition, demanding urgent treatment. Additionally, establishing an aseptic etiology early can prevent unnecessary treatment and days of hospitalization[3]. That being said, this distinction cannot be made on the basis of patients’ characteristics or clinical findings, such as headache, neck stiffness and fever[4,5]. Furthermore, CSF findings are also similar between DIAM and bacterial meningitis: pleocytosis with neutrophil predominance, hyperproteinorrachia and hypoglycorrachia are found in both forms (even though hypoglycorrachia is not always present in DIAM)[5,6]. This means that DIAM remains a diagnosis of exclusion and empirical antibiotics should be started in all cases, and continued until negative CSF cultures are obtained, at which point antibiotics can be stopped. Stopping antibiotics at this point is an effective strategy that also lowers costs and, potentially, antibiotic resistance[5].\n\nIn the cases presented, antibiotics were stopped early on, and both followed a typical DIAM course, with rapid clinical recovery and lowering of inflammatory markers, absence of neurological sequelae and no recurrence, substantiating the diagnosis. While some authors have suggested that some previous reports of DIAM could have been viral meningitis[6], it is important to note that in both these cases the most frequent viral agents were excluded using PCR techniques.\n\nIn both our patients, we diagnosed aseptic meningitis provoked by the anesthetic used in spinal anesthesia, with bupivacaine being the culprit in the first case, and ropivacaine in the second. Both drugs belong to the amino amide class of regional anesthetics[7]. Bupivacaine may provoke adverse neurological effects (dizziness, altered vision, etc.), but these effects are rare when it is administered correctly. Ropivacaine is a newer drug that shows better sensorimotor dissociation at lower doses and shorter action. While previous bupivacaine-induced aseptic meningitis cases have been reported[6,8] we have found only an isolated incident reported with ropivacaine[6]. While the summaries of the product characteristics for both drugs mention central nervous system adverse effects (ranging from anxiety to seizures), there is no mention of DIAM as a possible complication. In both the incidents described herein, the medical team discussed the case with the anesthesiology department in order to determine the anesthetics used, which was fundamental to the diagnosis.\n\nCONCLUSIONS\nAlthough very rare, meningitis is a possible complication of spinal anesthesia and the possibility of DIAM should always be borne in mind. In the cases presented, the diagnosis of DIAM was based on a high level of suspicion. These cases highlight the need to review drugs recently administered to patients. Only negative CSF definitively confirmed the diagnosis, allowing for a quick withdrawal of the antibiotics, shorter hospital stays and lower costs. Both patients had a fast and complete recovery. To our knowledge this is the first time ropivacaine-induced aseptic meningitis has been described in detail.\n\nConflicts of Interests: The Authors declare that there are no competing interest\n==== Refs\nREFERENCES\n1 Videira R Ruiz-Neto P Brandao Neto M Post spinal meningitis and asepsis Acta Anaesthesiol Scanda 2002 46 639 646 \n2 Jolles S Sewell W Leighton C Drug-induced aseptic meningitis: diagnosis and management Drug Saf 2000 22 215 226 10738845 \n3 Dubos F Lamotte B Bibi-Triki F Moulin F Raymond J Gendrel D Clinical decision rules to distinguish between bacterial and aseptic meningitis Arch Dis Child 2006 91 647 650 16595647 \n4 Moris G Garcia-Monco J The challenge of drug-Induced aseptic meningitis Arch Intern Med 1999 159 1185 1194 10371226 \n5 Zarrouk V Vassor I Bert F Bouccara D Kalamarides M Bendersky N Evaluation of the management of postoperative aseptic meningitis Clin Infect Dis 2007 44 1555 1559 17516398 \n6 Bihan K Weiss N Théophile H Funck-Brentano C Lebrun-Vignes B Drug-induced aseptic meningitis: 329 cases from the French pharmacovigilance database analysis Br J Clin Pharmacol 2019 85 240 246 30328132 \n7 Ruetsch Y Boni T Borgeat A From cocaine to ropivacaine: the history of local anesthetic drugs Curr Top Med Chem 2001 1 175 182 11895133 \n8 Tateno F Sakakibara R Kishi M Ogawa E Bupivacaine-induced chemical meningitis J Neurol 2010 257 1327 1329 20306069\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "7(1)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Aseptic meningitis; bupivacaine; drug-induced aseptic meningitis; ropivacaine",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001334",
"pmc": null,
"pmid": "32015967",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "16595647;31318079;11895133;10371226;10738845;20306069;17516398;12059885",
"title": "Drug-Induced Aseptic Meningitis Following Spinal Anesthesia.",
"title_normalized": "drug induced aseptic meningitis following spinal anesthesia"
} | [
{
"companynumb": "PT-FRESENIUS KABI-FK202006884",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROPIVACAINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 56-year-old man presented with massive right haemothorax 10 days following percutaneous nephrolithotomy (PCNL) for complex, large-bulk, right renal stones. Antiplatelet medication started following coronary stenting 7 months ago was stopped 5 days prior and resumed 2 days following surgery. Stones were cleared through two tracts, one supracostal, with placement of ureteral stent but no nephrostomy. He was discharged the next day with an unremarkable chest X-ray. He developed cough and fever after 1 week. Three days later he presented with acute dyspnoea, blood pressure of 100/60 mm Hg, pulse of 120/min and haemoglobin of 9.0 g/dL. Chest X-ray and CT scan showed a large right haemothorax. Two-litre haemothorax was drained by intercostal drainage with prompt recovery. Haemothorax is a rare complication following PCNL usually after supracostal access. Most occur at or immediately following surgery. Infection and early resumption of antiplatelet medication might have contributed to his presentation with delayed secondary haemorrhage from a pleural injury.",
"affiliations": "Urology, Apollo Hospitals, Hyderabad, Telangana, India.;Surgery, Apollo Hospitals, Hyderabad, Telangana, India.;Pulmonology, Apollo Hospitals, Hyderabad, Telangana, India.",
"authors": "Sinha|Sanjay|S|;Babu|Ramesh G|RG|;Rao|Mallikarjun S|MS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222953",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "respiratory medicine; respiratory system; urological surgery; urology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D006491:Hemothorax; D006801:Humans; D007669:Kidney Calculi; D008297:Male; D008875:Middle Aged; D000074642:Nephrolithotomy, Percutaneous; D019106:Postoperative Hemorrhage; D013997:Time Factors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29184010",
"pubdate": "2017-11-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14665341;22090044;24859439;27579431;23260552;19538762;20450501",
"title": "Delayed massive haemothorax 10 days following percutaneous nephrolithotomy.",
"title_normalized": "delayed massive haemothorax 10 days following percutaneous nephrolithotomy"
} | [
{
"companynumb": "IN-SCIEGEN PHARMACEUTICALS INC-2018SCILIT00041",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditio... |
{
"abstract": "A 28-year-old woman was admitted in a comatose state following ingestion of 5 g of amitriptyline. On arrival, there was intermittent seizure activity and a broad complex tachycardia on the ECG. Immediate resuscitation included 8 mg lorazepam, 2 L crystalloid fluid, 100 mL 8.4% sodium bicarbonate, 2 g of magnesium sulphate and lipid emulsion infusion. Despite this, the broad complex tachycardia persisted with haemodynamic instability. The case was discussed with the National Poisons Information Service, which advised further 8.4% sodium bicarbonate to achieve serum alkalinisation. Following this, the QRS duration reduced and haemodynamic stability was achieved. Serum alkalinisation continued in the intensive treatment unit before the patient was successfully extubated on day 5 and discharged on day 7 with no neurological sequelae. To our knowledge, this case is the largest recorded overdose of amitriptyline to have survived to discharge. The importance of serum alkalinisation in the management of tricyclic antidepressant poisoning is highlighted.",
"affiliations": "Intensive Care Unit, Ealing Hospital, London, UK.;Regional Drug and Therapeutics Centre, NPIS Newcastle, Newcastle upon Tyne, UK.;Intensive Care Unit, Ealing Hospital, London, UK.;National Poisons Information Service Edinburgh, NHS Lothian, Edinburgh, UK.",
"authors": "Ramasubbu|Benjamin|B|;James|David|D|;Scurr|Andrew|A|;Sandilands|Euan A|EA|",
"chemical_list": "D000863:Antacids; D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D017693:Sodium Bicarbonate",
"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": "D000328:Adult; D000639:Amitriptyline; D000863:Antacids; D000929:Antidepressive Agents, Tricyclic; D062787:Drug Overdose; D005260:Female; D006801:Humans; D017693:Sodium Bicarbonate; D013610:Tachycardia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": "10.1136/bcr-2016-214685",
"pmc": null,
"pmid": "27068728",
"pubdate": "2016-04-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16390221;16390222;17098328;20605670;22065274;22733724;24712820;28979404;4763225;6086872;64906;7416020;8216512",
"title": "Serum alkalinisation is the cornerstone of treatment for amitriptyline poisoning.",
"title_normalized": "serum alkalinisation is the cornerstone of treatment for amitriptyline poisoning"
} | [
{
"companynumb": "GB-ACCORD-039835",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": null,
"... |
{
"abstract": "Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine.\n\n\n\nIn this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246.\n\n\n\nStudy enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference -3·0%, 95% CI -8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths.\n\n\n\nTenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia.\n\n\n\nGilead Sciences Inc.",
"affiliations": "Imperial College London, London, UK.;Kings College Hospital, London, UK.;Orlando Immunology Center, Orlando, FL, USA.;Hospital Universitari de Bellvitge, Barcelona, Spain.;Dipartimento di Scienze Mediche, Università di Torino, Turin, Italy.;Hospital Clinico San Carlos, Madrid, Spain.;Department of Infectious and Tropical Diseases and CIC 1413, INSERM, University Hospital, Nantes, France.;Ruane Medical & Liver Health Institute, Los Angeles, CA, USA.;University of Louisville, Louisville, KY, USA.;Crofoot Research Center, Houston, TX, USA.;University College Dublin, Dublin, Ireland.;University of Brescia, Brescia, Italy.;Gilead Sciences Inc, Foster City, CA, USA.;Gilead Sciences Inc, Foster City, CA, USA.;Gilead Sciences Inc, Foster City, CA, USA.;Gilead Sciences Inc, Foster City, CA, USA.;Gilead Sciences Inc, Foster City, CA, USA. Electronic address: martin.rhee@gilead.com.",
"authors": "Winston|Alan|A|;Post|Frank A|FA|;DeJesus|Edwin|E|;Podzamczer|Daniel|D|;Di Perri|Giovanni|G|;Estrada|Vicente|V|;Raffi|François|F|;Ruane|Peter|P|;Peyrani|Paula|P|;Crofoot|Gordon|G|;Mallon|Patrick W G|PWG|;Castelli|Francesco|F|;Yan|Mingjin|M|;Cox|Stephanie|S|;Das|Moupali|M|;Cheng|Andrew|A|;Rhee|Martin S|MS|",
"chemical_list": "D044966:Anti-Retroviral Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; C492871:abacavir, lamivudine drug combination; C000613801:emtricitabine tenofovir alafenamide; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2352-3018(18)30010-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3018",
"issue": "5(4)",
"journal": "The lancet. HIV",
"keywords": null,
"medline_ta": "Lancet HIV",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents; D015224:Dideoxynucleosides; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D000068698:Tenofovir; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "101645355",
"other_id": null,
"pages": "e162-e171",
"pmc": null,
"pmid": "29475804",
"pubdate": "2018-04",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D000073843:Equivalence Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, non-inferiority phase 3 trial.",
"title_normalized": "tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed hiv 1 infected adults a randomised double blind active controlled non inferiority phase 3 trial"
} | [
{
"companynumb": "GB-MYLANLABS-2018M1030134",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
},
... |
{
"abstract": "Nab-paclitaxel (nab-PTX) is a nanoparticle albumin-bound paclitaxel and, as such, is free of solvents like ethanol and polyoxyethylene castor oil. The absence of solvents from this formulation has several practical advantages: it has a shorter infusion time, it negates the need for premedications for hypersensitivity reactions, and it can be administered to patients with alcoholic hypersensitivity. It is thought that nab-paclitaxel will be in widespread use in the near future because of its convenience and efficacy. Here, we report the case of a breast cancer patient who developed hemorrhagic cystitis potentially due to treatment with nab-paclitaxel. The patient was 69-year old lady with stage IIB left breast cancer. She was due to undergo neoadjuvant chemotherapy and started weekly treatment with nab-paclitaxel. On the second day of the first cycle of treatment, she experienced symptoms of cystitis, but was not hemorrhagic and the symptoms were managed with antibiotics. After the third cycle, the symptoms of cystitis became severe, and she was diagnosed with hemorrhagic cystitis and discontinued chemotherapy with nab-paclitaxel. This is the first case report of hemorrhagic cystitis associated with nab-paclitaxel.",
"affiliations": "1Department of Breast, Thyroid and Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, Japan.;2Department of Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;3Department of Urology, Faculty of Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.;1Department of Breast, Thyroid and Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, Japan.;1Department of Breast, Thyroid and Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, Japan.;1Department of Breast, Thyroid and Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, Japan.;1Department of Breast, Thyroid and Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, Japan.;2Department of Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;2Department of Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;2Department of Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.",
"authors": "Ichioka|Emika|E|;Iguchi-Manaka|Akiko|A|;Oikawa|Takehiro|T|;Sawa|Aya|A|;Okazaki|Mai|M|;Saito|Takeshi|T|;Kiyomatsu|Hiroko|H|;Ikeda|Tatsuhiko|T|;Bando|Hiroko|H|;Hara|Hisato|H|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-016-0255-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "5(4)",
"journal": "International cancer conference journal",
"keywords": "Hemorrhagic cystitis; Locally advanced breast cancer; Nab-paclitaxel",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "187-191",
"pmc": null,
"pmid": "31149452",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "11761677;12006516;16135470;16172456;16489089;18594000;20133335;20567631;21571619;21846069;22547591;23770008;24000900;2403595;24131140;24692580;26056183;26869049;3335893;7915156",
"title": "A case of hemorrhagic cystitis caused by nab-paclitaxel.",
"title_normalized": "a case of hemorrhagic cystitis caused by nab paclitaxel"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201609129",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null... |
{
"abstract": "Despite the widespread use of meperidine as an analgesic, its potential for producing delirium has been overlooked. Six cases demonstrating meperidine-induced behavioral toxicity are reported. Toxicity was more likely when meperidine was combined with cimetidine or drugs having anticholinergic activity. Discontinuation of meperidine and substitution of morphine for analgesia were usually successful in treating the delirium. Physostigmine reversed the delirium in one patient. The authors suggest that the delirium results from the excessive anticholinergic activity of meperidine or its only active metabolite, normeperidine.",
"affiliations": null,
"authors": "Eisendrath|S J|SJ|;Goldman|B|B|;Douglas|J|J|;Dimatteo|L|L|;Van Dyke|C|C|",
"chemical_list": "D010276:Parasympatholytics; D008614:Meperidine",
"country": "United States",
"delete": false,
"doi": "10.1176/ajp.144.8.1062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-953X",
"issue": "144(8)",
"journal": "The American journal of psychiatry",
"keywords": null,
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D000328:Adult; D000368:Aged; D003693:Delirium; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008614:Meperidine; D008875:Middle Aged; D010276:Parasympatholytics",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "1062-5",
"pmc": null,
"pmid": "3605428",
"pubdate": "1987-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Meperidine-induced delirium.",
"title_normalized": "meperidine induced delirium"
} | [
{
"companynumb": "US-PFIZER INC-2020374065",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEPERIDINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "It has recently been described that alternative oncogenic drivers may be found in KRAS wild-type (KRAS WT) pancreatic cancers. This study aimed to determine the incidence of targetable gene fusions present in KRAS WT pancreatic adenocarcinoma and response to targeted therapy.\n\n\nMETHODS\nOne hundred consecutive patients with pancreatic adenocarcinoma who underwent targeted next-generation sequencing using DNA sequencing with RNA sequencing (n = 47) or without RNA sequencing (n = 53) at a single institution were included in the study. The frequency and landscape of targetable fusions in KRAS WT pancreatic adenocarcinoma was characterized and compared with the frequency of fusions in KRAS-mutated (KRAS MUT) pancreatic adenocarcinoma. Results were validated in two independent cohorts using data from AACR GENIE (n = 1,252) and TCGA (n = 150). The clinical history of fusion-positive patients who received targeted treatment is described.\n\n\nRESULTS\nPancreatic cancers from 13 of 100 patients (13%) were found to be KRAS WT. Targetable fusions were identified in 4/13 (31%) KRAS WT tumors compared with 0/87 (0%) KRAS MUT pancreatic adenocarcinomas (P = .0002). One patient with a novel MET fusion had a complete response to targeted therapy with crizotinib that is ongoing at 12+ months of treatment. In the validation cohorts, gene fusions were identified in 18/97 (19%) and 2/10 (20%) KRAS WT tumors reported in the AACR GENIE and TCGA cohorts, respectively.\n\n\nCONCLUSIONS\nOncogene fusions are present in KRAS WT pancreatic adenocarcinomas at an increased frequency when compared with KRAS MUT pancreatic adenocarcinomas. As these fusions may be susceptible to targeted therapy, molecular analyses for the detection of fusions in KRAS WT pancreatic adenocarcinomas may warrant increased consideration.",
"affiliations": "Department of Individualized Cancer Management Section of Precision Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL.;Department of Individualized Cancer Management Section of Precision Oncology, Moffitt Cancer Center, Tampa, FL.;Geriatric Oncology Consortium, Tampa, FL.;Department of Individualized Cancer Management Section of Precision Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Senior Adult Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Individualized Cancer Management Section of Precision Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL.",
"authors": "Fusco|Michael J|MJ|;Saeed-Vafa|Daryoush|D|;Carballido|Estrella M|EM|;Boyle|Theresa A|TA|;Malafa|Mokenge|M|;Blue|Kirsten L|KL|;Teer|Jamie K|JK|;Walko|Christine M|CM|;McLeod|Howard L|HL|;Hicks|J Kevin|JK|;Extermann|Martine|M|;Fleming|Jason B|JB|;Knepper|Todd C|TC|;Kim|Dae Won|DW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/PO.20.00265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-4284",
"issue": "5()",
"journal": "JCO precision oncology",
"keywords": null,
"medline_ta": "JCO Precis Oncol",
"mesh_terms": null,
"nlm_unique_id": "101705370",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34250383",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "30835257;32213540;28572459;31196931;28754816;29674709;29903880;27748748;29367431;24265351;31375766;31976786;31028088;29102694;32135080;30745300;24142049;29284707;31605106;21969517;24122810;28476735;22374460;21561347;31912902;28502724;31068372;28179575;32203698;28235761;28667006;22588877;31007851;30857956;23558953;31157963;15710605;32495162;28810144;28297679;22124482;23550210;29802158;30836094;28806393;29527595",
"title": "Identification of Targetable Gene Fusions and Structural Rearrangements to Foster Precision Medicine in KRAS Wild-Type Pancreatic Cancer.",
"title_normalized": "identification of targetable gene fusions and structural rearrangements to foster precision medicine in kras wild type pancreatic cancer"
} | [
{
"companynumb": "US-MYLANLABS-2022M1034059",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": null,
... |
{
"abstract": "A 65-year-old woman with type II diabetes mellitus complicated by non-healing ulcers with recurrent osteomyelitis was admitted for progression of cellulitis after treatment failure with an outpatient course of amoxicillin-clavulanate. She was found to have persistent osteomyelitis and started on ceftazidime for a culture documented Pseudomonas aeruginosa infection. After two parenteral doses, she had a rapid rise in liver function tests (LFTs) in a hepatocellular pattern. Due to rapid identification, all medications with potential hepatotoxicity, including ceftazidime, were discontinued and the LFTs promptly returned to baseline over 3 days. Of note, the patient did not experience any symptoms of liver injury. Other causes of acute liver injury were effectively ruled out, but the case was confounded by usage of other potential hepatotoxic medications. Still, the most likely culprit was ceftazidime, a rare cause of drug induced liver injury with very few reports in the literature.",
"affiliations": "Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA tayyab.shah@yale.edu.;Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.;Internal Medicine/ Section of Geriatrics, Yale School of Medicine, New Haven, Connecticut, USA.",
"authors": "Shah|Tayyab|T|;Joslyn|James A|JA|;Lai|James|J|",
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"doi": "10.1136/bcr-2021-246571",
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"issn_linking": "1757-790X",
"issue": "14(12)",
"journal": "BMJ case reports",
"keywords": "gastrointestinal system; unwanted effects / adverse reactions",
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"pmid": "34887294",
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"publication_types": "D016428:Journal Article",
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"title": "Ceftazidime induced liver injury.",
"title_normalized": "ceftazidime induced liver injury"
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"abstract": "We present a 37-year-old lady who had liver transplantation for hepatitis B cirrhosis and was on immune suppressive treatment consisting of mycophenolate mofetil (MMF) and tacrolimus. She presented with undue fatigue and recurring pain in both arms. The diagnosis of Takayasu's arteritis was made, supported by angiographic findings of significant stenosis of the left subclavian and both renal arteries. She was managed by adjusting the immune suppressive medications and underwent a successful percutaneous transluminal balloon angioplasty (PTBA).",
"affiliations": "Department of Medicine, Rheumatology, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia.",
"authors": "Alokaily|Fahdah|F|;Bzeizi|Khalid|K|;Al-Nori|Rawad|R|;Alqahtani|Salem|S|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus",
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"fulltext": "\n==== Front\nSaudi J GastroenterolSaudi J GastroenterolSJGSaudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association1319-37671998-4049Medknow Publications & Media Pvt Ltd India 26458863SJG-21-33710.4103/1319-3767.166201Case ReportTakayasu's Arteritis and Liver Transplantation: Association and Implications Alokaily Fahdah 1Bzeizi Khalid 2Al-Nori Rawad 1Alqahtani Salem 1Department of Medicine, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia1 Department of Rheumatology, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia2 Department of Hepatology, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi ArabiaAddress for correspondence: Dr. Fahdah Alokaily, Department of Medicine, Division of Rheumatology, Prince Sultan Military Medical City, PO Box 7897, Riyadh - 11159, Kingdom of Saudi Arabia. E-mail: alokaily@yahoo.comSep-Oct 2015 21 5 337 340 16 4 2015 06 6 2015 Copyright: © 2015 Saudi Journal of Gastroenterology2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.We present a 37-year-old lady who had liver transplantation for hepatitis B cirrhosis and was on immune suppressive treatment consisting of mycophenolate mofetil (MMF) and tacrolimus. She presented with undue fatigue and recurring pain in both arms. The diagnosis of Takayasu's arteritis was made, supported by angiographic findings of significant stenosis of the left subclavian and both renal arteries. She was managed by adjusting the immune suppressive medications and underwent a successful percutaneous transluminal balloon angioplasty (PTBA).\n\nAngioplastyimmunosuppressionliver transplantTakayasu's arteritisvasculitis\n==== Body\nTakayasu's arteritis (TA) is a form of large vessel granulomatous vasculitis that affects the aorta and its major branches (pulseless disease). TA is a relatively rare disease characterized by chronic inflammatory vasculitic changes of the aorta and its major branches. It usually affects women under 40 years of age, particularly of Asian descent, and it may present as an acute and/or chronic illness. Fever, arthralgia, and skin rashes are the common manifestations during the acute phase of the disease. The significant complications that appear during the chronic phase include limb claudication due to subclavian artery stenosis and systemic hypertension secondary to renal artery stenosis. The disease can also lead to cerebral, coronary, or mesenteric ischemia with devastating effects.[12]\n\nMagnetic resonance angiography (MRA) and computed tomography (CT) angiography are widely used to diagnose TA; however, the gold standard test is angiography.[2]\n\nTA may precede or appear in patients with existing autoimmune disorders. There have been numerous reports of its association with Crohn's disease, sarcoidosis, spondyloarthropathies, and systemic lupus erythematosus (SLE). The role of autoimmunity in TA, however, is yet to be determined.\n\nTo our knowledge, this is the first reported case of TA post liver transplantation in the English literature.\n\nCASE REPORT\nWe present a case of 38-year-old female patient who underwent liver transplant in July 2001 for decompensated hepatitis B cirrhosis. The patient was followed up in the Transplant Clinic at Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia. She is currently on mycophenolate mofetil (MMF) 1 g twice daily, prednisolone 5 mg once daily, tacrolimus 1.5 mg twice daily, lamivudine 100 mg once daily, and immunoglobulin and hepatitis B human Immunoglobuline injection 400 U given intramuscularly (IM) once a month. She was initially treated with cyclosporin, hepatitis B virus immunoglobulin, and lamivudine to prevent recurrence of hepatitis B virus. Her immunosuppressive treatment was modified by replacing ciclosporin with tacrolimus, following an episode of acute graft rejection in 2007. MMF was added following the second episode of rejection that was confirmed histologically in June 2011. Her liver function tests have normalized.\n\nShe was also diagnosed to have hypertension in 2008 and was treated with amlodipine 5 mg and enalapril 5 mg. It was later changed to valsartan 160 mg once daily.\n\nShe gradually developed pain and claudication in both hands and arms in the last 3 years. She has a history of fatigue and headache, but no weight loss, fever, or rashes. Cardiovascular evaluation showed loss of radial and brachial pulses in the left upper limb. The lower limb pulses were normal. Blood pressure was 165/79 mmHg in the left upper limb and 115/60 mmHg in the right upper limb, and there was a bruit over the right subclavian artery. Abdominal examination showed Mercedes scar with no organomegaly. Respiratory and neurological examinations were unremarkable. A psychiatric evaluation was also satisfactory.\n\nHematological examination revealed normal complete blood count: WBC, Haemoglobin, and platelets. Serum electrolytes were normal. Other findings were: Urea 8.2 (2.0–6.7) mmol/l, creatinine 94 (87–108) mmol/l, gamma-glutamyl transpeptidase (GGT) 301 (7–32) U/l, total bilirubin 7 (2–22) mmol/l, albumin 43 g/l, alkaline phosphatase 104 U/l, alanine transaminase 52 (2–40) U/l, and FK-506 7.5 (4.0–20) μg/l. Erythrocyte sedimentation rate (ESR) was normal, extractable nuclear antigens was negative, dsDNA was negative, anti-nuclear antibody was 1/80, and C-reactive protein (CRP) level was 1 mg/l. Echocardiography showed normal ventricular function, normal aortic arch, normal valves, and no cortication. Chest radiography and ECG were both normal.\n\nThe patient had magnetic resonance imaging (MRI) [Figure 1] which demonstrated smooth narrowing of the short segment of the right subclavian artery by 30%, where it crosses between the first right rib and the right clavicle. The origin of the proximal left subclavian artery with marked stenosis of 99% was not visualized. In addition, there was bilateral renal artery stenosis of approximately 50% on the right side [Figure 2], but was not significant on the left side. The patient was diagnosed to have TA based on American College of Rheumatology (ACR) criteria 1990, since she met all the criteria. She received prednisolone 60 mg/day (increased from 10 mg/day), which was gradually tapered after 1 month. The dosage of cellcept was doubled to 1 g twice daily and the tacrolimus level was titerated to maintain a trough level of 5 ng/ml.\n\nFigure 1 MRA showing 99% stenosis of the left subclavian artery and 30% stenosis on the right side (arrows)\n\nFigure 2 Right renal artery with 50% stenosis\n\nShe underwent balloon angioplasty for the left subclavian artery, which resulted in excellent recanalization [Figure 3]. She also underwent balloon angioplasty of the right renal artery, which also resulted in good recanalization [Figure 4].\n\nFigure 3 Angiography showing left subclavian recanalization\n\nFigure 4 Right renal artery post-ballooning with good response\n\nIn addition to the angiographic recanalization of the stenotic lesions, the steroid dose was increased to 60 mg daily that was tapered after 1 month.\n\nDISCUSSION\nTA is a chronic inflammatory disease that affects aorta and its major branches. The exact etiology is unknown. The diagnosis is made clinically according to the ACR1990 criteria to diagnose TA, which depends on the presence of at least three criteria of the following six criteria: 1. age of onset less than 40; 2. claudication of extremities; 3. absence of brachial pulse; 4. blood pressure difference of 10 mmHg between the two arms; 5. bruit over the subclavian artery; and 6. abnormal angiogram. Our patient showed all these criteria. Autoantibodies against aortic endothelial cells were found to have a role in its pathogenesis.[1] In another study, TA patients demonstrated CD36 deficiency (CD36d). The human CD36 antigen is a multifunctional membrane glycoprotein that belongs to the class B scavenger receptor family. It is expressed on monocytes, platelets, and endothelial cells, and contributes to myocardial fatty acid transport. In patients with CD36d, myocardial I-15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid (BMIPP) uptake was absent.[3]\n\nHuman leukocyte antigen (HLA) associations have also been identified, of which the frequently reported were HLA-A10, B5, Bw52, DR2, DR4, B21, and B22. Many of these, however, remain unconfirmed and are variable across different ethnic groups.[3] HLA typing was not performed in this patient. It is our understanding that it was not required for the diagnosis. Also, there is no evidence that it has any bearing on the management plan or disease monitoring.\n\nTA has been reported in association with other autoimmune disorders such as Crohn's disease,[4] SLE,[5] sarcoidosis, and spondyloarthropathies, either as the primary disease or secondary to an existing autoimmune disorder.[6]\n\nThe diagnosis in our patient was carried out 2 years after the onset of the first symptoms. This is not surprising as the delay in diagnosing this condition is common with an average latency of 18 months. The immunosuppressive drugs might have masked some of the symptoms. Our patient had liver transplantation over 10 years ago and was maintained on cyclosporin for 6 years after which it was replaced with tacrolimus following an episode of acute rejection. Both drugs have been used to treat TA and have shown good results, and so it is plausible to believe that her symptoms and the arteritis activity were partially controlled with this treatment. The counter argument is that TA may manifest itself in patients who are well covered with immune suppressive treatment. The severe form of the disease can be refractory to high doses of corticosteroids and conventional immune suppressive medications such as azathioprine, methotrexate, and cyclophosphamide.\n\nTacrolimus was reported in early animal studies, particularly in dogs, to induce arteritis.[7] However, we are not aware of similar reports in humans, except for only report on a single case of cerebral vasculitis associated with neurotoxicity in a liver transplant patient treated with tacrolimus.[8]\n\nThis patient was transplanted for hepatitis B cirrhosis, a known association with arteritis such as polyarteritis nodosa, however, there areno reports of any link between hepatitis B and TA disease. The fact that this patient remained negative for both HbsAg and HBV-DNA throughout the post-transplantation period further rules out the association of these two conditions.\n\nThe difficulty in managing TA patients lies in the setting of the liver transplantation, the choice of treatment, and absence of reliable disease activity markers. Inflammatory markers like ESR and CRP may be normal even when the disease is very active. They have 72% sensitivity and 56% specificity. Other tests used to monitor TA activity are imaging modalities like digital subtracting angiography (DSA) and computed tomography angiography (CTA). These tests are used in screening, diagnosis, and in interventional treatment. MRI may also help to visualize the vessel wall stenosis and thickening and using T2 imaging, active inflammation of the vessel wall manifested by wall edema can be visualized. Ultrasonography (US) is another test that is cheap and convenient in diagnosing any structural wall abnormalities, but will not be able to detect disease activity. Positron emission tomography with radiolabeled glucose (FDG-PET) can highlight the region of inflammation with a sensitivity of 92% and specificity of 100%. It is more sensitive than MRI in detecting vascular involvement in early TA and it is helpful in monitoring response to treatment. It is however expensive and not widely available.[9] Corticosteroids remain the mainstay of medical treatment and appear to be effective in 20–75% of patients. Immune suppressive agents that include methotrexate, cyclophosphamide, and azathioprine may be effective. MMF has recently been introduced to treat TA. In a recent study, MMF was found to be a safe and effective steroid-sparing agent in treating patients with TA.[7]\n\nThe main treatment for TA is immune suppression, which is parallel to the treatment of patients post liver transplantation. The most widely used immune suppressives for TA such as steroids or mycophenolates are widely used post liver transplantation, and therefore, there is no concern with regard to graft rejection or hepatotoxicity. Selection of a therapeutic agent depends largely on the side effect profile, as the data remains limited on the treatment of choice of TA. Biological treatment with agents such as anti-tumor necrosis factor (anti-TNF), etanercept, and infliximab had been tried in refractory TA, and the response was variable. Anti-IL-6 has also been used in a few cases that were resistant to conventional immunosuppressant therapy, and anti-TNF-α and was found to be effective.[10]\n\nSurgical vascular reconstruction of the involved vessels used to be carried out in the past in the form of bypassing a stenotic segment, graft anastomosis, or end arterectomy. Recently, percutaneous transluminal angioplasty has emerged as the treatment of choice for stenotic lesions.\n\nCONCLUSION\nIn conclusion, this is the first report of TA post liver transplantation in the English literature. The immunosuppressive drugs might have reduced severity of the disease, but are not effective in preventing it. The standard measures for early diagnosis of this condition and other vasculitic disorders are not adequate in immune suppressed patients and a higher index of suspicion is needed.\n\nSource of Support: None of the authors received any fund for producing this article\n\nConflict of Interest: No one has any commercial associations that might cause a conflict of interest in relation to the submitted article.\n==== Refs\nREFERENCES\n1 Seko Y Giant cell and Takayasu arteritis Curr Opin Rheumatol 2007 19 39 43 17143094 \n2 Mwipatayi BP Jeffery PC Beningfield SJ Matley PJ Naidoo NG Kalla AA Takayasu arteritis: Clinical features and management: Report of 272 cases ANZ J Surg 2005 75 110 7 15777385 \n3 Yagi K Kobayashi J Yasue S Yamaguchi M Shiobara S Mabuchi H Four unrelated cases with Takayasu arteritis and CD36 deficiency: Possible link between these disorders J Intern Med 2004 6 255 688 9 15147534 \n4 Ashraf S Alkarawi MA Alokaily F Alkhushail A Alrobayan A Takayasu's arteritis associated with Crohn's disease: A case report and literature review BMJ Case Rep 2009 2009 pii bcr07.2008.0490 \n5 Sachetto Z Fernandes SR Del Rio AP Coimbra IB Bértolo MB Costallat LT Systemic lupus erythematosus associated with vasculitic syndrome (Takayasu's arteritis) Rheumatol Int 2010 30 1669 72 19789875 \n6 Yokoe I Haraoka H Harashima H A patient with Takayasu's arteritis and rheumatoid arthritis who responded to tacrolimus hydrate Intern Med 2007 46 1873 7 18025771 \n7 Ochiai T Hamaguchi K Isono K Histopathologic studies in renal transplant recipient dogs receiving treatment with FK-506 Transplant Proc 1987 19 Suppl 6 93 7 2445085 \n8 Salvarani C Magnani L Catanoso MG Pipitone N Versari A Dardani L Rescue treatment with tocilizumab for Takayasu arteritis resistant to TNF-α blockers Clin Exp Rheumatol 2012 30 Suppl 70 S90 3 22410150 \n9 O’Connor TE Carpenter HE Bidari S Waters MF Hedna VS Role of inflammatory markers in Takayasu arteritis disease monitoring BMC Neurol 2014 14 62 24678735 \n10 Comarmond C Plaisier E Dahan K Mirault T Emmerich J Amoura Z Anti TNF- α in refractory Takayasu's arteritis: Cases series and review of the literature Autoimmun Rev 2012 11 678 84 22155781\n\n",
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"issue": "21(5)",
"journal": "Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association",
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"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D009173:Mycophenolic Acid; D011239:Prednisolone; D016559:Tacrolimus; D013625:Takayasu Arteritis; D016896:Treatment Outcome",
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"title": "Takayasu's arteritis and liver transplantation: Association and implications.",
"title_normalized": "takayasu s arteritis and liver transplantation association and implications"
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"abstract": "Cangrelor is an intravenous P2Y12 receptor antagonist approved for use during percutaneous coronary intervention (PCI) to reduce ischemic events associated with new stent placement and has been used off-label at reduced doses guided by platelet function testing as a \"bridge\" from discontinuation of oral P2Y12 receptor antagonists to surgical procedures when the long-term effects of oral agents are undesirable.\n\n\n\nTo describe the dosing, laboratory monitoring, and clinical outcomes of a series of patients who received cangrelor as a \"bridging\" antiplatelet agent.\n\n\n\nThis study is a retrospective analysis of all patients within the study center with coronary stents who received cangrelor as a bridge to surgical procedure and had VerifyNow monitoring during treatment.\n\n\n\nA total of 11 patients were identified for inclusion. The median cangrelor dose was 0.5 µg/kg/min (interquartile range = 0.5-0.5) and was maintained in 7 of 11 patients. Doses ranged from 0.25 to 2 µg/kg/min during therapy, and 81.6% of VerifyNow results assessed were within goal range (⩽208 P2Y12 reaction units). Bleeding complications during therapy occurred in 3 patients, all of whom were receiving concomitant heparin infusions, and no stent thrombosis was reported. Conclusion and Relevance: Low-dose cangrelor may represent an effective option for bridging antiplatelet therapy in patients with coronary stents. This study demonstrated that the majority of patients received adequate platelet inhibition without any incidence of stent thrombosis on 0.5 µg/kg/min using the VerifyNow assay to monitor platelet inhibition, which represents a lower dose than previously reported in the literature.",
"affiliations": "1 Memorial Hermann Texas Medical Center, Houston, TX, USA.;1 Memorial Hermann Texas Medical Center, Houston, TX, USA.;1 Memorial Hermann Texas Medical Center, Houston, TX, USA.",
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"keywords": "acute coronary syndrome; antiplatelets; bare metal stent; cardiovascular drugs; coronary artery disease; drug eluting stent; ischemic heart disease; myocardial infarction; percutaneous coronary intervention",
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"mesh_terms": "D000249:Adenosine Monophosphate; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D003328:Coronary Thrombosis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D011182:Postoperative Care; D011183:Postoperative Complications; D058921:Purinergic P2Y Receptor Antagonists; D012189:Retrospective Studies; D015607:Stents; D016896:Treatment Outcome",
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"title": "Antiplatelet Therapy Bridging With Cangrelor in Patients With Coronary Stents: A Case Series.",
"title_normalized": "antiplatelet therapy bridging with cangrelor in patients with coronary stents a case series"
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"abstract": "We report a case of myelodysplastic syndrome (MDS) occurring in an African American boy with Gorlin syndrome with a novel PTCH1 mutation. Before developing MDS, the patient had been treated with chemotherapy and radiation for a medulloblastoma. He received a bone marrow transplant for the MDS and eventually died of treatment complications. Secondary hematologic malignancies are a known complication of certain chemotherapeutics, although whether a patient with Gorlin syndrome has a greater propensity for the development of such malignancies is unclear.",
"affiliations": "Division of Dermatology, School of Medicine, Washington University, St. Louis, Missouri.;Division of Pediatric Hematology-Oncology, School of Medicine, Washington University, St. Louis, Missouri.;Division of Dermatology, School of Medicine, Washington University, St. Louis, Missouri.",
"authors": "Mull|Jamie L|JL|;Madden|Lisa M|LM|;Bayliss|Susan J|SJ|",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001478:Basal Cell Nevus Syndrome; D016026:Bone Marrow Transplantation; D002648:Child; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes; D000072081:Patched-1 Receptor",
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"title": "Myelodysplastic Syndrome Occurring in a Patient with Gorlin Syndrome.",
"title_normalized": "myelodysplastic syndrome occurring in a patient with gorlin syndrome"
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"abstract": "Patients with inflammatory bowel disease are predisposed to opportunistic infections. We report 2 cases of disseminated tuberculosis in adolescents receiving a TNF antagonist, infliximab. Both had negative baseline tuberculin skin tests. Multimodal testing using tuberculin skin tests and interferon gamma release assays at the time of inflammatory bowel disease diagnosis and annually may increase the sensitivity of LTBI testing in these high risk children.",
"affiliations": "From the *Sections of Infectious Diseases; †Emergency Medicine; and †Gastroenterology and Nutrition, Department of Pediatrics; and §Department of Pediatric Radiology, Baylor College of Medicine, Houston, TX.",
"authors": "Cruz|Andrea T|AT|;Karam|Lina B|LB|;Orth|Robert C|RC|;Starke|Jeffrey R|JR|",
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"title": "Disseminated tuberculosis in 2 children with inflammatory bowel disease receiving infliximab.",
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"abstract": "Case reports of women sustaining multiple vertebral fractures (VF) soon afterdenosumab discontinuation are accumulating.\n\n\n\nWe report a woman with five new vertebral fractures in ~8 months following discontinuation of long-term odanacatib (ODN), an experimental cathepsin K inhibitor.\n\n\n\nDXA examination demonstrated an ~12% decline in bone mineral density (BMD) and ~9% decline in trabecular bone score (TBS) since ODN discontinuation. Laboratory evaluation did not reveal a secondary cause of bone loss.\n\n\n\nThis case mimics observations following denosumab discontinuation, but, to our knowledge, is the first reported with ODN and the first documenting substantial decline in TBS. While not directly clinically relevant as ODN is no longer being developed, this case raises the possibility that a syndrome of multiple vertebral fractures could follow discontinuation of various potent osteoporosis therapies that produce major BMD increases but do not have persisting bone effects (i.e., all non-bisphosphonates). Use of antiresorptive therapies to prevent rapid bone loss following discontinuation of potent bone active agents seems appropriate. Identification of those patients who could be at risk for the multiple VF syndrome is needed.",
"affiliations": "Osteoporosis Clinical Research Program, University of Wisconsin, 2870 University Avenue, Suite 100, Madison, WI, 53705, USA. nbinkley@wisc.edu.;Osteoporosis Clinical Research Program, University of Wisconsin, 2870 University Avenue, Suite 100, Madison, WI, 53705, USA.;Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.",
"authors": "Binkley|N|N|http://orcid.org/0000-0002-9905-461X;Krueger|D|D|;de Papp|A E|AE|",
"chemical_list": "D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; C527128:odanacatib",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-018-4385-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "29(4)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Odanacatib; Osteoporosis; Vertebral fracture",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D001713:Biphenyl Compounds; D015519:Bone Density; D050071:Bone Density Conservation Agents; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015663:Osteoporosis, Postmenopausal; D058866:Osteoporotic Fractures; D011859:Radiography; D012008:Recurrence; D016103:Spinal Fractures; D028761:Withholding Treatment",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "999-1002",
"pmc": null,
"pmid": "29455249",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26694598;18539106;21289258;27732330;28240371;28334908;25432773;22777865;21159841;28643265;28586451;29105841;26092650;27393301;20740685;26510845;26277849;28262693;14613308",
"title": "Multiple vertebral fractures following osteoporosis treatment discontinuation: a case-report after long-term Odanacatib.",
"title_normalized": "multiple vertebral fractures following osteoporosis treatment discontinuation a case report after long term odanacatib"
} | [
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"abstract": "Small cell lung cancer (SCLC) is the most malignant lung cancer with the highest mortality. At present, the first-line standard treatment is still based on Etoposide and Platinum chemotherapy. However, for SCLC that progresses after first-line therapy, the treatment options are still very limited. Since the molecular mechanism of first-line drug resistance of SCLC is still unclear, and the precision medicine strategy after first-line drug resistance is still in the pre-clinical stage. The proportion of secondary biopsy and genetic testing is very low after the progress of first-line treatment of SCLC. In this study, we report a case of a middle-aged woman who was first diagnosed with SCLC. Adenocarcinoma with sensitive gene mutations and repeated changes of small cell carcinoma were detected by multiple biopsies during the course of the disease, suggesting that the patient may be a special subtype of SCLC - mixed SCLC (M-SCLC). In this case, the patient has been treated with radiotherapy and chemotherapy, immunotherapy and targeted therapy successively, and the survival time has reached 2 years and 8 months. Through the case report and literature review retrospectively, this study aimed to explore the part patients may start to present hybrid histopathologic types or tissue type change after treatment of SCLC. Biopsy pathologic histology and genetic testing is necessary after disease progression to look for potential therapeutic targets, so as to give precise treatment based on molecular markers detection results and provide the patient with the benefit of survival for as long as possible.
.",
"affiliations": "Lung Cancer Center, West China Hospital, Sichuan University; Sichuan Lung Cancer Institute, Chengdu 610041, China.;Lung Cancer Center, West China Hospital, Sichuan University; Sichuan Lung Cancer Institute, Chengdu 610041, China.;Lung Cancer Center, West China Hospital, Sichuan University; Sichuan Lung Cancer Institute, Chengdu 610041, China.;Lung Cancer Center, West China Hospital, Sichuan University; Sichuan Lung Cancer Institute, Chengdu 610041, China.;Lung Cancer Center, West China Hospital, Sichuan University; Sichuan Lung Cancer Institute, Chengdu 610041, China.;Lung Cancer Center, West China Hospital, Sichuan University; Sichuan Lung Cancer Institute, Chengdu 610041, China.",
"authors": "Qu|Zihan|Z|;Liu|Jiewei|J|;Luo|Feng|F|;Li|Lu|L|;Zhu|Lingling|L|;Zhou|Qinghua|Q|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.3779/j.issn.1009-3419.2021.102.37",
"fulltext": "\n==== Front\nZhongguo Fei Ai Za Zhi\nZhongguo Fei Ai Za Zhi\nZGFAZZ\nChinese Journal of Lung Cancer\n1009-3419\n1999-6187\n中国肺癌杂志编辑部 天津市和平区南京路228号300020\n\nzgfazz-24-11-808\n10.3779/j.issn.1009-3419.2021.102.37\n病例报道\nCase Report\n小细胞肺癌合并腺癌MDT治疗报道及文献综述\nMDT Treatment of Small Cell Lung Cancer Complicated with Adenocarcinoma: A Case Report and Literature Review瞿 子涵 QU Zihan\n刘 洁薇 LIU Jiewei\n罗 锋 LUO Feng\n李 潞 LI Lu\n朱 玲玲 ZHU Lingling\n周 清华 ZHOU Qinghua zhouqh135@163.com\n*\n610041 成都，四川大学华西医院肺癌中心；四川省肺癌研究所 Lung Cancer Center, West China Hospital, Sichuan University; Sichuan Lung Cancer Institute, Chengdu 610041, China\n周清华, Qinghua ZHOU, E-mail: zhouqh135@163.com\n瞿子涵和刘洁薇为共同第一作者\n\nZihan QU and Jiewei LIU contributed equally to this paper.\n\n20 11 2021\n24 11 808814\n2 4 2021\n28 4 2021\n6 5 2021\n版权所有©《中国肺癌杂志》编辑部2021\nCopyright ©2021 Chinese Journal of Lung Cancer. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) License. See: https://creativecommons.org/licenses/by/3.0/.\n小细胞肺癌（small cell lung cancer, SCLC）是肺癌中恶性程度和死亡率最高的类型。目前的一线标准治疗方式仍是以依托泊苷和铂类为主的化疗方案。然而，对于一线治疗后进展的SCLC，治疗方式仍非常有限。由于目前对SCLC一线耐药的分子机制尚未明了，而且一线耐药后的精准医疗策略仍处于临床前期阶段，因而在SCLC一线治疗进展后，进行二次活检及基因检测的比例很低。本文通过报道1例初次诊断为SCLC的中年女性，病程中多次活检发现肿瘤组织病理学类型出现具有敏感基因突变的腺癌以及小细胞癌的反复转变，提示其可能为SCLC中的特殊亚型——混合型小细胞肺癌（mixed small cell lung cancer, M-SCLC）。本例患者在治疗过程中先后使用了放化疗、免疫治疗及靶向治疗，目前生存时间已达2年8个月。本文通过病例报道及回顾性文献复习，旨在探讨对一部分可能一开始就呈现混合型病理组织类型或在治疗后出现组织类型改变的SCLC，疾病进展时有必要再次活检明确病理组织学类型及基因学检测，寻找潜在治疗靶点，以便给予基于分子标志物检测结果的精准治疗，为患者提供尽可能长的生存获益。\n\nSmall cell lung cancer (SCLC) is the most malignant lung cancer with the highest mortality. At present, the first-line standard treatment is still based on Etoposide and Platinum chemotherapy. However, for SCLC that progresses after first-line therapy, the treatment options are still very limited. Since the molecular mechanism of first-line drug resistance of SCLC is still unclear, and the precision medicine strategy after first-line drug resistance is still in the pre-clinical stage. The proportion of secondary biopsy and genetic testing is very low after the progress of first-line treatment of SCLC. In this study, we report a case of a middle-aged woman who was first diagnosed with SCLC. Adenocarcinoma with sensitive gene mutations and repeated changes of small cell carcinoma were detected by multiple biopsies during the course of the disease, suggesting that the patient may be a special subtype of SCLC - mixed SCLC (M-SCLC). In this case, the patient has been treated with radiotherapy and chemotherapy, immunotherapy and targeted therapy successively, and the survival time has reached 2 years and 8 months. Through the case report and literature review retrospectively, this study aimed to explore the part patients may start to present hybrid histopathologic types or tissue type change after treatment of SCLC. Biopsy pathologic histology and genetic testing is necessary after disease progression to look for potential therapeutic targets, so as to give precise treatment based on molecular markers detection results and provide the patient with the benefit of survival for as long as possible.\n\n肺肿瘤\n混合型小细胞肺癌\n敏感性基因突变\n组织活检\n基因检测\nLung neoplasms\nMixed small cell lung cancer\nSensitive gene mutations\nBiopsy\nGene testing\n==== Body\npmc1 病例介绍\n\n患者，女性，56岁，因左侧胸背部剧烈疼痛伴咯血1+年就诊。既往无烟酒史，无传染病史，有肿瘤家族史。胸部计算机断层扫描（computed tomography, CT）提示：左肺上叶占位伴肺门及纵隔淋巴结增大。纤维支气管镜提示：左上叶上支开口浸润性新生物阻塞。病理诊断（Q1829316，2018年8月20日）示：（左肺上叶）小细胞癌。免疫组化示：磷酸烯醇丙酮酸羧激酶（phosphoenolpyruvate carboxykinase, PCK）和上皮膜抗原（epithelial membrane antigen, EMA）均（点状+）、P40（-）、甲状腺转录因子-1（thyroid transcription factor-1, TTF-1）（+）、嗜铬粒蛋白A（chromogranin A, CGA）（-）、CD56（+）、突触融合蛋白（synataxin, Syna）（部分+）、细胞角蛋白（cytokeratin 7, CK7）（-）、Ki-67（+, 70%）、程序性死亡配体1（programmed cell death ligand 1, PD-L1）（-）。全身骨扫描示：左侧髂骨骨代谢增高灶，肿瘤骨转移可能。\n\n随后患者接受6个周期EP（依托泊苷+顺铂）方案化疗，胸部病灶放疗原发肿瘤计划肿瘤靶区（planned gross target volume, PGTV）（左上肺原发灶+纵隔转移淋巴结+高危淋巴结引流区），调强适形放疗（intensity modulated radiation therapy, IMRT）60 Gy/30 F/6 wk；髂骨转移灶放疗PGTV（左髂骨翼转移灶），IMRT 60 Gy/20 F/4 wk。综合疗效评价为疾病缓解（partial response, PR）。患者拒绝行预防性颅脑照射（preventive craniocerebral irradiation, PCI）治疗。\n\n放化疗结束后3个月患者因突发视物旋转伴明显恶心、呕吐，行急诊头颅CT提示颅内多发转移瘤。立即予以甘露醇脱水治疗及头部放疗PGTV（脑转移灶），三维适形放疗（three dimension conformal radiotherapy, 3D-CRT）42 Gy/14 F/3 wk。放疗后颅内病灶疗效评价为PR。腹部CT提示双侧肾上腺多发转移瘤。考虑患者疾病进展（progressive disease, PD），遂开始行二线TC（脂质体紫杉醇+卡铂）方案化疗联合重组人血管内皮抑制素治疗。\n\n二线治疗2个周期后复查胸腹部CT提示：左侧中量胸腔积液，双侧肾上腺多发转移瘤较前明显增大。行左侧胸腔穿刺置管引流术，胸水送脱落细胞学显示（胸水涂片及细胞块）：查见腺癌细胞。免疫细胞化学染色示：TTF-1（+）、Napsin-A（+）、CD56（-）、Syn（-）、CgA（-），倾向肺来源。肿瘤细胞间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）（-）、c-ros肉瘤致癌因子-受体酪氨酸激酶（ROS proto-oncogene 1, receptor tyrosine kinase, ROS1）（-）。随即接受三线单药帕博利珠单抗（200 mg, ivgtt, q3w）免疫治疗共2个周期及双侧肾上腺放疗PGTV（双侧肾上腺转移灶），容积旋转调强技术（volume modulated arc therapy, VMAT）50 Gy/25 F/5 wk。2个周期后综合疗效评价为疾病稳定（stable disease, SD）（左侧肺门占位SD，双侧肾上腺转移瘤PR）。患者外周血基因检测[突变阻滞扩增系统聚合酶链反应（amplification refractory mutation system polymerase chain reaction, AMRS-PCR）]结果示：表皮生长因子受体（epidermal growth factor receptor, EGFR）L858R（+, 36.34%）。遂行吉非替尼250 mg qd治疗，靶向治疗后1个月复查胸部CT提示：左肺门病灶稍增大，纵隔淋巴结较前增多、增大。肿瘤再次进展，随后换用依托泊苷单药化疗联合安罗替尼抗血管生成治疗。治疗1个月后复查胸腹部CT后综合疗效评价为SD（左侧肺门占位稍增大）。服药期间患者出现手足综合症，症状明显，自行停药。\n\n停药1个月后患者无明显诱因出现无痛性血尿，为明确诊断行CT尿路造影提示：膀胱左侧局灶性增厚，强化，肿瘤性病变？考虑膀胱恶性肿瘤可能性大。排除手术禁忌，于2020年11月20日在全麻下行“经尿道膀胱肿瘤电切术”，术后病理诊断：（膀胱）恶性肿瘤，免疫组化染色：肿瘤细胞呈PCK（点灶状+）、Syn（+）、CgA（+）、CD56（+）、TTF-1（+）、GATA-3（-）、CDX2（-）、Ki-67（MIB-1）阳性率约为80%，结合病史支持为肺小细胞癌转移。术后患者恢复可，持续随访中。患者诊疗过程见图 1。\n\n图 1 患者诊疗经过概述\n\nOverview of the patient's diagnosis and treatment. ED: extensive disease; RT: radiation therapy; EP: etoposide+cisplatin; TC: paclitaxel+carboplatin; PR: partial response; PD: progressive disease; SD: stable disease; VP-16: etoposide; EGFR: epidermal growth factor receptor.\n\n2 文献回顾及讨论\n\n本文报道1例首诊为SCLC，接受标准一、二线治疗后出现PD，多次病理学活检提示肿瘤组织出现携带敏感性基因突变的腺癌与SCLC组织类型转变的患者，并且于PubMed上检索既往报道SCLC合并腺癌成分的类似病例，对患者的临床特点（性别、年龄、肺癌组织学类型、肿瘤分期）、合并基因突变、接受治疗/疗效评价及总生存期进行回顾及归纳（表 1）。\n\n表 1 文献回顾SCLC合并腺癌患者临床特征文献回顾\n\nLiterature review of clinical features of the patients with SCLC complicated with adenocarcinoma\n\nReference\tAge/Gender\tSmoking\tPathological diagnosis\tDiagnosis specimen type\tMutation gene\tStage\tTreatment\tResponse\tOS (mon)\t\n†: staging details not specific. ADC: adenocarcinoma; SCLC: small cell lung cancer; ED: extensive disease; OS: overall survival; EML4-ALK: echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase; F: female; M: male.\t\nTatematsu et al[26]\t69/M\tYes\tSCLC/ADC\tBiopsy specimen\tEGFR L858R\tIa\tSurgery and adjuvant chemotherapy\t-\t-\t\nTatematsu et al[26]\t65/M\tYes\tSCLC/ADC\tResected tumor (cytological diagnosis of SCLC prior to surgery)\tEGFR Ex19del\tIa\tAdjuvant chemotherapy and radiotherapy\t-\t-\t\nTatematsu et al[26]\t36/F\tNo\tSCLC/ADC\tResected tumor (diagnosis of ADC with a biopsy prior to surgery)\tEGFR L858R\tIV\tSurgery\t-\t-\t\nSiegele et al[27]\t82/M\tYes\tSCLC/ADC\tResected tumor\tEGFR D855H\tIa\tSurgery and adjuvant chemotherapy\t-\tLost to follow up\t\nShi et al[28]\t71/M\tYes\tSCLC/ADC\tResected tumor\tEGFR L858R\tI†\tSurgery\t-\t12\t\nLu et al[29]\t62/F\tNo\tSCLC/ADC\tResected tumor\tEGFR Ex19del\tIIIa\tSurgery\t-\t-\t\nWakuda et al[30]\t73/M\tYes\tSCLC/ADC\tResected tumor\tEGFR G719A\tIIb\tSurgery\t-\t-\t\nIijima et al[31]\t63/M\tYes\tSCLC/ADC\tResected tumor\tEGFR Ex19del\tIIb\tSurgery\t-\t-\t\nIijima et al[31]\t76/M\tYes\tSCLC/ADC\tResected tumor\tEGFR Ex19del\tIIIa\tSurgery\t-\t-\t\nLu et al[20]\t62/F\tNo\tSCLC/ADC\tResected tumor\tEGFR Ex19del\tIIIa\tSurgery and adjuvant chemotherapy\t-\t22\t\nNorkowski et al[32]\t66/F\tYes\tSCLC/ADC\tResected tumor\tEGFR Ex19del\tIIIa\t-\t-\t120\t\nNorkowski et al[32]\t62/M\tNo\tSCLC/ADC\tResected tumor\tEGFR Exon 18 G719A, Exon 21 L833_V834delinsFL\tIIIa\t-\t-\t8\t\nNorkowski et al[32]\t45/F\tYes\tSCLC/ADC\tResected tumor\tExon 21 L858R\tIIIa\t-\t-\t12\t\nYe Guo et al[22]\t61/M\tYes\tSCLC/ADC\tBiopsy specimen\tEGFR Ex19del\tED\tChemotherapy and Erlotinib\tSD\t-\t\nFukui et al[33]\t62/F\tNo\tSCLC/ADC\tResected tumor\tEGFR L858R\tIIIb\tSurgery\t-\t-\t\nLin et al[10]\t66/F\tNo\tSCLC/ADC\tResected tumor\tEGFR L858R\tIIIa\t-\t-\t-\t\nLin et al[10]\t77/F\tNo\tSCLC/ADC\tResected tumor\tEGFR L858R\tIIIa\tErlotinib\tNS\t-\t\nLin et al[10]\t63/F\tNo\tSCLC/ADC\tResected tumor\tEGFR G719A\tIVb\tAfatinib\tNS\t-\t\nTakagi et al[34]\t70/F\tNo\tSCLC/ADC\tBiopsy specimen\tEGFR L861Q\tIVb\tChemotherapy\tPR\t-\t\nTanaka et al[23]\t67/M\tNo\tSCLC/ADC\tBiopsy specimen\tEGFR Ex19del\tIVb\tChemotherapy and Afatinib\tPR\t-\t\nToyokawa et al[15]\t72/M\tYes\tSCLC/ADC\tResected tumor\tEGFR Ex19del, EML4-ALK\tIb\tSurgery\t-\t-\t\n\n由于一部分肺腺癌患者接受EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）治疗后以出现SCLC病理学改变作为获得性耐药机制，所以本文排除了接受病理活检前接受EGFR-TKIs治疗的患者。21例混合型小细胞肺癌（mixed small cell lung cancer, M-SCLC）合并EGFR敏感性基因突变的患者纳入文献回顾，患者中位年龄65.24岁（范围：36岁-82岁），其中女性11例（11/21, 52.38%），男性10例（10/21, 47.62%），52.38%（n=11）有明确吸烟史。80.95%（n=17）的患者通过手术切除标本获得病理诊断，其中1例患者术前经穿刺活检诊断为单纯型SCLC，另外1例诊断为肺腺癌。肿瘤分期方面仅有5例患者为Ia期-Ib期，其余16例患者于就诊时已处于（局部）晚期。关于基因型分析，42.86%（n=9）的患者合并EGFR外显子缺失突变（19del），33.33%（n=7）的患者合并EGFR外显子21突变，14.29%（n=3）的患者合并EGFR外显子18 G719A突变，另外，各有1例（4.76%）患者分别携带EFGR L833_V834delinsFL和EGFR D855H罕见突变。尽管本研究纳入的均为携带肿瘤驱动基因的患者，但仅有3例患者接受EGFR-TKIs治疗，大部分患者仍采用手术、全身化疗或局部放疗的治疗方法。由于本研究纳入的接受EGFR-TKIs治疗的样本量有限，靶向治疗对M-SCLC是否有效还需要后续大样本的临床研究证实。\n\nM-SCLC为SCLC的特殊病理类型，肿瘤组织中SCLC和任何非小细胞肺癌（non-small cell lung cancer, NSCLC）成分共存，最常见的NSCLC组织学亚型是大细胞癌（large cell carcinoma, LC）或大细胞神经内分泌癌（large cell neuroendocrine carcinoma, LCNEC），其余少见的为腺癌、鳞癌，极少合并梭形细胞癌或巨细胞癌（如果是LC或LCNEC至少应含10%肿瘤组织才能诊断）[1, 2]。M-SCLC的发生率为2%-28%[3]，该差异与肿瘤组织样本大小、完整性、病理诊断水平相关。由于SCLC大都位于段支气管以上，诊断主要依靠支气管镜、肺泡灌洗液或细针穿刺活检等方式，获得的组织样本有限，因此诊断率较低。而在手术标本中更容易被诊断，可能与出现在周围支气管及肿瘤切除率更高有关[4]。\n\nSCLC极易发生远处转移，前期通过对小鼠SCLC模型和循环肿瘤细胞（circulating tumor cells, CTCs）的研究发现，与NSCLC类似淋巴结转移在SCLC中很常见[5, 6]，但血行转移是SCLC的主要转移途径，肿瘤通常会转移至胸膜腔和远处脏器[7]，这一现象与本文报道的患者出现的情况类似，患者病程中先后出现纵隔淋巴结转移、颅内转移、胸膜转移及膀胱转移。\n\n本例患者随着疾病进展发生“SCLC-腺癌-SCLC”的病理组织类型改变且合并敏感基因突变，该现象或许可以解释为：①肿瘤组织中一开始就合并腺癌成分；②疾病进程中出现第二原发肿瘤；③腺癌成分为原发肿瘤分化而来；④治疗后SCLC发生细胞形态学改变。该患者通过支气管镜活检确诊SCLC，由于获取的样本量有限，未能准确反映该肿瘤的病理学特征，容易误诊；其次，患者除左肺门原发病灶外，其余胸腔内未见异常占位，因此胸腔积液中腺癌细胞来源于原发肿瘤的可能性大。另外，何佳林等[8]对175例SCLC患者接受放化疗前的活检组织及死亡后的尸检标本进行细胞组织形态的对比分析发现，治疗前约8.6%的患者为M-SCLC，而在单纯型SCLC中约9.7%的患者于治疗后出现组织学类型的改变，主要发生在原发灶与转移灶之间。Rudin等[9]报道13%-45%的单纯型SCLC治疗后出现获得性化疗耐药，其表现为细胞形态改变及混合型组织学类型。\n\n目前，SCLC合并腺癌的发生机制及组织起源仍不明确。TP53、RB1抑癌基因突变是SCLC发生所必需的分子生物学事件。Lin等[10]证实合并腺癌的M-SCLC中两种肿瘤组织中均存在EGFR、TP53、RB等基因突变，提示两者具有共同的组织遗传学背景。Swanton等[11]发现腺癌成分和SCLC或许是来源于同一肿瘤干细胞的不同亚克隆突变，且早于TP53基因突变。肿瘤干细胞的多个亚克隆受不同肿瘤微环境的作用而发生基因突变（例如PI3KCA[12]、Notch[13]等），进而影响肿瘤细胞的分化。另外，大部分SCLC起源于神经内分泌细胞，但有少数SCLC和肺腺癌的组织学起源相同，为II型肺泡上皮细胞[14]。Toyokaw等[15]报道1例合并腺癌成分且携带ALK及EGFR基因突变的M-SCLC患者，其仅在SCLC中检测到ALK重排，提示ALK重排或许与SCLC的发生有关。临床病理特征方面，携带敏感基因突变的患者多为不或少吸烟的女性，表明在分子生物学上类似于传统肺腺癌而非SCLC。\n\nM-SCLC与SCLC临床特点类似，多见于有吸烟史的中年男性，而对于无或有轻度吸烟史的年轻女性SCLC患者，疾病进展时应考虑到M-SCLC的可能，有必要重复活检明确诊断。SCLC多表现为肺门占位及纵隔淋巴结肿大，而合并腺癌成分的则更多见于周围支气管，且部分伴有恶性胸腔积液[16]，相反合并鳞癌成分的大多为中央型肺癌[17]。因此，通过细针穿刺活检或胸水脱落细胞学检查确诊的周围型SCLC，也应考虑到M-SCLC的可能。\n\n尽管当前诊疗技术已经可以区分SCLC的生物学亚型，但在治疗方面并未根据分型不同而详细划分治疗方案，仍采用手术切除、放化疗、靶向治疗和免疫治疗等多学科诊疗（multi-disciplinary therapy, MDT）手段。初始治疗方法与肿瘤分期相关，在临床实践中推荐使用肿瘤原发灶-淋巴结-转移（tumor-node-metastasis, TNM）分期，能较美国退伍军人肺癌协会（Veterans Administration Lung Study Group, VASLG）分期系统（局限期和广泛期）更为精确地提供原发灶部位、淋巴结及远处转移灶等解剖信息，有助于临床医生确定最优的治疗策略。He等[18]回顾了784例M-SCLC患者的临床资料，发现极早期（Ia期-Ib期）患者的主要治疗手段为手术切除和以铂类为基础的辅助化疗，对于IIa期-IV期的患者可同时接受全身化疗联合局部放疗，对已合并远处转移的患者则给予全身化疗联合或不联合免疫治疗。与单纯型SCLC不同的是，晚期M-SCLC化疗敏感性较单纯型SCLC差，预后较差，可能与混杂了NSCLC成分相关[19]。\n\n携带肿瘤驱动基因的SCLC非常少见，EGFR突变的发生率不到5%，而在M-SCLC中可达15%-20%[16]，多见于无或有轻度吸烟史、年轻女性且混合腺癌成分的SCLC[20]。已有个别案例[21-23]报道小分子TKIs对SCLC合并肺腺癌的患者有效，这表明靶向治疗可能是合并敏感性基因突变的M-SCLC患者的一种新的选择。但TKIs治疗混和腺癌成分且携带敏感基因突变的M-SCLC临床资料有限，其临床疗效仍待后续研究进一步证实。\n\n免疫治疗现已用于SCLC的三线治疗，SCLC存在基因组及染色体高度不稳定性，M-SCLC作为SCLC的特殊类型，理论上其可能对免疫治疗更加敏感。然而，目前尚无免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）治疗的报道，免疫治疗对于M-SCLC的疗效仍需未来进行深入探讨。\n\n本研究报道的病例，在检测到腺癌组织学类型且合并敏感靶点突变时，先后使用了免疫治疗、靶向治疗及抗血管生成治疗。从疗效评价分析，免疫治疗联合放疗期间，肺部病灶为SD，肾上腺病灶达到PR，表明免疫治疗可能有一定疗效。尽管过去有病例报道合并腺癌成分的M-SCLC患者接受靶向治疗后疗效明显，但本研究提及的患者在接受靶向治疗1个月后即出现PD，表明合并敏感靶点突变的SCLC并不一定对EGFR-TKIs靶向治疗敏感。提示M-SCLC可能与EGFR基因突变的单纯肺腺癌有不同的疾病起源或分子驱动事件。另外，在靶向治疗进展后，安罗替尼联合依托泊苷单药化疗方案对患者胸部及肾上腺病灶控制稳定，虽然患者不能耐受毒副反应，仍能提示安罗替尼对复发、转移的SCLC有一定的抗肿瘤活性。并且前期临床试验[24, 25]已证实在复发难治的SCLC中安罗替尼较安慰剂能明显改善患者的无疾病进展生存期（4.1个月vs 0.7个月，P < 0.000, 1）、总生存期（7.3个月vs 4.9个月，P=0.002, 9）并提高疾病控制率（71.6% vs 13.2%, P < 0.000, 1），且不良反应可控。\n\n对于广泛期患者，选择全身化疗为基础同时联合局部放疗、靶向治疗、免疫治疗等多种治疗手段是主要的治疗模式，需要依据患者病情制定个体化治疗策略。\n\n本研究结果帮助我们对合并肺腺癌成分的M-SCLC有了进一步的认识，在SCLC合并腺癌或不吸烟的患者中，应考虑是否携带EGFR突变或ALK重排，进行基因检测和重复活检有助于制定个体化MDT治疗策略。最佳的治疗手段应根据治疗过程中每个阶段的优势组织学类型来决定。明确肿瘤的组织学形态后，全基因组下一代测序技术（next generation sequencing, NGS）分析可能会揭示决定这些肿瘤的组织学和临床特征的因素。在重复活检有困难时，肿瘤标志物、循环肿瘤细胞以及利用血浆样本进行敏感基因的突变检测，可能会对医生和患者下一步治疗的决策有重要的帮助。\n==== Refs\nReferences\n\n1 Zhang C Yang H Zhao H Clinical outcomes of surgically resected combined small cell lung cancer: a two-institutional experience J Thorac Dis 2017 9 1 151 158 10.21037/jtd.2017.01.07 28203418\n2 Zhou L Ren BZ Cao S Mixed small cell and squamous cell lung cancer: a case report Zhongguo Zhong Liu Lin Chuang 2011 38 24 1527 10.3969/j.issn.1000-8179.2011.24.012\n周 莉 任 宝柱 曹 水 小细胞癌与鳞状细胞癌混合型肺癌1例 中国肿瘤临床 2011 38 24 1527 10.3969/j.issn.1000-8179.2011.24.012\n3 Gao GB Yao B Li Y Diagnosis and treatment of compound small cell lung cancer Hainan Yi Xue Za Zhi 2019 30 17 2285 2289 10.3969/j.issn.1003-6350.2019.17.034\n高 冠斌 姚 兵 李 勇 复合型小细胞肺癌的诊断及治疗方法 海南医学 2019 30 17 2285 2289 10.3969/j.issn.1003-6350.2019.17.034\n4 Mangum MD Greco FA Hainsworth JD Combined small-cell and non-small-cell lung cancer J Clin Oncol 1989 7 5 607 612 10.1200/JCO.1989.7.5.607 2540288\n5 Yang D Denny SK Greenside PG Intertumoral heterogeneity in SCLC is influenced by the cell type of origin Cancer Discov 2018 8 10 1316 1331 10.1158/2159-8290.CD-17-0987 30228179\n6 Niho S Fujii H Murakami K Detection of unsuspected distant metastases and/or regional nodes by FDG-PET [corrected] scan in apparent limited-disease small-cell lung cancer Lung Cancer 2007 57 3 328 333 10.1016/j.lungcan.2007.04.001 17537538\n7 Meuwissen R Linn SC Linnoila RI Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model Cancer Cell 2003 4 3 181 189 10.1016/s1535-6108(03)00220-4 14522252\n8 He JL Histological alterations in small cell lung cancer after treatment Guo Wai Yi Xue: Zhong Liu Xue Fen Ce 1996 4 244 245\n何 家林 小细胞肺癌治疗后的组织学改变 国外医学: 肿瘤学分册 1996 4 244 245\n9 Rudin CM Brambilla E Faivre-Finn C Small-cell lung cancer Nat Rev Dis Primers 2021 7 1 3 10.1038/s41572-020-00235-0 33446664\n10 Lin MW Su KY Su TJ Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer Lung Cancer 2018 125 282 290 10.1016/j.lungcan.2018.10.006 30429033\n11 Swanton C Govindan R Clinical implications of genomic discoveries in lung cancer N Engl J Med 2016 374 19 1864 1873 10.1056/NEJMra1504688 27168435\n12 Zhao X McCutcheon JN Kallakury B Combined small cell carcinoma of the lung: Is it a single entity? J Thorac Oncol 2018 13 2 237 245 10.1016/j.jtho.2017.10.010 29101056\n13 Meder L König K Ozretić L NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas Int J Cancer 2016 138 4 927 938 10.1002/ijc.29835 26340530\n14 Zhang H Liu J Cagle PT Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach Mod Pathol 2005 18 1 111 118 10.1038/modpathol.3800251 15309021\n15 Toyokawa G Taguchi K Ohba T First case of combined small-cell lung cancer with adenocarcinoma harboring EML4-ALK fusion and an exon 19 EGFR mutation in each histological component J Thorac Oncol 2012 7 12 e39 e41 10.1097/JTO.0b013e3182762bcb 23154565\n16 Qin J Lu H Combined small-cell lung carcinoma Onco Targets Ther 2018 11 3505 3511 10.2147/OTT.S159057 29950855\n17 Li G Liu SS Xu XY The current research status of combined small cell lung cancer Sichuan Yi Xue 2015 36 5 585 587\n李 根 刘 珊珊 徐 向英 复合型小细胞肺癌的研究现状 四川医学 2015 36 5 585 587 10.16252/j.cnki.issn1004-0501-2015.05.002\n18 He J Xu S Pan H Treatments for combined small cell lung cancer patients Transl Lung Cancer Res 2020 9 5 1785 1794 10.21037/tlcr-20-437 33209601\n19 Li T, Zhang J, Hu Y. Research progress of complex small cell lung cancer. Jie Fang Jun Yi Xue Za Zhi, 2018, 43(9): 799-805.\n\n李涛. 复合型小细胞肺癌研究进展. 解放军医学杂志, 2018, 43(9): 799-805.\n\n20 Lu HY Mao WM Cheng QY Mutation status of epidermal growth factor receptor and clinical features of patients with combined small cell lung cancer who received surgical treatment Oncol Lett 2012 3 6 1288 1292 10.3892/ol.2012.666 22783435\n21 Niitsu T Shiroyama T Miyake K Combined small cell lung carcinoma harboring ALK rearrangement: A case report and literature review Thorac Cancer 2020 11 12 3625 3630 10.1111/1759-7714.13716 33103386\n22 Guo Y, Qu L, Shao M, Wang X, et al. A case report of combined small cell lung cancer with EGFR mutation and treatment experience. Zhongguo Fei Ai Za Zhi, 2014, 17(6): 511-514.\n\n郭晔, 曲丽梅, 邵铭心, 等. 复合性小细胞肺癌伴EGFR基因突变1例报道及治疗体会. 中国肺癌杂志, 2014, 17(6): 511-514. doi: 10.3779/j.issn.1009-3419.2014.06.14\n\n23 Tanaka M Ishii H Moribuchi H Successful treatment with an EGFR tyrosine kinase inhibitor Afatinib in a patient with combined small-cell lung cancer with EGFR mutation Invest New Drugs 2018 36 4 715 717 10.1007/s10637-018-0586-9 29546681\n24 Cheng Y Wang Q Li K OA13.03 Anlotinib as third-line or further-line treatment in relapsed SCLC: A multicentre, randomized, double-blind phase 2 trial J Thorac Oncol 2018 13 10 Suppl S351 S352 10.1016/j.jtho.2018.08.308\n25 Wu D Nie J Hu W A phase II study of anlotinib in 45 patients with relapsed small cell lung cancer Int J Cancer 2020 147 12 3453 3460 10.1002/ijc.33161 32557583\n26 Tatematsu A Shimizu J Murakami Y Epidermal growth factor receptor mutations in small cell lung cancer Clin Cancer Res 2008 14 19 6092 6096 10.1158/1078-0432.CCR-08-0332 18829487\n27 Siegele BJ Shilo K Chao BH Epidermal growth factor receptor (EGFR) mutations in small cell lung cancers: two cases and a review of the literature Lung Cancer 2016 95 65 72 10.1016/j.lungcan.2016.02.012 27040854\n28 Shi X Duan H Liu X Genetic alterations and protein expression in combined small cell lung cancers and small cell lung cancers arising from lung adenocarcinomas after therapy with tyrosine kinase inhibitors Oncotarget 2016 7 23 34240 10.18632/oncotarget.9083 27145273\n29 Lu HY Sun WY Chen B Epidermal growth factor receptor mutations in small cell lung cancer patients who received surgical resection in China Neoplasma 2012 59 1 100 104 10.4149/neo_2012_013 22103903\n30 Wakuda K Kenmotsu H Serizawa M Molecular profiling of small cell lung cancer in a Japanese cohort Lung Cancer 2014 84 2 139 144 10.1016/j.lungcan.2014.02.013 24657128\n31 Iijima M Yokobori T Mogi A ASO author reflections: Genetic and immunohistochemical studies investigating the histogenesis of neuroendocrine and carcinomatous components of combined neuroendocrine carcinoma Ann Surg Oncol 2019 26 3 830 831 10.1245/s10434-019-07880-0 31712924\n32 Norkowski E Ghigna MR Lacroix L Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology J Thorac Oncol 2013 8 10 1265 1271 10.1097/JTO.0b013e3182a407fa 24457237\n33 Fukui T Tsuta K Furuta K Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung Cancer Sci 2007 98 11 1714 1719 10.1111/j.1349-7006.2007.00600.x 17784875\n34 Takagi Y Nakahara Y Hosomi Y Small-cell lung cancer with a rare epidermal growth factor receptor gene mutation showing \"wax-and-wane\" transformation BMC Cancer 2013 13 1 1 6 10.1186/1471-2407-13-529 23282137\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1009-3419",
"issue": "24(11)",
"journal": "Zhongguo fei ai za zhi = Chinese journal of lung cancer",
"keywords": "Biopsy; Gene testing; Lung neoplasms; Mixed small cell lung cancer; Sensitive gene mutations",
"medline_ta": "Zhongguo Fei Ai Za Zhi",
"mesh_terms": null,
"nlm_unique_id": "101126433",
"other_id": null,
"pages": "808-814",
"pmc": null,
"pmid": "34802214",
"pubdate": "2021-11-20",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": "15309021;31712924;30228179;23154565;27040854;22783435;33446664;22103903;14522252;29546681;26340530;17537538;18829487;29101056;27145273;30429033;28203418;24457237;24657128;29950855;32557583;33209601;27168435;17784875;2540288;33103386;24195468",
"title": "MDT Treatment of Small Cell Lung Cancer Complicated with Adenocarcinoma:
A Case Report and Literature Review.",
"title_normalized": "mdt treatment of small cell lung cancer complicated with adenocarcinoma a case report and literature review"
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{
"abstract": "In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting.",
"affiliations": "Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;Department of Medicine and Ageing Sciences, University G. D'Annunzio, Chieti, Italy.;Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;Department of Medicine I, University Hospital Dresden, Dresden, Germany.;Department of Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.;Department of Hematology, University of Washington, Seattle, Washington, United States.;Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States.;Thrombosis Research Institute, University College London, London, United Kingdom.;Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States.;Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;MD Anderson Cancer Center, University of Texas, Houston, Texas, United States.;Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.;Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States.;ITREAS, Academic Research Organization, Amsterdam, The Netherlands.;University Hospitals Leuven, University of Leuven, Leuven, Belgium.;The Ohio State University Wexner Medical Center, Columbus, Ohio, United States.;Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.;Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey, United States.;Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States.;Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;University of Oklahoma Health Sciences Center, College of Public Health, University of Oklahoma, Oklahoma City, Oklahoma, United States.",
"authors": "Kraaijpoel|Noémie|N|;Di Nisio|Marcello|M|;Mulder|Frits I|FI|;van Es|Nick|N|;Beyer-Westendorf|Jan|J|;Carrier|Marc|M|;Garcia|David|D|;Grosso|Michael|M|;Kakkar|Ajay K|AK|;Mercuri|Michele F|MF|;Middeldorp|Saskia|S|;Hernandez|Cristhiam Rojas|CR|;Santamaria|Amparo|A|;Schwocho|Lee|L|;Segers|Annelise|A|;Verhamme|Peter|P|;Wang|Tzu-Fei|TF|;Weitz|Jeffrey I|JI|;Zhang|George|G|;Zwicker|Jeffrey I|JI|;Büller|Harry R|HR|;Raskob|Gary E|GE|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban; D017985:Dalteparin",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0038-1667001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6245",
"issue": "118(8)",
"journal": "Thrombosis and haemostasis",
"keywords": null,
"medline_ta": "Thromb Haemost",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D000066491:Clinical Decision-Making; D017985:Dalteparin; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D018579:Patient Selection; D011725:Pyridines; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013844:Thiazoles; D013997:Time Factors; D016896:Treatment Outcome; D054556:Venous Thromboembolism",
"nlm_unique_id": "7608063",
"other_id": null,
"pages": "1439-1449",
"pmc": null,
"pmid": "30060256",
"pubdate": "2018-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study.",
"title_normalized": "clinical impact of bleeding in cancer associated venous thromboembolism results from the hokusai vte cancer study"
} | [
{
"companynumb": "NL-PFIZER INC-2018224045",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DALTEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "An 86-year-old woman was scheduled to undergo aortic valve replacement and coronary artery bypass graft. On postoperative day 3, she developed sudden-onset neck pain followed by weakness in the right arm. Her symptoms worsened with time, and she developed paraplegia. At 60 h after the first complaint, spontaneous spinal epidural hematoma (SSEH) from C2 to C6 with spinal cord compression was diagnosed from a magnetic resonance image of the cervical region. We decided on conservative therapy because operative recovery was impossible. Delayed diagnosis led to grievous results in the present case. When neurological abnormalities follow neck or back pain after open heart surgery, SSEH must be considered in the differential diagnosis. Further, if it is suspected, early cervical computed tomography/magnetic resonance imaging and surgery should be considered.",
"affiliations": "Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan. hkin@iwate-med.ac.jp.;Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan.;Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan.;Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan.;Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan.;Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan.;Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan.;Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, 19-1 Uchimaru, Morioka, 020-8505, Iwate, Japan.",
"authors": "Kin|Hajime|H|;Mukaida|Masayuki|M|;Koizumi|Junichi|J|;Kamada|Takeshi|T|;Mitsunaga|Yoshino|Y|;Iwase|Tomoyuki|T|;Ikai|Akio|A|;Okabayashi|Hitoshi|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s11748-014-0401-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1863-6705",
"issue": "64(3)",
"journal": "General thoracic and cardiovascular surgery",
"keywords": "Cardiac surgery; Magnetic resonance imaging; Paraplegia; Spinal epidural hematoma",
"medline_ta": "Gen Thorac Cardiovasc Surg",
"mesh_terms": "D000369:Aged, 80 and over; D006348:Cardiac Surgical Procedures; D001026:Coronary Artery Bypass; D003937:Diagnosis, Differential; D005260:Female; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D008279:Magnetic Resonance Imaging; D010264:Paraplegia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101303952",
"other_id": null,
"pages": "153-5",
"pmc": null,
"pmid": "24722959",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22217615;21533946;8568560;16758110;20034311;18358597;15041581;10945413;24148544;24211130;8668786;1402197",
"title": "Spontaneous spinal epidural hematoma presenting as paraplegia after cardiac surgery.",
"title_normalized": "spontaneous spinal epidural hematoma presenting as paraplegia after cardiac surgery"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1053177",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
... |
{
"abstract": "Ocular infections after a heart transplant are rare; but when present, they generally appear during the first year after surgery. Ocular infections may cause significant loss of vision and morbidity if not diagnosed early. For that reason, heart transplant patients should undergo a routine visual examination during follow-up. We report our experience regarding the followup and treatment of a case of toxoplasma retinitis diagnosed in one of our heart transplant recipients.",
"affiliations": "Cardiovascular Surgery Clinic, Türkiye Yüksek Ihtisas Education and Research Hospital, Ankara, Turkey.",
"authors": "Kervan|Umit|U|;Ozdamar|Yasemin|Y|;Yurdakok|Okan|O|;Kucuker|Seref Alp|SA|;Pac|Mustafa|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2012.0303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "12(1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000900:Anti-Bacterial Agents; D015822:Eye Infections, Parasitic; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D012173:Retinitis; D012307:Risk Factors; D013997:Time Factors; D014122:Toxoplasma; D014123:Toxoplasmosis; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "78-80",
"pmc": null,
"pmid": "24471726",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare ocular complication after a heart transplant: toxoplasma retinitis.",
"title_normalized": "a rare ocular complication after a heart transplant toxoplasma retinitis"
} | [
{
"companynumb": "PHHY2014TR013067",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nWe present a case of stress-induced cardiomyopathy (Takotsubo cardiomyopathy) caused by a venous air embolism during a craniotomy performed in the sitting position.\n\n\nMETHODS\nA 69-year-old woman was admitted to the neurosurgical department and scheduled for elective resection of a cerebellar metastasis in the sitting position. After craniotomy and opening of the posterior fossa, a venous air embolism was detected via transesophageal echocardiography. The patient immediately presented with cardiac decompensation with signs of takotsubo or stress-induced cardiomyopathy.\n\n\nCONCLUSIONS\nIntensivists and anesthesiologists in the operating room and in intensive care units need to be aware of stress-induced cardiomyopathy as a probably underdiagnosed disease entity, especially as management differs significantly from other forms of cardiogenic shock. Diagnosis can be accomplished quickly by bedside echocardiography, emphasizing the need for availability of this tool and the integration of stress-induced cardiomyopathy in diagnostic algorithms in the intensive care unit.",
"affiliations": "Department of Neurosurgery, Goethe-University, Frankfurt am Main, Germany; Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Goethe-University, Frankfurt am Main, Germany. Electronic address: Florian.Raimann@kgu.de.;Department of Neurosurgery, Goethe-University, Frankfurt am Main, Germany.;Department of Cardiology, Goethe-University, Frankfurt am Main, Germany.;Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Goethe-University, Frankfurt am Main, Germany.;Department of Neurosurgery, Goethe-University, Frankfurt am Main, Germany.;Department of Neurosurgery, Goethe-University, Frankfurt am Main, Germany; Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Goethe-University, Frankfurt am Main, Germany.",
"authors": "Raimann|Florian Jürgen|FJ|;Senft|Christian|C|;Honold|Jörg|J|;Zacharowski|Kai|K|;Seifert|Volker|V|;Mersmann|Jan|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2017.07.124",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "107()",
"journal": "World neurosurgery",
"keywords": "Craniotomy; Neurosurgical complication; Stress-induced cardiomyopathy; Takotsubo cardiomyopathy; Venous air embolism",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D003399:Craniotomy; D004618:Embolism, Air; D005260:Female; D006801:Humans; D056888:Patient Positioning; D011187:Posture; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "1045.e1-1045.e4",
"pmc": null,
"pmid": "28765018",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Takotsubo Cardiomyopathy Triggered by Venous Air Embolism During Craniotomy in the Sitting Position.",
"title_normalized": "takotsubo cardiomyopathy triggered by venous air embolism during craniotomy in the sitting position"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1084497",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NOREPINEPHRINE"
},
"drugadditional": "3",
... |
{
"abstract": "Here we describe a case of an HIV-infected young woman with extensive drug-resistant virus, who was successfully switched from a raltegravir-based regimen to a dolutegravir-based intensified antiretroviral regimen a few days before scheduled caesarean section because of the still detectable viral load. The trough concentrations of all antiretroviral drugs before and after delivery are also described. Our case underlines both the difficult management of young women, HIV-infected at young age with very limited treatment options and the great variability in the pregnancy-related physiological changes affecting the pharmacokinetics of antiretrovirals.",
"affiliations": "Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy.;Unit of Clinical Pharmacology, Luigi Sacco University Hospital, Milan, Italy.;Clinical Microbiology, Virology and Diagnosis of Bioemergency, Luigi Sacco University Hospital, Milan, Italy.;Clinic of Pediatrics, Luigi Sacco University Hospital, Milan, Italy.;Clinical Microbiology, Virology and Diagnosis of Bioemergency, Luigi Sacco University Hospital, Milan, Italy.;Department of Gynecology and Obstetrics, Luigi Sacco University Hospital, Milan, Italy.;Department of Infectious Diseases, Luigi Sacco University Hospital, Milan, Italy.",
"authors": "Simonetti|Francesco R|FR|;Cattaneo|Dario|D|;Zanchetta|Nadia|N|;Giacomet|Vania|V|;Micheli|Valeria|V|;Ciminera|Nadia|N|;Gervasoni|Cristina|C|",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; C562325:dolutegravir",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3122",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "22(4)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D001682:Biological Availability; D002585:Cesarean Section; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D024882:Drug Resistance, Viral; D057915:Drug Substitution; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011247:Pregnancy; D011728:Pyridones; D000068898:Raltegravir Potassium; D019562:Viral Load",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "361-363",
"pmc": null,
"pmid": "28051809",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnancy-related changes of antiretroviral pharmacokinetics: an argument for therapeutic drug monitoring.",
"title_normalized": "pregnancy related changes of antiretroviral pharmacokinetics an argument for therapeutic drug monitoring"
} | [
{
"companynumb": "IT-VIIV HEALTHCARE LIMITED-IT2017190823",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RALTEGRAVIR"
},
"drugadditional... |
{
"abstract": "To assess the frequency of adverse events associated with periendoscopic management of direct oral anticoagulants (DOACs) in patients undergoing elective GI endoscopy and the efficacy and safety of the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) recommendations (NCT02734316).\n\n\n\nConsecutive patients on DOACs scheduled for elective GI endoscopy were prospectively included. The timing of DOAC interruption and resumption before and after the procedures were recorded, along with clinical and procedural data. Procedures were stratified into low-risk and high-risk for GI-related bleeding, and patients into low-risk and high-risk for thromboembolic events. Patients were followed-up for 30 days for major and clinically relevant non-major bleeding events (CRNMB), arterial and venous thromboembolism and death.\n\n\n\nOf 529 patients, 38% and 62% underwent high-risk and low-risk procedures, respectively. There were 45 (8.5%; 95% CI 6.3% to 11.2%) major or CRNMB events and 2 (0.4%; 95% CI 0% to 1.4%) thromboembolic events (transient ischaemic attacks). Overall, the incidence of bleeding events was 1.8% (95% CI 0.7% to 4%) and 19.3% (95% CI 14.1% to 25.4%) in low-risk and high-risk procedures, respectively. For high-risk procedures, the incidence of intraprocedural bleeding was similar in patients who interrupted anticoagulation according to BSG/ESGE guidelines or earlier (10.3%vs10.8%, p=0.99), with a trend for a lower risk as compared with those who stopped anticoagulation later (10.3%vs25%, p=0.07). The incidence of delayed bleeding appeared similar in patients who resumed anticoagulation according to BSG/ESGE guidelines or later (6.6%vs7.7%, p=0.76), but it tended to increase when DOAC was resumed earlier (14.4%vs6.6%, p=0.27). The risk of delayed major bleeding was significantly higher in patients receiving heparin bridging than in non-bridged ones (26.6%vs5.9%, p=0.017).\n\n\n\nHigh-risk procedures in patients on DOACs are associated with a substantial risk of bleeding, further increased by heparin bridging. Adoption of the BSG/ESGE guidelines in periendoscopic management of DOACs seems to result in a favourable benefit/risk ratio.\n\n\n\nNCT02734316; Pre-results.",
"affiliations": "Gastroenterology Unit, Valduce Hospital, Como, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Gastroenterology Unit, Valduce Hospital, Como, Italy.;Gastroenterology Unit, Nuovo Regina Margherita Hospital, Rome, Italy.;Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Research and University Hospital, Rozzano, Milan, Italy.;Gastroenterology Unit, Valduce Hospital, Como, Italy.;Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Research and University Hospital, Rozzano, Milan, Italy.;Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Research and University Hospital, Rozzano, Milan, Italy.;Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Research and University Hospital, Rozzano, Milan, Italy.;Gastroenterology Unit, Valduce Hospital, Como, Italy.;Digestive Endoscopy Unit, European Institute of Oncology, Milan, Italy.;Digestive Endoscopy Unit, European Institute of Oncology, Milan, Italy.;Gastroenterology Unit, Santa Maria del Prato Hospital, Feltre, Italy.;Gastroenterology and Endoscopy Unit, Department of Abdominal Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy.;Gastroenterology and Endoscopy Unit, Department of Abdominal Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy.;Gastroenterology and GI Endoscopy Unit, Ospedale di Circolo e Fondazione Macchi, Varese, Italy.;Gastroenterology Unit, S. Giuseppe Hospital, Empoli, Italy.;Gastroenterology Unit, Città della Salute e della Scienza, Turin, Italy.;Digestive Endoscopy Unit, ASL 1 Liguria, Imperia Hospital, Imperia, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Gastroenterology and Digestive Endoscopy Unit, AUSL Bologna Bellaria-Maggiore Hospital, Bologna, Italy.;Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy.;Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy.;Gastroenterology and Digestive Endoscopy Unit, S. Agostino-Estense Hospital, Modena, Italy.;Gastroenterology Unit, University of Bari, Bari, Italy.;Department of Clinical Medicine, University of Insubria, Varese, Italy.",
"authors": "Radaelli|Franco|F|;Fuccio|Lorenzo|L|;Paggi|Silvia|S|;Hassan|Cesare|C|;Repici|Alessandro|A|;Rondonotti|Emanuele|E|;Semeraro|Rossella|R|;Di Leo|Milena|M|;Anderloni|Andrea|A|;Amato|Arnaldo|A|;Trovato|Cristina|C|;Bravi|Ivana|I|;Buda|Andrea|A|;de Bellis|Mario|M|;D'Angelo|Valentina|V|;Segato|Sergio|S|;Tarantino|Ottaviano|O|;Musso|Alessandro|A|;Fasoli|Renato|R|;Frazzoni|Leonardo|L|;Liverani|Elisa|E|;Fabbri|Carlo|C|;Di Giulio|Emilio|E|;Esposito|Gianluca|G|;Pigò|Flavia|F|;Iannone|Andrea|A|;Dentali|Francesco|F|;|||",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1136/gutjnl-2018-316385",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-5749",
"issue": "68(6)",
"journal": "Gut",
"keywords": "bleeding; therapeutic endoscopy",
"medline_ta": "Gut",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D015331:Cohort Studies; D017558:Elective Surgical Procedures; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005500:Follow-Up Studies; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D019990:Perioperative Care; D011446:Prospective Studies; D018570:Risk Assessment; D020521:Stroke; D013923:Thromboembolism; D013997:Time Factors; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "2985108R",
"other_id": null,
"pages": "969-976",
"pmc": null,
"pmid": "30064986",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Periendoscopic management of direct oral anticoagulants: a prospective cohort study.",
"title_normalized": "periendoscopic management of direct oral anticoagulants a prospective cohort study"
} | [
{
"companynumb": "PHHY2017IT203534",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Dabigatran is an oral direct thrombin inhibitor that is approved for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Dabigatran has several advantages over warfarin including predictable pharmacokinetics and pharmacodynamics which eliminates the need for routine laboratory monitoring, superiority over warfarin in preventing stroke, or systemic embolism without having an increased risk of bleeding. However, as with any anticoagulant, there remains a real chance of bleeding, including major or life-threatening hemorrhage. Many physicians feel comfortable managing bleeding complications on older anticoagulants like warfarin and heparin, due to extensive experience with the medications along with antidotes to reverse their effects as well as established protocols for treating anticoagulant-associated hemorrhage. However, most physicians have limited clinical experience with dabigatran, there is no specific antidote for dabigatran reversal and there is a paucity of protocols, guidelines, and recommendations for how to manage dabigatran-associated hemorrhage. In this review, we present a case series of patients admitted to our institution for management of bleeding while receiving dabigatran. We retrospectively reviewed these cases to evaluate the efficacy and rationale of the various anticoagulation reversal strategies employed in the context of the existing evidence found in the literature. Specific focus is placed on the therapies utilized and the coagulation studies used to manage these patients.",
"affiliations": "Division of Hematology-Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Division of Hematology-Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Cardiology and the Vascular Medicine Institute, University of Pittsburgh Medical Center Heart and Vascular Institute, Pittsburgh, PA, USA henrybl@upmc.edu.",
"authors": "Kumar|Rohit|R|;Smith|Roy E|RE|;Henry|Brian L|BL|",
"chemical_list": "D000925:Anticoagulants; D000931:Antidotes; D000991:Antithrombins; D002606:Charcoal; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1177/0885066614527417",
"fulltext": null,
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"issn_linking": "0885-0666",
"issue": "30(8)",
"journal": "Journal of intensive care medicine",
"keywords": "bleeding; coagulation; dabigatran; dialysis; thrombin",
"medline_ta": "J Intensive Care Med",
"mesh_terms": "D000925:Anticoagulants; D000931:Antidotes; D000991:Antithrombins; D002606:Charcoal; D000069604:Dabigatran; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006785:Hospitals, University; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D009102:Multiple Organ Failure; D010314:Partial Thromboplastin Time; D006435:Renal Dialysis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D020521:Stroke; D016896:Treatment Outcome",
"nlm_unique_id": "8610344",
"other_id": null,
"pages": "462-72",
"pmc": null,
"pmid": "24668159",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Review of and Recommendations for the Management of Patients With Life-Threatening Dabigatran-Associated Hemorrhage: A Single-Center University Hospital Experience.",
"title_normalized": "a review of and recommendations for the management of patients with life threatening dabigatran associated hemorrhage a single center university hospital experience"
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"companynumb": "US-BAYER-2016-008661",
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"abstract": "We reported 2 cases of colorectal cancer receiving neoadjuvant chemotherapy(NAC)with the aim of curative resection or anal preservation. Case 1: A 50-year-old man was diagnosed with locally advanced rectal cancer with sacral invasion. Because of the sacral invasion, we performed preoperative chemotherapy. He was treated with 12 courses of CapeOX plus Bmab and 3 courses of capecitabine plus radiation therapy(45 Gy in total). After chemoradiation therapy, a lower anterior resection was performed. The pathological finding was pT3pN0pM0, pStage Ⅱ. Case 2: A 69-year-old man was diagnosed with lower rectal cancer. Colonoscopy revealed a tumor near the dentate line. Because the patient desired anal preservation, we performed preoperative chemotherapy. He was treated with IRIS plus Bmab. After 3 courses of chemotherapy, the tumor had reduced in size. The pathological findings were no residual tumor cell, pN0. In our hospital, we have preserved the anus in 2 patients after NAC. Including the above 2 cases, we have performed curative resection in 7 cases. The mean observation period after surgery was 30 months; 1 case died from cancer recurrence(41 months after resection)and other 6 cases lived without cancer relapse.",
"affiliations": "Dept. of Surgery, Kamitsuga General Hospital.",
"authors": "Yamashita|Kazushi|K|;Chiku|Tsuyoshi|T|;Sano|Wataru|W|;Hashiba|Takahiro|T|;Shinoda|Kimio|K|;Togawa|Yasuhiro|Y|",
"chemical_list": "D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0385-0684",
"issue": "46(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D001003:Anal Canal; D000971:Antineoplastic Combined Chemotherapy Protocols; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "133-135",
"pmc": null,
"pmid": "30765665",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two Cases of Locally Advanced Rectal Cancer and Lower Rectal Cancer Resected Successfully That Enabled Anus Preservation after Preoperative Chemotherapy.",
"title_normalized": "two cases of locally advanced rectal cancer and lower rectal cancer resected successfully that enabled anus preservation after preoperative chemotherapy"
} | [
{
"companynumb": "JP-SA-2019SA094239",
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"abstract": "Painful seizures can be the only feature of focal epilepsy. Its localization on a limb favors the epileptic etiology, while abdominal or cephalic paroxysmal pain is not so specific. Painful somatosensory seizures arise from operculo-insular cortex.",
"affiliations": "Department of Neurology Instituto Português de Oncologia Francisco Gentil de Lisboa Lisboa Portugal.;Department of Neurology Instituto Português de Oncologia Francisco Gentil de Lisboa Lisboa Portugal.;Department of Neurology Instituto Português de Oncologia Francisco Gentil de Lisboa Lisboa Portugal.;Neurophysiology Laboratory Instituto Português de Oncologia Francisco Gentil de Lisboa Lisboa Portugal.",
"authors": "Garcez|Daniela|D|https://orcid.org/0000-0002-0684-7347;Marques|Joana|J|https://orcid.org/0000-0002-2242-3771;Fernandes|Mariana|M|https://orcid.org/0000-0003-3673-7576;Foreid|John Peter|JP|",
"chemical_list": null,
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"doi": "10.1002/ccr3.3143",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3143\nCCR33143\nCase Report\nCase Reports\nParoxysmal pain as the only presentation of focal epilepsy\nGARCEZ et al.Garcez Daniela https://orcid.org/0000-0002-0684-7347\n1\ndaniela-garcez@hotmail.com Marques Joana https://orcid.org/0000-0002-2242-3771\n1\n Fernandes Mariana https://orcid.org/0000-0003-3673-7576\n1\n Foreid John Peter \n2\n \n1 \nDepartment of Neurology\nInstituto Português de Oncologia Francisco Gentil de Lisboa\nLisboa\nPortugal\n\n\n2 \nNeurophysiology Laboratory\nInstituto Português de Oncologia Francisco Gentil de Lisboa\nLisboa\nPortugal\n\n* Correspondence\n\nDaniela Garcez, Department of Neurology, Instituto Português de Oncologia Francisco Gentil de Lisboa, R. Prof. Lima Basto 1099‐023, Lisboa, Portugal.\n\nEmail: daniela-garcez@hotmail.com\n\n20 7 2020 \n10 2020 \n8 10 10.1002/ccr3.v8.101971 1973\n31 3 2020 06 5 2020 26 5 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nPainful seizures can be the only feature of focal epilepsy. Its localization on a limb favors the epileptic etiology, while abdominal or cephalic paroxysmal pain is not so specific. Painful somatosensory seizures arise from operculo‐insular cortex.\n\nPainful seizures can be the only feature of focal epilepsy. Its localization on a limb favors the epileptic etiology, while abdominal or cephalic paroxysmal pain is not so specific. Painful somatosensory seizures arise from operculo‐insular cortex.\n\n\nglioblastomaictal paininsulapainful seizureparietal operculum source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:16.10.2020\n\n\nGarcez \nD \n, \nMarques \nJ \n, \nFernandes \nM \n, \nForeid \nJP \n. Paroxysmal pain as the only presentation of focal epilepsy\n. Clin Case Rep . 2020 ;8 :1971 –1973\n. 10.1002/ccr3.3143\n==== Body\n1 BACKGROUND\nA 55‐year‐old man with left temporo‐insulo‐parietal glioblastoma was admitted because of abrupt excruciating pain in the right arm and ipsilateral face. EEG showed a left central frontal rhythmic activity, and complaints were controlled with antiepileptic drugs. Paroxysmal pain is an unusual manifestation of focal seizures and can be the only symptom.\n\nIctal pain is a rare manifestation of focal seizures, with a frequency ranging from 0.2% to 2.8% in patients with epilepsy.\n1\n Classically, it is categorized according to its localization as cephalic, abdominal (visceral or pneumogastric), or unilateral somatosensory pain.\n2\n The last is usually striking and can be described as a burning, stabbing, prickling, throbbing, or tearing sensation. In most cases, they are accompanied by other motor, sensory, or behavioral features, which can denote their ictal origin.\n3\n When it occurs in isolation, seizures are often misdiagnosed and patients can go through unnecessary diagnostic procedures and inadequate treatment. While most patients who present with paroxysmal headache or abdominal pain do not have an epileptic cause in their origin, the localization of paroxysmal pain on a limb is more suggestive of an underlying epileptic cause.\n1\n\n\n\n2 CASE PRESENTATION\nA 55‐year‐old man was diagnosed with a left temporo‐insulo‐parietal left tumor after developing focal cognitive seizures with expressive aphasia or complex visual hallucinations (Figure 1). He underwent partial tumor resection resulting in persistent conduction aphasia, characterized by a slight difficulty repeating and naming everyday objects, with literal paraphasic errors. The histopathology diagnosis was compatible with a glioblastoma. Due to increase in seizure frequency, characterized by aphasic exacerbation afterward that included inability to understand language, he was medicated with successive and incremental doses of levetiracetam and sodium valproate until complete response with 3000 mg/day and 2000 mg/day, respectively. He started treatment with chemotherapy and radiotherapy according to STUPP protocol (temozolomide concomitant with radiotherapy and subsequent six cycles of adjuvant temozolomide), with an initial good radiological response. While undergoing his first adjuvant chemotherapy cycle, he was admitted in the emergency room, desperately screaming because of acute and excruciating pain on the right arm and ipsilateral face, described as shock‐like and stabbing. Each episode lasted a few seconds but they had been repeating in cluster for over an hour. General blood analyses were unremarkable; the electroencephalography showed a left central frontal rhythmic activity during the pain episodes (Figure 2). The add‐on of intravenous lacosamide (bolus of 200 mg) resolved the painful complaint in a few minutes, and he continued subsequent treatment with 200 mg of lacosamide every 12 hours. The brain MRI performed a few days later showed local tumor recurrence (Figure 2). After being discharged, he continued treatment regimen with lacosamide (400 mg/day), levetiracetam (3000 mg/day), and sodium valproate (2000 mg/day), along with oral temozolomide and dexamethasone. The follow‐up brain MRIs showed a very mild tumor growing, concurrent with the development of the right hemiparesis with brachial predominance. Although he remained seizure‐free, we had to reduce sodium valproate (1200 mg/day), because of the hepatic and hematologic toxicity induced by chemotherapy. Unfortunately, the patient died, 7 months after hospital discharge, because of infectious complications.\n\nFIGURE 1 (A) Coronal flair, (B) axial flair, and (C) axial T1 + gad brain MRI sequences showing a left temporo‐insulo‐parietal glioblastoma\n\nFIGURE 2 (A) EEG of painful seizure, which starts with diffuse attenuation of electrogenesis, followed by rhythmic theta activity (left fronto‐centro‐parietal and midline) with progressive slowing until the end of the painful episode; (B) Brain MRIs (T1 + gad and flair sequences) showing local tumor recurrence; (C) sLoreta (fast Fourier transform approximation) for the first seconds of the rhythmic theta activity. Inverse solution with a left parietal localization. ASA 4.7 software with standard MRI and electrode digitalization for the 10/20 system\n\n3 DISCUSSION\nThis case refers to a man with a temporo‐insulo‐parietal glioblastoma, partially removed, undergoing active oncological treatment and with controlled symptomatic focal epilepsy who presented to the hospital with sudden excruciating somatosensory pain. The pain was restricted to the right arm and face, which locates the site of the neurological dysfunction to the left cortical hemisphere. A clue to identifying its nature as epileptic may be its relatively brief and abrupt stereotypical paroxysmal occurrence. Although ictal pain is often associated with other seizure symptoms, it can be the only manifestation of focal epilepsy. Among patients with ictal pain, those who report it to their limbs are more likely to have an epileptic cause.\n1\n The presence of positive symptoms points to an irritative rather than destructive disturbance but in this context the most likely cause would be a tumor relapse. There is an inverse relationship between seizure prevalence and tumor growth rate,\n4\n and actually, in our case, although we were dealing with a highly aggressive tumor, the follow‐up brain MRIs did not show a fast‐growing rate, which could allow enough time for the tumor cells to re‐organize, vascularize, and develop mechanisms necessary for epileptogenesis.\n4\n Under some pathophysiological conditions, operculo‐insular lesions may produce location‐specific painful epileptic seizures. Functional imaging studies have identified several cortical areas activated by painful stimuli, referred as “pain matrix,” including, among others, the primary somatosensory area, the supplementary motor area, the insula, and the anterior frontal or the posterior parietal cortices.\n5\n Some cases of ictal pain with foci originating in the frontal, parietal, and temporal regions have been described with surface EEG.\n4\n, \n6\n However, data from functional cortical mapping by using direct cortical stimulation suggest that the origin of painful somatosensory seizures arises solely from the medial part of parietal operculum or the posterior and upper part of the insular cortex.\n7\n, \n8\n\n\n\nTaking into account the cortical mapping studies and the localization of our patient's glioblastoma, we suggest that the painful seizure has a left operculo‐insular origin and that the rhythmic activity captured on the surface EEG represents propagation to the primary parietal cortex.\n\nThe optimal antiepileptic therapy in patients with brain tumors and epilepsy remains to be defined. We decided to add lacosamide because it has a favorable pharmacokinetic profile, including a lack of induction or inhibition of hepatic enzymes, low protein binding, and low potential for drug interactions. Such characteristics make lacosamide an interesting therapeutic option for patients who are undergoing antineoplastic treatments.\n\nParoxysmal contralateral pain can be the only manifestation of epileptic seizures with operculo‐insular cortex involvement. This knowledge is useful to avoid misdiagnosis and to prompt appropriate management with antiepileptic drugs.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nDG: wrote the manuscript. JM and MF: evaluated the patient and revised the manuscript. and JF: carried out the EEG assessment. All authors approved the final version to be published.\n==== Refs\nREFERENCES\n1 \n\nAsadi‐Pooya \nAA \n, \nAsadollahi \nM \n, \nSperling \nMR \n. Ictal pain: occurrence, clinical features, and underlying etiologies\n. Epilepsy Behav . 2016 ;61 :59 ‐62\n.27315133 \n2 \n\nBryan Young \nG \n, \nBlume \nWT \n. Painful epileptic seizures\n. Brain . 1983 ;106 (3 ):537 ‐554\n.6640268 \n3 \n\nHwang \nST \n, \nGoodman \nT \n, \nStevens \nSJ \n. Painful seizures: a review of epileptic ictal pain\n. Curr Pain Headache Rep . 2019 ;23 :83 .31506775 \n4 \n\nChen \nDY \n, \nChen \nCC \n, \nCrawford \nJR \n, \nWang \nSG \n. Tumor‐related epilepsy: epidemiology, pathogenesis and management\n. J Neurooncol . 2018 ;139 :13 ‐21\n.29797181 \n5 \n\nPeyron \nR \n, \nLaurent \nB \n, \nGarcía‐Larrea \nL \n. Functional imaging of brain responses to pain. A review and meta‐analysis (2000)\n. Neurophysiol Clin . 2000 ;30 :263 ‐288\n.11126640 \n6 \n\nNair \nDR \n, \nNajm \nI \n, \nBulacio \nJ \n, \nLuders \nH \n. Painful auras in focal epilepsy\n. Neurology . 2001 ;57 (4 ):700 ‐702\n.11524483 \n7 \n\nMazzola \nL \n, \nIsnard \nJ \n, \nPeyron \nR \n, \nMauguière \nF \n. Stimulation of the human cortex and the experience of pain: wilder Penfield's observations revisited\n. Brain . 2012 ;135 (2 ):631 ‐640\n.22036962 \n8 \n\nMontavont \nA \n, \nMauguiere \nF \n, \nMazzola \nL \n, et al. On the origin of painful somatosensory seizures\n. Neurology . 2015 ;84 (6 ):594 ‐601\n.25589668\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(10)",
"journal": "Clinical case reports",
"keywords": "glioblastoma; ictal pain; insula; painful seizure; parietal operculum",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1971-1973",
"pmc": null,
"pmid": "33088531",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "31506775;29797181;11126640;25589668;11524483;6640268;22036962;27315133",
"title": "Paroxysmal pain as the only presentation of focal epilepsy.",
"title_normalized": "paroxysmal pain as the only presentation of focal epilepsy"
} | [
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"companynumb": "PT-ASPP-GLO2020PT011312",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
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... |
{
"abstract": "BACKGROUND\nHydroxychloroquine (HCQ) is most frequently used in the treatment of systemic inflammatory diseases. Cardiac complications of anti-malarial drugs are uncommon, and most of the time are the result of a long-term exposition. In this case, cardiotoxicity is the consequence of the lysosomal dysfunction and the result of intracytoplasmic granular material inclusions.\n\n\nMETHODS\nWe report a 77-year-old woman who presented a very early and reversible cardiotoxicity, probably related to the quinidine like effect of the HCQ, 10 days after initiation of therapy for Whipple endocarditis.\n\n\nCONCLUSIONS\nWe discuss the different mechanisms of cardiotoxicity of anti-malarial drugs and their clinical manifestations.",
"affiliations": "Service de médecine interne et RECIF, CHU Amiens-Picardie, Amiens, France. Electronic address: yoanz@hotmail.com.;Service de cardiologie, CHU Amiens-Picardie, Amiens, France.;Service de chirurgie cardiaque, CHU Amiens-Picardie, Amiens, France.;Service de médecine interne et RECIF, CHU Amiens-Picardie, Amiens, France; Inserm 1088, université de Picardie-Jules-Verne, Amiens, France.;Service de médecine interne et RECIF, CHU Amiens-Picardie, Amiens, France; Inserm 1088, université de Picardie-Jules-Verne, Amiens, France.",
"authors": "Zerbib|Y|Y|;Guillaumont|M P|MP|;Touati|G|G|;Duhaut|P|P|;Schmidt|J|J|",
"chemical_list": "D000962:Antimalarials; D006886:Hydroxychloroquine",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "37(3)",
"journal": "La Revue de medecine interne",
"keywords": "Cardiomyopathie; Cardiomyopathy; Cardiotoxicity; Cardiotoxicité; Endocardite; Endocarditis; Hydoxychloroquine; Hydroxychloroquine; Maladie de Whipple; Whipple's disease",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000368:Aged; D000962:Antimalarials; D066126:Cardiotoxicity; D004697:Endocarditis, Bacterial; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008061:Whipple Disease",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "209-11",
"pmc": null,
"pmid": "26320366",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early cardiotoxicity of Hydroxychloroquine.",
"title_normalized": "early cardiotoxicity of hydroxychloroquine"
} | [
{
"companynumb": "FR-CONCORDIA PHARMACEUTICALS INC.-CO-PL-FR-2015-225",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
... |
{
"abstract": "OBJECTIVE\nArnica montana, belonging to the Compositae family, is a plant with a longstanding tradition of relieving pain and/or inflammation in muscles and joints and may thus represent an alternative to nonsteroidal antiinflammatory drugs, which are often ineffective or lead to a number of adverse effects. A homeopathic arnica patch (3X dilution according to the Homeopathic Pharmacopoeia of the United States) was developed to alleviate pain symptoms in the back and neck muscles and joints.\n\n\nMETHODS\nThe present case report describes the treatment outcome after administration of the arnica patch in a 55-year-old female patient with pain in the right hand and numbness in the fourth finger after cellulitis in the palmar area. The cellulitis was treated with antibiotics, but pain symptoms remained at 7 points on a 0-to-10-point visual analog scale (VAS) for pain despite intake of oral ibuprofen and oral and topical application of an arnica-containing complex homeopathic ointment. Ten arnica patches were dispensed to the patient. She cut the patch into strips to cover all painful areas of the hand and applied them at night. After 3 days, she reported a substantial decrease in pain symptoms (VAS = 1) and a marked decrease in numbness and in the size of a tender nodule on the third metacarpal area. Moreover, the patient was able to sleep through the night without being awakened by the pain. The symptoms declined further during the next 2 days.\n\n\nCONCLUSIONS\nThis case demonstrates that after a relatively short period of time, the administration of the arnica patch on the hand provided a marked reduction of pain and recovery of functionality of the hand.",
"affiliations": "Elisabeth Barkey, MD, is specialized in internal medicine and practices in her private office in Santa Fe, New Mexico.",
"authors": "Barkey|Elisabeth|E|;Kaszkin-Bettag|Marietta|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"issn_linking": "2164-9561",
"issue": "1(2)",
"journal": "Global advances in health and medicine",
"keywords": "Arnica; cellulitis; homeopathy; inflammation; metacarpal; nodule; numbness; pain",
"medline_ta": "Glob Adv Health Med",
"mesh_terms": null,
"nlm_unique_id": "101584936",
"other_id": null,
"pages": "18-20",
"pmc": null,
"pmid": "24278813",
"pubdate": "2012-05",
"publication_types": "D002363:Case Reports",
"references": "17846846;12562974;21556350;17105693;20210866;16781589;20085178;17227743;18346625;15949781",
"title": "A Homeopathic Arnica Patch for the Relief of Cellulitis-derived Pain and Numbness in the Hand.",
"title_normalized": "a homeopathic arnica patch for the relief of cellulitis derived pain and numbness in the hand"
} | [
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"abstract": "A 40's year-old female patient with acute myeloblastic leukemia received high-dose cytarabine(HD-Ara-C)as her third induction therapy. Because the pharmacist in charge noticed on a prior interview that she had experienced a mild skin eruption similar to hand-foot syndrome(HFS)in the previous round oftherapy(idarubicin and cytarabine), heparinoid lotion and hypoallergenic soap were used to prevent HFS. However, HFS occurred on day 3, and further developed on day 6 to grade 3 with painful erythema, swelling, and paresthesia affecting the entire surface of both hands. We cared for her with moisturization, lifestyle guidance, rotation of steroid ointment, and occlusive dressing techniques according to a multidisciplinary team approach composed ofa hematologist, dermatologist, pharmacist, and nurse. Her symptoms resolved on day 40.",
"affiliations": "Dept. of Pharmacy, Ichinomiya Municipal Hospital.",
"authors": "Sakurada|Hiroaki|H|;Aoi|Miki|M|;Yuge|Masaaki|M|;Sugimura|Yuriko|Y|;Kitamura|Kunio|K|;Yamamura|Masumi|M|;Tachi|Tomoya|T|;Teramachi|Hitomi|H|",
"chemical_list": "D003561:Cytarabine; D015255:Idarubicin",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0385-0684",
"issue": "43(7)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D004890:Erythema; D005260:Female; D060831:Hand-Foot Syndrome; D006801:Humans; D015255:Idarubicin; D015470:Leukemia, Myeloid, Acute; D010348:Patient Care Team; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "917-9",
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"pmid": "27431642",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of a Multidisciplinary Team Approach to Serious Hand-Foot Syndrome Induced by High-Dose Cytarabine Therapy.",
"title_normalized": "a case of a multidisciplinary team approach to serious hand foot syndrome induced by high dose cytarabine therapy"
} | [
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"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
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"drugadditional": null,
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"abstract": "BACKGROUND\nAortic dissection (AoD) is a disease with a high mortality rate. Its clinical manifestations are diverse and covert, which makes diagnosis and treatment challenging. Here, we report a very rare case of aortic dissection leading to bilateral cerebral cortex ischaemia and epilepsy.\n\n\nMETHODS\nA 54-year-old man was admitted to the hospital with acute onset of right limb weakness accompanied by slurred speech. He had a history of hypertension as well as tobacco and alcohol use. The patient was found to have aphasia and right hemiplegia on physical examination. No bleeding was seen on the skull CT. Acute cerebral infarction was considered after admission, and rt-PA was administered for intravenous thrombolysis. During intravenous thrombolysis, the patient suddenly developed epilepsy, and diazepam was given immediately by intravenous injection to control the symptoms. Emergency skull diffusion-weighted imaging (DWI) was performed, and the results showed a small, patchy, high signal that was scattered throughout the left brain hemisphere, right frontal parietal lobe and centrum semiovale. Head and neck CT angiography (CTA) was performed; dissection was found in the ascending aorta, aortic arch, bilateral common carotid artery, proximal part of the internal carotid artery, and initial segment of the left external carotid artery. The laceration was located in the upper part of the ascending aorta. AoD complicated by acute cerebral infarction and epilepsy was considered, and the patient was immediately transferred to the cardiovascular surgery specialist hospital for surgical treatment.\n\n\nCONCLUSIONS\nSome aortic dissections have no typical manifestations of chest pain, and the onset is covert. Atypical clinical manifestations of epilepsy secondary to bilateral cerebral hemisphere infarction may appear. AoD with cerebral infarction is a contraindication for intravenous thrombolysis; surgical treatment is the best way to reduce mortality.",
"affiliations": "Department of Neurology, Chongqing City Hospital of Traditional Chinese Medicine, No. 6, Seventh Branch Road, Panxi, Jiangbei District, Chong qing, 400021, China. 870113579@qq.com.;Department of Neurology, Chongqing City Hospital of Traditional Chinese Medicine, No. 6, Seventh Branch Road, Panxi, Jiangbei District, Chong qing, 400021, China.;Department of Neurology, Chongqing City Hospital of Traditional Chinese Medicine, No. 6, Seventh Branch Road, Panxi, Jiangbei District, Chong qing, 400021, China.",
"authors": "Wang|Jie|J|;Wu|Li-Rong|LR|;Xie|Xin|X|",
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"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1832\n10.1186/s12883-020-01832-y\nCase Report\nStanford type a aortic dissection with cerebral infarction: a rare case report\nWang Jie 870113579@qq.com Wu Li-Rong Xie Xin Department of Neurology, Chongqing City Hospital of Traditional Chinese Medicine, No. 6, Seventh Branch Road, Panxi, Jiangbei District, Chong qing, 400021 China \n23 6 2020 \n23 6 2020 \n2020 \n20 25327 3 2020 18 6 2020 © The Author(s) 2020Open 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.Background\nAortic dissection (AoD) is a disease with a high mortality rate. Its clinical manifestations are diverse and covert, which makes diagnosis and treatment challenging. Here, we report a very rare case of aortic dissection leading to bilateral cerebral cortex ischaemia and epilepsy.\n\nCase presentation\nA 54-year-old man was admitted to the hospital with acute onset of right limb weakness accompanied by slurred speech. He had a history of hypertension as well as tobacco and alcohol use. The patient was found to have aphasia and right hemiplegia on physical examination. No bleeding was seen on the skull CT. Acute cerebral infarction was considered after admission, and rt-PA was administered for intravenous thrombolysis. During intravenous thrombolysis, the patient suddenly developed epilepsy, and diazepam was given immediately by intravenous injection to control the symptoms. Emergency skull diffusion-weighted imaging (DWI) was performed, and the results showed a small, patchy, high signal that was scattered throughout the left brain hemisphere, right frontal parietal lobe and centrum semiovale. Head and neck CT angiography (CTA) was performed; dissection was found in the ascending aorta, aortic arch, bilateral common carotid artery, proximal part of the internal carotid artery, and initial segment of the left external carotid artery. The laceration was located in the upper part of the ascending aorta. AoD complicated by acute cerebral infarction and epilepsy was considered, and the patient was immediately transferred to the cardiovascular surgery specialist hospital for surgical treatment.\n\nConclusions\nSome aortic dissections have no typical manifestations of chest pain, and the onset is covert. Atypical clinical manifestations of epilepsy secondary to bilateral cerebral hemisphere infarction may appear. AoD with cerebral infarction is a contraindication for intravenous thrombolysis; surgical treatment is the best way to reduce mortality.\n\nKeywords\nAortic dissectionCerebral infarctionIntravenous thrombolysisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAortic dissection (AoD) is a disease with a high mortality rate and an incidence of 2.5–3.5/100,000 people per year [1, 2]. Without early surgical intervention, the mortality of Stanford type A AoD at 3 days after onset is greater than 50% [3]. The most common initial manifestation of AoD is pain; however, there are certain patients with AoD who mainly present with neurological symptoms but do not have pain. These patients are likely to be missed clinically.\n\nThe latest guidelines currently treat acute cerebral infarction with AoD as a contraindication to intravenous thrombolytic therapy [4]. If AoD is not ruled out before intravenous thrombolytic therapy, the consequences will be disastrous and may result in a high mortality rate and poor prognosis [5]. A case of AoD with unusual cerebral infarction occurring at our hospital has now been analysed and reported; it is hoped that this case will serve as a reference for clinical practice.\n\nCase presentation\nThe patient was a 54-year-old middle-aged man who experienced acute-onset symptoms. He was admitted to the hospital due to acute onset of weakness in his right limbs accompanied by slurred speech for 2 h. He had a history of hypertension as well as tobacco and alcohol use. The admission examination revealed consciousness, incomplete mixed aphasia, and grade 4 right upper and lower limb muscle strength. No bleeding was seen on the skull CT. Blood tests showed D-dimer 177.60 mg/l and C-reactive protein 130.8 mg/l, and routine blood tests showed white blood cells 11.43 × 109/l, red blood cells 3.2 × 1012/l, and haemoglobin 106 g/l.\n\nAcute cerebral infarction was considered after admission. Recombinant tissue plasminogen activator (rt-PA; 45 mg) was administered for intravenous thrombolysis. During intravenous thrombolysis, the patient suddenly lost consciousness and exhibited involuntary convulsions in the limbs accompanied by increased salivation. Intravenous thrombolysis was immediately stopped, and 10 mg diazepam was given by intravenous injection. Emergency CT scan of the skull showed no bleeding after the cessation of convulsions. Emergency skull diffusion-weighted imaging (DWI) was performed 1 h after intravenous thrombolysis, and the results showed a small patchy high signal that was scattered throughout the left brain hemisphere, right frontal parietal lobe and centrum semiovale (Fig. 1). Therefore, acute cerebral infarction was considered. Head and neck CT angiography (CTA) was performed, and dissection was found in the ascending aorta, aortic arch, bilateral common carotid artery, proximal part of the internal carotid artery, and initial segment of the left external carotid artery. The laceration was located in the upper part of the ascending aorta (Fig. 2). Stanford type A AoD complicated by acute cerebral infarction and epilepsy was considered, and the patient was immediately transferred to the cardiovascular surgery specialist hospital for surgical treatment.\nFig. 1 DWI of the patient showed small patchy high signals scattered throughout the left brain hemisphere and right frontal parietal lobe\n\nFig. 2 CT angiography (CTA) images of the patient showed dissection of the ascending aorta, aortic arch and bilateral common carotid arteries\n\n\n\nDiscussion and conclusions\nThe pathogenesis of AoD is currently unclear, and the most common causes of AoD are hypertension and atherosclerosis, which account for approximately 80% of dissection cases. Other factors include trauma, Marfan syndrome, iatrogenic factors, bicuspid aortic valve deformities, familial asymptomatic aortic dissection, intramural haematoma expansion, pregnancy and arteritis [6]. This patient had no obvious history of trauma, but there was a history of untreated hypertension. Therefore, the possible causes of dissection were hypertension and atherosclerosis.\n\nThe primary manifestation of AoD is often sudden and persistent chest and back pain that cannot be relieved [7]. Approximately 1/3–1/2 of aortic dissections with neurological symptoms have no pain symptoms [8, 9]. The possible reason is that these patients often exhibit a disturbance of consciousness, aphasia and/or amnesia, and their ability to communicate is lost [5]. Clinical symptoms are closely related to dissection initiation and pathophysiological development. This patient presented with a bilateral common carotid artery dissection and first showed right hemiplegia. It is speculated that emboli in left common carotid artery dissections are unstable and easily dislodged, while right common carotid artery dissections are asymptomatic. Therefore, signs of damage to the left brain hemisphere were first manifested clinically in our patient. When alteplase was used for intravenous thrombolysis, the bilateral common carotid artery intimal thrombus disintegrated and dislodged, resulting in extensive embolization events in both hemispheres and eventually, secondary epilepsy.\n\nSome auxiliary examinations can also provide some clinical information. For example, 80% of patients with aortic dissection have a widened mediastinum and abnormal aortic shape when tested with chest X-ray [8]; echocardiography can prompt arterial lumen intimal stripping. Laboratory D-dimer tests can also provide valuable diagnostic information. A study showed that D-dimer levels were significantly higher in patients with ischemic stroke and AoD than in patients without AoD. This trend was evident within 6 h of the onset of symptoms [10]. Weber et al. found that elevated D-dimer levels are related to the severity of AoD [11].\n\nCurrently, the guidelines have recommended intravenous thrombolysis as the highest level of therapy for cerebral infarction within the time window [4]. At this stage, there are many hospitals in China that can perform intravenous thrombolysis, but the level of diagnosis and treatment is uneven. If a patient has AoD, intravenous thrombolysis can have catastrophic consequences, such as new embolic events caused by the disintegration of emboli in the dissection, enlargement of haematomas in the wall of the dissection or around the aorta, pericardial effusion and tamponade due to aortic rupture, and the delay of life-saving surgery [12]. Some AoD patients with neurological defects as the first symptoms have no pain (or the pain cannot be described). Such patients are prone to a missed or delayed diagnosis of AoD. Doctors should also pay attention to any unexplained hypotension, mild dyspnoea, chest discomfort, asymmetry of blood pressure between arms (more than 20 mmHg difference in systolic blood pressure), loss of consciousness, changes in the electrocardiogram, cardiac murmurs, and cold limbs [13]. If the above symptoms are present, aortic CT angiography and echocardiography should be supplemented to determine whether AoD is present.\n\nSurgery is still the best treatment to reduce the mortality of Stanford type A AoD [14]. Whether neurological complications will affect the prognosis of patients with AoD is still controversial. AoD patients need to maintain a low blood pressure to prevent further tearing or even rupture of the dissection, while low blood pressure will reduce stroke hemisphere perfusion and then enlarge the cerebral infarction [15]. Some researchers believe that concurrent ischaemic stroke is a predictor of poor prognosis in patients with AoD [16, 17]; however, with early diagnosis of AoD and appropriate surgical treatment, concurrent neurological symptoms have been reported to not be associated with increased mortality [8, 18, 19].\n\nStanford type A AoD is a high-risk fatal disease. The key to controlling it lies in early detection, early diagnosis, and timely surgical treatment. Approximately 1% of patients with ultra-acute ischaemic stroke have aortic dissection [20]. Prior to intravenous thrombolysis, it is necessary to increase risk awareness and exclude AoD as much as possible to avoid iatrogenic damage to patients.\n\nAbbreviations\nAoDAortic dissection\n\nDWIDiffusion weighted imaging\n\nCTACT angiography\n\nrt-PARecombinant tissue plasminogen activator\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nJie Wang and Li-Rong Wu contributed equally to this work.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nJW contributed to the conception, drafting, and reporting of the case. XX acquired the clinical data. LRW contributed to the revision of the manuscript. All authors have read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll data related to this case report are documented within this manuscript.\n\nEthics approval and consent to participate\nInformed consent was obtained from the patient’s wife to publish his case, and approval for this study was provided by the Research Ethics Committee of Chong qing City Hospital of Traditional Chinese Medicine.\n\nConsent for publication\nWritten informed consent for publication of this case report was obtained from the patient’s wife. A copy of the written consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Melvinsdottir IH Lund SH Agnarsson BA The incidence and mortality of acute thoracic aortic dissection: results from a whole nation study Eur J Cardiothorac Surg 2016 50 1111 1117 10.1093/ejcts/ezw235 27334108 \n2. Clouse WD Hallett JW Jr Schaff HV Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture Mayo Clin Proc 2004 79 176 180 10.4065/79.2.176 14959911 \n3. Coady MA Rizzo JA Goldstein LJ Natural history, pathogenesis, and etiology of thoracic aortic aneurysms and dissections Cardiol Clin 1999 17 615 635 10.1016/S0733-8651(05)70105-3 10589336 \n4. Chinese Neurology Association, Chinese Medical Association, China cerebrovascular disease group, Chinese Medical Association Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018[J] Chin J Neurol 2018 51 9 666 682 \n5. Sakamoto Y Koga M Ohara T Ohyama S Matsubara S Minatoya K Frequency and detection of Stanford type a aortic dissection in hyperacute stroke management Cerebrovasc Dis 2016 42 1–2 110 116 10.1159/000445528 27070149 \n6. Pasternak B Inghammar M Svanstrm H Fluoroquinolone use and risk of aortic aneurysm and dissection:nationwidecohortstudy [J] BMJ 2018 360 3 678 10.1136/bmj.k678 \n7. Bossone E Corteville DC Harris KM Stroke and outcomes in patients with acute type a aortic dissection [J] Circulation 2013 128 11 Suppl 1 S175 S179 10.1161/CIRCULATIONAHA.112.000327 24030403 \n8. Gaul C Dietrich W Friedrich I Neurological symptoms in type a aortic dissections Stroke 2007 38 292 297 10.1161/01.STR.0000254594.33408.b1 17194878 \n9. Hagan PG Nienaber CA Isselbacher EM The international registry of acute aortic dissection (IRAD):new insights into an old disease [J] JAMA 2000 283 7 897 903 10.1001/jama.283.7.897 10685714 \n10. Yoshimuta T Yokoyama H Okajima T Impact of elevated D-dimer on diagnosis of acute aortic dissection with isolated neurological symptoms in ischemic stroke [J] Circ J 2015 79 8 1841 10.1253/circj.CJ-15-0050 25993997 \n11. Weber T Högler S Auer J Berent R Lassnig E Kvas E D-dimer in acute aortic dissection Chest 2003 123 1375 1378 10.1378/chest.123.5.1375 12740250 \n12. Tsivgoulis G Safouris A Alexandrov AV Safety of intravenous thrombolysis for acute ischemic stroke in specific conditions Expert Opin Drug Saf 2015 14 845 864 10.1517/14740338.2015.1032242 25845759 \n13. Koga M, Iguchi Y, et al. Acute ischemic stroke as a complication of Stanford type A acute aortic dissection: a review and proposed clinical recommendations for urgent diagnosis. Gen Thor Cardiovasc Surg. 2018.\n14. Erbel R Aboyans V Boileau C ESC Committee for Practice Guidelines.2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The task force for the diagnosis and treatment of aortic diseases of the European Society of Cardiology (ESC)[J] Eur Heart J 2014 35 41 2873 2926 10.1093/eurheartj/ehu281 25173340 \n15. Guglielmi V, Groeneveld NS, Posthuma L, et al. Aortic dissection masquerading as a code stroke: a single-Centre cohort study [J]. Eur Stroke J. 2019;2396987319883713.\n16. Pansini S Gagliardotto PV Pompei E Parisi F Bardi G Castenetto E Early and late risk factors in surgical treatment of acute type a aortic dissection Ann Thorac Surg 1998 66 3 779 784 10.1016/S0003-4975(98)00555-4 9768930 \n17. Ehrlich MP Ergin MA McCullough JN Lansman SL Galla JD Bodian CA Results of immediate surgical treatment of all acute type a dissections Circulation. 2000 102 19 Suppl 3 III248 III252 11082396 \n18. Trimarchi S Nienaber CA Rampoldi V Myrmel T Suzuki T Mehta RH Contemporary results of surgery in acute type a aortic dissection: the international registry of acute aortic dissection experience J Thorac Cardiovasc Surg 2005 129 1 112 122 10.1016/j.jtcvs.2004.09.005 15632832 \n19. Ueyama K Otaki K Koyama M Kamiyama H Urgent simultaneous revascularization of the carotid artery and ascending aortic replacement for type a acute aortic dissection with cerebral malperfusion Gen Thorac Cardiovasc Surg 2007 55 7 284 286 10.1007/s11748-007-0126-6 17679256 \n20. Iguchi Y Kimura K Sakai K Hyper-acute stroke patients associated with aortic dissection [J] Intern Med 2010 49 6 543 547 10.2169/internalmedicine.49.3026 20228588\n\n",
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"abstract": "Two patients presented simultaneously to our hospital with distinct clinical features associated with the presence of anti-MDA5 antibodies: the first one was admitted for a skin rash resembling to a toxic epidermal necrosis (Lyell syndrome) and the second one presented with pulmonary manifestations attributed to a diffuse fibrosing interstitial pneumonitis on chest CT-scan. In addition to the skin lesions involving 40% of the body surface area, the first patient developed a rapid diffuse interstitial pneumonitis with respiratory distress justifying the initiation of a systemic immunosuppressive treatment. However, she died 3 weeks after her admission from mesenteric thrombosis associated with septic shock. The second patient respiratory condition worsened despite an intensive immunosuppressive treatment with high doses of intravenous methylprednisolone and cyclophosphamide and plasmapheresis, and required lung transplantation. Anti-MDA5 antibody titer declined and disappeared on anti-rejection treatment. These two cases underline the diagnostic conundrum and the therapeutic difficulties in patients with anti-MDA5 antibodies and clinically amyopathic dermatomyositis (CADM) or interstitial lung disease (ILD), who may undergo rapidly-progressive and fatal outcome. Presence of anti-MDA5 antibodies should always be suspected when confronted to CADM patients with cutaneous ulcerations or ILD to allow a rapid and adapted treatment initiation.",
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"doi": "10.3389/fmed.2020.00077",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X Frontiers Media S.A. \n\n10.3389/fmed.2020.00077\nMedicine\nCase Report\nInterstitial Lung Disease-Complicated Anti-MDA5 Antibody in Clinically Amyopathic Dermatomyositis Patients: Report of Two Cases With Distinct Clinical Features\nPacot Laurence 1 Pouchot Jacques 2 De Prost Nicolas 3 Senant Marie 14 Tartour Eric 14 Le Pimpec-Barthes Françoise 5 Israel-Biet Dominique 46 Dragon-Durey Marie-Agnes 14*† 1Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France\n2Service de Médecine Interne, Hôpital Européen Georges Pompidou, Paris, France\n3Service de Réanimation Médicale, Hôpital Henri Mondor, Créteil, France\n4Université Paris-Descartes, Paris, France\n5Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, Paris, France\n6Service de Pneumologie, Hôpital Européen Georges Pompidou, Paris, France\nEdited by: Hsiao-Chi Chuang, Taipei Medical University, Taiwan\n\nReviewed by: Le Thuong Vu, Ho Chi Minh City Medicine and Pharmacy University, Vietnam; Naoki Iwamoto, Nagasaki University Hospital, Japan\n\n*Correspondence: Marie-Agnes Dragon-Durey marie-agnes.durey@aphp.frThis article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine\n\n†ORCID: Marie-Agnes Dragon-Durey orcid.org/0000-0002-5809-8122\n\n\n10 3 2020 \n2020 \n7 7702 12 2019 25 2 2020 Copyright © 2020 Pacot, Pouchot, De Prost, Senant, Tartour, Le Pimpec-Barthes, Israel-Biet and Dragon-Durey.2020Pacot, Pouchot, De Prost, Senant, Tartour, Le Pimpec-Barthes, Israel-Biet and Dragon-DureyThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Two patients presented simultaneously to our hospital with distinct clinical features associated with the presence of anti-MDA5 antibodies: the first one was admitted for a skin rash resembling to a toxic epidermal necrosis (Lyell syndrome) and the second one presented with pulmonary manifestations attributed to a diffuse fibrosing interstitial pneumonitis on chest CT-scan. In addition to the skin lesions involving 40% of the body surface area, the first patient developed a rapid diffuse interstitial pneumonitis with respiratory distress justifying the initiation of a systemic immunosuppressive treatment. However, she died 3 weeks after her admission from mesenteric thrombosis associated with septic shock. The second patient respiratory condition worsened despite an intensive immunosuppressive treatment with high doses of intravenous methylprednisolone and cyclophosphamide and plasmapheresis, and required lung transplantation. Anti-MDA5 antibody titer declined and disappeared on anti-rejection treatment. These two cases underline the diagnostic conundrum and the therapeutic difficulties in patients with anti-MDA5 antibodies and clinically amyopathic dermatomyositis (CADM) or interstitial lung disease (ILD), who may undergo rapidly-progressive and fatal outcome. Presence of anti-MDA5 antibodies should always be suspected when confronted to CADM patients with cutaneous ulcerations or ILD to allow a rapid and adapted treatment initiation.\n\nautoantibodiesdermatomyositisskin rashinterstitial lung diseaseanti-rejection therapylung transplantationanti-MDA5\n==== Body\nBackground\nPolymyositis/dermatomyositis (PM/DM) are systemic inflammatory myopathies which involve skeletal muscles, skin and possibly other organs like joints and lung. Annual incidence of PM/DM is ~8.5 per million (1). In its clinically amyopathic form (CADM), which represents ~20% of all DM (2), the disease is mostly characterized by cutaneous lesions such as ulcerations, palm papules or Gottron's sign that persist for more than 6 months without sign of muscle weakness (Sontheimer criteria). Incidence of PM/DM-related interstitial lung diseases (ILD) ranges from 5 to 65%, depending on whether clinical, radiological, functional or histological criteria are used (3). Among these patients the presence of anti-synthetase antibodies seems to be of a relatively good prognosis (4, 5) whereas mortality rates can be high in other autoimmune-related ILD, with a poor response to immunosuppressive therapy, particularly in CADM-ILD. In 2005, Sato and collaborators described for the first time an antibody recognizing a 140 kDa protein (anti-CADM-140 antibodies) which was associated with CADM in Asian patients, who tended to develop rapidly-progressive ILD (RP-ILD) (6). They later on identified this 140 kDa protein as being melanoma differentiation–associated gene 5 (MDA5) (7), a protein implicated in long double-strand RNA recognition, notably picornaviruses RNAs, that activates the interferon signaling pathway through the adaptor molecule MAVS (8).\n\nSince then, many studies have confirmed that anti-MDA5 antibodies are most frequently detected in CADM patients, representing up to 50–73% of CADM (2), and are often associated with ILD (9). Moreover, skin ulcerations are more frequent and severe in anti-MDA5 positive patients than in DM/CADM patients without anti-MDA5 antibodies (10).\n\nWe here report on two Caucasian patients, positive for anti-MDA5 antibodies, who were simultaneously admitted to the same hospital, with distinct clinical features.\n\nCase Presentation\nCase #1\nA 59-year-old woman presenting with facial erythema and polyarthralgia was diagnosed with rheumatoid arthritis and treated by methotrexate (Figure 1). She rapidly developed hepatic cytolysis that persisted after a switch to hydroxychloroquine. Three months later, she developed vesicles and pustules on the shoulders, which firstly responded to a local corticosteroid treatment. The appearance of large cutaneous erosions on the back, chest, arms and the legs and necrotic skin lesions over the elbows and the ankles one month later led to suspect a Lyell syndrome, justifying her admission in the hospital. Cutaneous lesions of this patient have previously been described in a short letter (11). Her past medical history included a splenectomy for idiopathic thrombocytopenic purpura at the age of 37 years, an allergic asthma and a nasal polyposis.\n\nFigure 1 Chronological representation of the main clinical data of Case #1 (top) and Case #2 (bottom). AF, Atrial fibrillation; DIP, diffuse interstitial pneumonitis.\n\nAt the time of diagnosis, the patient showed anemia and moderate hepatic cytolysis (Table 1). Presence of antinuclear antibodies (ANA) was revealed by indirect immunofluorescence (IIF) on Hep-2 cells (Euroimmun©, Germany) with the association of a homogenous staining, multiple nuclear dots pattern, anti-Golgi apparatus pattern, and rare isolated cytoplasmic islets positivity (Figure 2). Antigenic specificity was studied by immunodots (Euroimmun©, Autoimmune Inflammatory Myopathies and Autoimmune Hepatopathies, Germany) using the systems EUROBlotMaster and EUROLineScan (Euroimmun©, Germany), and revealed high levels of anti-MDA5 (with an intensity of the antigen band superior to 10-fold the positive threshold), anti-SSA 52 (Trim 21) and anti-Sp-100 autoantibodies.\n\nTable 1 Biological findings at diagnosis.\n\n\tHb\n(Females 12–16 g/dL; males 13–17g/dL)\tPlatelets\n(150–450G/L)\tWBC\n(4–10G/L)\tCreatininemia\n(<80 μmol/L)\tALP\n(35–105 U/L)\t\nCase #1\t8.3\t425\t7,9\t52\t156\t\nCase #2\t11.9\t333\t11\t47\t82\t\n\tAST\n(<35 U/L)\tALT\n(<35 U/L)\tGGT\n(<40 U/L)\tBilirubin\n(<21\nμmol/L)\tLDH\n(<250 U/L)\t\nCase #1\t52\t21\t239\t11\t461\t\nCase #2\t27\t43\t97\t9\t348\t\nNormal ranges are indicated into brackets. Abnormal values are in bold characters. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma-glutamyltransferase; Hb, hemoglobin; LDH, lactate dehydrogenase; WBC, white blood cells.\n\nFigure 2 (A) ANA aspect of Case #1. IIF on Hep-2 (1/80) revealed presence of rare isolated cytoplasmic islets (1), homogenous staining (2), multiple nuclear dots pattern (3) and anti-Golgi apparatus pattern (4). (B) Radiographic imaging of Case #2. Thoracic computed tomography scan revealed bilateral interstitial lung disease with lower lung predominance, thickened alveolar septa, condensations, and traction bronchiectasis.\n\nDuring the time of her hospitalization, the cutaneous erosions spread rapidly and reached 40% of the body surface. Because of a concomitant respiratory distress, a systemic immunosuppressive treatment with 500 mg/day of methylprednisolone for 3 days was initiated, followed by 1.5 mg/kg of prednisone per day and one pulse of 0.6 g/m2 of cyclophosphamide. Despite this treatment, a diffuse interstitial pneumonitis rapidly developed, followed by a mesenteric thrombosis with multiple organ failure and a septic shock. The patient ultimately died from a systemic infection, 3 weeks only after diagnosis.\n\nCase #2\nA 51-year-old man presented with dyspnea associated with atrial fibrillation and an acute coronary syndrome treated by angioplasty (Figure 1). His past medical history revealed a 45 pack-year smoking and dyslipidemia. As the dyspnea persisted, a lung CT-scan showed a diffuse fibrosing interstitial pneumonitis (Figure 2). Immunological analysis revealed only very rare cytoplasmic islets positivity in IIF and anti-MDA5 associated with anti-SSA 52 antibodies were detected.\n\nAfter 5 days of bolus corticosteroids (500 mg) with only modest impact on respiratory distress, he received a first pulse of intravenous cyclophosphamide (600 mg/m2) associated with 1 mg/kg of oral corticosteroids then, 3 days afterwards, five sessions of plasmapheresis combined with 4 mg/kg/d of ciclosporin. A second pulse of cyclophosphamide was performed at D25 with a continued treatment with 400 mg/d of ciclosporin and 20 mg/d of corticosteroids. Respiratory failure required an extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation which was performed 7 weeks after diagnosis. Post-transplantation treatment included 1,500 mg of mycophenolate and 11 mg of tacrolimus twice a day, together with 1,000 mg of intravenous methylprednisolone. Since transplantation, the immunological monitoring has showed no reappearance of anti-MDA5 antibodies after 20 weeks of antirejection treatment and a slow normalization of ferritinemia, measured on DxI800 (Beckman-Coulter©, France), was observed (Figure 3). Three years after lung transplantation, the patient is alive.\n\nFigure 3 Biological follow-up and treatment of Case #2. The full curve represents the regression of anti-MDA5 antibodies titers (expressed as relative intensity) and the dotted curve the evolution of serum ferritin level. Five plasma exchanges were performed (arrows), preceded and followed by cyclophosphamide infusions (depicted with stars). MDA5, melanoma differentiation–associated gene 5.\n\nDiscussion\nThe cutaneous manifestations of dermatomyositis and clinically amyopathic dermatomyositis include Gottron papules, Gottron sign, which are almost pathognomonic of these pathologies, periorbital heliotrope erythema, periungual telangiectasias and photodistributed erythema or poikiloderma (12). The occurrence of skin ulcerations, which affect 3–19% of DM patients (13), is more frequently observed in CADM patients than in DM patients (12), especially when associated with anti-MDA5 antibodies (13, 14). In this latter form of CADM, cutaneous ulcerations may overlie Gottron papules over the digital pulp and periungual areas or Gottron sign over the elbows and knees, and may more generally develop on sun-exposed sites, such as chest, back, and arms. Vasculopathy may be a major actor in the development of such ulcerations (10). The other classical clinical features of anti-MDA5 positive patients include palmar papules, alopecia, painful oral ulcers, panniculitis, mechanic hands, arthritis, arthralgias, fever, and ILD (10, 13, 14). Biological findings may include lymphopenia and elevated levels of ferritin, erythrocyte sedimentation rate and interleukin 18 (12, 14) with no increase in serum creatinine kinase (CK). Our first patient indeed presented with fever and arthralgias and developed oropharyngeal ulcerations and ulcerative and necrotic lesions over the limbs with large skin erosions before the diagnosis of diffuse interstitial pneumonitis. Furthermore, she died of septic shock following mesenteric thrombosis, and polymyositis/dermatomyositis patients have an increased risk of venous thromboembolism (15). The mechanisms underlying this pro-thrombotic condition are still largely unknown but may be at least partially explained by a hypercoagulability state due to systemic inflammation in PM/DM patients (16). Concerning CK dosage, the first patient had a transient increase up to 4,100 U/L with an electromyogram compatible with a myogenic syndrome. Case #2 had normal CK levels.\n\nILD is frequently observed early in the disease course of PM/DM patients when using imaging even though respiratory symptoms may be absent (1). Its prognosis is particularly severe in CADM-ILD associated with anti-MDA5 antibodies (4, 5, 7) where it often progresses toward a rapidly progressive fibrosing ILD leading to respiratory failure despite intensive immunosuppression. Only few cases of lung transplantation have been reported in the context of dermatomyositis, often regarded as a contra-indication in these patients. Shoji et al. reported the case of a female patient with a rapidly progressive ILD associated with anti-MDA-5 antibodies that underwent successful lung transplantation after an intensive immunosuppressive therapy including cyclophosphamide and intravenous immunoglobulins (17). Other similar cases have been reported since then, with favorable outcomes (18, 19). Like our two patients, at least one of them had anti-SSA 52 antibodies (18), which are frequently associated with anti-MDA5 antibodies (10) and seem to be correlated with severe forms of ILD (2, 20). As illustrated by our patient #2, some cases may present with RP-ILD and poor or no cutaneous, articular or muscle involvement (2, 21), making diagnosis even more tricky and may delay proper support.\n\nSome biological parameters have been evaluated as potential predictive markers of outcome in anti-MDA5 positive patients. Serum ferritin level has been proposed as a predictor of RP-ILD (when ≥217 ng/mL) and fatal outcome (when ≥828 ng/mL) in these patients (22). This study also revealed that anti-MDA5 antibody titers and IL-18 levels decreased significantly after treatment in the RP-ILD patients who survived, meaning that sustained high levels or reappearance of these parameters represent potential biomarkers of unfavorable outcome or relapse in RP-ILD patients with positive anti-MDA5 antibodies (23). Anti-MDA5 antibody levels are also correlated to the severity of skin ulcerations and ILD, as well as with acute/subacute vs. chronic form of the lung disease, with a cutoff at 500 units/mL (9). However, this threshold has to be calculated for each anti-MDA5 assay due to a lack of standardization. The detection of anti-MDA5 antibodies among DM-associated ILD might be a keystone to anticipate resistance to treatment and survival, as anti-MDA5-positive patients who exhibit initial response to treatment achieve long-term survival (4).\n\nThere is currently no consensus on the best treatment of anti-MDA5 positive patients with RP-ILD. Treatments targeting B-cell functions, like the chimeric monoclonal anti-CD20 antibody rituximab, have shown some efficiency by reducing the production of anti-MDA5 antibodies (24). However, such molecules considerably increase the infectious risk. On the other hand, plasma exchanges represent a reasonable alternative for refractory cases, though adverse events such as allergy cannot be predicted (25). Altogether, combined immunosuppressive therapies, possibly by adjunction of mycophenolate and/or tacrolimus, give promising results (26). Large prospective studies are still lacking to identify the optimal treatment in anti-MDA5 positive patients with RP-ILD, but the scarcity of such patients will most likely require the set-up of multicenter clinical trials.\n\nIn the two patients presented here, the diagnostic delay was about 4 months. Because of its unique clinical presentation and very discrete aspect in IIF, most often described as negative in ANA (10), anti-MDA5-associated-DM is still a diagnostic challenge and its prevalence is probably underestimated. Patients often exhibit mild to absent increase of muscle enzymes, concordant with the amyopathic form of the disease.\n\nThe two cases described here exemplify the difficulties of diagnosing and treating patients with anti-MDA5 positive DM or ILD, who may undergo rapidly-progressive and fatal outcome. Anti-MDA5 antibodies must be suspected in CADM patients with cutaneous ulcerations or ILD to allow rapid treatment initiation.\n\nEthics Statement\nThis study was performed in accordance with the Helsinki Declaration as revised in 2013 and Good Clinical Practice guidelines. It has been approved by the Institutional Review Board according to standards currently applied in France (Commission Nationale de l'Informatique et des Libertés, CNIL N°1922081 from 02/02/2016). Written informed consent was obtained from the participants or from their relatives for the use of their social and medical data for publication of this case report.\n\nAuthor Contributions\nLP, MS, ET, and M-AD-D performed the biological analysis and wrote the manuscript. JP, ND, FL, and DI-B took care of the patients and wrote the manuscript.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Fathi M . Interstitial lung disease, a common manifestation of newly diagnosed polymyositis and dermatomyositis\n. Ann Rheum Dis . (2004 ) 63 :297 –301\n. 10.1136/ard.2003.006122 14962966 \n2. Ortiz-Santamaria V Babot A Ferrer C . Anti-MDA5-positive dermatomyositis: an emerging entity with a variable clinical presentation\n. Scand J Rheumatol . (2017 ) 46 :509 –11\n. 10.1080/03009742.2017.1340512 28795873 \n3. Arboleda R Gonzalez O Cortes M Perez-Cerda F . Recurrent polymyositis-associated lung disease after lung transplantation\n. Interact Cardiovascular Thorac Surg . (2015 ) 20 :560 –2\n. 10.1093/icvts/ivu423 25574033 \n4. Hozumi H Fujisawa T Nakashima R Johkoh T Sumikawa H Murakami A . Comprehensive assessment of myositis-specific autoantibodies in polymyositis/dermatomyositis-associated interstitial lung disease\n. Respir Med . (2016 ) 121 :91 –9\n. 10.1016/j.rmed.2016.10.019 27888997 \n5. Chen F Li S Wang T Shi J Wang G \nClinical heterogeneity of interstitial lung disease in polymyositis and dermatomyositis patients with or without specific autoantibodies\n. Am J Med Sci . (2018 ) 355 :48 –53\n. 10.1016/j.amjms.2017.07.013 29289262 \n6. Sato S Hirakata M Kuwana M Suwa A Inada S Mimori T . Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis\n. Arthritis Rheum . (2005 ) 52 :1571 –6\n. 10.1002/art.21023 15880816 \n7. Sato S Hoshino K Satoh T Fujita T Kawakami Y Fujita T . RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease\n. Arthritis Rheum (2009 ) 60 :2193 –200\n. 10.1002/art.24621 19565506 \n8. del Toro Duany Y Wu B Hur S \nMDA5—filament, dynamics and disease\n. Curr Opin Virol . (2015 ) 12 :20 –5\n. 10.1016/j.coviro.2015.01.011 25676875 \n9. Cao H Pan M Kang Y Xia Q Li X Zhao X . Clinical manifestations of dermatomyositis and clinically amyopathic dermatomyositis patients with positive expression of anti-melanoma differentiation-associated gene 5 antibody\n. Arthritis Care Res . (2012 ) 64 :1602 –10\n. 10.1002/acr.21728 22623119 \n10. Fiorentino D Chung L Zwerner J Rosen A Casciola-Rosen L . The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study\n. J Am Acad Dermatol . (2011 ) 65 :25 –34\n. 10.1016/j.jaad.2010.09.016 21531040 \n11. Dumas M Hua C Hotz C Velter C Duong TA Maraffi T . Epidermal necrolysis and autoimmune diseases: two more observations supporting the concept that ‘toxic' epidermal necrolysis can be ‘non-toxic'\n. J Eur Acad Dermatol Venereol . (2018 ) 32 :e360 –1\n. 10.1111/jdv.14935 29524279 \n12. Cao H Xia Q Pan M Zhao X Li X Shi R . Gottron papules and gottron sign with ulceration: a distinctive cutaneous feature in a subset of patients with classic dermatomyositis and clinically amyopathic dermatomyositis\n. J Rheumatol . (2016 ) 43 :1735 –42\n. 10.3899/jrheum.160024 27307530 \n13. Narang NS Casciola-Rosen L Li S Chung L Fiorentino DF . Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease\n. Arthritis Care Res. (2015 ) 67 :667 –72\n. 10.1002/acr.22498 25331610 \n14. Kurtzman DJB Vleugels RA . Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise review with an emphasis on distinctive clinical features\n. J Am Acad Dermatol . (2018 ) 78 :776 –85\n. 10.1016/j.jaad.2017.12.010 29229575 \n15. Lee YH Song GG . Idiopathic inflammatory myopathy and the risk of venous thromboembolism: a meta-analysis\n. Rheumatol Int . (2017 ) 37 :1165 –73\n. 10.1007/s00296-017-3735-0 28493173 \n16. Li Y Wang P Li L Wang F Liu Y . Increased risk of venous thromboembolism associated with polymyositis and dermatomyositis: a meta-analysis\n. Ther Clin Risk Manag . (2018 ) 14 :157 –65\n. 10.2147/TCRM.S157085 29416342 \n17. Shoji T Bando T Fujinaga T Chen F Sasano H Yukawa N . Living-donor lobar lung transplantation for rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis: report of a case\n. Gen Thor Cardiovasc Surg. (2013 ) 61 :32 –4\n. 10.1007/s11748-012-0106-3 22618987 \n18. Leclair V Labirua-Iturburu A Lundberg IE . Successful lung transplantation in a case of rapidly progressive interstitial lung disease associated with antimelanoma differentiation-associated gene 5 antibodies\n. J Rheumatol . (2018 ) 45 :581 –3\n. 10.3899/jrheum.171047 29606647 \n19. Deitchman AR Kalchiem-Dekel O Todd N Reed RM . Rapidly progressive interstitial lung disease due to anti-melanoma differentiation associated protein-5 requiring a bilateral lung transplant, and complicated by kennel cough\n. Respir Med Case Rep . (2019 ) 28 :100886 . 10.1016/j.rmcr.2019.100886 31249780 \n20. Huang K Vinik O Shojania K Yeung J Shupak R Nimmo M . Clinical spectrum and therapeutics in Canadian patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis: a case-based review\n. Rheumatol Int . (2019 ) 39 :1971 –81\n. 10.1007/s00296-019-04398-2 31375890 \n21. Sakamoto N Ishimoto H Nakashima S Yura H Miyamura T Okuno D . Clinical features of anti-MDA5 antibody-positive rapidly progressive interstitial lung disease without signs of dermatomyositis\n. Intern Med . (2019 ) 58 :837 –41\n. 10.2169/internalmedicine.1516-18 30449789 \n22. Gono T Sato S Kawaguchi Y Kuwana M Hanaoka M Katsumata Y . Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis\n. Rheumatology . (2012 ) 51 :1563 –70\n. 10.1093/rheumatology/kes102 22589330 \n23. Matsushita T Mizumaki K Kano M Yagi N Tennichi M Takeuchi A . Antimelanoma differentiation-associated protein 5 antibody level is a novel tool for monitoring disease activity in rapidly progressive interstitial lung disease with dermatomyositis\n. Br J Dermatol . (2017 ) 176 :395 –402\n. 10.1111/bjd.14882 27452897 \n24. So H Wong VTL Lao VWN Pang HT Yip RML . Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis\n. Clin Rheumatol . (2018 ) 37 :1983 –9\n. 10.1007/s10067-018-4122-2 29713969 \n25. Abe Y Kusaoi M Tada K Yamaji K Tamura N . Successful treatment of anti-MDA5 antibody-positive refractory interstitial lung disease with plasma exchange therapy\n. Rheumatology. (2019 ) kez357. 10.1093/rheumatology/kez357 31504956 \n26. Hoa S Troyanov Y Fritzler MJ Targoff IN Chartrand S Mansour AM . Describing and expanding the clinical phenotype of anti-MDA5-associated rapidly progressive interstitial lung disease: case series of nine Canadian patients and literature review\n. Scand J Rheumatol . (2018 ) 47 :210 –24\n. 10.1080/03009742.2017.1334814 29065773\n\n",
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"journal": "Frontiers in medicine",
"keywords": "anti-MDA5; anti-rejection therapy; autoantibodies; dermatomyositis; interstitial lung disease; lung transplantation; skin rash",
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"title": "Interstitial Lung Disease-Complicated Anti-MDA5 Antibody in Clinically Amyopathic Dermatomyositis Patients: Report of Two Cases With Distinct Clinical Features.",
"title_normalized": "interstitial lung disease complicated anti mda5 antibody in clinically amyopathic dermatomyositis patients report of two cases with distinct clinical features"
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"abstract": "OBJECTIVE\nTo evaluate the long-term outcomes of anti-vascular endothelial growth factor (VEGF) therapy for polypoidal choroidal vasculopathy (PCV) with feeder vessels and to investigate fellow-eye findings.\n\n\nMETHODS\nThis retrospective observational study included 14 eyes with treatment-naïve PCV accompanied by feeder vessels that were treated with anti-VEGF monotherapy. The best-corrected visual acuity (BCVA) at baseline was compared with that at the last follow-up. The fellow-eye indocyanine green angiography findings were also analyzed.\n\n\nRESULTS\nThe mean follow-up period was 28.1 ± 19.2 months (range, 12 to 60 months). During the follow-up period, 5.9 ± 2.5 anti-VEGF injections were administered. The logarithm of the minimal angle of resolution (logMAR) BCVAs at the time of diagnosis, at 3 months, and at the last follow-up were 0.81 ± 0.49, 0.55 ± 0.44, and 0.71 ± 0.54, respectively. Although the BCVA at the last follow-up was not different from the baseline value (p=0.809), an improvement of ≥0.2 logMAR BCVA was observed in seven eyes (50.0%). In 11 eyes that underwent bilateral indocyanine green angiography at diagnosis, PCV, branching vascular networks, and late geographic hyperfluorescence were noted in two (18.2%), five (45.4%), and three (27.3%) fellow eyes, respectively. During the follow-up period, the development of polypoidal lesions in the fellow eye was observed in three patients.\n\n\nCONCLUSIONS\nIn this study, long-term improvement in BCVA was noted in 50% of the included patients who received anti-VEGF monotherapy. A relatively high incidence of pathological findings in the fellow eye and bilateral involvement suggest the need for bilateral examinations.",
"affiliations": "Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea.;Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea. kimoph@gmail.com.;Department of Ophthalmology, Konyang University College of Medicine, Daejeon, Korea.;Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea.;Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea.",
"authors": "Hwang|Hyun Ji|HJ|;Kim|Jae Hui|JH|;Chang|Young Suk|YS|;Kim|Jong Woo|JW|;Kim|Chul Gu|CG|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000069579:Ranibizumab",
"country": "Korea (South)",
"delete": false,
"doi": "10.3341/kjo.2016.0035",
"fulltext": "\n==== Front\nKorean J OphthalmolKorean J OphthalmolKJOKorean Journal of Ophthalmology : KJO1011-89422092-9382The Korean Ophthalmological Society 10.3341/kjo.2016.0035Original ArticlePolypoidal Choroidal Vasculopathy with Feeder Vessels: Characteristics, Fellow Eye Findings, and Long-term Treatment Outcomes Hwang Hyun Ji 1Kim Jae Hui 1Chang Young Suk 2Kim Jong Woo 1Kim Chul Gu 11 Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea.2 Department of Ophthalmology, Konyang University College of Medicine, Daejeon, Korea.\nCorresponding Author: Jae Hui Kim, MD. Department of Ophthalmology, Kim's Eye Hospital, #136 Yeongsin-ro, Yeongdeungpo-gu, Seoul 07301, Korea. Tel: 82-2-2639-7664, Fax: 82-2-2639-7824, kimoph@gmail.com6 2017 12 5 2017 31 3 230 239 11 4 2016 27 6 2016 © 2017 The Korean Ophthalmological Society2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nTo evaluate the long-term outcomes of anti-vascular endothelial growth factor (VEGF) therapy for polypoidal choroidal vasculopathy (PCV) with feeder vessels and to investigate fellow-eye findings.\n\nMethods\nThis retrospective observational study included 14 eyes with treatment-naïve PCV accompanied by feeder vessels that were treated with anti-VEGF monotherapy. The best-corrected visual acuity (BCVA) at baseline was compared with that at the last follow-up. The fellow-eye indocyanine green angiography findings were also analyzed.\n\nResults\nThe mean follow-up period was 28.1 ± 19.2 months (range, 12 to 60 months). During the follow-up period, 5.9 ± 2.5 anti-VEGF injections were administered. The logarithm of the minimal angle of resolution (logMAR) BCVAs at the time of diagnosis, at 3 months, and at the last follow-up were 0.81 ± 0.49, 0.55 ± 0.44, and 0.71 ± 0.54, respectively. Although the BCVA at the last follow-up was not different from the baseline value (p=0.809), an improvement of ≥0.2 logMAR BCVA was observed in seven eyes (50.0%). In 11 eyes that underwent bilateral indocyanine green angiography at diagnosis, PCV, branching vascular networks, and late geographic hyperfluorescence were noted in two (18.2%), five (45.4%), and three (27.3%) fellow eyes, respectively. During the follow-up period, the development of polypoidal lesions in the fellow eye was observed in three patients.\n\nConclusions\nIn this study, long-term improvement in BCVA was noted in 50% of the included patients who received anti-VEGF monotherapy. A relatively high incidence of pathological findings in the fellow eye and bilateral involvement suggest the need for bilateral examinations.\n\nChoroidal neovascularizationMacular degenerationPolypoidal choroidal vasculopathyRanibizumabKim's Eye Hospitalhttp://dx.doi.org/10.13039/100010778\n==== Body\nPolypoidal choroidal vasculopathy (PCV) is a subtype of choroidal neovascularization (CNV) that is characterized by polypoidal lesions and branching vascular networks (BVNs) [12]. Several groups have attempted to classify PCV on the basis of indocyanine green angiography (ICGA) findings. Yuzawa et al. [3] classified PCV into two subtypes according to the presence of a feeder and a draining vessel [4]. More recently, Tan et al. [5] suggested classifying PCV into three subtypes based on the characteristics of the BVNs and leakage on fluorescein angiography. The classification of PCV is important because treatment outcomes and genetic background may differ depending on the subtype of PCV [56789].\n\nIntravitreal anti-vascular endothelial growth factor (VEGF) is an effective treatment for exudative age-related macular degeneration [10]. Although the efficacy is limited in some cases [11], this therapy has been found to be generally effective in the treatment of PCV [12131415]. A previous study showed that the outcomes of anti-VEGF therapy for PCV with feeder vessels were not different from those for PCV without feeder vessels [16]. However, detailed analyses focused on PCV with feeder vessels have not been performed. In addition, previous studies investigating PCV with feeder vessels primarily focused on the characteristics and treatment outcomes of the involved eye. Findings of the fellow eye in patients with this peculiar type of PCV have not been heavily studied.\n\nThe purpose of the present study was to evaluate the long-term outcomes of anti-VEGF therapy for PCV with feeder vessels (which corresponds to PCV type 1 in Yuzawa and colleagues' classification system [34]) and determine the factors associated with visual outcomes. We additionally investigated the findings of the fellow and involved eyes.\n\nMaterials and Methods\nThis single-institutional, retrospective observational study was approved by the institutional review board and was conducted in accordance with the tenets of the Declaration of Helsinki.\n\nThe study included patients diagnosed with treatment-naïve PCV accompanied by feeder vessels. Eyes exhibiting polypoidal lesions on ICGA with or without BVNs were diagnosed with PCV. The presence of feeder vessels was determined on the basis of early-phase ICGA images. The additional inclusion criteria for this study were as follows: (1) follow-up data for at least 12 months, (2) receipt of three monthly intravitreal ranibizumab injections as initial treatment, and (3) receipt of anti-VEGF monotherapy throughout the entire follow-up period. All subjects underwent a comprehensive ophthalmologic examination, including best-corrected visual acuity (BCVA) measurements, 90-diopter lens slit-lamp biomicroscopy, fundus photography, and spectral-domain optical coherence tomography (OCT; Spectral OCT/SLO, OTI Ophthalmic Technologies, Miami, FL, USA). Fluorescein angiography and ICGA were additionally performed using a confocal laser scanning system (HRA-2; Heidelberg Engineering, Dossenheim, Germany). Enhanced-depth imaging OCT [17] (Spectralis, Heidelberg Engineering) was performed at the discretion of each physician. The exclusion criteria for this study were as follows: severe media opacity, a history of photodynamic therapy, a history of vitreoretinal surgery, evidence of end-stage age-related macular degeneration such as central geographic atrophy or disciform scarring, evidence of a macroaneurysm, proliferative diabetic retinopathy, and retinal vascular occlusion. If PCV was bilateral, the eye that was first affected was included.\n\nThe visual acuity values were converted to the logarithm of the minimal angle of resolution (logMAR) values for analysis. Central foveal thickness (CFT) was defined as the distance between the internal limiting membrane and Bruch's membrane at the fovea. This measurement was obtained using the calipers provided by an OCT software program. The greatest linear dimension, including the entire BVN and polypoidal lesions, was measured on the ICGA images. The distance between the fovea and the closest polypoidal lesion was also measured. In addition, the incidence of choroidal vascular hyperpermeability, punctate hyperfluorescent spots, and late geographic hyperfluorescence was estimated. Choroidal vascular hyperpermeability was defined as the presence of multifocal hyperfluorescent areas on late-phase ICGA images [18]. A punctate hyperfluorescent spot was defined as a focal hyperfluorescent spot observed on mid-to-late-phase ICGA images [19]. Late geographic hyperfluorescence was defined as a hyperfluorescent lesion with a clearly demarcated geographic margin, which became apparent approximately 10 minutes after the injection of indocyanine green dye [20].\n\nAll patients were initially treated with three monthly intravitreal ranibizumab injections. Following initial treatment, the patients were scheduled to visit the hospital once every 1 to 4 months depending on the patient's status. Repeat treatment was performed with intravitreal anti-VEGF (either ranibizumab or bevacizumab) if intraretinal/subretinal fluid remained after the initial injections or if intraretinal/subretinal fluid or retinal/subretinal hemorrhage recurred along with an increase in macular thickness.\n\nThe baseline BCVA, BCVA at 3 and 6 months, and BCVA at the final visit were compared. The same comparison was performed with CFT values. The associations of BCVA at the final visit with age, baseline BCVA, baseline CFT, BCVA at 3 months, greatest linear dimension, distance between the fovea and the closest polypoidal lesion, number of anti-VEGF injections, and follow-up duration were also analyzed. Furthermore, the included eyes were divided into two groups according to the morphology of the lesion [4]: an umbrella-like pattern (vessels radiating from a feeder vessel, spreading outward in a radial configuration) and a rake-like pattern (vessels extending from a feeder vessel, resembling the teeth of a rake). The treatment outcomes were evaluated for each group. The incidence of pathological ICGA findings, including PCV, BVNs, and late geographic hyperfluorescence, was evaluated.\n\nData were recorded as mean ± standard deviation where applicable. All statistical analyses were performed using SPSS ver. 12.0 for Windows (SPSS Inc., Chicago, IL, USA). Differences among various time points were analyzed using repeated-measures analysis of variances, and individual comparisons were performed using Bonferroni's method. Pearson correlation analysis was performed to verify any associations between variables. Multivariable analysis was performed using multiple stepwise linear regressions. Differences between groups were compared using the Mann-Whitney U-test with or without Bonferroni's method. A p-value <0.05 was considered statistically significant.\n\nResults\nFourteen patients (nine men [60.9%] and five women [39.1%]; mean age, 66.7 ± 6.7 years) satisfied all the eligible criteria and were included in the study. Table 1 summarizes the baseline characteristics of the included patients. Choroidal vascular hyperpermeability and punctate hyperf luorescent spots were observed in two (14.3%) and 10 (71.4%) eyes, respectively. Choroidal thickness measurements were performed for 10 eyes with available enhanced-depth imaging OCT findings; the mean thickness was 245.4 ± 52.2 µm.\n\nThe mean follow-up period was 28.1 ± 19.2 months (range, 12 to 60 months). All included eyes were initially treated with three monthly intravitreal ranibizumab injections. During the follow-up period, a total of 5.9 ± 2.5 injections, including 4.5 ± 2.1 ranibizumab injections and 1.4 ± 0.8 bevacizumab injections, were administered. Eleven eyes were treated with both ranibizumab and bevacizumab. The remaining four eyes were treated with ranibizumab only.\n\nFig. 1A-1D shows a representative case of an eye treated with intravitreal anti-VEGF therapy. The BCVAs at baseline, 3 months, and the last follow-up were 0.81 ± 0.49 (Snellen equivalent, 20 / 129), 0.55 ± 0.44 (Snellen equivalent, 20 / 70), and 0.71 ± 0.54 (Snellen equivalent, 20 / 102), respectively (Fig. 2A). At 3 months, complete resolution of fluid in the fovea was observed in 11 eyes (78.6%). At the last follow-up, an improvement of ≥0.2 logMAR BCVA was observed in seven eyes (50.0%), whereas deterioration by ≥0.2 logMAR BCVA was observed in four eyes (28.6%). The remaining three eyes exhibited stable visual acuity (21.4%). BCVA at 3 months was significantly improved compared with that at baseline (p=0.004). However, BCVA at the last follow-up showed no significant differences from the baseline value (p=0.809). CFTs at baseline, 3 months, and the last follow-up were 435.3 ± 153.5 µm, 274.2 ± 128.7 µm, and 296.1 ± 145.0 µm, respectively (Fig. 2B). The CFT measurements obtained at the time of diagnosis were significantly different from those obtained at 3 months and the last follow-up (p<0.001 and p=0.045, respectively).\n\nTable 2 summarizes the results of analyses to determine the factors associated with BCVA at the last follow-up. Univariate analysis revealed baseline BCVA and BCVA at 3 months to be significantly associated with the final BCVA, while multivariate analysis revealed BCVA at 3 months to be the most significantly associated factor.\n\nIn total, nine eyes exhibited an umbrella-like pattern and five exhibited a rake-like pattern. The greatest linear dimension, baseline BCVA, and BCVA at the last follow-up were not significantly different between the two groups (p=0.699, p=0.380, and p=0.596, respectively).\n\nPathologic ICGA findings for the fellow eyes were available for 11 patients (84.6%). Table 3 shows the findings for the fellow eyes of the included patients. Two eyes (18.2%) were diagnosed with bilateral PCV, and five (45.4%) exhibited BVNs only, without polypoidal lesions. Late geographic hyperfluorescence without definite BVNs was observed in three eyes (27.3%). During the follow-up period, the development of polypoidal lesions in the fellow eyes was observed in three of the 12 patients (25.0%) with initially unilateral PCV (Fig. 3A-3F and 4A-4F). Two of these patients exhibited active leakage on fluorescein angiography.\n\nDiscussion\nIn the present study, the short-term outcomes of anti-VEGF therapy for PCV with feeder vessels were favorable. A significant improvement in visual acuity and a marked decrease in CFT were observed after three monthly ranibizumab injections. However, the visual acuity at a mean of 28.7 months was not significantly different from baseline, even though 50% of the included eyes exhibited an improvement of ≥0.2 logMAR BCVA. The visual acuity measured at 3 months was found to be the most reliable predictor of the final visual outcome.\n\nYuzawa et al. [3] classified PCV into two types: PCV in the narrow sense (PCV type 2) and polypoidal CNV (PCV type 1) [4]. PCV type 1 was characterized by the presence of feeder vessels and draining venules. PCV type 2 was defined as vascular lesions caused by inner choroidal vessel abnormalities, not by CNV. The size of the lesion was larger in PCV type 1 than in type 2 [4]. In addition, plaque in the late phase ICGA, which is reported to be a characteristic finding of CNV [21], was more frequently noted in PCV type 1 than in PCV type 2 [4]. In OCT images, the highly reflective line representing Bruch's membrane was straight in PCV type 1, whereas the line exhibited irregular thickness and had highly reflective substances adhering to its lower portion in PCV type 2. One of the notable findings in the previous study was that the choroidal thickness was markedly thinner in PCV type 1 than PCV type 2 [4]. A thick choroid is one of the characteristics of PCV that distinguishes it from exudative age-related macular degeneration [2223]. The associated pathological process was suggested to be closely associated with PCV development [24]. For this reason, it is possible that the pathogenesis of the two different subtypes of PCV may differ. Recent genetic studies demonstrated different associations in the genetic variants of the complement factor H gene, age-related maculopathy susceptibility 2 gene, and elastin between the different subtypes of PCV [678]. This result also suggests pathogenic differences between the different subtypes of PCV.\n\nTan et al. [5] introduced another classification system of the vascular patterns of PCV based on the characteristics of the BVNs and leakage on fluorescein angiography. In their study, cases showing polyps supplied by interconnecting channels were classified as type A PCV, whereas cases showing a distinct BVN were classified as type B (cases without leakage on fluorescein angiography) or type C (cases showing significant late leakage on fluorescein angiography) PCV. The lesion size was smallest for type A and largest for type C. Tan et al. [5] suggested that type A and type B/C PCV may correspond to PCV type 1 and type 2 under the classification system of Yuzawa et al. [3], respectively. Kawamura et al. [4] suggested that efficacy of treatments may differ depending on the type of PCV. In a study by Honda et al. [9], a significant visual improvement after photodynamic therapy was noted in PCV type 2, whereas the visual improvement was limited in PCV type 1. In a study by Tan et al. [5], the treatment outcome was also associated with the subtype of PCV; the best treatment outcome was noted in type A, whereas the worst treatment outcome was noted in type C. These results suggest that classifying PCV is important in establishing a treatment plan and understanding the origin of the disorder.\n\nIn a previous study reporting the outcomes of ranibizumab therapy in PCV, the visual prognosis was not associated with the presence of feeder vessels [25]. However, a recent study demonstrated that the treatment outcomes for PCV with a large lesion size were generally poorer than those for PCV with a small lesion size [26]. Considering that PCV with feeder vessels usually exhibits large lesions [45], the treatment outcomes are speculated to be limited. In the present study, the short-term treatment outcomes were favorable. Subretinal or intraretinal fluid in the fovea completely disappeared after the initial three monthly ranibizumab injections in 11 of 14 patients (78.6%). Although the visual acuity at the last follow-up was not significantly different from the baseline value, a definite improvement was observed in 50% of patients. This result suggests that anti-VEGF therapy has a valid effect in some proportion of PCV with feeder vessels.\n\nA large lesion size is associated with poor treatment outcome, regardless of the treatment method [526]. However, the size of the lesion itself was not closely associated with the long-term visual outcomes in our patients. Instead, the visual acuity at 3 months was found to be the most significant predictor of the final visual outcome. In particular, the visual acuity at 3 months, and not the baseline visual acuity, was more closely associated with the final visual outcome, suggesting that the response to anti-VEGF therapy is important for predicting the long-term visual outcome.\n\nA notable finding in the present study was the relatively high incidence of pathological findings in the fellow eye. Two patients were initially diagnosed with bilateral PCV. In these patients, PCV in the fellow eye showed definite feeder vessels. With regard to the remaining nine eyes with available ICGA findings for the fellow eye, 88.9% showed BVNs, late geographic hyperfluorescence, or both. The presence of BVNs or late geographic hyperfluorescence is associated with the development of PCV [27]. In a study by Kim et al. [27], late geographic hyperfluorescence was observed in 23 of 47 eyes (48.9%) with unilateral PCV, six of which also exhibited BVNs. In previous cross-sectional studies, bilateral PCV was observed in approximately 10% to 24% of patients from Asian populations [2829]. In follow-up studies for unilateral PCV, involvement of the fellow eye was observed in 19.1% of patients during a mean follow-up period of 30.3 months [27] and in 11.1% of patients during a 5-year follow-up [30]. The incidence of involvement of the fellow eye in our patients was relatively greater than that reported previously. We postulate that the high incidence of pathological findings in the fellow eye at baseline may have contributed to this finding.\n\nIn the present study, the exact symptom duration was either not determined accurately or was longer than 3 months in eight eyes (57.1%). Although the exact reason is uncertain, previous studies have shown that PCV can develop from long-standing Type 1 neovascularization [31]. It is also reported that some patients with Type 1 neovascular tissue are relatively asymptomatic [32]. We postulate that the growth and expansion of feeder vessels may not induce visual disturbances until the polypoidal lesions finally develop. In addition, in the present study, the mean distance between the fovea and polypoidal lesions was approximately one disc diameter. This relatively peripheral location of polyps may also contribute to the delayed recognition of visual disturbances.\n\nChoroidal vascular hyperpermeability and punctate hyperfluorescent spots are frequently observed in PCV patients. The incidence of choroidal vascular hyperpermeability and punctate hyperfluorescent spots was reported to be between 9.8% and 43.5% [33343536] and between 72.4% and 80% [3537], respectively. In the present study, we first evaluated the incidence of these findings in PCVs with feeder vessels. As a result, the incidence of punctate hyperfluorescent spots (71.4%) was comparable with that reported in previous studies, whereas the incidence of choroidal vascular hyperpermeability (14.3%) was relatively lower in our patients. The origin of PCV is not fully understood. The relatively high incidence of choroidal vascular hyperpermeability and punctate hyperfluorescent spots in both patients with PCV and those with central serous chorioretinopathy suggests that these two disorders share a common pathological mechanism [3337]. A previous study showed that the mean choroidal thickness in patients with PCV accompanied by feeder vessels was only 199 µm, whereas that in patients with PCV without feeder vessels was 288 µm [4]. Although the mean choroidal thickness in our patients with available enhanced-depth imaging OCT results (245.4 µm) was relatively greater than the previously reported value for patients with PCV accompanied by feeder vessels, the thickness was also relatively less than that reported for patients with PCV [2223].\n\nKawamura et al. [4] classified the patterns of PCV with feeder vessels as an umbrella-like pattern and a rake-like pattern. In their study, however, a detailed comparison between the two subtypes was not performed. In the present study, the greatest linear dimension and visual acuity were not different between the two subtypes. Because only a small number of eyes were included, however, further studies with a larger study population are necessary to evaluate the clinical significance of this classification.\n\nThe present study had several limitations. First, it was a retrospective study with a small sample size. Second, because enhanced-depth imaging OCT was not routinely performed, the choroidal thickness was measured in a limited proportion of patients. Third, there was no common treatment protocol. Therefore, differences in treatment decisions among clinicians may have influenced the study results.\n\nIn summary, anti-VEGF therapy showed short-term benefits for PCV with feeder vessels. Although the long-term efficacy was limited, 50% of the included patients showed a definite improvement in the visual acuity. The visual acuity after three monthly ranibizumab injections was the most reliable predictor of long-term visual outcomes. A relatively high incidence of pathological findings in the fellow eye and bilateral involvement suggest the need for bilateral angiographic and tomographic examinations at the time of diagnosis. Close monitoring of the fellow eye during follow-up is also essential.\n\nAcknowledgements\nThis study was supported by Kim's Eye Hospital Research Center.\n\nConflict of Interest: No potential conflict of interest relevant to this article was reported.\n\nFig. 1 Fluorescein angiography (A), indocyanine green angiography (B), and optical coherence tomography (C,D) findings at time of diagnosis (A,B,C) and at 57 months after diagnosis (D) in a patient with polypoidal choroidal vasculopathy. The pattern of polypoidal choroidal vasculopathy is classified as an umbrella-like pattern. The patient's visual acuity was 20 / 30 at diagnosis. During the 57-month follow-up period, the patient was treated with 10 intravitreal anti-vascular endothelial growth factor injections, including eight ranibizumab injections and two bevacizumab injections. At 57 months, there was no fluid (D) and an improvement in the visual acuity to 20 / 20.\nFig. 2 Changes in best-corrected visual acuity (BCVA, A) and central foveal thickness (CFT, B) in eyes treated with anti-vascular endothelial growth factor, according to the follow-up (FU) period. BCVA significantly improved, while CFT significantly decreased after the initial three monthly ranibizumab injections. However, the values at the last follow-up (mean, 29.6 ± 19.6 months) were not significantly different from those at baseline.\nFig. 3 A representative case of polypoidal choroidal vasculopathy (PCV) with feeder vessels. The pattern of PCV is classified as a rake-like pattern. A the time of diagnosis (A-C), polypoidal lesion (A) and subretinal fluid (C) were noted in the right eye, whereas a branching vascular network and late geographic hyperfluorescence (B, arrowheads) were noted in the left eye. The visual acuity in the right eye was 20 / 60. During the 60-month follow-up period, the right eye was treated with nine intravitreal anti-vascular endothelial growth factor injections, including seven ranibizumab injections and two bevacizumab injections. At 60 months (D-F), there is no fluid in the right eye (F) and an improvement in the visual acuity to 20 / 30. However, marked nasal extension of the PCV lesion was observed (D, arrows). In the left eye, polypoidal lesions developed at the margin of the previously noted late geographic hyperfluorescence (E, double arrowheads). (A,B,D,E) Indocyanine green angiography, (C,F) optical coherence tomography.\nFig. 4 A representative case of polypoidal choroidal vasculopathy with feeder vessels. At diagnosis (A-D), polypoidal lesions (A) and subretinal fluid (B) were observed in the right eye, whereas the left eye showed type 3 neovascularization without fluid accumulation (C,D). The visual acuity in the right eye was 20 / 100. During the 42-month follow-up period, the right eye was treated with 11 intravitreal anti-vascular endothelial growth factor injections, including eight ranibizumab injections and three bevacizumab injections. At 42 months (E,F), a small amount of subretinal fluid was observed in the right eye (E). The visual acuity in the right eye improved to 20 / 50. In the left eye, however, polypoidal lesions (F, arrowheads) developed. (A,C,F) Indocyanine green angiography, (B,D,E) optical coherence tomography.\nTable 1 Baseline characteristics of the patients\nValues are presented as mean ± standard deviation or number (%).\n\nBCVA = best-corrected visual acuity; logMAR = logarithm of the minimal angle of resolution.\n\n*Values for 10 eyes with available enhanced-depth imaging optical coherence tomography findings.\n\nTable 2 Results of analyses to determine factors associated with BCVA at the last follow-up\nBCVA = best-corrected visual acuity; CI = confidence interval; VEGF = vascular endothelial growth factor.\n\n*Statistics were analyzed by univariate linear regression analysis; †Statistically significant when tested by stepwise multiple linear regression; ‡Values were measured after three monthly ranibizumab injections.\n\nTable 3 Findings for the fellow eye in 11 patients with available indocyanine green angiography findings\n==== Refs\n1 Spaide RF Yannuzzi LA Slakter JS Indocyanine green videoangiography of 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"fulltext_license": "CC BY-NC",
"issn_linking": "1011-8942",
"issue": "31(3)",
"journal": "Korean journal of ophthalmology : KJO",
"keywords": "Choroidal neovascularization; Macular degeneration; Polypoidal choroidal vasculopathy; Ranibizumab",
"medline_ta": "Korean J Ophthalmol",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D002829:Choroid; D015862:Choroid Diseases; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D011127:Polyps; D000069579:Ranibizumab; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome",
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"pages": "230-239",
"pmc": null,
"pmid": "28534339",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "25775011;21457926;23022162;23612049;22760488;21878855;7542796;26635457;24993059;23848133;15834093;9003339;22127224;1693009;20337606;21896867;22850219;18612226;24997181;17011852;21274555;22465366;17021318;20094008;14557174;19304584;23289808;18639219;18369702;25480464;18439567;19403115;25127698;25158945;23876867;25722216;1553221",
"title": "Polypoidal Choroidal Vasculopathy with Feeder Vessels: Characteristics, Fellow Eye Findings, and Long-term Treatment Outcomes.",
"title_normalized": "polypoidal choroidal vasculopathy with feeder vessels characteristics fellow eye findings and long term treatment outcomes"
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"abstract": "People living with HIV should be considered candidates for solid-organ transplantation (SOT). However, managing HIV-infected patients undergoing SOT represents a major challenge due to the potential drug-drug interactions between antiretroviral drugs and immunosuppressive agents, particularly when resorting to antiretroviral drugs that require pharmacokinetic enhancers. We report three cases of cobicistat-tacrolimus co-administration, two of which also include the co-administration of mTOR inhibitors, in HIV-positive patients undergoing SOT (2 kidney and 1 liver recipient). We review previously reported cases and provide recommendations for initial management following transplantation.",
"affiliations": "Infectious Diseases Service, Hospital Cuenca Alta, Cañuelas, Argentina.;HIV Unit and Infectious Diseases Service, Hospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain. Jambrosioni@intramed.net.;Pharmacy Service, Hospital Clinic-IDIBAPS, Barcelona, Spain.;Pharmacology and Toxicology, SBGM, Hospital Clinic-IDIBAPS, Barcelona, Spain.;Nephrology Service, Hospital Clinic-IDIBAPS, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.;Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research-REDINREN, Barcelona, Spain.;Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research-REDINREN, Barcelona, Spain.;Pharmacy Service, Hospital del Mar, Barcelona, Spain.;HIV Unit and Infectious Diseases Service, Hospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain.;HIV Unit and Infectious Diseases Service, Hospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain. jmmiro@ub.edu.",
"authors": "Diaz|Natalia A|NA|http://orcid.org/0000-0003-0048-5506;Ambrosioni|Juan|J|http://orcid.org/0000-0001-9931-6686;Tuset|Montserrat|M|http://orcid.org/0000-0002-9153-6956;Brunet|Mercé|M|;Cofan|Frederic|F|;Crespo|Gonzalo|G|;Ruiz|Pablo|P|http://orcid.org/0000-0002-5810-8802;Redondo-Pachón|Dolores|D|http://orcid.org/0000-0002-0458-0052;Crespo|Marta|M|http://orcid.org/0000-0001-6992-6379;Marín-Casino|Mónica|M|http://orcid.org/0000-0001-7307-5917;Moreno|Asunción|A|;Miró|José M|JM|;|||",
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"country": "New Zealand",
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"doi": "10.1007/s40121-021-00430-w",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n33830489\n430\n10.1007/s40121-021-00430-w\nCase Series\nTacrolimus, Sirolimus and Everolimus Doses in HIV-Infected Solid-Organ Recipients, Requiring a Cobicistat-Based Antiretroviral Regimen: Report of Three Cases and Review\nhttp://orcid.org/0000-0003-0048-5506\nDiaz Natalia A. 12\nhttp://orcid.org/0000-0001-9931-6686\nAmbrosioni Juan Jambrosioni@intramed.net\n\n2\nhttp://orcid.org/0000-0002-9153-6956\nTuset Montserrat 3\nBrunet Mercé 4\nCofan Frederic 5\nCrespo Gonzalo 6\nhttp://orcid.org/0000-0002-5810-8802\nRuiz Pablo 6\nhttp://orcid.org/0000-0002-0458-0052\nRedondo-Pachón Dolores 7\nhttp://orcid.org/0000-0001-6992-6379\nCrespo Marta 7\nhttp://orcid.org/0000-0001-7307-5917\nMarín-Casino Mónica 8\nMoreno Asunción 2\nMiró José M. jmmiro@ub.edu\n\n2\nHospital Clinic and Hospital del Mar SOT in HIV Investigators\n1 Infectious Diseases Service, Hospital Cuenca Alta, Cañuelas, Argentina\n2 grid.5841.8 0000 0004 1937 0247 HIV Unit and Infectious Diseases Service, Hospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain\n3 grid.410458.c 0000 0000 9635 9413 Pharmacy Service, Hospital Clinic-IDIBAPS, Barcelona, Spain\n4 grid.410458.c 0000 0000 9635 9413 Pharmacology and Toxicology, SBGM, Hospital Clinic-IDIBAPS, Barcelona, Spain\n5 grid.410458.c 0000 0000 9635 9413 Nephrology Service, Hospital Clinic-IDIBAPS, Barcelona, Spain\n6 Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain\n7 grid.411142.3 0000 0004 1767 8811 Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research-REDINREN, Barcelona, Spain\n8 grid.411142.3 0000 0004 1767 8811 Pharmacy Service, Hospital del Mar, Barcelona, Spain\n8 4 2021\n8 4 2021\n6 2021\n10 2 10551064\n28 1 2021\n2 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.\nPeople living with HIV should be considered candidates for solid-organ transplantation (SOT). However, managing HIV-infected patients undergoing SOT represents a major challenge due to the potential drug-drug interactions between antiretroviral drugs and immunosuppressive agents, particularly when resorting to antiretroviral drugs that require pharmacokinetic enhancers. We report three cases of cobicistat-tacrolimus co-administration, two of which also include the co-administration of mTOR inhibitors, in HIV-positive patients undergoing SOT (2 kidney and 1 liver recipient). We review previously reported cases and provide recommendations for initial management following transplantation.\n\nKeywords\n\nART\nCobicistat\nHIV\nSOT\nTransplant recipient\nTransplantation\nInstitut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS)REDINRENRD16/0009/0013 RD16/0009/0013 Crespo Marta Marín-Casino Mónica issue-copyright-statement© The Author(s) 2021\n==== Body\nKey Summary Points\n\nDrug-drug interactions between antiretrovirals and immunosuppressors in HIV-infected patients undergoing solid organ transplantation are extremely complex\t\nData are lacking on the clinical and pharmacological management of HIV-infected transplant recipients receiving cobicistat-containing ART regimens and tacrolimus or mTOR inhibitors\t\nFavourable outcomes are possible in these patients if tacrolimus doses are significantly reduced and daily therapeutic-drug monitoring performed\t\nDespite careful therapeutic drug monitoring some level of tacrolimus toxicity, e.g., chronic renal failure, may be difficult to avoid\t\n\nDigital features\n\nThis article is published with digital features, including summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.14135549.\n\nIntroduction\n\nManaging HIV-infected patients undergoing solid-organ transplantation (SOT) represents a major challenge due to the potential drug-drug interactions (DDI) between antiretroviral (ART) drugs and immunosuppressive agents, some of which have a narrow therapeutic index [1]. Data about interactions and dose adjustment are still limited. Where possible, ART drugs with lower potential for DDIs are used, such as regimens based on non-boosted integrase-strand-transfer inhibitors (InSTI), but when ART resistance is known or suspected, other families of ART are required.\n\nWith the improvements in hepatitis C virus (HCV) therapy in the past few years, the proportion of patients with HIV/HCV co-infection who will need a liver transplantation may decrease [2–4]. On the other hand, HIV-infected patients now have a near-normal life span, and comorbidities such as end-stage kidney disease, non-alcoholic-steatohepatitis or cardiovascular disease are on the rise [5]. Thus, the numbers of experienced ART patients requiring SOT may increase in the coming years.\n\nCobicistat is a potent and selective inhibitor of cytochrome P450 3A (CYP3A), used as pharmacokinetic booster for first-generation integrase inhibitors (e.g., elvitegravir) and protease inhibitors (PIs) (e.g., darunavir or DRV) in the management of HIV infections [6]. Calcineurin inhibitors, such as cyclosporine and tacrolimus, which are frequently used in SOT recipients, and mTOR inhibitors, such as sirolimus and everolimus, are both CYP3A substrates [7]. Thus, careful therapeutic drug monitoring (TDM) is recommended when these drugs are used together. Although there is some experience with ritonavir, another PI booster, clinical experience with cobicistat and immunosuppressants is extremely scarce, since it has only recently been developed. It offers, however, the benefit of a more selective cytochrome inhibition and co-formulation [6, 8].\n\nWe report three cases of cobicistat-tacrolimus co-administration, including one also with sirolimus and one with everolimus co-administration, in HIV-positive patients who underwent SOT and review previously reported cases. The Institutional Ethics Committee approved the Liver Transplant and Kidney Transplant in HIV Infection Cohorts in Hospital Clinic-IDIBAPS of Barcelona as medical records were used to identify cases. Patients provided their informed consent for the publication of their data.\n\nClinical cases and review of previously reported cases\n\nCase 1\n\nA 40-year-old man with end-stage renal disease on peritoneal dialysis was referred to our centre for evaluation for kidney transplantation. He had a history of HIV infection, diagnosed in 2006, due to HIV-associated nephropathy. There was no history of opportunistic infections, nor was HCV co-infection reported. Hepatitis B core antibody (Anti-HBc), CMV and toxoplasmosis IgG were positive. He had had received several ART regimens since 2006 with poor compliance, although HIV resistance was not documented. Previous ART included atazanavir/ritonavir (ATV/r)-lamivudine (3TC)–zidovudine (AZT), DRV/ritonavir (DRV/r)–3TC-AZT, DRV/r–3TC-abacavir (ABC) and DRV/r–raltegravir (RAL), ongoing at the time of referral. Persistently detectable HIV viral load (VL), around 200–300 copies/ml, was documented while receiving DRV/r-RAL over several months and 595 CD4 T cells/µl, during pre- transplant evaluation. HBV VL was undetectable.\n\nA genotypic resistance performed on plasma samples test did not amplify the virus. A pro-viral resistance test was then performed. Protease and reverse transcriptase (RT) genes were amplified, with no detectable mutations; integrase gene was not amplified. Given the low genetic barrier to resistance of raltegravir and the inability to exclude resistance to InSTIs, the decision taken was to modify ART to DRV/r 600/100 mg BID + dolutegravir (DTG) 50 mg BID. Kidney transplantation was deferred until undetectable VL and proper adherence to ARTs were achieved. The patient became rapidly undetectable (< 50 copies/ml). Later, the regimen was simplified to darunavir/cobicistat (DRV/c) 800/150 mg QD + DTG 50 mg BID to reduce the pill burden. He maintained good adherence and VL remained undetectable at subsequent checkups. The patient received a living-donor kidney transplantation in June 2017.\n\nImmunosuppression consisted of induction with basiliximab, mycophenolate mofetil (MMF) and tacrolimus. Initially, 1.5 mg of tacrolimus was given with TDM performed 48 and 72 h post-dose. Trough concentrations increased up to 34.8 ng/ml. Thus, doses were adapted and the patient was finally discharged on tacrolimus 1.5 mg/48 h. Creatinine serum levels were between 2.0 and 2.4 mg/dl. Later, tacrolimus was modified to 0.5 mg/72 h maintaining whole blood concentrations between 7 and 14 ng/ml (Fig. 1a). Post-transplantation course was uncomplicated without rejection episodes.Fig. 1 a Case 1. Tacrolimus and sirolimus whole blood concentrations and dosing interval after kidney transplantation. b Case 2. Tacrolimus and everolimus whole blood concentrations and dosing interval after kidney transplantation. c Case 3. Tacrolimus whole blood concentrations and dosing interval after liver transplantation\n\nFourteen months after kidney transplantation, not having changed the ART regimen, the patient developed cutaneous Kaposi sarcoma (KS). He received local treatment and, as there is evidence that sirolimus can delay progression of cutaneous KS, MMF was switched to sirolimus [9, 10]. The initial dose was 1 mg/48 h, then 0.5 mg/4 days. Levels ranged between 3.2 and 6 ng/ml, while tacrolimus doses were continued 0.5 mg/72 h (Fig. 1a).\n\nThree years later, the patient is well, with no evidence of KS progression, stable renal function (serum creatinine around 1.8 mg/dl), undetectable plasma HIV VL and CD4 T cells > 1000/µl.\n\nCase 2\n\nA 59-year-old man had been HIV infected since 1994 with end-stage renal disease due to focal segmental glomerulosclerosis. He had a history of pulmonary tuberculosis in 1994 and cutaneous KS in 2012. He had a 23-year history of ART. Initially receiving zidovudine monotherapy and then other sub-optimal ART regimens based on a combination of thymidine analogues (nucleoside RT inhibitors) and the first protease inhibitors, which led to virological failures and ART-related complications, e.g., lipodystrophy, dyslipidaemia and gynecomastia. A genotypic resistance test in 2009 revealed the presence of mutations in the reverse transcriptase region and in the protease region that limited the available treatment options.\n\nAt the time of kidney-transplant evaluation, he was receiving DRV/c 800/150 mg QD and DTG 50 mg QD with stable virological suppression (HIV VL < 50 copies/ml) and CD4 T cells of 247/µl. Thus, in November 2019 he underwent kidney transplantation from an HLA-identical living donor.\n\nImmunosuppression consisted of basiliximab, prednisone, tacrolimus and everolimus. The last two immunosuppressants were initiated 1 week before kidney transplantation, 1 mg/week and 0.5 mg/48 h, respectively, with careful TDM. After transplantation, tacrolimus was modified to 1.5 mg/week. The patient experienced delayed graft function and proteinuria (protein/creatinine ratio > 2000 mg/g). Therefore, a biopsy was performed 2 weeks after transplantation. It revealed acute tubular necrosis. Graft rejection and segmental hyalinosis lesions were ruled out. Then, due to the possible association of acute tubular necrosis with everolimus [11], the latter was substituted with mycophenolate mofetil.\n\nDuring the following months, additional tacrolimus dose adjustments were necessary. Stable whole blood concentrations between 3.8 and 7.2 ng/ml were achieved with 0.5 mg/week (Fig. 1b). Eleven months after kidney transplantation the patient is still on the same ART regimen, serum creatinine is stable between 1.9 and 2.2 mg/dl, HIV VL remains undetectable and the last CD4 T cell count was 477/µl. A new KS was diagnosed, and then it was decided to discontinue tacrolimus.\n\nCase 3\n\nA 57-year-old man had been HIV/HCV co-infected for 30 years due to intravenous drug abuse. He had a history of chronic renal failure (creatinine serum level 1.7 mg/dl, GFR 42 ml/min), cirrhosis due to HCV, treated with direct-acting antivirals (DAAs) and ribavirin for 6 months with sustained virological response (SVR). He had presented opportunistic infections, including Pneumocystis jirovecii pneumonia and genitourinary tuberculosis several years ago, both of which were adequately treated. There was no history of HBV co-infection or vaccination. During the months leading up to the referral to our centre, he had several hepatic encephalopathy episodes and refractory ascites. Therefore, liver transplant evaluation was performed.\n\nHe received multiple ART regimens. At the time of referral, he was receiving DRV/c 800/150 mg QD and RAL 400 mg BID. HIV VL was < 50 copies/ml and CD4 T cells 124/µl. Resistance to other families of ART was suspected although not detected in previous genotypic tests. To reduce the pill burden and increase the genetic barrier of the ART regimen, RAL was switched to DTG 50 mg QD while DRV/c was continued. CD4 T cells increased up to 213/µl (30%), and 3 months later, in June 2019, the patient underwent liver transplantation.\n\nImmunosuppression consisted of MMF, basiliximab, prednisone and tacrolimus. Initially, 1 mg of tacrolimus was given with daily TDM. He continued with 2 mg/day until target concentrations were reached and was discharged on 1.5 mg/day. Subsequently, doses were adjusted and stable whole blood levels between 6.7 and 10.4 ng/ml were maintained with 1 mg/48 h. Post-transplantation, he presented partial portal vein thrombosis, treated with acenocoumarol. Transient transaminase elevations suggestive of graft rejection occurred, decreasing with tacrolimus dose adjustment and leading to tacrolimus nephrotoxicity (creatinine levels rose to 2.3 mg/dl). HBV vaccination was completed post-transplantation.\n\nFourteen months later, the patient remains on the same ART regimen; HIV VL is undetectable. Tacrolimus was reduced to 0.5 mg/72 h (Fig. 1c). Liver function is normal. Creatinine serum levels were around 2.1 mg/dl. There were no signs of graft rejection or pharmacologic toxicity.\n\nPreviously Reported Cases\n\nThree additional cases of tacrolimus and cobicistat co-administration (all kidney recipients) were previously published. The main characteristics of these cases and those reported here are summarized in Table 1.Table 1 Main characteristics, clinical course and outcome of HIV-positive solid organ-transplant recipients receiving cobicistat-based regimens\n\nCase\tReference\tType of SOT\tART regimen\tRejection\tToxicity\tOther complications\tOutcome\t\n1\t19\tKidney\tEVG/c/FTC/TDF 150/150/200/300 mg QD\tNo\tYes\tNo\tAlive, no graft dysfunction\t\n2\t20\tKidney\tEVG/c/FTC/TDF 150/150/200/300 mg QD\tNo\tYes\tNo\tAlive, no graft dysfunction\t\n3\t21\tKidney\tDRV/c 800/150 mg QDa\tNo\tYes\tNo\tAlive, no graft dysfunction\t\n4\tReported here\tKidney\tDRV/c 800/150 QD—DTG 50 mg BID\tNo\tNo\tKaposi sarcoma\tAlive, no graft dysfunction\t\n5\tReported here\tKidney\tDRV/c 800/150 QD—DTG 50 mg QD\tNo\tNo\tKaposi sarcoma; acute tubular necrosis\tAlive, no graft dysfunction\t\n6\tReported here\tLiver\tDRV/c 800/150 QD—DTG 50 mg QD\tNo\tNo\tPortal vein thrombosis\tAlive, no graft dysfunction\t\nCases are reported in chronological order or publication. Cases 4, 5 and 6 of the table correspond, respectively, to cases 1, 2 and 3 in the text\n\naOne day of lopinavir/ritonavir 400/100 mg BID\n\nDiscussion\n\nAlthough there is some experience with tacrolimus and mTOR inhibitors co-administered with ritonavir boosted PIs, most data on how to manage DDIs with cobicistat are theoretical. Cobicistat has been developed more recently, and thus, there are fewer cases using this booster, since other more convenient ARV drugs, e.g., non-boosted InSTIs, have become available in recent years. However, when PIs are required, cobicistat offers several advantages, such as co-formulation and a more favourable DDI profile. In contrast to ritonavir, cobicistat is a more specific CYP3A inhibitor and its affinity to other cytochrome P450 isoenzymes is different. It is a weak inhibitor of CYP2D6 and does not inhibit or induce other CYP enzymes [6, 12, 13].\n\nHowever, the absence of clinical studies providing information about dose adjustment represents a major challenge in terms of pharmacological management.\n\nNot only were significant tacrolimus (and mTOR inhibitors in cases 1 and 2) dose reductions necessary in the three cases presented here, but also prolongation of the dosing interval with careful TDM to maintain the target concentration and avoid toxicity. It is worth noting that tacrolimus doses were slightly higher than those used when ritonavir is given [14–19].\n\nFinding appropriate tacrolimus doses to avoid graft rejection without harming kidney function, especially in patients with a history of chronic renal disease as in case 3, is another important issue in these complex scenarios. Although the three patients had successful outcomes, it was difficult to stabilize creatinine serum levels and a slight deterioration of renal function in the three cases due to tacrolimus nephrotoxicity could not be excluded.\n\nTo our knowledge, only three additional cases of tacrolimus and cobicistat co-administration have been published previously (cases 1–3 in Table 1) and all of them reported serious tacrolimus toxicity. Han et al. and Patel et al. reported significant increases in tacrolimus serum levels when Stribild (tenofovir–emtricitabine–elvitegravir–cobicistat) was initiated in two HIV infected kidney transplant recipients, which led to tacrolimus discontinuation and ART substitution with a non-boosted integrase-based regimen in both cases (2 mg BID and 3 mg BID of tacrolimus were administered, respectively) [20, 21]. Likewise, Bartiromo et al. published a case of a kidney transplant recipient, receiving tacrolimus 5 mg BID, who developed COVID-19 pneumonia at the beginning of the SARS-CoV-2 pandemic and was medicated with DRV/c as an antiviral for SARS-CoV-2 (and 1 day of lopinavir/ritonavir before DRV/c, with the same indication), with tacrolimus dose reduction to 3 mg BID. The whole blood concentration of tacrolimus reached 90.5 ng/ml causing serious drug toxicity. Thus, both medications were suspended [22]. It is worth mentioning that recent evidence shows no activity of darunavir-cobicistat against SARS-CoV-2 but it was under consideration at the time of this reported case [23].\n\nThese situations with extremely complex DDIs are becoming more frequent since transplantation has become the standard of care for patients with HIV and end-stage kidney or liver disease. In fact, kidney and liver transplants are the most common transplant procedures performed in patients with HIV [24]. Current criteria for SOT in people living with HIV (PLWH) state that patients must be on stable ART therapy with proper compliance, HIV plasmatic VL must be undetectable, there should be an absence of active opportunistic infections and the CD4 T cell count should ideally be > 200 cells/µl when there is a history of opportunistic infection [24]. As previously explained, given the near-normal life expectancy of HIV-infected individuals, end-stage organ dysfunction due to causes other than HCV may increase.\n\nOutcomes of liver and kidney transplant in PLWH have been consistent with those in HIV-uninfected people, especially in the absence of HCV co-infection [24]. Although higher rates of acute graft rejection in PLWH undergoing SOT are still a matter of concern (in part consequent to difficulties in adapting immunosuppressors concomitantly with certain ARTs), several studies have reported patient and graft survival rates in long-term follow-up of HIV-positive kidney-transplant recipients similar to those who were HIV negative [25–27]. Regarding liver transplantation in HIV/HCV co-infected patients, since DAAs became available, SVRs prior to and post liver transplantation are comparable to those of HCV-mono-infected patients [28, 29]. Thereby, graft and patient survival has shown improvement over time and outcomes of co-infected liver recipients are expected to match those of HCV-mono-infected patients.\n\nNevertheless, the inadequate management of DDIs can impact in HIV control and graft survival, including increased HIV viremia or graft rejection due to sub-therapeutic ART or immunosuppressant levels as well as the emergence of opportunistic infections or toxicity due to over-immunosuppression [30]. To the best of our knowledge, this is the first report of a successful outcome in patients receiving tacrolimus and cobicistat. A multidisciplinary approach and frequent communication between health care providers are mandatory to avoid dosage errors and prescription issues and to ensure successful management.\n\nGiven our own experience with these three cases and those reported, we suggest that, in patients already taking cobicistat, tacrolimus (and other calcineurin and mTOR inhibitors) should be started as a single low dose (e.g., 1 mg) and daily TDM performed, only repeating doses when levels reach the lowest desired target levels. Then, a single dose should be repeated and TDM performed daily again until establishing an initial appropriate dose interval. If the situation is the opposite (a patient already taking tacrolimus initiates a cobicistat-based regimen), tacrolimus should be stopped and only resumed when levels decrease to the minimum therapeutic level, following the same principle described above. Since cobicistat lengthens the half-life of immunosuppressants, it will take longer to reach steady-state pharmacokinetics. Early dosage changes before it has been achieved may contribute to greater difficulty in dose adjustment.\n\nIn conclusion, for HIV-infected transplant recipients on tacrolimus where it is impossible to avoid ART regimens containing cobicistat, a significant dose reduction made on a case-by-case basis with close TDM remains essential, as the final doses of tacrolimus are difficult to predict. Despite the difficulties in establishing the final doses of immunosuppressants, the outcome seems favourable, although some level of chronic renal toxicity may be present as a consequence of dose adjustments.\n\nAcknowledgements\n\nHospital Clinic of Barcelona SOT in HIV-infected Patients Working Group Investigators: Infectious Diseases Service: J. M. Miro, J. Ambrosioni, C. Manzardo, A. Castelli, O. Roman, M. Bodro, L. Linares, M. Laguno, A. Moreno; Liver Transplant Unit: A. Rimola, A. Forner, P. Ruiz, G. Crespo, M. Londoño, X. Forns, J. Garcia-Valdecasas; Renal Transplant Unit: F. Cofan, F. Diekmann, F. Oppenheimer; Cardiac Transplant Unit: M. A. Castel, F. Perez-Villa, M. Farrero, D. Pereda, E. Quintana; Toxicology Service: M. Brunet; Farmacy Service: M. Tuset; Transplant Coordination Unit: D. Paredes; Psychiatry Service: A. Lligoña; Statistician: E. de Lazzari; Clinical Trials Unit: A. Cruceta; E. Bonfill; J. A. Arnaiz; Hospital del Mar of Barcelona SOT in HIV-infected patients Working Group Investigators: Department of Nephrology: M. J. Pérez-Sáez, C. Arias; and, HIV Unit: H. Knobel.\n\nFunding\n\nJosé M. Miró received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–2021. MCB and MMC were funded by REDINREN (RD16/0009/0013). No funding or sponsorship was received for this study or publication of this article.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthorship Contributions\n\nNatalia A Diaz and Juan Ambrosioni contributed equally to this work.\n\nPrior Presentation\n\nPreliminary results from this paper were presented at the International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs 2020, October 2020. Case #1 was awarded as best reported case in 2019 in http://www.clinicalcasesddi.com.\n\nDisclosures\n\nJuan Ambrosioni has received consulting honoraria and/or research grants from Gilead Sciences, Janssen, and ViiV Healthcare, outside the submitted work. José M. Miró has received consulting honoraria and/or research grants from AbbVie, Angelini, Contrafect, Cubist, Genentech, Gilead Sciences, Jansen, Medtronic, MSD, Novartis, Pfizer, and ViiV Healthcare, outside the submitted work. Natalia A. Diaz, Montserrat Tuset, Mercé Brunet, Frederic Cofan, Gonzalo Crespo, Pablo Ruiz, Dolores Redondo-Pachón, Marta Crespo, Mónica Marín-Casino and Asunción Moreno have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nInstitutional Ethics Committee approved the Liver Transplant and Kidney Transplant in HIV Infection Cohorts in Hospital Clinic-IDIBAPS of Barcelona as medical records were used to identify cases. Patients have provided their informed consent for the publication of their data.\n==== Refs\nReferences\n\n1. Van Maarseveen EM Rogers CC Trofe-Clark J Van Zuilen AD Mudrikova T Drug–drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review AIDS Patient Care STDS 2012 26 568 581 10.1089/apc.2012.0169 23025916\n2. Schlabe S Rockstroh JK Advances in the treatment of HIV/HCV coinfection in adults Expert OpinPharmacother 2018 19 49 64 10.1080/14656566.2017.1419185\n3. Wyles DL Ruane PJ Sulkowski MS Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1 N Engl J Med 2015 373 714 725 10.1056/NEJMoa1503153 26196502\n4. Naggie S Cooper C Saag M Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1 N Engl J Med 2015 373 705 713 10.1056/NEJMoa1501315 26196665\n5. Farahani M Mulinder H Farahani A Marlink R Prevalence and distribution of non-AIDS causes of death among HIV-infected individuals receiving antiretroviral therapy: a systematic review and meta-analysis Int J STD AIDS 2017 28 636 650 10.1177/0956462416632428 26868158\n6. Shah BM Schafer JJ Priano J Squires KE Cobicistat: a new boost for the treatment of human immunodeficiency virus infection Pharmacotherapy 2013 33 1107 1116 10.1002/phar.1237 23471741\n7. Barbarino JM Staatz CE Venkataramanan R PharmGKB summary: cyclosporine and tacrolimus pathways PharmacogenetGenom 2013 23 563 585\n8. Curran A Pérez-Valero I Moltó J Rezolsta® (darunavir/cobicistat): first boosted protease inhibitor co-formulated with cobicistat AIDS Rev 2015 17 114 120 26035169\n9. Salgo R Gossman J Schöfer H Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial Am J Transplant 2010 10 1385 1393 10.1111/j.1600-6143.2009.02997.x 20121752\n10. Kearney L Hogan D Conlon P Roche M O’Neill JP Sullivan JB High-risk cutaneous malignancies and immunosuppression: challenges for the reconstructive surgeon in the renal transplant population J PlastReconstrAesthetSurg 2017 70 922 930\n11. Nguyen LS Vautier M Allenbach Y Sirolimus and mTOR inhibitors: a review of side effects and specific management in solid organ transplantation Drug Saf 2019 42 813 825 10.1007/s40264-018-0758-8 30868436\n12. Mathias AA German P Murray BP Pharmacokinetics and pharmacodynamics of gs-9350: a novel pharmacokinetic enhancer without anti-HIV activity ClinPharmacolTher 2010 87 322 329\n13. Sherman EM Worley MV Unger NR Gauthier TP Schafer JJ Cobicistat: review of a pharmacokinetic enhancer for HIV infection ClinTher 2015 37 1876 1893\n14. Van Maarseveen EM Crommelin HA Mudrikova T van den Broek MPH van Zuilen AD Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study Transplantation 2013 95 397 402 10.1097/TP.0b013e3182734651 23250333\n15. Barau C Blouin P Creput C Taburet AM Durrbach A Furlan V Effect of coadministered HIV-protease inhibitors on tacrolimus and sirolimus blood concentrations in a kidney transplant recipients FundamClinPharmacol 2009 23 423 425\n16. Bickel M Anadol E Vogel M Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir J AntimicrobChemother 2010 65 999 1004\n17. Mertz D Battegay M Marzolini C Mayr M Drug–drug interaction in a kidney transplant recipient receiving HIV salvage therapy and tacrolimus Am J Kidney Dis 2009 54 e1 e4 10.1053/j.ajkd.2009.01.268 19346040\n18. Schonder KS Shullo MA Okusanya O Tacrolimus and lopinavir/ritonavir interaction in liver transplantation Ann Pharmacother 2003 37 1793 1796 10.1345/aph.1D076 14632538\n19. Jain AB Venkataramanan R Eghtesad B Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients Liver Transplant 2003 9 954 960 10.1053/jlts.2003.50171\n20. Han Z Kane BM Petty LA Josephson MA Sutor J Pursell KJ Cobicistat significantly increases tacrolimus serum concentrations in a renal transplant recipient with human immunodeficiency virus infection Pharmacotherapy 2016 36 e50 e53 10.1002/phar.1752 27041642\n21. Patel SJ Kuten SA Musick WL Gaber AO Monsour HP Knight RJ Combination drug products for HIV—a word of caution for the transplant clinician Am J Transplant 2016 16 2479 2482 10.1111/ajt.13826 27089541\n22. Bartiromo M Borchi B Botta A Threatening drug–drug interaction in a kidney transplant patient with coronavirus disease 2019 (COVID-19) Transpl Infect Dis 2020 22 1 4 10.1111/tid.13286\n23. De Meyer S Bojkova D Cinatl J Lack of antiviral activity of darunavir against SARS-CoV-2 Int J Infect Dis 2020 97 7 10 10.1016/j.ijid.2020.05.085 32479865\n24. Blumberg EA Rogers CC Solid organ transplantation in the HIV-infected patient: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 1 15 10.1111/ctr.13499\n25. Trullas JC Cofan F Tuset M Renal transplantation in HIV-infected patients: 2010 update Kidney Int 2011 79 825 842 10.1038/ki.2010.545 21248716\n26. Locke JE Mehta S Reed R A national study of outcomes among HIV-infected kidney transplant recipients J Am SocNephrol 2015 26 2222 2229\n27. Zheng X Gong L Xue W Kidney transplant outcomes in HIV-positive patients: a systematic review and meta-analysis BioMed Central 2019 16 37\n28. Grottenthaler JM Werner CR Steurer M Successful direct acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation PLoS ONE 2018 13 1 12 10.1371/journal.pone.0197544\n29. Manzardo C Lodoño MC Castells L Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: a prospective nationwide cohort study Am J Transplant 2018 18 2513 2522 10.1111/ajt.14996 29963780\n30. Hemmersbach-Miller M Berg CL Messina JA Wolfe CR Transplant drug interactions and a word of caution for the HIV provider. A case report Open Forum Infect Dis 2018 5 4 5 10.1093/ofid/ofy070\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2193-6382",
"issue": "10(2)",
"journal": "Infectious diseases and therapy",
"keywords": "ART; Cobicistat; HIV; SOT; Transplant recipient; Transplantation",
"medline_ta": "Infect Dis Ther",
"mesh_terms": null,
"nlm_unique_id": "101634499",
"other_id": null,
"pages": "1055-1064",
"pmc": null,
"pmid": "33830489",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "26035169",
"title": "Tacrolimus, Sirolimus and Everolimus Doses in HIV-Infected Solid-Organ Recipients, Requiring a Cobicistat-Based Antiretroviral Regimen: Report of Three Cases and Review.",
"title_normalized": "tacrolimus sirolimus and everolimus doses in hiv infected solid organ recipients requiring a cobicistat based antiretroviral regimen report of three cases and review"
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"abstract": "Gemcitabine plus cisplatin (GC) remains the standard, frontline therapy for advanced biliary tract cancer (ABTC). The JCOG1113 study suggested that gemcitabine plus S-1 (GS) had noninferior median overall survival and comparable incidence of significant neutropenia as compared to GC treatments. This study evaluates the efficacy and safety of a modified GS regimen.\n\n\n\nThe eligible patients with chemonaive, measurable ABTC received 800 mg/m2 of gemcitabine on day 1 and 80 mg/m2 /day of S-1 (80/100/120 mg for patients with body surface <1.25/ ≥1.25 and <1.5/ ≥1.5 m2 respectively). The primary endpoint was the 12-week disease control rate (12-week DCR: objective response and stable disease ≥ 12 weeks). Per the p0 = 40% and p1 = 60% (α/β = 0.05/0.2) assumption, Simon's optimal two-stage design indicated 12-week DCR in ≥ 24 of 46 evaluable patients for significant activity. Tumour responses were assessed every 6 weeks.\n\n\n\nFifty-one patients were enrolled and most of them had intrahepatic cholangiocarcinoma (64.7%), metastatic disease (84.3%) and disease-related symptoms (82.4%). On intention-to-treat analysis, 11 (21.6%) patients showed partial response, whereas 21 (41.2%) showed stable disease ≥ 12 weeks. The progression-free and overall survival were 5.4 months (95% confidence interval [CI]: 3.5-7.0), and 12.7 months (95% CI: 6.1-15.6) respectively. The study met its primary endpoint with a 12-week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment-related adverse eventsoccurred in < 6% of patients of all individual items. The mean dose intensities of S-1 and gemcitabine were 87.1% and 92.5% respectively.\n\n\n\nModified GS showed moderate efficacy with a favourable safety profile in ABTC patients, thus mandating further assessment. ClinicalTrials.gov number: NCT02425137.",
"affiliations": "Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.;Department of Oncology, National Taiwan University Hospital and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Oncology, National Taiwan University Hospital and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Division of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.",
"authors": "Chiang|Nai-Jung|NJ|0000-0003-2743-9702;Chen|Ming-Huang|MH|;Yang|Shih-Hung|SH|;Hsu|Chiun|C|;Yen|Chia-Jui|CJ|;Tsou|Hsiao-Hui|HH|0000-0001-6773-4111;Su|Yung-Yeh|YY|;Chen|Jen-Shi|JS|;Shan|Yan-Shen|YS|;Chen|Li-Tzong|LT|0000-0003-3250-7167",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
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"doi": "10.1111/liv.14538",
"fulltext": "\n==== Front\nLiver Int\nLiver Int\n10.1111/(ISSN)1478-3231\nLIV\nLiver International\n1478-3223 1478-3231 John Wiley and Sons Inc. Hoboken \n\n10.1111/liv.14538\nLIV14538\nOriginal Article\nLiver Cancer\nMulticentre, phase II study of gemcitabine and S‐1 in patients with advanced biliary tract cancer: TG1308 study\nCHIANG et al.Chiang Nai‐Jung https://orcid.org/0000-0003-2743-9702\n1\n\n2\n\n3\n Chen Ming‐Huang \n4\n\n5\n Yang Shih‐Hung \n6\n Hsu Chiun \n6\n Yen Chia‐Jui \n1\n\n3\n Tsou Hsiao‐Hui https://orcid.org/0000-0001-6773-4111\n7\n\n8\n Su Yung‐Yeh \n1\n\n2\n\n3\n Chen Jen‐Shi \n9\n Shan Yan‐Shen \n1\n\n10\n Chen Li‐Tzong https://orcid.org/0000-0003-3250-7167\n2\n\n3\n\n11\nleochen@nhri.org.tw \n1 \nInstitute of Clinical Medicine\nCollege of Medicine\nNational Cheng Kung University\nTainan\nTaiwan\n\n\n2 \nNational Institute of Cancer Research\nNational Health Research Institutes\nTainan\nTaiwan\n\n\n3 \nDivision of Hematology and Oncology\nDepartment of Internal Medicine\nNational Cheng Kung University Hospital\nTainan\nTaiwan\n\n\n4 \nDepartment of Oncology\nTaipei Veterans General Hospital\nTaipei\nTaiwan\n\n\n5 \nSchool of Medicine\nNational Yang Ming University\nTaipei\nTaiwan\n\n\n6 \nDepartment of Oncology\nNational Taiwan University Hospital and Graduate Institute of Oncology\nNational Taiwan University College of Medicine\nTaipei\nTaiwan\n\n\n7 \nInstitute of Population Health Sciences\nNational Health Research Institutes\nZhunan\nTaiwan\n\n\n8 \nGraduate Institute of Biostatistics\nCollege of Public Health\nChina Medical University\nTaichung\nTaiwan\n\n\n9 \nDivision of Hematology and Oncology\nDepartment of Internal Medicine\nLinkou Chang Gung Memorial Hospital and Chang Gung University\nTaoyuan\nTaiwan\n\n\n10 \nDepartment of Surgery\nNational Cheng Kung University Hospital\nTainan\nTaiwan\n\n\n11 \nDepartment of Internal Medicine\nKaohsiung Medical University Hospital and Kaohsiung Medical University\nKaohsiung\nTaiwan\n\n* Correspondence\n\nLi‐Tzong Chen, National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng‐Li Road, Tainan 704, Taiwan, ROC.\n\nEmail: leochen@nhri.org.tw\n\n09 6 2020 \n10 2020 \n40 10 10.1111/liv.v40.102535 2543\n11 1 2020 17 5 2020 18 5 2020 © 2020 The Authors. Liver International published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nBackground & Aims\nGemcitabine plus cisplatin (GC) remains the standard, frontline therapy for advanced biliary tract cancer (ABTC). The JCOG1113 study suggested that gemcitabine plus S‐1 (GS) had noninferior median overall survival and comparable incidence of significant neutropenia as compared to GC treatments. This study evaluates the efficacy and safety of a modified GS regimen.\n\nMethods\nThe eligible patients with chemonaive, measurable ABTC received 800 mg/m2 of gemcitabine on day 1 and 80 mg/m2/day of S‐1 (80/100/120 mg for patients with body surface <1.25/ ≥1.25 and <1.5/ ≥1.5 m2 respectively). The primary endpoint was the 12‐week disease control rate (12‐week DCR: objective response and stable disease ≥ 12 weeks). Per the p0 = 40% and p1 = 60% (α/β = 0.05/0.2) assumption, Simon's optimal two‐stage design indicated 12‐week DCR in ≥ 24 of 46 evaluable patients for significant activity. Tumour responses were assessed every 6 weeks.\n\nResults\nFifty‐one patients were enrolled and most of them had intrahepatic cholangiocarcinoma (64.7%), metastatic disease (84.3%) and disease‐related symptoms (82.4%). On intention‐to‐treat analysis, 11 (21.6%) patients showed partial response, whereas 21 (41.2%) showed stable disease ≥ 12 weeks. The progression‐free and overall survival were 5.4 months (95% confidence interval [CI]: 3.5‐7.0), and 12.7 months (95% CI: 6.1‐15.6) respectively. The study met its primary endpoint with a 12‐week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment‐related adverse eventsoccurred in < 6% of patients of all individual items. The mean dose intensities of S‐1 and gemcitabine were 87.1% and 92.5% respectively.\n\nConclusions\nModified GS showed moderate efficacy with a favourable safety profile in ABTC patients, thus mandating further assessment.\n\nClinicalTrials.gov number: NCT02425137.\n\nbiliary tract cancergemcitabineS‐1Taiwan Cooperative Oncology Group05‐07A1‐CAPP23‐01408A1‐CASP01‐014TTY Biopharma Company Limited, Taiwan.National Health Research Institutes, TaiwanCA‐108‐PP‐22CA‐108‐PP‐23CA‐108‐GP‐01Taiho Pharmaceutical Co., Ltd. Japan.Taiwan upper gastrointestinal cancers clinical trial consortium108‐2321‐B‐006‐014 source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:07.10.2020\n\n\nChiang \nN‐J \n, \nChen \nM‐H \n, \nYang \nS‐H \n, et al. Multicentre, phase II study of gemcitabine and S‐1 in patients with advanced biliary tract cancer: TG1308 study\n. Liver Int . 2020 ;40 :2535 –2543\n. 10.1111/liv.14538 \n\n\n\nJen‐Shi Chen, Yan‐Shen Shan, and Li‐Tzong Chen contributed equally to the manuscript.\n\n\nFunding information\n\n\nS‐1 was sponsored by Taiho Pharmaceutical Co., Ltd. Japan; while gemcitabine (Gemmis®) and budget were supported by TTY Biopharma Company Limited, Taiwan. The trial was conducted by Taiwan Cooperative Oncology Group (05‐07A1‐CAPP23‐014 and 08A1‐CASP01‐014), National Institute of Cancer Research, National Health Research Institutes, Taiwan (CA‐108‐PP‐22, CA‐108‐PP‐23 and CA‐108‐GP‐01), with the support from Taiwan Upper Gastrointestinal Cancers Clinical Trial Consortium (108‐2321‐B‐006‐014).\n==== Body\nAbbreviations\nABTCadvanced biliary tract cancer\n\nALTalanine transaminase\n\nAVCampulla of vater cancer\n\nBSAbody surface area\n\nBTCbiliary tract cancer\n\nCA19‐9carbohydrate antigen 19‐9\n\nCEAcarcinoembryonic antigen\n\nCIconfidence interval\n\nCRcomplete response\n\nDCRdisease control rate\n\nEHCCextrahepatic cholangiocarcinoma\n\nGBCgallbladder cancer\n\nGCgemcitabine and cisplatin\n\nGSgemcitabine and S‐1\n\nHRhazard ratio\n\nIHCCintrahepatic cholangiocarcinoma\n\nITTintention‐to‐treat\n\nmFOLFOXmodified oxaliplatin and 5‐FU plus leucovorin\n\nORRobjective response rate\n\nOSoverall survival\n\nPFSprogression‐free survival\n\nPPper‐protocol\n\nPRpartial response\n\nRECISTresponse evaluation criteria in solid tumors\n\nSDstable disease\n\nSLOGGS plus oxaliplatin and leucovorin\n\nTCOGTaiwan Cooperative Oncology Group\n\nULNupper limit of normal\n\n\nLay Summary/Key Points\nThe modified GS regimen showed acceptable treatment efficacy and favourable safety and thus can be considered an alternative doublet regimen or backbone regimen to develop a triplet regimen for the treatment of patients with advanced biliary tract cancer.\n\n\n\n\n1 BACKGROUND\nBiliary tract cancers (BTCs) are classified as intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), gallbladder cancer (GBC), and ampulla of vater cancer (AVC) based on the anatomic origin. The incidence of BTC is increasing globally and generally higher in Asian countries than in Western countries.\n1\n According to the Taiwan Cancer Registration, 1637 new, cyto‐/pathologically proven cases of biliary tract adenocarcinoma were reported in 2016, including 837 and 800 cases of IHCC and EHCC/GBC respectively.\n2\n Complete surgical resection remains the mainstay of treatment for patients with early‐stage disease.\n3\n However, most patients present with unresectable, advanced BTC (ABTC) at diagnosis,\n4\n and intravenous administration of 1000 mg/m2 of gemcitabine plus 25 mg/m2 of cisplatin on days 1 and 8, every 21 days (GC regimen) has been considered the standard frontline therapy according to the UK ABC‐02 and Japanese BT‐22 studies.\n5\n, \n6\n, \n7\n However, treatment with GC requires vigorous hydration and administration of potent antiemetics to prevent cisplatin‐related adverse events,\n7\n and results in grade 3/4 neutropenia significantly frequently in the Asian population (56.1% in BT‐22 and 25.3% in ABC‐02).\n5\n, \n6\n\n\n\nS‐1, the newer‐generation oral fluoropyrimidine, was approved for treatment of patients with ABTC in Japan in 2007 on the basis of the results of a multicentre phase II trial, with an objective response rate (ORR) of 35% and median progression‐free survival (PFS) and overall survival (OS) rates of 3.7 and 9.4 months respectively.\n8\n In the randomised phase II JCOG0805 study, patients treated with GS, comprising gemcitabine (1000 mg/m2 on days 1 and 8) plus a reduced dose of S‐1 (60 mg/m2, 60/80/100 mg/day on the basis of the body surface area [BSA]) on days 1‐14 every 3 weeks showed better median OS (12.5 months vs 9.0 months) than those treated with S‐1 monotherapy at the regular dose (80 mg/m2, 80/100/120 mg/day based on BSA) on days 1‐28 every 6 weeks.\n9\n In a subsequent randomized phase III JCOG1113 trial, patients treated with GS showed non‐inferior median OS compared with those treated with GC (15.1 months vs 13.4 months, hazard ratio [HR]=0.945 with one‐sided, non‐inferiority P = .046),\n10\n validating the GS regimen as an alternative standard of care for Japanese patients with ABTC.\n\nDespite being more effective, the treatment with GS resulted in consistent 60% of grade 3/4 neutropenia, and required frequent dose modification in both the JCOG0805 and JCOG1113 studies.\n9\n, \n10\n In the GS arm of JCOG1113, the relative mean dose intensity (DI) of gemcitabine and S‐1 was 76.2% and 75.3% respectively.\n10\n Furthermore, comparison of the monotherapy arm in the BT‐22 and JCOG0805 studies indicated that patients treated with S‐1 had comparable but numerically better ORR (17.4% vs 11.9%), median PFS (4.2 months vs 3.7 months), median OS (9.0 months vs 7.7 months), and safety profiles (grade 3/4 neutropenia, 4.0% vs 38.1%) than those treated with gemcitabine.\n5\n, \n10\n Therefore, considering S‐1 to have better a therapeutic index than that of gemcitabine, we investigated whether the modified GS regimen, comprising higher DI of S‐1 and lower DI of gemcitabine can improve the therapeutic index of GS in ABTC. The aim of the current phase II trial was to evaluate the efficacy and safety of biweekly gemcitabine in combination with a full 80 mg/m2/day (80/100/120 mg/day by BSA) dose of S‐1 on days 1‐10 every 2 weeks, termed the ‘modified GS’ regimen, as frontline treatment in patients with ABTC. The planned DI of S‐1 would be 400 mg/m2/wk in the current modified GS regimen, as opposed to 373 mg/m2/wk in S‐1monotherapy arm of the JCOG0805 and 280 mg/m2/wk in GS arm of both the JCOG0805 and JCOG1113 studies.\n9\n, \n10\n\n\n\n2 PATIENTS AND METHODS\n2.1 Patient eligibility\nThe inclusion criteria for patients were as follows: (a) histologically confirmed adenocarcinoma of the biliary tract that was unresectable or metastatic, including IHCC, EHCC, GBC, and AVC, with at least 1 measurable lesion according to the response evaluation criteria in solid tumours (RECIST) version 1.1; (b) patient age ≥ 20 years; (c) an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; (d) adequate bone marrow, hepatic, and renal functions (absolute neutrophil count ≥ 1500/µL, platelets ≥ 100 000/µL, haemoglobin ≥ 9 g/dL, serum total bilirubin level ≤ 1.5 times the upper limit of normal [ULN] and < 2 mg/dL [or < 3 mg/dL if biliary drainage was present], alanine transaminase (ALT) level ≤ 3 times the ULN [or ≤ 5 times the ULN in the presence of liver metastasis], and creatinine clearance (Ccr) ≥60 mL/min calculated by 24‐hour urine collection or the Cockcroft‐Gault formula); and (e) no prior chemotherapy or radiotherapy. All the patients provided written informed consent as a condition for enrolment.\n\nThe exclusion criteria were as follows: (a) the presence of grade 2 or above ascites, pleural effusion, or diarrhoea; (b) previous or current brain metastasis; (c) uncontrolled active infection or other concomitant serious disease; (d) pregnancy or breast‐feeding; (e) active cardiopulmonary disease, history of ischaemic heart disease, and/or serious concomitant systemic disorders; and (f) concurrent malignancy, except for those with adequately treated in situ carcinoma of the cervix, adequately treated basal cell carcinoma of the skin, or a disease‐free status for ≥ 5 years after initial curative treatment for any prior malignancy.\n\nThis phase II study was conducted at four member hospitals of the Taiwan Cooperative Oncology Group (TCOG). The protocol was approved by the independent ethics committees of the individual participating hospital and National Health Research Institutes, and the Department of Health, Executive Yuan, Taiwan. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation ‘Good Clinical Practice’ guideline. The study is registered at ClinicalTrials.gov (NCT02425137).\n\n2.2 Study treatment and dose modification\nThe modified GS regimen consisted of intravenous infusion of 800 mg/m2 gemcitabine on day 1 plus 40 mg/m2 oral S‐1 twice daily after meals, accounting for a total daily dose of 80/100/120 mg on the basis of the BSA (<1.25/m2; ≥1.25/m2 and < 1.5/m2; or ≥ 1.5/m2), administered on days 1‐10 every 2 weeks/cycle. Premedication included an intravenous bolus injection of metoclopramide and chlorpheniramine with or without dexamethasone. Prophylactic granulocyte‐colony stimulating factor was administered in only those patients with either grade 4 or complicated neutropenia after the first treatment cycle. The subsequent cycle could be started only if the following criteria were met on day 1: neutrophil count ≥ 1500/mm3, platelet count ≥ 75 000/mm3, total bilirubin ≤ 2 times the ULN, ALT ≤ 3 times the ULN, and all other non‐haematological toxicities recovered to < grade 2. If the patient failed to meet these criteria before commencing the next cycle, the chemotherapy may be delayed by up to 2 weeks. If febrile or grade 4 neutropenia, grade 4 thrombocytopenia (or grade 3 that required platelet transfusion), or grade 3‐4 non‐haematological toxicities, which were considered to be gemcitabine‐related, occurred, then the subsequent dose of gemcitabine would be reduced by 200 mg/m2. If grade 3‐4 diarrhoea, stomatitis, rash, or non‐haematological toxicities associated with S‐1 occurred, then the subsequent S‐1 dose would be reduced by 20 mg/day. Dose reduction of either drug was allowed only twice, with the permitted nadir dose being 400 mg/m2 for gemcitabine and 60 mg/day for S‐1. However, no further dose reescalation was permitted. The treatment regimen was continued until disease progression, unacceptable toxicity, patient refusal, adoption of other systemic or definitive local therapy, or death. The actual DI was defined as the total amount of drug administered per week divided by the baseline BSA of an individual patient (mg/m2/wk) during the 12 cycles from the start of chemotherapy, with reference to the JCOG0805 study.\n9\n\n\n\n2.3 Pre‐treatment and follow‐up evaluation\nPre‐treatment evaluation included a review of the patient's medical history, physical examination, assessment of blood cell counts, serum biochemical tests, electrocardiography, chest radiography, and contrast‐enhanced computed tomography or magnetic resonance imaging. Physical examinations and blood tests were scheduled on day 1 of each treatment cycle. The levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA 19‐9) were measured at baseline and every 2 cycles thereafter. Radiographic follow‐up was performed every 6 weeks. The tumour response would be assessed based on the RECIST version 1.1 with confirmation of objective response using 2 successive imaging studies. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4.0. The survival status was checked at least monthly after the end of treatment until death or loss to follow‐up.\n\n2.4 Statistical analysis\nThe primary endpoint was the 12‐week DCR, defined as the percentage of patients with complete/partial response [CR/PR] or stable disease [SD] for ≥ 12 weeks. The secondary endpoints included objective response rate (ORR), PFS, OS, and safety profiles. Considering the DCR of patients treated with gemcitabine alone was 50% at 6 weeks in BT‐22 and 45% at 8 weeks in our previous study,\n5\n, \n11\n the p0 was set as 40% of the 12‐week DCR in this study. The sample size was calculated on the basis of Simon's optimal two‐stage design of p1 = 60%, with a significance level of 0.05 and a power of 80%.\n12\n Sixteen evaluable patients will be accrued in the first stage; if 8 or more of them have CR/PR or SD ≥ 12 weeks, the study would be extended to the second stage, in which 30 additional evaluable patients would be accrued. The null hypothesis would be rejected if ≥ 24 patients of the 46 evaluable patients achieve CR/PR or SD at ≥ 12 weeks. All efficacy analyses were applied to the intention‐to‐treat (ITT) population, wherein the main assessment primary endpoint of ≥ 12‐week DCR, depending on the per protocol (PP) population, was defined as patients who completed at least 2 treatment cycles and underwent a scheduled follow‐up tumour assessment. The safety population consisted of subjects who received at least one dose of treatment. The PFS and OS were estimated using the Kaplan‐Meier method. PFS was calculated from the date of enrolment to the date of first radiographically evident disease progression or death or was censored at the subsequent date for patients who withdrew informed consent, underwent either conversion surgery or consolidation local radiotherapy, or received other chemotherapy agent(s) at the discretion of the physician in charge before documentation of disease progression, whichever occurred first. The OS was defined as the time from the initiation of therapy to the date of death from any cause or censored at the date of final follow‐up for survivors and those loss of follow‐up. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). A two‐sided P value < 0.05 was considered statistically significant.\n\n3 RESULTS\n3.1 Patient characteristics\nA total of 51 patients were enrolled between May 2015 and May 2017. The baseline demographics of all patients are summarised in Table 1. The patients had a median age of 63 years (range, 32‐77 years), 29 were men (57%), 42 (82.4%) had an ECOG PS of 1, 43 (84.3%) had metastatic disease, and 33 (64.7%) and 10 (19.6%) had primary IHCC and GBC respectively. Fourteen of the 51 patients (28%) had recurrent disease after a previous curative surgery.\n\nTABLE 1 Baseline demographics and clinical characteristics (N = 51)\n\n\tITT population\t\nAge (y)\t\t\nMedian (range)\t63 (32‐77)\t\n<65\t34 (66.7)\t\n≥65\t17 (33.3)\t\nGender\t\t\nMale\t29 (56.9)\t\nFemale\t22 (43.1)\t\nECOG performance status\t\t\n0\t9 (17.6)\t\n1\t42 (82.4)\t\nPrimary site\t\t\nIntrahepatic\t33 (64.7)\t\nExtrahepatic\t5 (9.8)\t\nGallbladder\t10 (19.6)\t\nAmpulla vater\t3 (5.9)\t\nDisease status at entry\t\t\nLocally advanced\t8 (15.7)\t\nDistant Metastasis\t43 (84.3)\t\nPrevious surgery\t\t\nYes\t14 (27.5)\t\nNo\t37 (72.5)\t\nStent or drainage\t\t\nNo\t41 (80.4)\t\nYes\t10 (19.6)\t\nPTCD\t5 (9.8)\t\nStent\t5 (9.8)\t\nMetastatic sites\t\t\nLiver\t37 (72.5)\t\nLung\t6 (11.7)\t\nLymph node\t30 (58.8)\t\nBone\t1 (2.0)\t\nCA199 (U/mL)\t\t\nMedian (range)\t140 (9‐516340)\t\nCEA (ng/mL)\t\t\nMedian (range)\t3.1 (0.5‐4070)\t\nAbbreviations: ECOG, Eastern Cooperative Oncology Group; ITT, intention‐to‐treat.\n\nJohn Wiley & Sons, Ltd3.2 Treatment delivery\nAt the data cut‐off date (31 May 2017), one patient remained on treatment and 13 were alive with a median follow‐up duration of 13.3 months (95% confidence interval [CI], 8.0‐18.6 months). The main reasons for discontinuation were disease progression in 32 (62.7%), intolerable toxicities in 9 (17.6%), and withdrawal of informed consent in 5 patients (9.8%). In 4 (7.8%) patients, treatment was discontinued at the investigator's discretion. The starting dose of S‐1 was 120 mg/day in 38 patients (74.5%) and 100 mg/day in the rest. Patients with a starting S‐1 dose of 120 and 100 mg/day had a mean BSA of 1.74 m2 (range, 1.51‐2.72 m2) and 1.40 m2 (range, 1.27‐1.49 m2) respectively. The average initial dose of S‐1 was 35.1 mg/m2 (range, 26.4‐39.8 mg/m2). The median number of treatment cycles was 10.5 (range, 3‐48). Ten (20%) and 17 (33%) patients required gemcitabine and S‐1 dose modification, respectively. The mean delivered DI was 305.5 mg/m2/wk (87.1% of planned DI) for S‐1 and 369.8 mg/m2/wk (92.5% of planned DI) for gemcitabine.\n\n3.3 Treatment efficacy\nOf the 16 evaluable patients in the first stage, 8 had ≥ 12‐week disease control, and thus met the criteria for proceeding to the second stage. In the ITT population, inclusive of 46 evaluable and 5 non‐evaluable patients, the best tumour responses were confirmed partial response in 11 (21.6%), stable disease in 27 (52.9%), and progressive disease or unevaluable status in 13 patients (25.5%). Furthermore, 32 (62.7%) patients had a DCR ≥ 12‐weeks. The median PFS was 5.4 months (95% CI, 3.5‐7.0 months), as shown in Figure 1A, whereas the median OS was 12.7 months (95% CI, 6.1‐15.6 months), with 1‐ and 2‐year OS rates of 51% and 14% respectively (Figure 1B). Additionally, in the PP analysis that included the 46 evaluable patients only, the 12‐week DCR was 69.6%, with a PFS and OS of 5.7 and 14.5 months respectively (Table 2).\n\nFIGURE 1 Kaplan‐Meier estimates of progression‐free survival (A) and overall survival (B) in 51 patients in the ITT population\n\nTABLE 2 Efficacy results\n\n\tITT (N = 51)\tPP (N = 46)\t\nBest overall response\t\t\t\nComplete response (CR)\t0\t0\t\nPartial response (PR)\t11 (21.6%)\t11 (23.9%)\t\nStable disease (SD)\t27 (52.9%)\t27 (58.7%)\t\nProgressive disease\t8 (15.7%)\t8 (17.4%)\t\nNot evaluated\t5 (9.8%)\t0\t\nLong‐term DCR\t32 (62.7%)\t32 (69.6%)\t\nMedian PFS (mo, 95% CI)\t5.4 (3.5‐7.0)\t5.7 (4.2‐7.1)\t\nMedian OS (mo, 95% CI)\t12.7 (6.1‐15.6)\t14.5 (7.6‐16.6)\t\nAbbreviations: CI, confidence interval; DCR, disease control rate; ITT, intention‐to‐treat; Long‐term DCR, CR, PR and SD ≥ 12 wks; OS, overall survival; PFS, progression‐free survival; PP, per protocol.\n\nJohn Wiley & Sons, Ltd3.4 Toxicity\nOf the 51 patients, the most common all grade treatment‐related toxicities were anaemia (49%), anorexia (39.2%) and fatigue (35.3%), as summarised in Table 3. The incidence of grade 3/4 adverse events was < 6% for all individual items, including 5.9% for skin rashes and 3.9% each for neutropenia, thrombocytopenia, elevated ALT levels and hyperbilirubinemia. There was one possible treatment‐related death that manifested as liver failure secondary to reactivation of hepatitis B virus infection after 4 cycles of treatment in a patient with a negative hepatitis B surface antigen serology test at study inclusion.\n\nTABLE 3 Treatment‐related adverse events (N = 51)\n\n\tAll grades\tGrade 3/4\t\nN\t%\tn\t%\t\nHaematological toxicities\t\nLeucopenia\t5\t9.8\t1\t2.0\t\nNeutropenia\t6\t11.8\t2\t3.9\t\nFebrile neutropenia\t1\t2.0\t1\t2.0\t\nThrombocytopenia\t9\t17.6\t2\t3.9\t\nAnaemia\t25\t49.0\t0\t0\t\nNon‐ haematological toxicities\t\nAnorexia\t20\t39.2\t0\t0\t\nFatigue\t18\t35.3\t1\t2.0\t\nNausea\t7\t13.7\t0\t0\t\nVomiting\t7\t13.7\t0\t0\t\nDiarrhoea\t9\t17.6\t1\t2.0\t\nStomatitis\t13\t25.5\t1\t2.0\t\nElevated AST\t5\t9.8\t1\t2.0\t\nElevated ALT\t3\t5.9\t2\t3.9\t\nHyperbilirubinemia\t2\t3.9\t2\t3.9\t\nSkin rash\t12\t23.6\t3\t5.9\t\nPruritus\t11\t21.6\t0\t0\t\nAllergic reaction\t4\t7.8\t1\t2.0\t\nSkin hyperpigmentation\t15\t29.3\t0\t0\t\nAlopecia\t3\t5.9\t0\t0\t\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.\n\nJohn Wiley & Sons, Ltd3.5 Post‐study treatment and evaluation of CA 19‐9/CEA\nOf the 46 patients in the PP cohort, 32 (69.6%) received post‐study treatment. Among them, 16 patients (50%) received 5‐fluorouracil and platinum‐based regimens (oxaliplatin in 11 and cisplatin in 5), while 5 (15.6%) received a gemcitabine‐based regimen. The other treatments included radiotherapy with or without concurrent chemotherapy (N = 4), 5‐FU monotherapy (N = 1), recruitment in clinical trial with tyrosine kinase inhibitor (N = 2), paclitaxel‐based regimens (N = 2) and pembrolizumab (N = 1). One patient underwent salvage surgery involving a partial hepatectomy with lymph node dissection and adhesiolysis. Series follow‐up data were available for 32 (69.6%) and 16 (34.8%) patients with elevated baseline CA 19‐9 and CEA levels respectively. Of these, patients with a biomarker response, defined as a more than 50% decrease in tumour marker levels during the study treatment, had better therapeutic outcomes than did those without such a biomarker response. Of the former 32 patients, 17 (56.3%) patients with a CA 19‐9 response showed a better ORR (41.2% vs 6.7%, P = .041), median PFS (9.9 months vs 5.3 months, P = .114), and median OS (19.9 months vs 6.6 months, P = .001) than did those without a CA 19‐9 response (Table S1). Furthermore, of the latter 16 patients, 6 (37.5%) with a CEA response showed a better ORR (66.7% vs 10%, P = .036), median PFS (8.5 months vs 3.2 months, P = .018) and median OS (19.9 months vs 5.3 months, P = .132) than did those without a CEA response (Table S2).\n\n4 DISCUSSION\nThe modified GS regimen was designed to investigate whether the therapeutic index of GS can be improved by adjusting the dosing schedule and thus modifying the DI of the study drugs. The current study achieved its primary endpoint with a 12‐week DCR of 69.6% in the PP population. Additionally, the secondary endpoints were favourable, and an excellent toxicity profile was observed. Upon administering 800 mg/m2 of gemcitabine on day 1 and 80 mg/m2/day of S‐1 on days 1‐10 every 2 weeks, the mean relative DI achieved was 92.7% and 87.1% for gemcitabine and S‐1 respectively. Assuming that patients in the GS arm in the JCOG1113 and JCOG0805 studies had a similar planned DI (280 mg/m2/wk),\n9\n, \n10\n it appears that the mean DI for S‐1 and gemcitabine in the TG1308 study was 44.7% higher (305.5 mg/m2/wk vs 211.1 mg/m2/wk) and 27.2% lower (369.8 mg/m2/wk vs 508.2 mg/m2/wk) than that in the GS arm in the JCOG1113 study, respectively.\n10\n These findings could likely raise concerns regarding the numerically inferior therapeutic outcomes of the modified GS regimen when compared with those of the GS regimen used in JCOG1113, with the ORR, median PFS, and median OS being 21.6% vs 29.8%, 5.4 vs 6.8 months and 12.7 vs 15.7 months respectively. This discrepancy may partially be explained by differences in the study design and demographic characteristics of the patients recruited in the two studies. First, ORR required confirmation in the current study but not in JCOG1113. Second, in the GS arm of JCOG1113, 31% patients had an ECOG PS of 1 and 61% patients had metastatic disease, whereas in our study, these values were 82.4% and 84.3% respectively. Poorer OS had been reported in patients with metastatic disease under treatment with GS, both in the JCOG0805 and a Korean phase II studies, in which the median OS of patients with metastatic disease was 10.6 and 5.6 months (vs 13.0 and 16.6 months in those with locally advanced disease) respectively\n9\n, \n13\n In our post hoc analyses, the median OS of patients with metastatic and locally advanced disease was 8.7 and 23.6 months, respectively, whereas that for patients with an ECOG PS of 1 and 0 was 7.9 and 16.5 months respectively (data not shown). The incidence of grade 3/4 neutropenia was significantly lower in those treated with the modified GS regimen, 3.9% vs 59.9‐60.7% in the JCOG1113 and JCOG0805 studies and 25.7% in a Korean study, all of which used the GS regimen (Table S3).\n9\n, \n10\n, \n13\n The results suggest that treatment with a biweekly modified GS regimen has a better therapeutic index and comparable efficacies to those of treatment with GS regimens used in previous ABTC studies, but a better safety profile.\n\nFurthermore, the therapeutic efficacy of the modified GS regimen, an ORR of 21.6%, median PFS of 5.4 months, and median OS of 12.7 months, were comparable to those obtained with global standard GC regimens used in three Japanese ABTC trials, the BT‐22, JCOG1113 and KHBO1401‐MITSBA studies in which the median (range) ORR, median PFS, and median OS were 19.5% (15.0‐32.4%), 5.8 months (5.5‐5.8 months) and 12.6 months (11.2‐13.4 months) respectively,\n5\n, \n10\n, \n14\n these values were 25.5%, 8.0 months and 11.7 months respectively, in the ABC‐02 study.\n6\n However, the safety profile of the modified GS regimen was much better than that of conventional GC regimens, especially in studies conducted on Asian populations. The incidence of both grade 3/4 neutropenia and thrombocytopenia was 3.9% with the modified GS regimen, whereas it was 25.3% and 8.6%, respectively, in the ABC‐02 study,\n6\n with a median (range) incidence of 56.1% (48‐60.8%) and 21% (16.4‐39.0%), respectively, in the three Japanese studies mentioned above.\n5\n, \n10\n, \n14\n These findings indicate that the modified GS regimen may serve as a gemcitabine‐based doublet option in Asian patients with ABTC. It could also be a favourable regimen for borderline fit, cisplatin‐ineligible or older patients because of advantages such as low peripheral neurotoxicity, low incidence of severe haematological toxicities, and no requirement for vigorous hydration, unlike in treatment with GC regimens. However, the delayed urinary excretion of 5‐chloro‐2,4‐dihydroxypyridine, an inhibitor of the dihydropyrimidine dehydrogenase that degrades 5‐FU, will lead to an increase in the area under the curve for 5‐FU and associated grade 3/4 adverse events.\n15\n Therefore, similar to cisplatin, S‐1 should be cautiously administered in patients with renal function impairment. Furthermore, serum creatinine levels ≤ 1.2 mg/dL and creatinine clearance (Ccr) ≥50 mL/min were common inclusion criteria for clinical trials involving S‐1, such as the JCOG1113 and GEST pancreatic cancer studies.\n10\n, \n16\n The combination of gemcitabine plus oxaliplatin could be a better option than GC and the modified GS regimen in ABTC patients with moderate to severe renal function impairment.\n\nThe active compounds used for the treatment of ABTC are limited globally. However, S‐1 has rarely, if ever, been tested in Caucasian ABTC patients because of the perception of relatively poor compliance and lower maximum tolerated and recommended S‐1 doses in the Western population than in Asians. This has largely been attributed to population differences in polymorphisms of the CYP2A6 gene, which encodes an enzyme responsible for converting tegafur to 5‐FU, and the pharmacokinetics of oxanate, which inhibits the phosphorylation of 5‐FU within the small intestinal mucosa related to gastrointestinal toxicities.\n17\n However, a more detailed review of the literature does not support the notion that S‐1 is a ‘tough’ drug for Caucasian cancer patients. In Western studies, the maximum tolerated dose of S‐1 using a 3‐4‐weeks‐on/1‐week‐off schedule has been reported to be 50 mg/m2 daily or 30 mg/m2 twice daily in previously treated patients, and 40 mg/m2 in chemo‐naïve patients, with the primary dose‐limiting toxicity being grade 3/4 diarrhoea.\n18\n, \n19\n, \n20\n In a phase II study by the European Organisation for Research and Treatment of Cancer (EORTC) Early Clinical Trial Group that included chemo‐naïve gastric cancer patients, 35 mg/m2 of S‐1 administered twice daily for 28 days every 5 weeks was well‐tolerated, with grade 3 diarrhoea being observed in 12% of patients and 4% of treatment cycles.\n21\n Furthermore, a recent randomized phase III trial, the SALTO study, which compared the compliance for first‐line 30 mg/m2 S‐1 and 1000‐1250 mg/m2 capecitabine administered twice daily, with a 2‐weeks‐on/1‐week‐off schedule, showed that treatment with S‐1 was associated with a significantly lower incidence of grade 3 hand‐foot syndrome (4% vs 21%; P = .003), but a higher incidence of grade 3 anorexia (13% vs 3%; P = .03) than capecitabine in Dutch patients with metastatic colorectal cancer.\n22\n While the incidence of grade 3/4 diarrhoea (16% vs 12%; P = .65) and therapeutic efficacy were comparable in both groups, the median relative DI was 95% and 88% for S‐1 and capecitabine, respectively. With the unique dosing schedule of S‐1, 120 mg/day for individuals with a BSA > 1.5 m2, the initial dose would be 40, 35, and 30 mg/m2 for patients with a BSA of 1.5, 1.71 and 2.0 m2 respectively. In this study, the average initial dose of S‐1 according to individual BSA was 35.1 mg/m2 (range, 26.4‐39.8 mg/m2), which was equivalent to the 35.9 mg/m2 (range, 31.7‐39.7 mg/m2) reported by Hirata et al.\n23\n In a recent retrospective analysis, the median BSA of 1650 Caucasian adult cancer patients was 1.86 m2 (interquartile range, 1.68‐2.00).\n24\n In the SALTO study in which 30 mg/m2 of S‐1 was administered twice daily, 75% of Caucasian patients would have an initial S‐1 dose of more than 100 mg/day, the assigned dose for patients with a BSA ≥ 1.5 m2 in Japanese GS studies.\n9\n, \n10\n, \n22\n As S‐1 is an anti‐metabolite cytotoxic compound, the compliance to treatment with S‐1 is expected to be schedule‐dependent. In a previous trial for gastric cancer, the completion rates for 12 months of adjuvant S‐1 at a dose of 80/100/120 mg/day with the conventional 4‐weeks‐on/2‐weeks‐off and the modified 2‐weeks‐on/1‐week‐off schedules were 49% and 89% respectively.\n25\n However, whether the 10‐days‐on and 4‐days‐off schedule can improve compliance with S‐1 treatment and thus ensure the feasibility of the modified GS regimen in Caucasian patients warrants further investigation.\n\nA recent trend has been to develop triplet chemotherapy regimens, such as GC combined with either S‐1 or abraxane, as first‐line treatment for ABTC.\n26\n, \n27\n A Japanese phase III study showed a significantly improved ORR (41.5% vs 15%), longer median PFS (7.4 months vs 5.5 months, HR 0.75; P = .0015) and longer median OS (13.5 months vs 12.6 months, HR 0.79; P = .046) in patients receiving GC plus S‐1 than in those receiving GC.\n14\n In a single‐arm phase II trial involving patients with ABTC (N = 60), Shroff et al showed promising treatment efficacies (ORR of 45%, PFS of 11.8 months, and OS of 19.2 months) in patients receiving GC plus nab‐paclitaxel.\n27\n A phase III trial, SWOG S1815, comparing the outcomes of treatment with GC plus nab‐paclitaxel and GC alone in patients with newly diagnosed ABTC is currently underway. Furthermore, we have previously tested the triplet regimen of GS plus oxaliplatin and leucovorin (SLOG) in patients with advanced pancreatic cancer, and found that the treatment efficacy was encouraging, and the safety profile was acceptable.\n28\n The TCOG‐T3217 (NCT03406299) randomised phase II trial, comparing SLOG and GC as first‐line treatment for ABTC, is currently on‐going. Owing to its favourable therapeutic index, the modified GS regimen is an ideal backbone chemotherapy for ABTC patients in combination with additional cytotoxic chemotherapies, molecular targeted agents, or immune checkpoint inhibitors. Our investigator‐initiated phase II trial, TCOG‐T1219, which examines the efficacy of the modified GS regimen plus nivolumab in patients with ABTC is currently underway (NCT04172402).\n\nAs for the post‐study treatment in our study, platinum plus 5‐fluorouracil was the most common regimen, especially in combination with oxaliplatin. The recent ABC‐06 trial showed that a modified oxaliplatin and 5‐FU plus leucovorin (mFOLFOX) regimen significantly improved the OS in patients showing disease progression after treatment with GC. Thus, mFOLFOX was proposed as the standard second‐line regimen for the treatment of patients with ABTC.\n29\n Moreover since peripheral neuropathy is an adverse event noted in patients treated with both cisplatin (GC) and oxaliplatin (mFOLFOX), GS or a modified GS followed by mFOLFOX may be considered as a reasonable and favourable sequential therapeutic strategy.\n\n5 CONCLUSIONS\nThis modified GS regimen, which can easily be administered in an outpatient setting, shows acceptable efficacy with a favourable safety profile in Taiwanese patients with ABTC. Further studies with the modified GS regimen administered either alone in older or cisplatin‐ineligible patients, except those with moderate to severe renal function impairment, or as backbone chemotherapy in combination with other potentially active agents for fit patients, are warranted.\n\nCONFLICT OF INTEREST\nCH received research grants from BMS/ONO, Roche, and Ipsen and honorarium from the following pharmaceutical companies: AstraZeneca, Bayer, BMS/ONO, Eisai, Eli Lilly, Ipsen, Merck Serono, MSD, Novartis, Roche, TTY Biopharm. JSC received research grants from BMS/ONO, MSD, and MedImmune, Lilly, TTY Biopharm, Merck KGaA, Roche, and AstraZenecaand. LTC received honorariums from Taiho, TTY Biopharm and Eli Lilly, and study medication from TTY Biopharm for other investigator‐initiated trials.\n\nAUTHOR CONTRIBUTIONS\nNJC, JSC, YSS, and LTC contributed to the protocol development and manuscript preparation. NJC, MHC, SHY, CH, CJY, JSC, YSS, and LTC enrolled the patients. NJC, YSS, HHT, YYS, and LTC collected and analysed data. All authors participated in data interpretation, final manuscript review and approval. JSC, YSS, and LTC are responsible for submission and publication decisions.\n\nETHICAL APPROVAL AND CONSENT TO PARTICIPATE\nThis trial was approved by the Institutional Review Board (IRB) of all four participating institutes with reference number: AB‐CR‐104‐007, 103‐7658A2, 2015‐04‐011AU, and 201412001MSA. All patients had signed inform consent forms.\n\nSupporting information\nTable S1‐S3\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThe authors thank all the patients and their family who participated in this study and clinicians from medical centres in this study: Chang‐Gung Memorial Hospital, Linkou (Wen‐Chi Shen, Hung‐Chih Hsu, Tsai‐Sheng Yang, and Yung‐chia Kuo) and National Taiwan University Hospital (Chih‐Hung Hsu). The authors thank the research nurses of the Taiwan Cooperative Oncology Group (Wei‐Lien Feng, Cheng‐Yu Chu, Ling‐Fang Lin, Tzu‐Hsuan Juan, and Li‐Ju Lu) for their assistance in conducting this study, as well as Mei‐Hsing Chuang for her friendly assistance with data consultation.\n==== Refs\nREFERENCES\n1 \n\nTariq \nNU \n, \nMcNamara \nMG \n, \nValle \nJW \n. Biliary tract cancers: current knowledge, clinical candidates and future challenges\n. Cancer Manag Res . 2019 ;11 :2623 ‐2642\n. 10.2147/CMAR.S157092 . eCollection 15201931015767 \n2 \nCancer registry annual report 2016\n. R.O.C.,Taiwan : Health Promotion Administration, Ministry of Health and Welfare, Executive Yuan \n2018 .\n3 \n\nCidon \nEU \n. Resectable cholangiocarcinoma: reviewing the role of adjuvant strategies\n. Clin Med Insights: Oncol . 2016 ;10 :CMO.S32821 .\n4 \n\nValle \nJW \n, \nLamarca \nA \n, \nGoyal \nL \n, \nBarriuso \nJ \n, \nZhu \nAX \n. New horizons for precision medicine in biliary tract cancers\n. 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Cancer Chemother Pharmacol . 2008 ;62 :849 ‐855\n.18214482 \n9 \n\nMorizane \nC \n, \nOkusaka \nT \n, \nMizusawa \nJ \n, et al. Randomized phase II study of gemcitabine plus S‐1 versus S‐1 in advanced biliary tract cancer: a Japan Clinical Oncology Group trial (JCOG 0805)\n. Cancer Sci . 2013 ;104 :1211 ‐1216\n.23763511 \n10 \n\nMorizane \nC \n, \nOkusaka \nT \n, \nMizusawa \nJ \n, et al. Combination gemcitabine plus S‐1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA‐BT (JCOG1113) randomized phase III clinical trial\n. Ann Oncol . 2019 ;30 :1950 ‐1958\n. 1910.1093/annonc/mdz1402\n31566666 \n11 \n\nLin \nMH \n, \nChen \nJS \n, \nChen \nHH \n, \nSu \nWC \n. A phase II trial of gemcitabine in the treatment of advanced bile duct and periampullary carcinomas\n. Chemotherapy . 2003 ;49 :154 ‐158\n. 110.1159/000070622\n12815209 \n12 \n\nChow \nSC \n, \nShao \nJ \n, \nWang \nH \n. Sample size calculation in clinical research . 2nd edn \nNew York, NY :Chapman and Hall/CRC ; 2007 .\n13 \n\nKim \nHS \n, \nKim \nHY \n, \nZang \nDY \n, et al. Phase II study of gemcitabine and S‐1 combination chemotherapy in patients with metastatic biliary tract cancer\n. Cancer Chemother Pharmacol . 2015 ;75 :711 ‐718\n. 710.1007/s00280‐00015‐02687‐x. Epub 02015 Jan 0022925630414 \n14 \n\nSakai \nD \n, \nKanai \nM \n, \nKobayashi \nS \n, et al. 615ORandomized phase III study of gemcitabine, cisplatin plus S‐1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401‐MITSUBA)\n. Ann Oncol . 2018 ;29 :viii205 .\n15 \n\nInoue \nK \n, \nNagasawa \nY \n, \nYamamoto \nR \n, et al. Severe adverse effects of 5‐fluorouracil in S‐1 were lessened by haemodialysis due to elimination of the drug\n. NDT Plus . 2008 ;2 :152 ‐154\n.25949315 \n16 \n\nUeno \nH \n, \nIoka \nT \n, \nIkeda \nM \n, et al. Randomized phase III study of gemcitabine plus S‐1, S‐1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study\n. J Clin Oncol . 2013 ;31 :1640 ‐1648\n. 1610.1200/JCO.2012.1643.3680. Epub 2013 Apr 164123547081 \n17 \n\nFujita \nK‐I \n, \nYamamoto \nW \n, \nEndo \nS \n, et al. CYP2A6 and the plasma level of 5‐chloro‐2, 4‐dihydroxypyridine are determinants of the pharmacokinetic variability of tegafur and 5‐fluorouracil, respectively, in Japanese patients with cancer given S‐1\n. Cancer Sci . 2008 ;99 :1049 ‐1054\n. 1010.1111/j.1349‐7006.2008.00773.x\n18380793 \n18 \n\nChu \nQS‐C \n, \nHammond \nLA \n, \nSchwartz \nG \n, et al. Phase I and pharmacokinetic study of the oral fluoropyrimidine S‐1 on a once‐daily‐for‐28‐day schedule in patients with advanced malignancies\n. Clin Cancer Res . 2004 ;10 :4913 ‐4921\n.15297391 \n19 \n\nCohen \nSJ \n, \nLeichman \nCG \n, \nYeslow \nG \n, et al. Phase I and pharmacokinetic study of once daily oral administration of S‐1 in patients with advanced cancer\n. Clin Cancer Res . 2002 ;8 :2116 ‐2122\n.12114411 \n20 \n\nHoff \nPM \n, \nSaad \nED \n, \nAjani \nJA \n, et al. Phase I study with pharmacokinetics of S‐1 on an oral daily schedule for 28 days in patients with solid tumors\n. Clin Cancer Res . 2003 ;9 :134 ‐142\n.12538461 \n21 \n\nChollet \nP \n, \nSchöffski \nP \n, \nWeigang‐Köhler \nK \n, et al. Phase II trial with S‐1 in chemotherapy‐naïve patients with gastric cancer. A trial performed by the EORTC Early Clinical Studies Group (ECSG)\n. Eur J Cancer . 2003 ;39 :1264 ‐1270\n. 1210.1016/s0959‐8049(1203)00237‐00235\n12763215 \n22 \n\nKwakman \nJ \n, \nSimkens \nL \n, \nvan Rooijen \nJM \n, et al. Randomized phase III trial of S‐1 versus capecitabine in the first‐line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group\n. Ann Oncol . 2017 ;28 :1288 ‐1293\n. 1210.1093/annonc/mdx1122\n28383633 \n23 \n\nHirata \nK \n, \nHorikoshi \nN \n, \nAiba \nK \n, et al. Pharmacokinetic study of S‐1, a novel oral fluorouracil antitumor drug\n. Clin Cancer Res . 1999 ;5 :2000 ‐2005\n.10473078 \n24 \n\nBaker \nSD \n, \nVerweij \nJ \n, \nRowinsky \nEK \n, et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991–2001\n. J Natl Cancer Inst . 2002 ;94 :1883 ‐1888\n.12488482 \n25 \n\nAjani \nJA \n, \nFaust \nJ \n, \nIkeda \nK \n, et al. Phase I pharmacokinetic study of S‐1 plus cisplatin in patients with advanced gastric carcinoma\n. J Clin Oncol . 2005 ;23 :6957 ‐6965\n. 6910.1200/JCO.2005.6901.6917. Epub 2005 Sep 695616145066 \n26 \n\nKanai \nM \n, \nHatano \nE \n, \nKobayashi \nS \n, et al. A multi‐institution phase II study of gemcitabine/cisplatin/S‐1 (GCS) combination chemotherapy for patients with advanced biliary tract cancer (KHBO 1002)\n. Cancer Chemother Pharmacol . 2015 ;75 :293 ‐300\n.25477010 \n27 \n\nShroff \nRT \n, \nJavle \nMM \n, \nXiao \nL \n, et al. Gemcitabine, Cisplatin, and nab‐Paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial\n. JAMA Oncol . 2019 ;5 :824 ‐830\n. 810.1001/jamaoncol.2019.0270\n30998813 \n28 \n\nChiang \nNJ \n, \nTsai \nKK \n, \nHsiao \nCF \n, et al. A multicenter, phase I/II trial of biweekly S‐1, leucovorin, oxaliplatin and gemcitabine in metastatic pancreatic adenocarcinoma–TCOG T1211 study\n. Eur J Cancer . 2020 ;124 :123 ‐130\n.31765987 \n29 \n\nLamarca \nA \n, \nPalmer \nDH \n, \nWasan \nHS \n, et al. ABC‐06 | A randomised phase III, multi‐centre, open‐label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5‐FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously‐treated with cisplatin/gemcitabine (CisGem) chemotherapy\n. J Clin Oncol . 2019 ;37 :4003 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1478-3223",
"issue": "40(10)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "S-1; biliary tract cancer; gemcitabine",
"medline_ta": "Liver Int",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001650:Bile Duct Neoplasms; D001661:Biliary Tract Neoplasms; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D006801:Humans; D016896:Treatment Outcome",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "2535-2543",
"pmc": null,
"pmid": "32463975",
"pubdate": "2020-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "12538461;25630414;30998813;23763511;28818953;20628385;15297391;18380793;12815209;27199577;31015767;25949315;10473078;24351397;25477010;31566666;31765987;12488482;23547081;12114411;18214482;28383633;16145066;12763215;20375404;32463975",
"title": "Multicentre, phase II study of gemcitabine and S-1 in patients with advanced biliary tract cancer: TG1308 study.",
"title_normalized": "multicentre phase ii study of gemcitabine and s 1 in patients with advanced biliary tract cancer tg1308 study"
} | [
{
"companynumb": "TW-PFIZER INC-2020228258",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBusulfan (Bu) and cyclophosphamide (Cy) are frequently included in conditioning regimens before hematopoietic stem cell transplantation (HSCT). Both drugs are detoxified by glutathione transferases (GST), and GST gene variants may explain some of the interindividual variability in pharmacokinetics and drug toxicity.\n\n\nMETHODS\nThe study investigated adult patients (n = 114) receiving oral Bu pre-HSCT. Bu doses were adjusted to obtain an average steady-state concentration (Css) of 900 mcg/L.\n\n\nRESULTS\nMedian first dose Bu Css was 1000 mcg/L (600-1780 mcg/L). Patients carrying 1 and 2 GSTA1*B (rs3957357) alleles demonstrated median 12% and 16% higher Bu Css (P ≤ 0.05). Bu exposure (average Css; odds ratio = 1.009, 95% confidence interval = 1.002-1.017, P = 0.013) and GSTM1 gene copy number (odds ratio = 17.1, 95% confidence interval = 1.46-201, P = 0.024) were significant predictors of mortality ≤30 days. The mortality was 25% versus 2% among carriers of 2 versus no GSTM1 copies (P = 0.021). Mortality ≤3 months was associated with higher first dose Bu exposure (1090 versus 980 mcg/L, P = 0.021). GSTM1 expression and high Bu exposure may increase Cy toxicity by reducing intracellular glutathione.\n\n\nCONCLUSIONS\nGST genotyping before HSCT may allow better prediction of Bu pharmacokinetics and drug toxicity, and thereby improve outcome after BuCy conditioning.",
"affiliations": "Departments of *Medical Biochemistry, †Hematology, and ‡Pharmacology, Oslo University Hospital, Rikshospitalet; and §School of Pharmacy, University of Oslo, Norway.",
"authors": "Bremer|Sara|S|;Fløisand|Yngvar|Y|;Brinch|Lorentz|L|;Gedde-Dahl|Tobias|T|;Bergan|Stein|S|",
"chemical_list": "C484555:GSTA1 protein, human; D005982:Glutathione Transferase; C117740:glutathione S-transferase M1; D002066:Busulfan",
"country": "United States",
"delete": false,
"doi": "10.1097/FTD.0000000000000180",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4356",
"issue": "37(4)",
"journal": "Therapeutic drug monitoring",
"keywords": null,
"medline_ta": "Ther Drug Monit",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002066:Busulfan; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D005982:Glutathione Transferase; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7909660",
"other_id": null,
"pages": "493-500",
"pmc": null,
"pmid": "25565670",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": "21135089;23252950;23583825;16448639;16415899;10455367;9415705;8886613;6996481;4153799;15142875;11751440;11692074;10975610;10800057;10655267;10570028;9108645;21736681;21215809;20548339;20672371;20540773;20237319;19584821;19891548;19611402;19361744;18635758;18641537;17425746;18214047;18666253",
"title": "Glutathione Transferase Gene Variants Influence Busulfan Pharmacokinetics and Outcome After Myeloablative Conditioning.",
"title_normalized": "glutathione transferase gene variants influence busulfan pharmacokinetics and outcome after myeloablative conditioning"
} | [
{
"companynumb": "NO-ASPEN PHARMA TRADING LIMITED US-AG-2015-000164",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nTo describe a patient with visually symptomatic circumscribed choroidal hemangioma (CCH) treated successfully with intravitreal beta-blocker.\n\n\nMETHODS\nThis is an interventional single case report of a 63 year-old man with a juxtafoveal CCH and extensive subretinal fluid (SRF) unsuccessfully treated with intravitreal anti-VEGF. Off-label intravitreal use of metoprolol (50μg/0.05 ml) was then performed. Main outcome measures were resolution or decreased subretinal fluid on OCT, visual stability or improvement, lack of retinal/ocular toxicity.\n\n\nRESULTS\nFollowing 2 intravitreal injections of metoprolol (1 month apart), significant response was observed with decrease of SRF and visual improvement to 20/400 during a 9-week follow-up after the injections.\n\n\nCONCLUSIONS\nThese preliminary findings suggest that intravitreal metoprolol can be a safe alternative treatment for patients with CCH. This off-label therapy could represent another option for patients with this condition.",
"affiliations": "Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.;Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.;Faculty of Pharmacy, Minas Gerais Federal University, Belo Horizonte, Minas Gerais, Brazil.;Departments of Ophthalmology and Oncology, Wilmer Eye Institute, Sidney Kimmel Comprehensive Cancer Institute, John Hopkins Medicine, Baltimore, Maryland.",
"authors": "Jorge|Rodrigo|R|;Chaves|Leandro|L|;Cunha|Armando da Silva|ADS|;Correa|Zelia M|ZM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000917",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": null,
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31517744",
"pubdate": "2019-09-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ALTERNATIVE MANAGEMENT OF CIRCUMSCRIBED CHOROIDAL HEMANGIOMA USING INTRAVITREAL METOPROLOL.",
"title_normalized": "alternative management of circumscribed choroidal hemangioma using intravitreal metoprolol"
} | [
{
"companynumb": "BR-ALKEM LABORATORIES LIMITED-BR-ALKEM-2022-00071",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METOPROLOL SUCCINATE"
},
... |
{
"abstract": "BACKGROUND\nThe efficacy and safety of chemotherapy for patients with lung cancer who are in need of intensive care, such as invasive mechanical ventilation, have not been established.\n\n\nMETHODS\nA 59-year-old woman consulted a doctor with complaints of dyspnea.She was intubated because of acute respiratory failure and transferred to our hospital.Enhanced CT images revealed advanced stenosis of her trachea due to a bulky mediastinal tumor.Cervical lymph node biopsy was performed, and she was diagnosed with mediastinal small cell lung cancer.She received combination chemotherapy with carboplatin and etoposide along with invasive mechanical ventilation.Chemotherapy was effective, and extubation was performed under careful bronchoscopic observation.Her general condition improved gradually, and she was discharged from our hospital on foot with ambulatory chemotherapy.\n\n\nCONCLUSIONS\nEven though patients with lung cancer develop respiratory failure and need invasive mechanical ventilation, they may be treated with effective chemotherapy and may be weaned from ventilation.",
"affiliations": "Dept. of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine.",
"authors": "Koba|Taro|T|;Hirata|Haruhiko|H|;Kijima|Takashi|T|;Naito|Yujiro|Y|;Hamaguchi|Masanari|M|;Suga|Yasuhiko|Y|;Kuroyama|Muneyoshi|M|;Koyama|Shohei|S|;Iwahori|Kota|K|;Takimoto|Takayuki|T|;Nagatomo|Izumi|I|;Takeda|Yoshito|Y|;Kida|Hiroshi|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(9)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D060666:Airway Extubation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D012131:Respiratory Insufficiency; D055752:Small Cell Lung Carcinoma; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1335-1337",
"pmc": null,
"pmid": "30237376",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Mediastinal Small Cell Lung Cancer in a Patient Receiving Mechanical Ventilation Who Was Successfully Treated with Chemotherapy and Finally Extubated.",
"title_normalized": "a case of mediastinal small cell lung cancer in a patient receiving mechanical ventilation who was successfully treated with chemotherapy and finally extubated"
} | [
{
"companynumb": "JP-ACCORD-096354",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
"druga... |
{
"abstract": "3-methylfentanyl (3-MF), N-(3-methyl-1-phenethyl-4-piperidyl)-N-phenyl-propanamide, has reappeared on the US illicit drug market since its disappearance after a series of overdose deaths in 1988. 3-MF presents an analytical challenge, due to presence of cis and trans stereoisomers, each with different potencies, and ultimately very low concentrations in the blood after use. A method was developed using liquid chromatography-time-of-flight-mass spectrometry for the analysis of (±)-cis-3-MF and (±)-trans-3-MF in blood specimens after solid phase extraction. The linear dynamic range of this method was 0.1-10 ng/mL. Blood samples from 25 postmortem cases and 2 human performance case involving 3-MF were submitted for quantitative analysis. The mean and median concentration for the (±)-cis-3-MF were 0.84 ng/mL (±0.81) and 0.67 ng/mL, respectively, range 0.14-3.43 ng/mL. The resulting (±)-trans-3-MF mean concentration was 0.46 ng/mL (±0.38) and the median concentration was 0.37 ng/mL with a range of 0.11-1.90 ng/mL. The resulting (±)-cis-3-MF and (±)-trans-3-MF concentrations were summed to give the total amount of 3-MF present in the case with the resulting average concentration at 1.28 ng/mL (±1.16), median at 1.01 ng/mL and range 0.18-5.18. As the estimated dose of this compound is approximately 0.1 mg-0.5 mg with the resulting concentrations in the sub-nanogram range, it is necessary for forensic toxicology laboratories to obtain instruments sensitive enough to detect these substances in driving under the influence of drugs and postmortem cases. Quantitation of 3-MF with separation of (±)-cis and (±)-trans-3-MF provides additional detail for more specific toxicological interpretation.",
"affiliations": "The Center for Forensic Science Research and Education (CFSRE) at the Fredric Rieders Family Foundation, Willow Grove, Pennsylvania.;NMS Labs, Willow Grove, 19090, Pennsylvania.;The Center for Forensic Science Research and Education (CFSRE) at the Fredric Rieders Family Foundation, Willow Grove, Pennsylvania.",
"authors": "Fogarty|Melissa F|MF|http://orcid.org/0000-0002-8846-9780;Papsun|Donna M|DM|;Logan|Barry K|BK|",
"chemical_list": "D013287:Illicit Drugs; C030592:3-methylfentanyl; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1002/dta.2414",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1942-7603",
"issue": "10(9)",
"journal": "Drug testing and analysis",
"keywords": "3-methylfentanyl; LC-QToF; high resolution mass spectrometry; toxicology",
"medline_ta": "Drug Test Anal",
"mesh_terms": "D000328:Adult; D002138:Calibration; D002423:Cause of Death; D002851:Chromatography, High Pressure Liquid; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D053593:Forensic Toxicology; D006801:Humans; D013287:Illicit Drugs; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D012015:Reference Standards; D015203:Reproducibility of Results; D013237:Stereoisomerism; D015813:Substance Abuse Detection; D055815:Young Adult",
"nlm_unique_id": "101483449",
"other_id": null,
"pages": "1474-1482",
"pmc": null,
"pmid": "29801193",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of cis and trans 3-methylfentanyl by liquid chromatography-high resolution mass spectrometry and findings in forensic toxicology casework.",
"title_normalized": "analysis of cis and trans 3 methylfentanyl by liquid chromatography high resolution mass spectrometry and findings in forensic toxicology casework"
} | [
{
"companynumb": "US-SA-2018SA276022",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLPIDEM TARTRATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim of this study is to report two interesting cases of cytomegalovirus (CMV) anterior uveitis following topical prostaglandin analogue administration for glaucoma. Two retrospective case studies are presented.\n\n\nRESULTS\nA 40-year-old immunocompetent lady with a history of Fuchs heterochromic iridocyclitis with secondary glaucoma in the right eye since 2005 was diagnosed to have CMV anterior uveitis by a multiplex polymerase chain reaction (PCR) in 2009. She developed a reactivation of anterior uveitis following the addition of latanoprost 0.005% eye drops unknowingly by her local ophthalmologist. The pattern of endothelial deposits seen with this reactivation of uveitis was different from that seen in earlier or in subsequent reactivations. A 46-year-old immunocompetent lady with a history of primary open-angle glaucoma and no history of uveitis presented with anterior uveitis with medium-sized keratic precipitates following administration of travatoprost 0.004% eye drops. In both cases, the CMV antigen was demonstrated in the aqueous by multiplex PCR at the time of reactivation. Both cases required treatment with dexamethasone eye drops, ganciclovir 1% gel and oral valganciclovir for the control of inflammation along with antiglaucoma medications.\n\n\nCONCLUSIONS\nWe report two immunocompetent cases with the development of CMV-related anterior uveitis following administration with prostaglandin analogues. These cases increase the awareness of CMV anterior uveitis in immunocompetent individuals and the need to use prostaglandin analogues with caution.",
"affiliations": "Vittala International Institute of Ophthalmology, Bangalore, India. kalpana@prabhaeyeclinic.com.",
"authors": "Babu|Kalpana|K|;Murthy|Gowri Jaydev|GJ|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/1869-5760-3-55",
"fulltext": "\n==== Front\nJ Ophthalmic Inflamm InfectJ Ophthalmic Inflamm InfectJournal of Ophthalmic Inflammation and Infection1869-5760Springer 1869-5760-3-552383744410.1186/1869-5760-3-55Brief ReportCytomegalovirus anterior uveitis in immunocompetent individuals following topical prostaglandin analogues Babu Kalpana 12kalpana@prabhaeyeclinic.comMurthy Gowri Jaydev 12gowrijmurthy@gmail.com1 Vittala International Institute of Ophthalmology, Bangalore, India2 Prabha Eye Clinic and Research Centre, 504, 40th Cross, Jayanagar 8th Block, Bangalore 560070, India2013 9 7 2013 3 55 55 21 5 2013 2 7 2013 Copyright ©2013 Babu and Murthy; licensee Springer.2013Babu and Murthy; licensee Springer.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThe aim of this study is to report two interesting cases of cytomegalovirus (CMV) anterior uveitis following topical prostaglandin analogue administration for glaucoma. Two retrospective case studies are presented.\n\nFindings\nA 40-year-old immunocompetent lady with a history of Fuchs heterochromic iridocyclitis with secondary glaucoma in the right eye since 2005 was diagnosed to have CMV anterior uveitis by a multiplex polymerase chain reaction (PCR) in 2009. She developed a reactivation of anterior uveitis following the addition of latanoprost 0.005% eye drops unknowingly by her local ophthalmologist. The pattern of endothelial deposits seen with this reactivation of uveitis was different from that seen in earlier or in subsequent reactivations. A 46-year-old immunocompetent lady with a history of primary open-angle glaucoma and no history of uveitis presented with anterior uveitis with medium-sized keratic precipitates following administration of travatoprost 0.004% eye drops. In both cases, the CMV antigen was demonstrated in the aqueous by multiplex PCR at the time of reactivation. Both cases required treatment with dexamethasone eye drops, ganciclovir 1% gel and oral valganciclovir for the control of inflammation along with antiglaucoma medications.\n\nConclusions\nWe report two immunocompetent cases with the development of CMV-related anterior uveitis following administration with prostaglandin analogues. These cases increase the awareness of CMV anterior uveitis in immunocompetent individuals and the need to use prostaglandin analogues with caution.\n\nCytomegalovirusAnterior uveitisProstaglandin analoguesGlaucoma\n==== Body\nFindings\nIntroduction\nTopical prostaglandin analogues used to treat glaucoma are known to cause exacerbations of uveitis\n[1,2]. Reactivation of herpex simplex keratitis following its use has been described in the literature\n[3]. We report two interesting cases of cytomegalovirus (CMV) anterior uveitis in immunocompetent individuals following administration of topical prostaglandin analogues. To our knowledge, this is the first case series of reactivation of CMV following topical prostaglandin analogues (Medline search).\n\nCase 1\nA 40-year-old immunocompetent lady initially diagnosed to have Fuchs heterochromic iridocyclitis with secondary glaucoma (OD) in 2005 (Figure \n1A) had a history of ocular inflammations with fluctuations in intraocular pressure (IOP) for which she was using fluorometholone eye drops (on and off) and antiglaucoma medications (betaxolol 0.5% twice a day). In 2009, an aqueous tap done for persistently high IOP (42 mmHg) showed positive for CMV antigen by a multiplex PCR and negative for herpes simplex virus (HSV), varicella zoster virus (VZV), rubella, chikungunya, toxoplasma and Mycobacterium tuberculosis (MTb). Serology for CMV IgG was positive but negative for CMV IgM. A moth-eaten appearance of the iris with no posterior synechiae, 1 + AC reaction (SUN) and medium-sized pigmented keratic precipitates located centrally with a surrounding halo was seen on slit-lamp examination. The inflammation and IOP stabilized with oral valganciclovir (900 mg bid for 3 weeks followed by 450 mg bid for 1 month), dexamethasone eye drops (tapered weekly from an initial dose of six times a day) and ganciclovir eye gel 0.15% five times a day. Since then, she has been on a fixed combination of 0.2% brimonidine and 0.5% timolol eye drops twice a day. In 2010, she was shifted to latanoprost 0.005% eye drops due to a skin allergy to the above. A quiet eye with a pigmented central keratic precipitate with a clear halo and no AC reaction (Figure \n1B) was recorded before starting the drops. She came back with blurring of vision (OD) 4 days later. Her best-corrected visual acuity (BCVA) was 6/6 (OU). Slit-lamp examination (OD) showed multiple map lesions on the endothelium along with fresh, fine and medium-sized keratic precipitates (Figure \n1C) and an IOP of 50 mmHg. Aqueous tap (OD) was again positive for CMV antigen by multiplex PCR. Her uveitis and IOP stabilized with discontinuation of the drug and administration of dexamethasone eye drops. She eventually required a filtering surgery. She developed a reactivation once after the filtering surgery (Figure \n1D), which settled with oral valganiciclovir, dexamethasone eye drops and ganciclovir gel. At 2 years follow-up, ocular inflammation and IOP are stable.\n\nFigure 1 Slit-lamp examination of the right eye of case 1. Showing (A) iris moth-eaten pattern with keratic precipitates located centrally, (B) pigmented keratic precipitate with a clear halo located centrally in a quiet eye, (C) multiple map-like lesions (arrow) and fine and medium-sized keratic precipitates on the endothelium following latanoprost 0.005% eye drops and (D) reactivation of anterior uveitis with fine to medium-sized keratic precipitates post-filtering surgery.\n\nCase 2\nA 46-year-old immunocompetent lady with a history of primary open-angle glaucoma (OU) since 2006 presented with blurring of vision (OD) after starting travoprost 0.004% eye drops for the right eye a week ago. She had no history of uveitis. At the time of presentation, her BCVA was 6/6 (OU). Slit-lamp evaluation (OD) showed medium-sized keratic precipitates located inferiorly and centrally (Figure \n2) and an IOP of 52 mmHg. Multiplex PCR on the aqueous tap (OD) showed a positive CMV antigen and negative for HSV, VZV, rubella, chikungunya, toxoplasma and MTb. Serology for CMV IgG was positive but negative for CMV IgM. Her uveitis and IOP settled with discontinuation of travoprost 0.004%, addition of dexamethasone eye drops and oral valganciclovir (900 mg bid for 3 weeks followed by 450 mg bid for 1 month). At 6 months follow-up, her inflammation and IOP are stable.\n\nFigure 2 Slit-lamp examination of the right eye of case 2. Showing inferiorly located medium-sized keratic precipitate after travoprost 0.004% eye drops.\n\nDiscussion\nCMV is known to cause anterior uveitis in immunocompetent patients\n[4-6]. Reactivation of CMV anterior uveitis has been reported following fluocinolone-sustained steroid drug delivery implant\n[4]. Our first case had a prior history of CMV anterior uveitis and was started on latanoprost leading to reactivation of anterior uveitis. The pattern of multiple map-like lesions on the endothelium along with keratic precipitates was seen only during the reactivation following the prostaglandin analogues (Figure \n1C was different compared to that seen in Figure \n1A,D). The second case did not have a history of uveitis and developed a CMV anterior uveitis only after administration of travoprost eye drops. In both cases, the serology showed increased titres of CMV IgG. We speculate that CMV remains latent in the anterior chamber in some individuals, and this may reactivate when the local milieu is altered, such as with the administration of prostaglandin analogues. Ophthalmologists must be aware of this presentation of CMV anterior uveitis following usage of prostaglandin analogues.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nKB and GJM carried out the diagnosis and management of these cases and drafted the manuscript. Both authors read and approved the final manuscript.\n==== Refs\nAlm A Grierson I Shields MB Side effects associated with prostaglandin analog therapy Surv Ophthalmol 2008 3 Suppl 1 S93 105 19038628 \nKumarasamy M Desai SP Anterior uveitis is associated with travoprost BMJ 2004 3 7459 205 10.1136/bmj.329.7459.205 15271831 \nKroll DM Schuman JS Reactivation of herpes simplex virus keratitis after initiating bimatoprost treatment for glaucoma Am J Ophthalmol 2002 3 401 403 10.1016/S0002-9394(01)01360-5 11860979 \nSims JL Chee SP Cytomegalovirus endotheliitis following fluocinolone acetonide (Retisert) implant Eye 2010 3 197 198 19325574 \nChee SP Bacsal K Jap A Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients Am J Ophthalmol 2008 3 5 834 840 10.1016/j.ajo.2007.12.015 18255045 \nChee SP Jap A Cytomegalovirus anterior uveitis: outcome of treatment Br J Ophthalmol 2010 3 12 1648 52 10.1136/bjo.2009.167767 20576767\n\n",
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"title": "Cytomegalovirus anterior uveitis in immunocompetent individuals following topical prostaglandin analogues.",
"title_normalized": "cytomegalovirus anterior uveitis in immunocompetent individuals following topical prostaglandin analogues"
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"abstract": "Hyponatremia is a well-known medication related side effect of selective serotonin reuptake inhibitors; despite its association with escitalopram, the newest SSRI is very rare. We did a review of literature and came across only 14 reported case of this rare association of SIADH with escitalopram. We hereby report a case of a 93-year-old female who presented with generalized tonic-clonic seizure and was diagnosed with severe hyponatremia due to escitalopram-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). With this article, we want to emphasize clinicians about this rare side effect of escitalopram use and look for the risk factors leading to SIADH.",
"affiliations": "University of Kentucky, Lexington, KY 40536, USA.;University of Kentucky, Lexington, KY 40536, USA.;Monmouth Medical Center, Long Branch, NJ 07740, USA.;Monmouth Medical Center, Long Branch, NJ 07740, USA.;Monmouth Medical Center, Long Branch, NJ 07740, USA.",
"authors": "Raj|Rishi|R|0000-0002-4151-3246;Jacob|Aasems|A|0000-0002-7783-3786;Venkatanarayan|Ajay|A|;Doraiswamy|Mohankumar|M|;Ashok|Manjula|M|0000-0002-8725-1915",
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"doi": "10.1155/2018/3697120",
"fulltext": "\n==== Front\nCase Rep NephrolCase Rep NephrolCRINCase Reports in Nephrology2090-66412090-665XHindawi 10.1155/2018/3697120Case ReportSevere Symptomatic Hyponatremia Secondary to Escitalopram-Induced SIADH: A Case Report with Literature Review http://orcid.org/0000-0002-4151-3246Raj Rishi rishiraj91215@gmail.com\n1\nhttp://orcid.org/0000-0002-7783-3786Jacob Aasems \n1\nVenkatanarayan Ajay \n2\nDoraiswamy Mohankumar \n2\nhttp://orcid.org/0000-0002-8725-1915Ashok Manjula \n2\n\n1University of Kentucky, Lexington, KY 40536, USA\n2Monmouth Medical Center, Long Branch, NJ 07740, USAAcademic Editor: Yoshihide Fujigaki\n\n2018 5 9 2018 2018 36971201 7 2018 19 8 2018 Copyright © 2018 Rishi Raj 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.Hyponatremia is a well-known medication related side effect of selective serotonin reuptake inhibitors; despite its association with escitalopram, the newest SSRI is very rare. We did a review of literature and came across only 14 reported case of this rare association of SIADH with escitalopram. We hereby report a case of a 93-year-old female who presented with generalized tonic-clonic seizure and was diagnosed with severe hyponatremia due to escitalopram-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). With this article, we want to emphasize clinicians about this rare side effect of escitalopram use and look for the risk factors leading to SIADH.\n==== Body\n1. Background\nThe syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a well-known cause of hyponatremia. It is a diagnosis of exclusion and can be secondary to pulmonary disorders, infections, malignant diseases, central nervous system disorders, or drugs [1]. Selective serotonin reuptake inhibitors (SSRIs) are a well-known cause of SIADH with a threefold increased risk compared to other antidepressants [2]. Hyponatremia from escitalopram, one of the newest SSRI is rare with only few reported cases in literature. Here, we report a case of severe hyponatremia which was associated with escitalopram. The importance of the report lies in the fact that SSRIs are one of the most widely used antidepressants and it is imperative for the clinicians to be more widely aware of the life-threatening nature of the side effect of this seemingly benign medication.\n\n2. Case Presentation\nA 93-year-old Caucasian female was brought to emergency room for gradual decline in mental status over a course of one week. Her past medical history was significant for coronary artery disease, hypertension, diabetes mellitus, hyperlipidemia, and mild cognitive dysfunction. Her medications included aspirin 81 mg daily, metoprolol 25 mg daily, amlodipine 10 mg daily, and atorvastatin 20 mg daily. Four days prior to the onset of symptoms, she was started on escitalopram 10 mg daily by her primary care physician for newly diagnosed depression. She had a routine blood work immediately prior to the outpatient visit and on retrospective review was found to have a serum sodium level of 136 mEq/L. Patient developed drowsiness and inability to maintain conversation after four days of starting escitalopram. Her mental status continued to gradually decline over the course of next few days and on the day of presentation, which was seven days from the onset of symptoms, she was noted to have intermittent severe agitation. She did not have fever, chills, neck rigidity, myalgia, recent trauma, or fall. There was no reported seizure activity or loss of consciousness. At the time of admission, patient was afebrile, blood pressure was 134/57 mm Hg, pulse rate was 75 beats/min, and respiratory rate of 18 and saturating was 99% on room air. Her BMI was 27.1. She was noted to be lethargic and was only responsive to painful stimuli. Mucous membranes were moist, and the skin turgor was intact. Her GCS score was 7 (E2V1M4). Neurological examination was negative for any gross focal neurological deficits. The rest of the physical examination was unremarkable. While, in the emergency room, patient was noted to have generalized tonic-clonic seizure which was controlled with a single dose of intravenous lorazepam 1 mg. Initial laboratory investigation results are presented in Table 1, along with reference range values. Notably, patient's serum osmolality was 234mosm/kg (normal range: 275–295 mosm/kg), urine osmolality was 468 mosm/kg, serum sodium was 105 mEq/L (normal range: 135–145 mEq/L), and urinary sodium was 68 mEq/L (normal range 25-150 mEq/L). Her thyroid-stimulating hormone (TSH) and early morning free cortisol were 0.8μIU/mL (normal range 0.5-5.0 μIU/mL) and 49.2 μg/dL (normal range 1-75 μg/dL), respectively. Chest X-ray as well as CT Head without contrast were unremarkable.\n\n3. Diagnosis\nBased on her clinical findings of witnessed seizure, laboratory findings of severe hyponatremia, hypoosmolality, elevated urine osmolality, and elevated urinary sodium in the presence of normal adrenal and thyroid function, a diagnosis of acute severe symptomatic hypotonic hyponatremia or SIADH was made based on the diagnostic criteria (Table 2). The current symptoms were attributed to initiation of escitalopram due to the temporal relation.\n\n4. Treatment\nEscitalopram was discontinued on the day of admission. She was started on 3% hypertonic saline at 20 ml/hr with frequent monitoring of her sodium levels with a goal sodium correction of less than 10 mEq/L in 24 hrs. Patient was put on water restriction to less than one liter per day. She was also given 2 doses of Tolvaptan 15 mg on Day 3 and Day 5 of hospitalization. Patient did not have any further episodes of seizures. Her sodium levels started to trend up and her sodium levels became normal on the 6th day of hospitalization (Figure 1). The patient was finally discharged home on Day 6. Sodium levels on discharge were 135 mEq/L. She was discharged without any SSRI. Repeat sodium levels on 1 week and 2 weeks were 138 mEq/L and 142 mEq/L, respectively. She was eventually started on Mirtazapine 15 mg at bedtime on outpatient follow-up and her sodium levels remained within normal range at 3 and 6 months.\n\n5. Discussion & Review of Literature\nSIADH is defined as euvolemic hypotonic hyponatremia (serum sodium level of less than 135mmol/L), inappropriately elevated urine osmolality (usually more than 200 mmol/kg) relative to plasma osmolality, and an elevated urine sodium level (typically greater than 20 mmol/L) with normal renal, adrenal, and thyroid functions. Since Schwartz et al. first described it about 6 decades ago in 1957 in two patients, SIADH now has a long list of potential causes including malignant neoplasms, nonmalignant pulmonary diseases, central nervous system disorders, and drugs. In a single center retrospective study, Shepshelovich et al. compared different drug classes and showed a higher incidence of SIADH with antidepressants mainly SSRIs compared to other drug classes [3]. SSRIs are becoming increasingly leading because of SIADH with a reported incidence of 1 out of 200 patients per year [4]. SSRIs are first-line drugs for the treatment of geriatric depression owing to their safety, easy dose titration, and low rates of anticholinergic and cardiovascular adverse events [5]. Among SSRIs, escitalopram is the newest SSRI and was FDA approved in 2002. It is composed of only (S)-enantiomer of citalopram and inhibits the binding of serotonin (5-HT) to serotonin transporter (SERT), resulting in increased 5-HT concentration in synaptic cleft, which leads to increased binding of 5-HT to postsynaptic receptors causing improvement in the depression symptoms [6]. Experimental studies have revealed that enhanced serotonergic tone result in stimulation of antidiuretic hormone (ADH) secretion resulting in hyponatremia, provided water intake is sufficient [7]. As a matter of fact, since the publication of the above literature, there has been increasingly higher number of reports on escitalopram-induced SIADH. We aimed to identify these cases with detailed characteristics and present an extensive review of SIADH associated with escitalopram use which has not been included in the previous reviews. We reviewed literature published between January 1, 2002, and March 31, 2018, through search on Medline and found fourteen reported cases of SIADH associated with escitalopram use (Table 3). We also went through reference sections of each of these reports to identify other missing articles.\n\nNashoni et al. reported the first case of hyponatremia associated with escitalopram in 2004 in a 62-year-old female which occurred 3 weeks following initiation of escitalopram [8]. Majority of these reported escitalopram-induced SIADH were in females (64.28%). While age more than 65 years was found to be risk factor for SSRI-induced SIADH [2], this association was not seen with escitalopram, although the number of cases were limited to draw a definitive statistical conclusion. 50% of reported cases were in patients below 65 years of age. The youngest reported case was in a 47-year-old male who presented with seizures within 4 days of initiation of the drug while the oldest patient was a 97-year-old female [9, 10]. The mean serum sodium levels on presentation were 115 mEq/L.\n\nThe most common symptoms at presentation included confusion, seizures, and weakness. None of the reported cases had asymptomatic presentation which signifies underreporting of the association between escitalopram and SIADH. Similar to other SSRIs, the risk of hyponatremia is the highest during the first weeks with the earliest onset being within 2 days of starting escitalopram but can also occur even after 2 months of medication initiation [10, 11]. The median time of onset of symptoms was 7 days. Many of the patients reported in the literature were on multiple medications known to cause hyponatremia especially thiazide, proton pump inhibitor, and other psychiatric medications; however, a temporal association was drawn to escitalopram in all the cases [8, 9, 12–15]. Diken et al. reported a case of a 59-year-old male who underwent coronary artery bypass graft and developed hyponatremia with sodium levels of 107 mEq/L about 1 week following concomitant use of escitalopram 10 mg once daily and hydrochlorothiazide 50 mg once daily. Interestingly, this particular patient had prior history of use of escitalopram without any side effects [15].\n\nThe main modality of management in SIADH is water restriction, although in severe symptomatic cases hypertonic saline (3%) and drugs such as loop diuretics (furosemide), demeclocycline, and vaptans should be used [16]. Water restriction is the most important treatment modality in patients with SIADH. Those who do not respond fully or respond only partially can be treated with salt tablets and diuretics. Demeclocycline has been used previously which lead to acute kidney injury and hence its use has been limited. Vaptans, a selective V2 receptor antagonist (Tolvaptan and Conivaptan) can be safely used for treatment of SIADH in carefully monitored patients [17, 18]. High cost and overcorrection remain a potential risk for vaptans [18]. In all 14 cases, hyponatremia improved after discontinuation of the drug and active treatment for SIADH with fluid restriction and administration of hypertonic saline. However, in our case Tolvaptan was used for correction of hyponatremia. Rapid correction of hyponatremia leads to serious neurologic problems with the most severe including osmotic demyelination syndrome and hence close monitoring of sodium during the treatment of SIADH is of paramount importance [16, 19]. One patient had complication secondary to treatment of hyponatremia resulting in central pontine myelinolysis [20].\n\nIn 2012, Tsai et al. reported a case of 73-year-old female with history of dementia with Lewy bodies who developed delirium after being on escitalopram for 2 months. She was found to have serum sodium of 124 mEq/L on presentation. She recovered to baseline within 2 weeks following discontinuation of medication. Her delirium and hyponatremia (122 mEq/L), however, recurred after escitalopram was rechallenged. During the rechallenge phase, she had an early onset of symptomatic hyponatremia at 4 days [11]. This case signifies that rechallenge of escitalopram leads to SIADH with early initiation of the medication. The mean time for normalization of serum sodium levels after discontinuation of escitalopram and active treatment was found to be 5.8 days among the ten reported cases with data on resolution time. Mirtazapine was noted to be a good choice of antidepressant for those patients who developed escitalopram associated SIADH on review of literature [8, 14].\n\n6. Conclusion\nOur case highlights the clear association of escitalopram use with SIADH in the absence of any significant medical comorbidity or concomitant drug use. With our literature review of all the published case reports, we could infer that female gender and use of concomitant medication may be the risk factors for SIADH in patients taking escitalopram. However, more data is needed for obtaining meaningful conclusion regarding the risk factors and associations. Hyponatremia in most cases started within first week of treatment and resolved within 2 weeks after discontinuation of the medication. Patients being started on escitalopram and other SSRIs should be informed about this life-threatening adverse effect and the warning signs. Factors leading to overhydration like water intake for urinary tract infections and ingestion of excess water during exercise can lead to precipitation of SIADH [21]. We suggest regular serum electrolyte monitoring in patients receiving escitalopram and always evaluate patients for hyponatremia when presenting with symptoms of weakness, confusion, or seizures. Patient who once developed SIADH on escitalopram should not be ideally rechallenged with the same medication due to risk of causing more severe SIADH and may be started on alternative antidepressants like Mirtazapine.\n\nConflicts of Interest\nThe authors have no potential conflicts of interest that are directly relevant to the contents of this report. No sources of funding were used to assist in the preparation of this report.\n\nFigure 1 Sodium levels of the patient during the course of treatment.\n\nTable 1 Laboratory results at admission.\n\nLaboratory Test\tLevels\tReference Range\t\nSerum Sodium\t105 mEq/L\t135 –145 mEq/L\t\nSerum Chloride\t74 mEq/L\t99-109 mEq/L\t\nSerum Osmolality\t234mosm/kg\t275–295 mosm/kg\t\nSerum Creatinine\t0.69 mg/dL\t0.40-1.10 mg/dL\t\nBlood Urea Nitrogen (BUN)\t10 mg/dL\t5-21 mg/dL\t\nUrine Sodium\t68 mEq/L\t25-150 mEq/L\t\nUrine Chloride\t75 mEq/L\t75-170 mEq/L\t\nUrine Osmolality\t468 mosm/kg\t50-1400 mosm/kg\t\nMorning Cortisol\t49.2 mcg/dL\t1.0-75.0 mcg/dL\t\nThyroid Stimulating Hormone (TSH)\t0.86 mcIU/mL\t0.5- 5.0 mcIU/mL\t\nTable 2 Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH).\n\n\nEssential criteria\n\t\n\n\n\t\n1. True plasma hypoosmolality (<275 mOsm/kg H2O)\t\n2. Inappropriate urinary response to hypoosmolality (urine osmolality >100 mOsm/kg H2O)\t\n3. Euvolemia; no edema, ascites, or signs of hypovolemia\t\n4. Elevated urine sodium (>30 mEq/L) during normal sodium and water intake\t\n5. No other causes of euvolemic hyponatremia\t\n\n\n\t\n\nSupplemental criteria\n\t\n\n\n\t\n1. No significant increase in serum sodium after volume expansion, but improvement with fluid restriction.\t\n2. Unable to excrete >80% of a water load (20 cc/kg) in 4 hours and/or failure to achieve urine osmolality <1mOsm/kg H2O\t\nTable 3 Summary of all reported cases of SIADH associated with escitalopram.\n\nCase Report\tAge\tSex\tEscitalopram Dose\tOnset\n(Days)\tSodium\nLevels (mEq/L)\tPresenting Symptoms\tTreatment given\tResolution\n(Weeks)\tComorbid conditions\tMedications\tRemarks\t\nNashoni et al, 2004 [8]\t62\tF\t10 mg\t21\t110\tSyncope\tMedication discontinuation\t1 week\tHypertension, Hyperlipidemia\nAtrial fibrillation\nProtein C deficiency\nOsteoporosis\tLosartan\nSimvastatin\nSotalol\nWarfarin\nCalcium\nVitamin D\tPatient was later treated with Mirtazapine for depression\t\n\n\n\t\nNirmalani et al, 2006 [22]\t50\tM\t20 mg\t28\t121\tWeakness\nDizziness\tMedication discontinuation\nFluid Restriction\t5 days\tDepression with Psychotic features,\nHypertension,\nCOPD\nOsteoarthritis\nGERD\tRisperidone\t \t\n\n\n\t\nAdiga et al, 2006 [12]\t81\tF\t10 mg\t21\t120\tGeneralized weakness &\nRecurrent Falls\tMedication discontinuation\nHypertonic saline\t1 week\tAlzheimer's' disease Hypertension\nOsteoporosis\tRamipril\nAlendronic acid\nDonepezil\nMirtazapine\nHCTZ\tPatient noted to have Renal tubular defect\t\n\n\n\t\nGrover et al, 2007 [14]\t67\tF\t10 mg\t28\n\t127\tDelirium\tMedication discontinuation\n\t4 weeks\tBipolar affective disorder\nHypertension\nDiabetes mellitus\tSodium valproate\nHCTZ\nGliclazide\nAspirin\nLosartan\tPatient was later treated with Mirtazapine & Valproate for Moderate depression\t\n\n\n\t\nGrover et al, 2007 [14]\t75\tM\t10 mg\t10\t126\tSeizures\tMedication discontinuation\n\t2 weeks\tHypertension\nGeneralized anxiety disorder\tAtenolol\nAmlodipine\tPatient was later treated with Mirtazapine for Generalized Anxiety disorder\t\n\n\n\t\nCovyeou et al, 2007 [13]\t75\tF\tUnknown\t5\t116\tUnknown\tMedication discontinuation\n\t5 days\tHypertension\tAmlodipine\nHCTZ\nAspirin\nOmeprazole\nAlprazolam\t \t\n\n\n\t\nKoski et al, 2009 [9]\t97\tF\t5 mg\t7\t113\n\tRecurrent Falls & Confusion\tMedication discontinuation\nFluid restriction\nHypertonic saline\tUnknown\tHypertension, Anxiety\nUTI (diagnosed 1 day prior to hospitalization)\tTolterodine\nAtenolol\nFurosemide\nLisinopril\nDocusate\nCiprofloxacin\n(started 1 day prior to hospitalization)\t \t\n\n\n\t\nTsai et al\n2012 [11]\t73\tF\t10 mg\t>60\n\t124\n122\tDelirium\tMedication discontinuation\nFluid restriction\t2 weeks\n1 week\tLewy body dementia\tTrihexyphenidyl Bethanechol\nTamsulosin\tFailed rechallenge of escitalopram as patient developed Hyponatremia\t\n\n\n\t\nPae et al, 2013 [10]\t47\tM\t5 mg\t2\t110\tSeizure\tMedication discontinuation\n\t4 days\tQuadriplegia with Spinal A-V Malformation\nDepression\tNo other medication\n\t \t\n\n\n\t\nSoysal et al, 2014 [23]\t76\tF\t10mg\t28\t113\tConfusion\nLethargy\nIncontinence\tMedication discontinuation\nHypertonic saline\n\tUnknown\tHypertension Diabetes mellitus, Alzheimer's disease\nSleep disorder\n\tLosartan\nSitagliptin\nRivastigmine\nMemantine\nTrazodone\n\t \t\n\n\n\t\nDiken et al, 2016 [15]\t59\tM\t10 mg\t7\t107\tConfusion, Hallucination, Drowsiness\n\tMedication discontinuation\nFluid restriction\nHypertonic saline\n\t4 days\tCOPD\nDiabetes mellitus\n\tAspirin, metoprolol perindopril amiodarone\nSpironolactone Hydrochlorothiazide\n\tRecent introduction of hydrochlorothiazide\t\n\n\n\t\nParmar et al, 2016 [20]\t50\tM\t10 mg\t3\t94\tSeizure\tMedication discontinuation\n\t5 days\tHypertension\nPanic disorder\n\tTelmisartan\nAspirin\tDeveloped central pontine myelinolysis from rapid correction of sodium\t\n\n\n\t\nRawal et al, 2017 [24]\t54\tF\tUnknown\t4\t116\tSeizure\tMedication discontinuation\nFluid restriction\tUnknown\tHypertension\nDepression\tTelmisartan\nSalt restriction\n\t \t\n\n\n\t\nVidyasagar et al, 2017 [25]\t58\tF\tUnknown\t14\t107\tSevere Constipation\tMedication discontinuation\nHigh salt diet\nFluid restriction\tUnknown\tSeronegative spondyloarthropathy\nDiabetes mellitus\nDysthymia\tPrednisolone, Hydroxychloroquine\nMethotrexate\nInsulin\t \n==== Refs\n1 Sahay M. Sahay R. Hyponatremia: A practical approach Indian Journal of Endocrinology and Metabolism 2014 18 6 p. 760 10.4103/2230-8210.141320 \n2 Movig K. L. Leufkens H. G. Lenderink A. W. Association between antidepressant drug use and hyponatraemia: a case-control study British Journal of Clinical Pharmacology 2002 53 4 363 369 10.1046/j.1365-2125.2002.01550.x 11966666 \n3 Shepshelovich D. Schechter A. Calvarysky B. Diker-Cohen T. Rozen-Zvi B. Gafter-Gvili A. Medication-induced SIADH: distribution and characterization according to medication class British Journal of Clinical Pharmacology 2017 83 8 1801 1807 2-s2.0-85014125970 10.1111/bcp.13256 28168757 \n4 Fonzo-Christe C. Vogt N. Susceptibility of the elderly patient to hyponatremia induced by selective serotonin reuptake inhibitors Therapie 2000 55 5 597 604 http://www.ncbi.nlm.nih.gov/pubmed/Available from 11201974 \n5 Bowen P. D. Use of Selective Serotonin Reuptake Inhibitors in the Treatment of Depression in Older Adults: Identifying and Managing Potential Risk for Hyponatremia Geriatric Nursing 2009 30 2 85 89 10.1016/j.gerinurse.2008.04.007 19345847 \n6 Stahl S. M. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects Journal of Affective Disorders 1998 51 3 215 235 10.1016/s0165-0327(98)00221-3 2-s2.0-0032440963 10333979 \n7 Kovacs L. Robertson G. L. Syndrome of Inappropriate Antidiuresis Endocrinology and Metabolism Clinics of North America 1992 21 4 859 875 10.1016/S0889-8529(18)30192-0 1486879 \n8 Nahshoni E. Weizman A. Shefet D. Pik N. A Case of Hyponatremia Associated With Escitalopram Journal of Clinical Psychiatry 2004 65 12 p. 1722 10.4088/JCP.v65n1219c \n9 Koski R. R. Covyeou J. A. Morissette M. Case Report of SIADH Associated With Escitalopram Use Journal of Pharmacy Practice 2009 22 6 594 599 10.1177/0897190009333359 \n10 Pae C.-U. Park G.-Y. Im S. Ko S. B. Lee S.-J. Low-dose escitalopram-associated hyponatremia Asia-Pacific Psychiatry 2013 5 2 E90 E90 2-s2.0-84878190874 10.1111/j.1758-5872.2012.00230.x 23857817 \n11 Tsai P. Chen H. Liao S. Tseng M. M. Lee M. Recurrent escitalopram-induced hyponatremia in an elderly woman with dementia with Lewy bodies General Hospital Psychiatry 2012 34 1 101.e5 101.e7 10.1016/j.genhosppsych.2011.06.007 \n12 Adiga GU. Dharmarajan TS. Renal tubular defects from antidepressant use in an older adult: an uncommon but reversible adverse drug effect Clin Drug Investi 2006 26 10 607 611 http://go.galegroup.com.ezproxy2.library.drexel.edu/ps/i.do?p=AONE&u=drexel_main&id=GALE%7CA199858434&v=2.1&it=r&sid=summon \n13 Covyeou J. A. Jackson C. W. Hyponatremia Associated with Escitalopram The New England Journal of Medicine 2007 356 1 94 95 10.1056/NEJMc062840 17202465 \n14 Grover S. Biswas P. Bhateja G. Kulhara P. Escitalopram-associated hyponatremia [4] Psychiatry and Clinical Neurosciences 2007 61 1 132 133 2-s2.0-33846165526 10.1111/j.1440-1819.2007.01625.x 17239054 \n15 Diken A. I. Yalçinkaya A. Erçen Diken Ö. Hyponatremia due to escitalopram and thiazide use after cardiac surgery Journal of Cardiac Surgery 2016 31 2 96 97 10.1111/jocs.12681 2-s2.0-84957895181 26687322 \n16 Gross P. Clinical management of SIADH Therapeutic Advances in Endocrinology and Metabolism 2012 3 2 61 73 2-s2.0-84859367204 10.1177/2042018812437561 23148195 \n17 Zmily H. D. Daifallah S. Ghali J. K. Tolvaptan, hyponatremia, and heart failure International Journal of Nephrology and Renovascular Disease 2011 4 57 71 2-s2.0-79958776450 10.2147/IJNRD.S7032 21694950 \n18 Humayun M. A. Cranston I. C. In-patient Tolvaptan use in SIADH: care audit, therapy observation and outcome analysis BMC Endocrine Disorders 2017 17 1 10.1186/s12902-017-0214-2 \n19 Sterns R. H. Treatment of Severe Hyponatremia Clinical Journal of the American Society of Nephrology 2018 13 4 641 649 10.2215/CJN.10440917 29295830 \n20 Arpit P. Piyali M. Manjari T. Rajesh S. Escitalopram Induced Hyponatremia Escitalopram Induc Hyponatremia ASEAN J Psychiatry 2016 17 2 \n21 Hew-Butler T. Rosner M. H. Fowkes-Godek S. Statement of the 3rd International Exercise-Associated Hyponatremia Consensus Development Conference, Carlsbad, California, 2015 British Journal of Sports Medicine 2015 49 22 1432 1446 10.1136/bjsports-2015-095004 26227507 \n22 Nirmalani A. Stock S. L. Catalano G. Syndrome of Inappropriate Antidiuretic Hormone Associated with Escitalopram Therapy CNS Spectrums 2006 11 06 429 432 10.1017/S1092852900014620 16816780 \n23 Soysal P. Isik A. T. Severe Hyponatremia Due to Escitalopram Treatment in an Elderly Adult with Alzheimer's Disease Journal of the American Geriatrics Society 2014 62 12 2462 2463 10.1111/jgs.13149 25516055 \n24 Rawal G. Kumar R. Yadav S. Severe hyponatremia associated with escitalopram Journal of Family Medicine and Primary Care 2017 6 2 p. 453 10.4103/2249-4863.220043 \n25 Vidyasagar S. Rao K. Verma M. Tripuraneni AD. Patil N. Bhattacharjee D. Escitalopram induced SIADH in an elderly female: A case study Psychopharmacol Bull 2017 47 64 67 http://www.ncbi.nlm.nih.gov/pubmed/2893601 28936011\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-665X",
"issue": "2018()",
"journal": "Case reports in nephrology",
"keywords": null,
"medline_ta": "Case Rep Nephrol",
"mesh_terms": null,
"nlm_unique_id": "101598418",
"other_id": null,
"pages": "3697120",
"pmc": null,
"pmid": "30254775",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "25364669;28936011;16816780;29302568;26227507;15641882;29110656;17202465;1486879;10333979;19345847;23148195;21831444;29295830;11201974;17163295;23857817;11966666;26687322;28168757;25516055;17239054;21694950",
"title": "Severe Symptomatic Hyponatremia Secondary to Escitalopram-Induced SIADH: A Case Report with Literature Review.",
"title_normalized": "severe symptomatic hyponatremia secondary to escitalopram induced siadh a case report with literature review"
} | [
{
"companynumb": "US-ALLERGAN-1848487US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drugadditional": "1",
... |
{
"abstract": "Rituximab is a chimeric anti-CD20 monoclonal antibody that is a widely used for the treatment of B cells non-Hodgkin lymphoma. The use of chemotherapy regimens containing rituximab in HCV-positive patients with non-Hodgkin lymphoma has been associated with liver dysfunction, but no cases of cholestatic hepatitis C were described. To our knowledge, this is the first case of cholestatic hepatitis C in an HCV-positive patient with diffuse large B-cell lymphoma describes in the literature. We discuss the pathogenetic mechanisms underlying this severe form of hepatitis and describe its evolution after antiviral treatment.",
"affiliations": "Liver Unit, Azienda Ospedaliera San Camillo Forlanini, Italy.;Liver Unit, Azienda Ospedaliera San Camillo Forlanini, Italy.;Department of Hematology Istituti Fisoterapici Ospedalieri, Italy.;Liver Unit, Azienda Ospedaliera San Camillo Forlanini, Italy.;Liver Unit, Azienda Ospedaliera San Camillo Forlanini, Italy.;Liver Unit, Azienda Ospedaliera San Camillo Forlanini, Italy.;Department of Pathology, Azienda Ospedaliera San Camillo Forlanini, Italy.;Liver Unit, Azienda Ospedaliera San Camillo Forlanini, Italy.",
"authors": "Pellicelli|Adriano M|AM|;D'Ambrosio|Cecilia|C|;Dessanti|Maria L|ML|;Villani|Roberto|R|;Fondacaro|Lucia|L|;Miglioresi|Lucia|L|;Grillo|Lucia R|LR|;Andreoli|Arnaldo|A|",
"chemical_list": "D000998:Antiviral Agents; D000069283:Rituximab",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "14(5)",
"journal": "Annals of hepatology",
"keywords": null,
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D001706:Biopsy; D002779:Cholestasis; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D014775:Virus Activation",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "756-61",
"pmc": null,
"pmid": "26256907",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cholestatic hepatitis C after chemotherapy containing rituximab in diffuse large B cell lymphoma.",
"title_normalized": "cholestatic hepatitis c after chemotherapy containing rituximab in diffuse large b cell lymphoma"
} | [
{
"companynumb": "PHHY2015IT168449",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Desmopressin acetate (DDAVP), a medication used in the treatment of bleeding and polyuric disorders, has the potential to cause hyponatremia when free water is not appropriately restricted with its use. This free water retention is reversible when DDAVP is discontinued. We report a case of symptomatic DDAVP-induced hyponatremia in which discontinuation of DDAVP led to a rapid increase of serum sodium. In order to prevent rapid free water excretion, DDAVP and hypertonic saline were used concurrently. With close monitoring, this can be an effective treatment strategy in patients with DDAVP-induced hyponatremia.",
"affiliations": null,
"authors": "Shirazian|Shayan|S|;Ali|Nicole|N|;Fishbane|Steven|S|",
"chemical_list": "D012462:Saline Solution, Hypertonic; D003894:Deamino Arginine Vasopressin",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN107292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "80(5)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003894:Deamino Arginine Vasopressin; D005260:Female; D006801:Humans; D007010:Hyponatremia; D012462:Saline Solution, Hypertonic",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "385-7",
"pmc": null,
"pmid": "22579272",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treating desmopressin-induced hyponatremia: a case using hypertonic saline.",
"title_normalized": "treating desmopressin induced hyponatremia a case using hypertonic saline"
} | [
{
"companynumb": "PHHY2013US139528",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "Primary intraocular lymphoma (IOL) has a propensity for central nervous system (CNS) relapse within 2 years of initial diagnosis, affecting clinical outcome. To reduce CNS relapse, we performed the combination treatment protocols of intravitreal methotrexate injections, methotrexate-based systemic induction chemotherapy and consolidation high-dose cytarabine and reduced-dose whole brain radiation therapy (rdWBRT, 23·4 Gy) for B-cell primary IOL with or without newly diagnosed CNS involvement. All patients underwent longitudinal brain magnetic resonance imaging (MRI) and cognitive assessment for evaluation of treatment-induced leucoencephalopathy. Seventeen patients initiated and 16 completed the protocol treatment. CNS relapse occurred in 2 patients and intraocular relapse in 3. Four-year progression-free survival (PFS) was 74·9% and 4-year overall survival (OS) was 86·3%, with a median follow-up period of 48·9 months. Of 11 patients without CNS involvement, 1 had CNS relapse and 3 intraocular relapse, and 4-year PFS and OS was 72·7% and 88·9%, respectively. Although white matter abnormalities shown by MRI were significantly increased at 4 years after rdWBRT, only one patient developed mild cognitive impairment. The combination of intravitreal chemotherapy, prophylactic systemic chemotherapy and rdWBRT for primary IOL showed a potential to reduce CNS relapse rate and improved 4-year PFS and OS without increase of cognitive dysfunction.",
"affiliations": "Department of Ophthalmology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Haematology and Oncology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Ophthalmology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Ophthalmology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Ophthalmology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Haematology and Oncology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Haematology and Oncology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Haematology and Oncology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Ophthalmology, The University of Tokyo Hospital, Tokyo, Japan.",
"authors": "Kaburaki|Toshikatu|T|0000-0003-1132-6148;Taoka|Kazuki|K|;Matsuda|Junko|J|;Yamashita|Hideomi|H|;Matsuda|Izuru|I|;Tsuji|Hideki|H|;Tanaka|Rie|R|;Nakazaki|Kumi|K|;Nakamura|Fumihiko|F|;Kamiya|Kohei|K|;Kurokawa|Mineo|M|0000-0001-6458-4787;Ohtomo|Kuni|K|;Aihara|Makoto|M|",
"chemical_list": "D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14848",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "179(2)",
"journal": "British journal of haematology",
"keywords": "central nervous system lymphoma; methotrexate; primary intraocular lymphoma; radiotherapy; treatment",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001921:Brain; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007167:Immunotherapy; D064090:Intraocular Lymphoma; D058449:Intravitreal Injections; D016393:Lymphoma, B-Cell; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D015996:Survival Rate",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "246-255",
"pmc": null,
"pmid": "28699673",
"pubdate": "2017-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Combined intravitreal methotrexate and immunochemotherapy followed by reduced-dose whole-brain radiotherapy for newly diagnosed B-cell primary intraocular lymphoma.",
"title_normalized": "combined intravitreal methotrexate and immunochemotherapy followed by reduced dose whole brain radiotherapy for newly diagnosed b cell primary intraocular lymphoma"
} | [
{
"companynumb": "JP-TEVA-824840ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Myoclonus-dystonia due to SGCE mutations (OMIM: 159900) most commonly presents during childhood with mainly upper body myoclonus, and mild dystonia affecting the neck and arms.\n\n\n\nHerein, we report patients misdiagnosed during childhood with Tourette syndrome and dyskinetic cerebral palsy, and, during adulthood, found to harbor SGCE frameshift mutations.\n\n\n\nMyoclonus-dystonia may be underdiagnosed due to phenotypic misclassification during childhood. SGCE mutations should be included in the differential diagnosis of childhood movement disorders that ostensibly manifest with tics, myoclonus, or abnormal posturing secondary to dystonia and/or spasticity.\n\n\n\nDue to pleiotropy, variable penetrance, broad differential, and hereditary effects of imprinting, the diagnosis of a disorder of childhood onset, myoclonus-dystonia due to SGCE mutations, may be delayed until adulthood, often compromising appropriate clinical management and genetic counseling.",
"affiliations": "Parkinson Disease Movement Disorders Clinic, Austin, Texas, US.;The University of Texas Health Science Center at Houston, Houston, Texas, US.;University of Memphis, and Veracity Neuroscience LLC, Memphis, Tennessee, US.",
"authors": "Varga|M Georgeta|MG|;Nand|Nikita P|NP|;LeDoux|Mark S|MS|",
"chemical_list": "C526572:SGCE protein, human; D049031:Sarcoglycans",
"country": "England",
"delete": false,
"doi": "10.5334/tohm.334",
"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)\nTremor Other Hyperkinet Mov (N Y)\n2160-8288\nTremor and Other Hyperkinetic Movements\n2160-8288 Ubiquity Press \n\n10.5334/tohm.334\nCase Report\nDelayed Diagnoses of SGCE Myoclonus-Dystonia\nVarga M. Georgeta MDmvarga@movementdisorderclinic.com1 Nand Nikita P. 2 LeDoux Mark S. 3 1 Parkinson Disease Movement Disorders Clinic, Austin, Texas, US\n2 The University of Texas Health Science Center at Houston, Houston, Texas, US\n3 University of Memphis, and Veracity Neuroscience LLC, Memphis, Tennessee, US\nCorresponding author: M. Georgeta Varga, MD (mvarga@movementdisorderclinic.com)\n28 7 2020 \n2020 \n10 2313 5 2020 17 5 2020 Copyright: © 2020 The Author(s)2020This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.Background:\nMyoclonus-dystonia due to SGCE mutations (OMIM: 159900) most commonly presents during childhood with mainly upper body myoclonus, and mild dystonia affecting the neck and arms.\n\nCase reports:\nHerein, we report patients misdiagnosed during childhood with Tourette syndrome and dyskinetic cerebral palsy, and, during adulthood, found to harbor SGCE frameshift mutations.\n\nDiscussion:\nMyoclonus-dystonia may be underdiagnosed due to phenotypic misclassification during childhood. SGCE mutations should be included in the differential diagnosis of childhood movement disorders that ostensibly manifest with tics, myoclonus, or abnormal posturing secondary to dystonia and/or spasticity.\n\nHighlights:\nDue to pleiotropy, variable penetrance, broad differential, and hereditary effects of imprinting, the diagnosis of a disorder of childhood onset, myoclonus-dystonia due to SGCE mutations, may be delayed until adulthood, often compromising appropriate clinical management and genetic counseling.\n\nSGCEmyoclonusdystoniaticscerebral palsyTourette syndromeDr. LeDoux was funded by the Dystonia Medical Research Foundation and Benign Essential Blepharospasm Research Foundation. Dr. Varga is a consultant for USWorldMeds, Medtronic, and Abbott; speaker for Adamas Pharmaceuticals, Acadia Pharmaceuticals, Teva Pharmaceutical Industries, USWorldMeds, Acorda Therapeutics and Lundbeck; and received research funding from The Military Order of the Purple Heart and research equipment from Boston Scientific. Dr. LeDoux is a consultant for USWorldMeds; speaker for Adamas Pharmaceuticals, Acadia Pharmaceuticals, Teva Pharmaceutical Industries, USWorldMeds, Kyowa Kirin, and Acorda Therapeutics; and receives publishing royalties from Elsevier (Animal Models of Movement Disorders, and Movement Disorders: Genetics and Models) and TheBookPatch (Parkinson’s Disease Poetry). Dr. LeDoux’s research has been funded by the Michael J. Fox Foundation, National Institutes of Health, Axovant Sciences, Wave Life Sciences, Teva Pharmaceutical Industries, Pharma Two B, Dystonia Medical Research Foundation, and Benign Essential Tremor Research Foundation.\n==== Body\nMutations in SGCE (Chr 7q21.3), a maternally imprinted gene, have been causally linked to Myoclonus-Dystonia syndrome (M-D, DYT-SGCE, OMIM: 159900) [1]. Classically and most commonly, this disorder is characterized by childhood onset of myoclonus and dystonia [2]. Patients typically present with upper-body predominant, alcohol-responsive myoclonic jerks, along with cervical and arm dystonia [2]. Psychiatric co-morbidities including depression, anxiety, bipolar disorder, phobias, alcoholism, and obsessive-compulsive disorder have also been associated with M-D and tend to worsen over the disease course [34]. These psychiatric manifestations may occur in isolation in some members of affected pedigrees. In addition, the neuropsychiatric spectrum of SGCE mutations is broad and may include early gait dysfunction with leg involvement [5] and, more rarely, cognitive dysfunction [6]. Penetrance is incomplete and notable intrafamilial and extrafamilial phenotypic variability is well established [7]. Early and correct diagnosis may facilitate appropriate pharmacological and surgical interventions, and genetic counseling. We present two cases of genetically confirmed SGCE myoclonus dystonia, initially misdiagnosed as Tourette syndrome (Case 1) and dyskinetic cerebral palsy (Case 2), respectively.\n\nCase 1. A 32-year-old right-handed female presented to our movement disorders clinic with abnormal movements with onset at 7 years of age. Historically, these movements were described as involuntary, brief, jerky movements of the hands, shoulders, neck and trunk. These movements were previously classified as tics by prior treating neurologists, and she had been diagnosed with Tourette syndrome. During her adult years, she recognized that her involuntary movements were exacerbated by caffeine intake and improved with alcohol. She reported a history of abnormal vocalization described as “throat clearing” but compatible with laryngeal myoclonus. There was no history of head trauma or neuroleptic use. Neuropsychiatric review of systems was pertinent for mild anxiety of 20 years’ duration. Family history was significant for reported “tic-like” movements in her father and obsessive-compulsive disorder (OCD) in her mother (Figure 1, Pedigree 1). Previously, she had been treated with tetrabenazine 12.5 mg PO TID and clonazepam 0.5 mg PO BID. Tetrabenazine was not tolerated due to worsened anxiety. Clonazepam showed no significant clinical benefit. On neurological examination, action myoclonus of the arms and trunk was apparent. There was no dystonia, motor tics, phonic tics, or phonic myoclonus. There has been a greater than 50% improvement in myoclonus with deutetrabenazine (6 mg PO BID) The positive response to deutetrabenazine has been sustained for over one year and the patient has not been interested in taking higher dosages of deutetrabenazine. Testing for an SGCE mutation was pursued given the characteristic historical and visual presence of upper body action myoclonus of childhood onset, positive family history of a movement disorder and OCD, and alcohol responsiveness. Bidirectional Sanger sequencing identified a heterozygous single base pair deletion (GRCh38/hg38, NC_000007.14: g.94603404delT, NM_001099401.1(SGCE_v001): c.711delA, p.Glu238Lysfs*9). This frameshift mutation is predicted to alter the length of the ε-sarcoglycan reference protein of 462 residues to a protein of 245 residues. The location of the mutation most likely leads to nonsense mediated decay of SGCE transcripts.\n\nFigure 1 Pedigree 1: I, II, III Generation, Full symbols symptomatic individuals, Slashed symbols deceased individuals, II-2 Father with tic-like movements, III-3 Mother with OCD, III-1 Patient with + DyT11.\n\nPedigree 2: I, II, III Generation, Full symbols symptomatic individuals, Slashed symbols deceased individuals, I-1 Paternal Granfather with tic-like movements, deceased, III-1 Sister with jerky movements, III-2 Patient with + DyT11.\n\nCase 2. A 64-year-old left-handed male presented to our movement disorders clinic with a history of involuntary movements since childhood and mild developmental delay. He was delivered by Cesarean section (C-section) at 7 months of gestation due to fetal distress and was diagnosed with pulmonary hypoplasia. However, he experienced an unremarkable early postnatal course. He had mildly delayed gross and fine motor milestones without intellectual disability. At 8 years of age, he began to manifest involuntary “jerky” movements mainly involving his upper extremities. During childhood and early adulthood, he was assessed by two independent neurologists. Diagnostic work-up included a normal brain magnetic resonance imaging (MRI) brain scan and normal electroencephalogram. One neurologist provided a provisional diagnosis of dyskinetic cerebral palsy. Reportedly, the “jerky” movements were mild but persistent over the subsequent four decades and did not interfere with physical activity. However, at age 45, he experienced worsening of clinical signs with more pronounced “jerking” of his arms, neck and shoulders. Changes in speech with a weak and breathy voice that improved with whispering were also reported. Amelioration of symptoms could only be achieved by drinking alcohol. He had long-standing mild generalized anxiety. Previous treatment with phenobarbital, levetiracetam, and clonazepam had been ineffective. Family history was significant for mild “jerky” movements in his sister and paternal grandfather (Figure 1, Pedigree 2). Clinical examination was notable for spontaneous myoclonic movements involving the axial and shoulder girdle muscles and arms that worsened with activity. Additionally, mild cervical dystonia and mixed vocal dystonia (clinically pharyngeal and laryngeal involvement) was noted. However, this patient was not assessed with laryngoscopy and videostroboscopy. The remainder of the general physical and neurological examinations was unremarkable. Deutetrabenazine caused fatigue and was of no significant clinical benefit at a dosage of 9 mg PO BID. Given his characteristic myoclonic and dystonic features on clinical examination, positive family history, and response to alcohol, SGCE was assessed with bidirectional Sanger sequencing which permitted identification of a heterozygous single base pair deletion (GRCh38/hg38, NC_000007.14: g.94618801delT, NM_001099401.1(SGCE_v001): c.619delA, p.Arg207Glyfs*12). Rather than translation of a truncated protein of 217 residues, the location of the stop codon most likely precipitates nonsense mediated decay of SGCE transcripts. This patient has been offered deep brain stimulation (bilateral globus pallidus internus) for treatment of his myoclonus-dystonia.\n\nDiscussion\nUnfortunately, our two cases illustrate the poignant realty that the diagnosis of childhood onset myoclonus-dystonia can be delayed for decades. The delayed diagnoses in our two pedigrees also suggests that myoclonus-dystonia and SGCE-associated neuropsychiatric disorders may be significantly underdiagnosed. For patients with a characteristic clinical picture, SGCE mutations are the most common known etiology for this neuropsychiatric disorder [8] and genetic testing should be pursued in these cases unless limited by financial considerations. SGCE-linked myoclonus-dystonia may show clinical similarities to tics, spasticity, dystonic tremor, epilepsy, and conversion disorders with positive motor features. While characterized by mainly upper body (arms and trunk) myoclonus and mild focal or segmental dystonia (neck, distal arms), a broad array of atypical neuropsychiatric presentations and manifestations are well documented in the existing literature [9].\n\nUse of a published diagnostic algorithm for myoclonus [10], and then diagnostic criteria for M-D [8], are the first steps in differentiating M-D from other neurological disorders. Generally, in patients with M-D, myoclonus predominates over dystonia and onset is prior to adulthood. Our two patients had been incorrectly diagnosed with Tourette syndrome and dyskinetic cerebral palsy. In contrast to myoclonus, tics are typically more complex, suppressible for brief periods, and often precipitated by a premonitory urge. Brain MRI is frequently abnormal in dyskinetic cerebral palsy and the dystonic and choreoathetoid movements characteristic of this disorder are usually much slower than myoclonus. The developmental time course of disease manifestations can also help to distinguish M-D from other pediatric movement disorders. In this regard, some M-D patients exhibit mild lower extremity dystonia and associated gait dysfunction during childhood or adolescence that subsequently resolves [11].\n\nThere are other potential reasons for a delay in diagnosis. Maternal imprinting and intrafamilial phenotypic variability can complicate interpretation of family history and lead to dismissal of hereditary etiologies in differential diagnoses. Although useful historical information, the response to consumption of alcoholic beverages is uncommonly available in children and adolescents. In some cases, no connection is made between the psychiatric and motor phenotypes, which may be considered as separate diseases. Neurological manifestations, particularly dystonia, may be subtle and mild psychiatric manifestations such as anxiety and depression may have not undergone treatment for decades. Finally, dystonia can be present in childhood and then abate.\n\nDelayed diagnosis of M-D can have a significant impact on patients and their families. In particular, a prompt etiological diagnosis can inform treatment decisions and caregiver concerns [12]. M-D may benefit from occupational and physical therapy, and often responds to specific pharmacological interventions (tetrabenazine, anticholinergics, and zonisamide) and electrical stimulation of the globus pallidus [8131415], and, as reported here, deutetrabenazine may be an additional therapeutic option. Earlier surgical intervention in patients with severe disease and inadequately responsive to oral pharmacotherapy and/or injections of botulinum toxin may improve long-term outcomes [16]. Earlier diagnosis may reduce alcoholism [4] and prompt recognition of psychiatric co-morbidities allowing these to be symptomatically managed before they exert deleterious effects on academic performance, work productivity and social interactions. Prompt etiological diagnosis of M-D may also facilitate academic, career and family planning [12].\n\nGenetic testing should begin with Sanger or next-generation sequencing and, ideally, confirmation with bidirectional Sanger sequencing. Sequencing should cover all coding exons, exon-intron boundaries, and the core promoter region of SGCE. Genetic testing should also include exclusion of exonic, multi-exonic and interstitial deletions, particularly in patients with typical clinical presentations and absence of single nucleotide changes or small indels [17]. Genetic testing for SGCE mutations should be considered in “scan normal” cases of putative cerebral palsy [18]. Genetic counseling should include consideration of maternal imprinting, pleiotropy, and variable penetrance.\n\nEthics and Consent\nOur case reports do not meet the definition of human experimentation. No personally identifiable information has been included in case descriptions.\n\nFunding Information\nDr. LeDoux was funded by the Dystonia Medical Research Foundation and Benign Essential Blepharospasm Research Foundation.\n\nDr. Varga is a consultant for USWorldMeds, Medtronic, and Abbott; speaker for Adamas Pharmaceuticals, Acadia Pharmaceuticals, Teva Pharmaceutical Industries, USWorldMeds, Acorda Therapeutics and Lundbeck; and received research funding from The Military Order of the Purple Heart and research equipment from Boston Scientific. Dr. LeDoux is a consultant for USWorldMeds; speaker for Adamas Pharmaceuticals, Acadia Pharmaceuticals, Teva Pharmaceutical Industries, USWorldMeds, Kyowa Kirin, and Acorda Therapeutics; and receives publishing royalties from Elsevier (Animal Models of Movement Disorders, and Movement Disorders: Genetics and Models) and TheBookPatch (Parkinson’s Disease Poetry). Dr. LeDoux’s research has been funded by the Michael J. Fox Foundation, National Institutes of Health, Axovant Sciences, Wave Life Sciences, Teva Pharmaceutical Industries, Pharma Two B, Dystonia Medical Research Foundation, and Benign Essential Tremor Research Foundation.\n\nCompeting Interests\nThe authors have no competing interests to declare.\n==== Refs\n1 Zimprich \nA , Grabowski \nM , Asmus \nF , Naumann \nM , Berg \nD , Bertram \nM , et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome\n. Nat Genet . 2001 ; 29 (1 ): 66 –9\n. DOI: 10.1038/ng709 11528394 \n2 Roze \nE , Apartis \nE , Clot \nF , Dorison \nN , Thobois \nS , Guyant-Marechal \nL , et al. Myoclonus-dystonia: clinical and electrophysiologic pattern related to SGCE mutations\n. Neurology . 2008 ; 70 (13 ): 1010 –6\n. DOI: 10.1212/01.wnl.0000297516.98574.c0 18362280 \n3 Timmers \nER , Smit \nM , Kuiper \nA , Bartels \nAL , van der Veen \nS , van der Stouwe \nAMM , et al. Myoclonus-dystonia: Distinctive motor and non-motor phenotype from other dystonia syndromes\n. Parkinsonism & related disorders . 2019 ; 69 : 85 –90\n. DOI: 10.1016/j.parkreldis.2019.10.015 31706131 \n4 Peall \nKJ , Dijk \nJM , Saunders-Pullman \nR , Dreissen \nYE , van Loon \nI , Cath \nD , et al. Psychiatric disorders, myoclonus dystonia and SGCE: an international study\n. Ann Clin Transl Neurol . 2016 ; 3 (1 ): 4 –11\n. DOI: 10.1002/acn3.263 26783545 \n5 Koukouni \nV , Valente \nEM , Cordivari \nC , Bhatia \nKP , Quinn \nNP . Unusual familial presentation of epsilon-sarcoglycan gene mutation with falls and writer’s cramp. Movement disorders: official journal of the Movement Disorder Society\n. 2008 ; 23 (13 ): 1913 –5\n. DOI: 10.1002/mds.21935 \n6 Multani \nN , Moro \nE , Lang \nA , Zurowski \nM , Duff Canning \nS , Tartaglia \nMC . Progression of neuropsychiatric and cognitive features due to exons 2 to 5 deletion in the epsilon-sarcoglycan gene: a case report\n. Neurocase . 2016 ; 22 (2 ): 215 –9\n. DOI: 10.1080/13554794.2015.1120312 26652670 \n7 Raymond \nD , Saunders-Pullman \nR , de Carvalho Aguiar \nP , Schule \nB , Kock \nN , Friedman \nJ , et al. Phenotypic spectrum and sex effects in eleven myoclonus-dystonia families with epsilon-sarcoglycan mutations. Movement disorders: official journal of the Movement Disorder Society\n. 2008 ; 23 (4 ): 588 –92\n. DOI: 10.1002/mds.21785 \n8 Roze \nE , Lang \nAE , Vidailhet \nM . Myoclonus-dystonia: classification, phenomenology, pathogenesis, and treatment\n. Curr Opin Neurol . 2018 ; 31 (4 ): 484 –90\n. DOI: 10.1097/WCO.0000000000000577 29952836 \n9 Drivenes \nB , Born \nAP , Ek \nJ , Dunoe \nM , Uldall \nPV . A child with myoclonus-dystonia (DYT11) misdiagnosed as atypical opsoclonus myoclonus syndrome\n. Eur J Paediatr Neurol . 2015 ; 19 (6 ): 719 –21\n. DOI: 10.1016/j.ejpn.2015.07.010 26278497 \n10 Zutt \nR , van Egmond \nME , Elting \nJW , van Laar \nPJ , Brouwer \nOF , Sival \nDA , et al. A novel diagnostic approach to patients with myoclonus\n. Nat Rev Neurol . 2015 ; 11 (12 ): 687 –97\n. DOI: 10.1038/nrneurol.2015.198 26553594 \n11 Tian \nXJ , Ding \nCH , Zhang \nYH , Dai \nLF , Chen \nCH , Li \nJW , et al. [Clinical and genetic analysis of childhood-onset myoclonus dystonia syndrome caused by SGCE variants]\n. Zhonghua Er Ke Za Zhi . 2020 ; 58 (2 ): 123 –8\n.32102149 \n12 Lumsden \nDE , Gimeno \nH , Tustin \nK , Kaminska \nM , Lin \nJP . Interventional studies in childhood dystonia do not address the concerns of children and their carers\n. Eur J Paediatr Neurol . 2015 ; 19 (3 ): 327 –36\n. DOI: 10.1016/j.ejpn.2015.01.003 25661063 \n13 Kosutzka \nZ , Tisch \nS , Bonnet \nC , Ruiz \nM , Hainque \nE , Welter \nML , et al. Long-term GPi-DBS improves motor features in myoclonus-dystonia and enhances social adjustment\n. Movement disorders: official journal of the Movement Disorder Society . 2019 ; 34 (1 ): 87 –94\n. DOI: 10.1002/mds.27474 30302819 \n14 Luciano \nAY , Jinnah \nHA , Pfeiffer \nRF , Truong \nDD , Nance \nMA , LeDoux \nMS . Treatment of myoclonus-dystonia syndrome with tetrabenazine\n. Parkinsonism & related disorders . 2014 ; 20 (12 ): 1423 –6\n. DOI: 10.1016/j.parkreldis.2014.09.029 25406829 \n15 Hainque \nE , Vidailhet \nM , Cozic \nN , Charbonnier-Beaupel \nF , Thobois \nS , Tranchant \nC , et al. A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia\n. Neurology . 2016 ; 86 (18 ): 1729 –35\n. DOI: 10.1212/WNL.0000000000002631 27053715 \n16 Moro \nE , LeReun \nC , Krauss \nJK , Albanese \nA , Lin \nJP , Walleser Autiero \nS , et al. Efficacy of pallidal stimulation in isolated dystonia: a systematic review and meta-analysis\n. Eur J Neurol . 2017 ; 24 (4 ): 552 –60\n. DOI: 10.1111/ene.13255 28186378 \n17 Xiao \nJ , Nance \nMA , LeDoux \nMS . Incomplete nonsense-mediated decay facilitates detection of a multi-exonic deletion mutation in SGCE\n. Clinical genetics . 2013 ; 84 (3 ): 276 –80\n. DOI: 10.1111/cge.12059 23140253 \n18 Springer \nA , Dyck Holzinger \nS , Andersen \nJ , Buckley \nD , Fehlings \nD , Kirton \nA , et al. Profile of children with cerebral palsy spectrum disorder and a normal MRI study\n. Neurology . 2019 ; 93 (1 ): e88 –e96\n. DOI: 10.1212/WNL.0000000000007726\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2160-8288",
"issue": "10()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "SGCE; Tourette syndrome; cerebral palsy; dystonia; myoclonus; tics",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D000328:Adult; D002547:Cerebral Palsy; D057210:Delayed Diagnosis; D020821:Dystonic Disorders; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D049031:Sarcoglycans; D005879:Tourette Syndrome",
"nlm_unique_id": "101569493",
"other_id": null,
"pages": "23",
"pmc": null,
"pmid": "32775037",
"pubdate": "2020-07-28",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "31127072;25406829;27053715;23140253;26278497;28186378;26553594;29952836;18702114;26783545;18175340;31706131;18362280;26652670;32102149;30302819;11528394;25661063",
"title": "Delayed Diagnoses of SGCE Myoclonus-Dystonia.",
"title_normalized": "delayed diagnoses of sgce myoclonus dystonia"
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"abstract": "The effectiveness of paclitaxel-cisplatin-ifosfamide triplet regimen (TIP) was reported to be superior to that of paclitaxel-cisplatin doublet. However, the efficacy of paclitaxel-cisplatin-bevacizumab triplet (TPA) and TIP has not been compared. Here, we compared the efficacy and safety of TIP and TPA in patients with metastatic, recurrent, or persistent cervical cancer.\n\n\n\nWe retrospectively reviewed the medical records of patients with recurrent, persistent, or metastatic cervical cancer who were at the Samsung Medical Center, Seoul, Korea between January 2005 and September 2018. Of the 161 patients included in the study, 92 had received TIP and 71 had received TPA. For the study, we compared the response rates, progression-free survival (PFS), overall survival (OS), and safety in the 2 treatment groups.\n\n\n\nThe response rates of patients who received TIP and TPA were comparable (64.1% vs 73.2%, P = 0.239). Histology (squamous vs nonsquamous) was the only prognostic factor that affected the response to therapy (odds ratio, 0.259; 95% confidence interval [CI], 0.119-0.562; P = 0.001). The PFS after TIP and TPA treatment was similar: 12.0 months (95%CI, 10.26-13.74) vs 11.5 months (95%CI, 10.18-12.83), respectively. In a Cox proportional hazard model, objective response to therapies was the only independent prognostic factor for both PFS and OS. However, different types of therapy (TIP vs TPA) did not affect the oncological outcomes for either PFS or OS. Although hematologic toxicity was significantly higher in the TIP-treated group than in the TPA-treated group, both regimens were safe and well-tolerated.\n\n\n\nThe effectiveness and safety of TIP was comparable to TPA in terms of response rates, survival, and adverse effects. TIP could be an effective alternative in the treatment of cervical cancer when TPA is contraindicated or unaffordable.",
"affiliations": "Department of Obstetrics and Gynecology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: yooyoung.lee@samsung.com.;Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: bgkim@skku.edu.",
"authors": "Choi|Hyun-Jin|HJ|;Lee|Yoo-Young|YY|;Choi|Chel Hun|CH|;Kim|Tae-Joong|TJ|;Lee|Jeong-Won|JW|;Bae|Ji Hye|JH|;Bae|Duk-Soo|DS|;Kim|Byoung-Gie|BG|",
"chemical_list": "D000068258:Bevacizumab; D017239:Paclitaxel; D002945:Cisplatin; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.currproblcancer.2020.100557",
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"issn_linking": "0147-0272",
"issue": "44(5)",
"journal": "Current problems in cancer",
"keywords": "Bevacizumab; Cisplatin; Paclitaxel; Uterine cervical neoplasms",
"medline_ta": "Curr Probl Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002945:Cisplatin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "7702986",
"other_id": null,
"pages": "100557",
"pmc": null,
"pmid": "32067746",
"pubdate": "2020-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Triplet chemotherapy vs doublet chemotherapy plus bevacizumab in metastatic, recurrent, and persistent cervical cancer.",
"title_normalized": "triplet chemotherapy vs doublet chemotherapy plus bevacizumab in metastatic recurrent and persistent cervical cancer"
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"abstract": "Ectopic adrenocorticotropic hormone (ACTH) production leading to ectopic ACTH syndrome accounts for a small proportion of all Cushing's syndrome (CS) cases. Thymic neuroendocrine tumors are rare neoplasms that may secrete ACTH leading to rapid development of hypercortisolism causing electrolyte and metabolic abnormalities, uncontrolled hypertension and an increased risk for opportunistic infections. We present a unique case of a patient who presented with a mediastinal mass, revealed to be an ACTH-secreting thymic neuroendocrine tumor (NET) causing ectopic CS. As the diagnosis of CS from ectopic ACTH syndrome (EAS) remains challenging, we emphasize the necessity for high clinical suspicion in the appropriate setting, concordance between biochemical, imaging and pathology findings, along with continued vigilant monitoring for recurrence after definitive treatment. Learning points: Functional thymic neuroendocrine tumors are exceedingly rare. Ectopic Cushing's syndrome secondary to thymic neuroendocrine tumors secreting ACTH present with features of hypercortisolism including electrolyte and metabolic abnormalities, uncontrolled hypertension and hyperglycemia, and opportunistic infections. The ability to undergo surgery and completeness of resection are the strongest prognostic factors for improved overall survival; however, the recurrence rate remains high. A high degree of initial clinical suspicion followed by vigilant monitoring is required for patients with this challenging disease.",
"affiliations": "Departments of Endocrinology, Diabetes & Metabolism, Cleveland Clinic, Cleveland, Ohio, USA.;Departments of Pulmonary Medicine & Critical Care, Cleveland Clinic, Cleveland, Ohio, USA.;Departments of Pulmonary Medicine & Critical Care, Cleveland Clinic, Cleveland, Ohio, USA.;Departments of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio, USA.;Departments of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA.;Departments of Diagnostic Radiology, Cleveland Clinic, Cleveland, Ohio, USA.;Departments of Endocrinology, Diabetes & Metabolism, Cleveland Clinic, Cleveland, Ohio, USA.",
"authors": "Lawrence|Lima|L|;Zhang|Peng|P|;Choi|Humberto|H|;Ahmad|Usman|U|;Arrossi|Valeria|V|;Purysko|Andrei|A|;Makin|Vinni|V|",
"chemical_list": null,
"country": "England",
"delete": false,
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-19-0002EDM190002Unique/Unexpected Symptoms or Presentations of a DiseaseA unique case of ectopic Cushing’s syndrome from a thymic neuroendocrine carcinoma L Lawrence and othersEctopic Cushing’s syndromeLawrence Lima 1Zhang Peng 2Choi Humberto 2Ahmad Usman 3Arrossi Valeria 4Purysko Andrei 5Makin Vinni 11 Departments of Endocrinology, Diabetes & Metabolism, Cleveland Clinic, Cleveland, Ohio, USA2 Departments of Pulmonary Medicine & Critical Care, Cleveland Clinic, Cleveland, Ohio, USA3 Departments of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio, USA4 Departments of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA5 Departments of Diagnostic Radiology, Cleveland Clinic, Cleveland, Ohio, USACorrespondence should be addressed to L Lawrence; Email: lawrenl4@ccf.org27 2 2019 2019 2019 19-000228 1 2019 05 2 2019 © 2019 The authors2019The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nEctopic adrenocorticotropic hormone (ACTH) production leading to ectopic ACTH syndrome accounts for a small proportion of all Cushing’s syndrome (CS) cases. Thymic neuroendocrine tumors are rare neoplasms that may secrete ACTH leading to rapid development of hypercortisolism causing electrolyte and metabolic abnormalities, uncontrolled hypertension and an increased risk for opportunistic infections. We present a unique case of a patient who presented with a mediastinal mass, revealed to be an ACTH-secreting thymic neuroendocrine tumor (NET) causing ectopic CS. As the diagnosis of CS from ectopic ACTH syndrome (EAS) remains challenging, we emphasize the necessity for high clinical suspicion in the appropriate setting, concordance between biochemical, imaging and pathology findings, along with continued vigilant monitoring for recurrence after definitive treatment.\n\nLearning points:\nFunctional thymic neuroendocrine tumors are exceedingly rare.\n\nEctopic Cushing’s syndrome secondary to thymic neuroendocrine tumors secreting ACTH present with features of hypercortisolism including electrolyte and metabolic abnormalities, uncontrolled hypertension and hyperglycemia, and opportunistic infections.\n\nThe ability to undergo surgery and completeness of resection are the strongest prognostic factors for improved overall survival; however, the recurrence rate remains high.\n\nA high degree of initial clinical suspicion followed by vigilant monitoring is required for patients with this challenging disease.\n==== Body\nBackground\nCushing’s syndrome (CS) results in hypercortisolism as a result of excess glucocorticoid production from endogenous sources (adrenals, pituitary, ectopic) or exogenous administration. The incidence of endogenous CS varies from 0.2 to 5 cases per million per year, with a median age of onset around 41.4 years and a female preponderance in a 3:1 ratio (1). CS may be ACTH-dependent or ACTH-independent from adrenal origin. Cushing disease (CD) due to an ACTH-secreting pituitary adenoma are more commonly seen compared to ectopic ACTH syndrome (EAS), while corticotropin-releasing hormone producing tumors causing CS are exceedingly rare (<1%). Liddle and colleagues first described ‘ectopic ‘adrenocorticotropin’ produced by nonpituitary neoplasms as a cause of Cushing’s syndrome’ in 1962 (2). EAS is most commonly seen in association with small cell lung carcinoma or carcinoid tumors originating in the lungs or gastrointestinal tract. While the clinical presentation of CS is highly variable making diagnosis challenging, it is crucial that patients with EAS are identified and treated in a timely manner. They have features of severe hypercortisolism and have a florid presentation with significant derangements in electrolytes, uncontrolled hypertension and hyperglycemia, with an increased risk for life-threatening opportunistic infections. Herein, we present a unique case of ectopic CS caused by an ACTH-secreting thymic NET, initially misdiagnosed as a benign lipoma.\n\nCase presentation\nA 54-year-old gentleman presented to the emergency department with new-onset oral thrush and right-sided facial swelling after dental work. He had extensive recent evaluation for various complaints including weight gain, near-syncopal episodes, pleuritic chest pain and exertional dyspnea. Eight months ago, patient presented to his dermatologist with increasing photosensitivity and darkening of the skin. A high ACTH level was noted, which led to additional evaluation with 24 h urinary free cortisol (Table 1). The patient was referred to endocrinology for further testing but failed to do so. One month after the abnormal adrenal testing results, a chest X-ray following a motor vehicle accident revealed a mediastinal mass measuring approximately 13.5 × 11.0 cm. Computed tomography (CT) chest confirmed a large anterior mediastinal mass measuring 10.7 × 6.3 cm in transverse and anteroposterior dimensions and 11.0 cm in craniocaudad dimensions, extending above the level of the clavicle and displacing the trachea to the right. No hilar, paratracheal, axillary or subpectoral lymphadenopathy was noted. A biopsy performed at an outside hospital via video-assisted thoracoscopic surgery revealed well-differentiated adipose tissue. However, a question was raised by the pathologist about possible sampling error as the biopsied material could represent normal adipose tissue adjacent to or associated with an unsampled neoplasm.Table 1 Trend of pertinent laboratory findings.\n\n\tReference range\t8 months ago\tHospital admission\tPost 8 mg dexamethasone suppression test\t\nPotassium (mmol/L)\t3.5–5.1\t\t1.7\t\t\nBicarbonate (mmol/L)\t22–30\t\t46\t\t\nCreatinine kinase (U/L)\t55–170\t\t4828\t\t\nWhite blood cells (k/µL)\t4.5–11.0\t\t26.58\t\t\nRandom cortisol (µg/dL)\t1.7–22.7\t\t146.9\t133.9\t\nACTH (pg/mL)\t<47\t231\t1037\t1135\t\n24 h urinary free cortisol (µg/day)\t≤60\t68.1\t\t\t\nDexamethasone (ng/dL)\t>200\t\t\t427.0\t\n\n\n\nInvestigation\nDuring the current inpatient admission, patient reported proximal muscle weakness, myalgias and unintentional central weight gain of 25 pounds. Physical exam was remarkable for an obese man with a cushingoid appearance, facial fullness and plethora. He had dorsocervical and supraclavicular fat pads with hyperpigmentation of the sun-exposed regions. No abdominal striae, lower extremity edema or proximal muscle weakness was noted on strength testing. Labs revealed severe hypokalemia refractory to replacement, metabolic alkalosis, rhabdomyolysis and leukocytosis without fever. Given the clinical presentation, labs and history of elevated ACTH with a mediastinal mass, there arose a concern for ectopic ACTH production resulting in CS. Repeat random cortisol and ACTH were elevated and remained non-suppressed after an 8 mg dexamethasone suppression test (Table 1). Prior CT chest images were reviewed to localize the source of ectopic cushings, which revealed that the mediastinal mass lacked fat attenuation, inconsistent with the presumed prior diagnosis of lipoma. Repeat imaging redemonstrated an 11.7 × 7.9 cm bilobed anterior mediastinal mass extending above the thoracic inlet with extrinsic compressive effect on the esophagus and trachea. Bilateral hilar and perihilar lymphadenopathy was noted along with new-onset bilateral adrenal hyperplasia (Fig. 1). Whole-body positron emission tomography (PET)-CT revealed a mild-to-moderately fludeoxyglucose (FDG) avid mass extending across the anterior mediastinum, with symmetric thickening and hypermetabolism of the adrenal glands, likely due to adrenal hyperplasia (Fig. 2). Magnetic resonance imaging (MRI) of the pituitary noted normal size and configuration of the pituitary gland without evidence of an adenoma or suprasellar mass (Fig. 3). Figure 1 Chest CT with IV contrast. Axial (A), coronal (B) and sagittal (C) images of the chest demonstrate a bilobed mass (arrow) centered in the anterior mediastinum insinuating into the left paratracheal region displacing the aortic arch branch vessels, and extending in the thoracic inlet.\n\n\nFigure 2 Whole-body 18F-FDG-PET/CT. 3D volume-rendered CT image (A) demonstrate central obesity and cushingoid facies. Fused coronal PET/CT image demonstrates moderate and heterogeneous FDG uptake by the mediastinal mass (arrow, B) and intense, symmetric uptake by the adrenal glands (arrows, C).\n\n\nFigure 3 MRI pituitary with and without contrast. The pituitary gland (circled, A) is within normal limits of size and configuration without pituitary adenoma or suprasellar mass. Symmetric calcifications (arrows, B) within the caudate heads, and lentiform nucleus suggests dystrophic calcification.\n\n\n\n\nTreatment\nFor treatment of EAS, patient was started on a regimen of ketoconazole 300 mg twice daily and mifepristone 300 mg daily for 1 week prior to surgical removal of the mediastinal mass. A combination regimen of ketoconazole and mifepristone was used in a multipronged approach against hypercortisolism, as ketoconazole inhibits multiple enzymes in cortisol synthesis, while mifepristone exerts its actions against the glucocorticoid receptor. Hypokalemia was aggressively repleted, along with controlling new-onset hypertension and hyperglycemia. Patient underwent surgical removal of the large mediastinal mass along with pericardial resection and wedge resection of the left upper lobe of the lung. In the immediate postoperative period, patient experienced no arrhythmias, but developed hypotension refractory to fluid resuscitation, requiring initiation of vasopressors and intravenous dexamethasone. It is likely that glucocorticoid receptor blockade by mifepristone and inhibition of cortisol synthesis by ketoconazole, along with operative removal of the ACTH source contributed to the resulting adrenal insufficiency. A significant decline in ACTH and cortisol levels was noted postoperatively and the patient was transitioned to oral hydrocortisone.\n\nOutcome and follow-up\nPathology revealed a large thymic neuroendocrine carcinoma measuring 12.5 × 8.0 × 4.5 cm with less than two mitoses per ten high power fields without necrosis and a Ki proliferative index of 5%. According to the World Health Organization (WHO) classification of NETs, based on mitotic count and absence of necrosis, the tumor was classified as a typical low-grade carcinoid (3, 4). Staging was classified as T3N1M0 due to direct invasion of the tumor into the lung and metastases to regional lymph nodes in the anterior mediastinum. Immunohistochemical staining for ACTH on a single block of tumor was negative; however, it is likely that ACTH is variably expressed in different regions of this large tumor (Figs 4 and 5). As the mass was completely excised with only microscopic-positive margins (R1 resection), postoperative radiation was not recommended as adjuvant treatment. Radiation has not been shown to affect overall survival for resected typical carcinoid tumors, regardless of nodal involvement or tumor size. This collaborative recommendation was made during a multidisciplinary meeting, and active surveillance was initiated.Figure 4 (A) Low power showing a cellular highly vascularized neoplasm (H&E, 0.4×). (B) Solid nests of polygonal cells with round to slightly oval nuclei with finely granular chromatin, inconspicuous nucleoli and ample eosinophilic cytoplasm. No mitotic figures or necrosis are present (H&E, 25×).\n\n\nFigure 5 Immunohistochemical markers confirm neuroendocrine immunophenotype of the tumor cells (A) synaptophysin, (B) chromogranin (10×).\n\n\n\n\nPatient has had regular follow-up for the past 8 months after hospital discharge, with remarkable improvement in electrolyte abnormalities, weight loss greater than 65 pounds and normalization of blood glucose, blood pressure, ACTH and cortisol levels. He has not required reinitiation of medications for hypertension or glycemic control. Patient has been tapered off hydrocortisone therapy with recovery of adrenal function confirmed on an ACTH stimulation test.\n\nDiscussion\nWe present a unique case of ectopic CS caused by an ACTH-secreting thymic NET initially misdiagnosed as a lipoma. Thymic NETs are exceedingly rare accounting for 2% of all mediastinal tumors and 5% of all thymic tumors. Thymic NETs are three times more commonly seen in men, with a peak incidence around 54 years of age, and are biochemically active in 30–50% of all cases (5). EAS from thymic NETs are seen in 40–50% of hormonally active thymic NETs. A meta-analysis of EAS cases reported in literature have suggested a slight male preponderance and earlier presentation in the second and third decades of life (6). EAS from thymic NETs have a worse outcome than biochemically inactive thymic tumors, likely due to its inherent aggressiveness coupled with the devastating metabolic derangements resulting from CS. Patients present with features of severe, rapid-onset hypercortisolism including profound hypokalemia due to the action of cortisol on mineralocorticoid receptors, metabolic alkalosis, resistant hypertension, hyperglycemia, hyperpigmentation, edema and proximal muscle weakness, while features of long-term hypercortisolism such as significant weight gain, obesity and violaceous striae are infrequently seen (7). Hypercortisolemia also places these patients at increased risk for bacterial or opportunistic infections, as noted in our patient who presented with oral thrush in the absence of human immunodeficiency virus infection (8).\n\nInvestigation of EAS begins with clinical suspicion confirmed with biochemical evidence of hypercortisolism and elevated ACTH, followed by localization of the source: pituitary versus ectopic. Various case series have established that an ACTH level >200 pg/mL suggests EAS over CD (9). Imaging studies including CT, 18FDG PET or 68Ga-DOTATATE PET are useful in visualizing the extent of tumor and evaluating metastatic disease. Complete R0 surgical resection is the only curative method, while the ability to undergo surgery and completeness of the resection are the strongest prognostic factors for improved overall survival (5). Unfortunately, even with radical surgery and lymph node dissection, the recurrence rate remains high. Incompletely resected tumors may be treated with postoperative chemotherapy and radiation; however, no statistically significant improvement in outcomes are seen with adjuvant therapy. Therefore, patients with EAS from thymic NETs have a challenging condition that need aggressive surgical resection followed by close monitoring to evaluate for recurrence of disease.\n\nOur patient was initially found to have biochemical evidence of hypercortisolism and failed to follow-up with endocrinology as recommended. Subsequently, a large mediastinal mass was discovered and falsely identified as a lipoma due to sampling error on biopsy. Finally, eight months after detection of elevated cortisol, and six months after discovery of the mediastinal mass, the patient underwent definitive surgical resection of the thymic NET causing ectopic CS. There are several unique features of this case that warrant emphasizing. The mediastinal mass was falsely identified as a lipoma due to sampling error on biopsy in spite of the biochemical evidence of hypercortisolism, and imaging characteristics on CT where the mediastinal mass lacked fat attenuation, inconsistent with the presumed diagnosis of lipoma. This highlights the need for a high clinical suspicion for CS in the appropriate setting and to evaluate the biochemical, imaging and pathology results cohesively to ensure the findings lead to a unified diagnosis. On initial presentation, the patient was found to have severe electrolyte abnormalities including refractory hypokalemia and metabolic alkalosis. Preoperative management of the patient included addressing the hypercortisolemia with ketoconazole and mifepristone. This combination therapy is typically contraindicated as both drugs can lead to QT prolongation and strong inhibition of CYP3A by ketoconazole, which increases the levels of mifepristone in the blood (10). However, concurrent therapy in this patient was medically necessary to rapidly ameliorate severe hypercortisolism, and patient was monitored very closely for medication tolerability in an inpatient setting. Although medical treatment of CS is possible by inhibition of ACTH secretion (octreotide, pasireotide, cabergoline), inhibition of adrenal steroidogenesis (ketoconazole, metyrapone, mitotane, etomidate) or by glucocorticoid receptor blockade (mifepristone), the definitive treatment of ectopic CS is by surgical removal of the tumor. Emergency treatment of severe ectopic CS may require combination therapy or parenteral etomidate under vigilant supervision in an intensive care unit setting. Bilateral adrenalectomy may be considered in select patients with uncontrolled, life-threatening hypercortisolemia refractory to medical management.\n\nWe present a case of EAS due to a large thymic NET initially misdiagnosed as a lipoma. Our patient underwent successful surgical resection of the tumor with the development of postoperative adrenal insufficiency and subsequent recovery of adrenal function. As the diagnosis of CS from EAS remains challenging, we emphasize the need for high clinical suspicion in the appropriate setting, confirmation of the diagnosis on biochemical, imaging and pathology findings, along with continued vigilant monitoring for recurrence.\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 did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nThe patient has given written informed consent.\n\nAuthor contribution statement\nAll authors contributed equally to the conception, writing and editing of the manuscript. L Lawrence: Endocrinology fellow took care of the patient in the hospital and currently in the outpatient office. P Zhang: Pulmonary-Critical Care fellow took care of the patient in the hospital. H Choi: Pulmonary-Critical Care attending took care of the patient in the hospital. U Ahmad: Cardiothoracic surgeon performed the surgical resection and currently following the patient in the outpatient office. V Arrossi: Pathologist provided the pathology report and images. A Purysko: Radiologist provided the radiographic findings and images. V Makin: Endocrinology attending took care of the patient in the hospital.\n==== Refs\nReferences\n1 Lacroix A Feelders RA Stratakis CA Nieman LK. \nCushing’s syndrome . Lancet \n2015 \n386 \n913 –927 . (10.1016/S0140-6736(14)61375-1 )26004339 \n2 Liddle GW Island DP Ney RL Nicholson WE Shimizu N. \nNonpituitary neoplasms and Cushing’s syndrome. Ectopic ‘adrenocorticotropin’ produced by nonpituitary neoplasms as a cause of Cushing’s syndrome . Archives of Internal Medicine \n1963 \n111 \n471 –475 . (10.1001/archinte.1963.03620280071011 )13930496 \n3 Travis W Brambilla E Burke A , Marx A & Nicholson AG. WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart . Lyon : IARC Press , 2015 .\n4 Gaur P Leary C Yao JC. \nThymic neuroendocrine tumors: a SEER database analysis of 160 patients . Annals of Surgery \n2010 \n251 \n1117 –1121 . (10.1097/SLA.0b013e3181dd4ec4 )20485130 \n5 Filosso PL Yao X Ahmad U Zhan Y Huang J Ruffini E Travis W Lucchi M Rimner A Antonicelli A , et al\nOutcome of primary neuroendocrine tumors of the thymus: a joint analysis the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases . Journal of Thoracic and Cardiovascular Surgery \n2015 \n149 \n103.e2 –109.e2 . (10.1016/j.jtcvs.2014.08.061 )25308116 \n6 Neary NM Lopez-Chavez A Abel BS Boyce AM Schaub N Kwong K Stratakis CA Moran CA Giaccone G Nieman LK. \nNeuroendocrine ACTH-producing tumor of the thymus – experience with 12 patients over 25 years . Journal of Clinical Endocrinology and Metabolism \n2012 \n97 \n2223 –2230 . (10.1210/jc.2011-3355 )22508705 \n7 Isidori AM Kaltsas GA Pozza C Frajese V Newell-Price J Reznek RH Jenkins PJ Monson JP Grossman AB Besser GM. \nThe ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up . Journal of Clinical Endocrinology and Metabolism \n2006 \n91 \n371 –377 . (10.1210/jc.2005-1542 )16303835 \n8 Sarlis NJ Chanock SJ Nieman LK. \nCortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin . Journal of Clinical Endocrinology and Metabolism \n2000 \n85 \n42 –47 . (10.1210/jcem.85.1.6294 )10634361 \n9 Yogi-Morren D Habra MA Faiman C Bena J Hatipoglu B Kennedy L Weil RJ Hamrahian AH. \nPituitary MRI findings in patients with pituitary and ectopic ACTH-dependent Cushing syndrome: does a 6-mm pituitary tumor size cut-off value exclude ectopic ACTH syndrome? \nEndocrine Practice \n2015 \n21 \n1098 –1103 . (10.4158/EP15662.OR )26121435 \n10 Fleseriu M Molitch ME Gross C Schteingart DE Vaughan TB Biller BM. \nA new therapeutic approach in the medical treatment of Cushing’s syndrome: glucocorticoid receptor blockade with mifepristone . Endocrine Practice \n2013 \n19 \n313 –326 . (10.4158/EP12149.RA )23337135\n\n",
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"issue": "2019()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2019; ACTH; ACTH stimulation; Adrenal; Adult; Bicarbonate; Bilateral adrenal hyperplasia; Biopsy; Blood pressure; Buffalo hump; CT scan; Chest pain; Chest pain (pleuritic); Chromogranin A; Cortisol; Cortisol, free (24-hour urine); Creatine kinase; Cushing's syndrome; Dexamethasone; Dexamethasone suppression; Dyspnoea; Ectopic ACTH syndrome; Ectopic Cushing's syndrome; Facial fullness; Facial plethora; February; Glucocorticoids; Glucose (blood); Histopathology; Hypercortisolaemia; Hyperglycaemia; Hyperpigmentation; Hypertension; Hypokalaemia; Hypotension; Immunohistochemistry; Ketoconazole; Leukocytosis; Lymphadenitis; Lymphadenopathy; MRI; Male; Metabolic alkalosis; Myasthaenia; Neuroendocrine tumour; Obesity; PET scan; Photosensitivity; Pituitary; Potassium; Resection of tumour; Rhabdomyolysis; Steroids; Supraclavicular fat pads; Synaptophysin; Syncope; Thymus; Unique/unexpected symptoms or presentations of a disease; United Kingdom; Weight gain; White; White blood cell count; X-ray",
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"title": "A unique case of ectopic Cushing's syndrome from a thymic neuroendocrine carcinoma.",
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"abstract": "The COVID-19 pandemic has dramatically challenged care for cancer patients, especially those with active treatment who represent a vulnerable population for SARS-CoV-2 infection. Aggressive lymphoid neoplasms, such as diffuse large B cell lymphoma and high-grade B cell lymphoma, need to be treated without delay in order to get the best disease outcome. Because of that, our clinical practice was changed to minimise the risk of SARS-CoV-2 infection while continuing haematological treatment. In this report, we analyse the management of front-line therapy in 18 patients during the COVID-19 outbreak, as well as the results of the implemented measures in their outcome.",
"affiliations": "Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Pharmacy Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.;Haematology Department, La Paz University Hospital, Madrid, Spain.",
"authors": "de la Cruz-Benito|Beatriz|B|0000-0002-3223-0121;Lázaro-Del Campo|Paula|P|0000-0001-9089-4789;Ramírez-López|Andrés|A|;de Soto-Álvarez|Teresa|T|;Sánchez-Vadillo|Irene|I|;García-Pérez|Eduardo|E|;Dos Santos-Ortas|Abel|A|;Humala-Barbier|Karem|K|;López-de la Guía|Ana|A|;Casado-Abad|Gema|G|;Jiménez-Yuste|Victor|V|;Canales-Albendea|Miguel|M|0000-0002-6550-2621",
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"title": "Managing the front-line treatment for diffuse large B cell lymphoma and high-grade B cell lymphoma during the COVID-19 outbreak.",
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"abstract": "The aim of the present study was to evaluate the role of a weekly preoperative chemotherapy in locally advanced, unresectable gastric cancer. In all, 82 patients with an Eastern Oncology Cooperative Group PS <or=2 and normal cardiac function were enrolled onto the study. Surgical unresectability was confirmed in 52 patients (63%) at laparotomy, and in 30 (27%) cases by CT scan of the abdomen and endoscopic ultrasonography. Chemotherapy treatment was: cisplatin 40 mg x m(-2); 5-fluorouracil 500 mg x m(-2); epidoxorubicin 35 mg x m(-2); 6S-leucovorin 250 mg x m(-2) and glutathione 1.5 g x m(-2) (PELF). One cycle consisted of 8 weekly treatments. Response to chemotherapy was observed in 40 of 82 patients (49%): six (7%) complete and 34 (41%) partial responses, and in four (5%) cases a complete pathological response was confirmed. Of the 40 responding patients, 37 (45%) had potentially curative surgery. Grade 3/4 leucopenia and thrombocytopenia occurred in three and two patients. At a median follow-up of 48 months, 25 of the 37 resected patients (68%) were alive and 24 (65%) were disease free. The median and 4-year survival for the whole group was 17 months and 31%, respectively. The median survival was 12 months for inoperable patients and it was not reached in resected patients.",
"affiliations": "Clinica di Oncologia, Università Politecnica delle Marche-Azienda Ospedaliera Umberto I, via Conca, Ancona 60020, Italy. cascinu@yahoo.com",
"authors": "Cascinu|S|S|;Scartozzi|M|M|;Labianca|R|R|;Catalano|V|V|;Silva|R R|RR|;Barni|S|S|;Zaniboni|A|A|;D'Angelo|A|A|;Salvagni|S|S|;Martignoni|G|G|;Beretta|G D|GD|;Graziano|F|F|;Berardi|R|R|;Franciosi|V|V|;|||",
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"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group\n\n6601752\n10.1038/sj.bjc.6601752\n15083179\nClinical\nHigh curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)\nChemotherapy in unresectable gastric cancer\nCascinu S 1*\nScartozzi M 1\nLabianca R 2\nCatalano V 3\nSilva R R 4\nBarni S 5\nZaniboni A 6\nD'Angelo A 7\nSalvagni S 7\nMartignoni G 8\nBeretta G D 2\nGraziano F 9\nBerardi R 1\nFranciosi V 7\n1 Clinica di Oncologia, Università Politecnica delle Marche-Azienda Ospedaliera Umberto I, via Conca, Ancona 60020, Italy\n2 Medical Oncology, Ospedali Riuniti, Bergamo, Italy\n3 Medical Oncology, Azienda Ospedaliera S Salvatore, Pesaro, Italy\n4 Medical Oncology, Ospedale di Fabriano, Italy\n5 Medical Oncology, Azienda Ospedaliera di Treviglio, Italy\n6 Medical Oncology, Casa di Cura Poliambulanza, Brescia, Italy\n7 Medical Oncology, Azienda Ospedaliera-Universitaria, Parma, Italy\n8 Medical Oncology, Azienda Ospedaliera S Carlo Borromeo, Milano, Italy\n9 Medical Oncology, Ospedale di Urbino, Italy\n* Clinica di Oncologia, Università Politecnica delle Marche-Azienda Ospedaliera Umberto I, via Conca, Ancona 60020, Italy. E-mail: cascinu@yahoo.com\n19 04 2004\n30 03 2004\n90 8 15211525\n24 09 2003\n04 02 2004\n04 02 2004\nCopyright © 2004 Cancer Research UK\n2004\nCancer Research UK\nhttps://creativecommons.org/licenses/by/4.0/ This 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 license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license 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 license, visit https://creativecommons.org/licenses/by/4.0/.\nThe aim of the present study was to evaluate the role of a weekly preoperative chemotherapy in locally advanced, unresectable gastric cancer. In all, 82 patients with an Eastern Oncology Cooperative Group PS ⩽2 and normal cardiac function were enrolled onto the study. Surgical unresectability was confirmed in 52 patients (63%) at laparotomy, and in 30 (27%) cases by CT scan of the abdomen and endoscopic ultrasonography. Chemotherapy treatment was: cisplatin 40 mg m−2; 5-fluorouracil 500 mg m−2; epidoxorubicin 35 mg m−2; 6S-leucovorin 250 mg m−2 and glutathione 1.5 g m−2 (PELF). One cycle consisted of 8 weekly treatments. Response to chemotherapy was observed in 40 of 82 patients (49%): six (7%) complete and 34 (41%) partial responses, and in four (5%) cases a complete pathological response was confirmed. Of the 40 responding patients, 37 (45%) had potentially curative surgery. Grade 3/4 leucopenia and thrombocytopenia occurred in three and two patients. At a median follow-up of 48 months, 25 of the 37 resected patients (68%) were alive and 24 (65%) were disease free. The median and 4-year survival for the whole group was 17 months and 31%, respectively. The median survival was 12 months for inoperable patients and it was not reached in resected patients.\n\ngastric cancer\npreoperative chemotherapy\ncurative resection\nneoadjuvant\n==== Body\npmcAlthough the incidence of gastric cancer has gradually decreased in many Western Countries, it remains one of the leading causes of cancer-related deaths worldwide, and it now ranks second only to lung cancer with about 755 000 new cases per year (Karpeh et al, 2001). Since screening for early detection is not performed in Western Countries, in approximately 50% of newly diagnosed cases, the tumour is beyond its local–regional margins (Kelsen, 1996; Karpeh et al, 2001). Surgery remains the mainstay of any curative treatment, but only when a radical resection is feasible (removal of all gross cancer cells at the resection margins as determined by histopathological examination). Those patients who are considered not amenable of curative resection generally receive chemotherapy in order to obtain palliation of symptoms and improved survival. Since there is no evidence that a more aggressive treatment could result in a better survival, most of the patients receive a combination of 5-fluorouracil (5-FU), mitomycin C or cisplatin (Karpeh et al, 2001). Only a few studies have focused on the role of preoperative chemotherapy in unresectable gastric cancer. Comprehensively, these trials suggested that chemotherapy could allow radical surgery in approximately 40% of all cases not amenable of curative resection at presentation, but at the cost of severe toxicity (Kelsen, 1996). In a pilot trial, we observed that a preoperative chemotherapy with weekly cisplatin (CDDP), epidoxorubicin (epi-ADR), 5-FU, 6S-leucovorin, glutathione and bone marrow support (filgastrim) could allow a radical resection in 13 out of 32 (41%) patients previously considered unresectable (Cascinu et al, 1998). These encouraging findings followed our demonstration of activity (62% overall response rate in 105 patients) of this chemotherapy regimen in patients with advanced gastric cancer. In this latter trial, five of 11 (45%) patients with exclusively locally advanced unresectable disease could undergo a curative resection after chemotherapy (Cascinu et al, 1997). In order to test whether the hypothesis of a more aggressive and expensive approach in this subset of gastric cancer patients could be justifiable, we prospectively analysed the effects of this intensive weekly treatment in a larger group of gastric cancer patients not amenable of curative resection.\n\nMATERIALS AND METHODS\n\nPatients’ selection\n\nPatients with previously untreated, histologically confirmed, locally confined, gastric adenocarcinoma were eligible for the study, only after the primary tumour was considered not amenable of surgical resection. Unresectable disease was defined jointly by a medical oncologist, a gastroenterologist and an abdominal surgeon on the basis of the laparotomy findings and/or CT scan images (tumour size >7 cm, invasion of adjacent structures, such as pancreas, omentum, aorta, oesophagus, liver), endoscopy and endoscopic ultrasonography (EUS). Patients with distant, liver and peritoneal metastases were excluded. The American Joint Committee on Cancer staging system (6th edition) was applied. Patients were also required to have an Eastern Oncology Cooperative Group (ECOG) performance status ⩽2, an adequate hepatic (serum bilirubin <1.5 mg dl−1), renal (serum creatinine <1.5 mg dl−1) and bone marrow function (white blood cell (WBC) >4000 cells μl−1 with an absolute granulocyte count >1500 cells μl−1, platelet count >100 000 cells μl−1) and aged between 18 and 70 years. As a potential cardiotoxic drug (epi-ADR) was included in the chemotherapy regimen, patients with a New York Heart Association class >2 were excluded from the study. Pretreatment assessment included complete blood cell count with WBC differential and platelet count, biochemical screening profile, serum creatinine and/or creatinine clearance, CT scan or radiograph of the chest, CT scan of the abdomen, endoscopy and a bone scan. Gated pool scan was not routinely performed unless the patient had a history of cardiac disease, in which case it was mandatory and the patient was ineligible for the study if the left ventricular ejection fraction was <45%. The protocol was approved by the institutional review board, and all patients gave informed consent, which indicated that they were fully aware of the investigational nature of the study itself.\n\nChemotherapy\n\nAll patients underwent chemotherapy according to the weekly PELF regimen, which consisted of a once a week administration of CDDP 40 mg m−2 as a 30 min infusion in 250 ml of normal saline, 5-FU 500 mg m−2 as a 15 min infusion in 100 ml of normal saline and epi-ADR 35 mg m−2 by intravenous bolus injection. A dose of 250 mg m−2 of 6S-stereoisomer of leucovorin as a 4 h infusion in 250 ml of normal saline was administered concurrently with hydration and glutathione 1.5 g m−2 in 100 ml of normal saline over 15 min, which was infused before each cisplatin administration in order to prevent CDDP-related neurotoxicity (Figure 1Figure 1 Diagram showing the treatment given in the first 2 weeks of therapy. The same treatment schedule was administered for 8 consecutive weeks.\n\n). Antiemetic treatment with dexamethasone 20 mg and ondansetron 8 mg both given intravenously was administered, respectively, 45 and 15 min before CDDP infusion. At 2 h before CDDP administration, patients received intravenous hydration with 1500 ml of normal saline plus 20 mEq of potassium chloride and 15 mEq of magnesium sulphate. Intravenous fluids administration proceeded for 2 h after CDDP with 1000 ml of normal saline. All patients received filgastrim 5 μg kg−1 by subcutaneous injection from the day after to the day before each chemotherapy administration. One cycle of chemotherapy consisted of 8 weekly chemotherapy administrations. Patients only received 8 weeks of treatment (one cycle). In the event of toxicity, chemotherapy administration was delayed by a week or until full recover in case of WBC count <4000 cells μl−1, platelet count <100 000 cells μl−1 or if grade 2 and 3 mucositis and diarrhoea occurred. The criteria for patient withdrawal from study were patient's refusal, tumour progression and any grade 4 toxicities. Chemotherapy was administered as an outpatient procedure in all cases. The planned delay between the last week of treatment and surgery was 6–8 weeks.\n\nEvaluation of response and toxicity\n\nObjective response to chemotherapy was assessed after 8 weeks of therapy, combining findings from both CT scan of the abdomen and endoscopy, including a new biopsy of the tumour, if still visible, or a biopsy of the area originally involved by the tumour. Endoscopy and endoscopic ultrasonography was performed when clinically indicated. Partial response (PR) was defined as having both CT scan evidence of PR, according to the World Health Organisation (WHO) criteria, and endoscopy showing a >50% reduction of the visible tumour, or complete disappearance of the tumour, but positive histology on biopsy of the previously involved area. Complete response (CR) was defined as a complete disappearance of the tumour as seen by CT scan of the abdomen and a complete resolution of the endoscopic findings without histological evidence of neoplastic cells on biopsy of the original site of the tumour. Toxicity was evaluated weekly according to the National Cancer Institute Common Toxicity Criteria (NCICTC). The decision to perform a laparotomy with the aim of a radical excision was evaluated each time a complete removal of the tumour was jointly judged feasible by a medical oncologist, a gastroenterologist and an abdominal surgeon.\n\nRESULTS\n\nIn all, 82 patients were enrolled onto this study by coinvestigators from seven Italian centres. The median age at diagnosis was 57 years (range 29–68 years); 57 (69.5%) patients were male and 25 (30.5%) were female, most of the patients enrolled were in good general condition as PS (ECOG) was 0–1 in 72 (88%) patients and two in the remaining 10 (12%) patients. The primary tumour was located in the body of the stomach in 40 (49%) cases, in the gastro-oesophageal junction in 18 (22%) cases, in the distal stomach in 18 (22%) cases and in the proximal stomach in six (7%) cases. In all, 52 (63%) patients underwent laparotomy, as a part of a failed attempt at radical primary surgery, before study entry, in these cases laparotomy confirmed the presence of locally advanced, unresectable disease, whereas in the remaining 30 (37%) patients the diagnosis of locally advanced disease was confirmed by CT scan of the abdomen (23 patients) and EUS (seven patients). All patients received eight weekly treatments (one cycle of chemotherapy). Patient characteristics are summarised in Table 1 Table 1 Patient characteristics\n\nNo of patients\t82\t\nAge (years)\t \t\n Median\t57\t\n Range\t29–68\t\n \t \t\nSex\t \t\n Male/female\t57/25\t\n \t \t\nPS (ECOG)\t \t\n 0\t39\t\n 1\t33\t\n 2\t10\t\n \t \t\nSites of primary tumor\t \t\n Gastro-oesophageal junction\t18\t\n Proximal stomach\t6\t\n Body\t40\t\n Distal stomach\t18\t\n \t \t\nInitial stages\t \t\n T4 N0 M0\t13\t\n T4 N1-2 M0\t51\t\n T3 N1-2 M0\t18\t\n \t \t\nLaparotomy\t \t\n Yes\t52\t\n No\t30\t\nCOG=Eastern Oncology Cooperative Group.\n\n.\n\nWe observed a response to chemotherapy in 40 of 82 patients (49%), six (7%) patients had a CR and 34 (41%) had a PR. Of these, 30 (36%) patients showed disease stabilisation, whereas 12 (15%) patients progressed on chemotherapy. Among the 40 responding patients, 37 (45%) had potentially curative radical surgery and three (4%) were found not resectable at laparotomy. In four (5%) cases, a complete pathological response was confirmed (Table 2 Table 2 Stage at surgery (37 patients)\n\nStage\tPatients\t\npT0N0\t4\t\npT1N0\t1\t\nPT2N0\t2\t\nPT3N0\t12\t\nPT2N1\t5\t\nPT3N1\t13\t\n\n). Among the 37 patients who received radical surgery after chemotherapy, 16 (50%) had a failed initial laparotomy. At a median follow-up from the start of the treatment of 48 months (range 30–60 months), 25 of the 37 resected patients (68%) were alive and 24 (65%) were disease free, the 4-year survival rate for the whole group was 31%. The median survival was 17 months for the whole group and 12 months for inoperable patients, while it was not reached in resected patients (Figure 2Figure 2 (A) Kaplan–Meier overall survival (OS) curve for the whole group of 82 patients. (B) Kaplan–Meier survival curves for patients who underwent curative resection of primary gastric tumour after chemotherapy (resected, - - - - -), and for not resected patients (not resected, ———).\n\n). There were no deaths associated with chemotherapy or major surgical complications in this study and the toxicity profile was globally acceptable. We observed mainly haematological toxicities of grade 2: leucopenia and thrombocytopenia in five and six patients, respectively, while grade 3–4 haematological toxicities were rare events (three cases of grade 3–4 leucopenia and two cases of grade 3–4 thrombocytopenia). Nonhaematological toxicities were uncommon and moderate (Table 3 Table 3 Treatment toxicity (NCICTC): worst toxicity per patient\n\n \tGrade I\tGrade II\tGrade III\tGrade IV\t\nLeucopenia\t6\t5\t2\t1\t\nThrombocytopenia\t5\t6\t1\t1\t\nAnaemia\t5\t3\t2\t—\t\nMucositis\t4\t3\t—\t—\t\nDiarrhoea\t—\t2\t—\t—\t\nNausea/vomiting\t6\t10\t1\t—\t\nNeurotoxicity\t1\t2\t—\t—\t\nNCICTC=National Cancer Institute common toxicity criteria.\n\n). Dose delays and dose reductions were applied in 25 (30%) and seven (8.5%) patients, respectively. No unplanned admissions were required at any stage during the course of chemotherapy. All patients considered suitable for surgery after chemotherapy underwent laparotomy within 6–8 weeks (median 48 days) from the end of chemotherapy, accordingly to what was originally planned in the protocol. The median hospital stay for surgery was 10 days (range 8–20 days), accordingly to what was expected. We did not observe relevant 30-day medical or surgical complications and no patients required return to operating Theatre.\n\nDISCUSSION\n\nAdvanced gastric cancer patients are a heterogeneous population and at least two different clinical conditions should be considered if the best treatment approach is to be defined. Patients with metastatic tumours often present in poor general conditions and with several disease-induced symptoms. In this subset of patients, a palliative treatment is a reasonable option and a careful evaluation of the therapy-related toxicity is of primary relevance in the selection of the appropriate chemotherapy regimen. On the other hand, many patients present with a locally advanced disease not amenable of a radical resection, but without metastatic involvement of distant sites. These patients are reported to have a longer survival and a globally better prognosis (Lowy et al, 1999; Yano et al, 2002). Furthermore, they are potential candidates for a treatment with curative intent, as an objective response to chemotherapy may allow a radical resection of the tumour. In these latter cases, an active chemotherapy regimen should be preferred even when this implies a greater risk of moderate–severe toxicity.\n\nWe investigated the role of an intensive weekly chemotherapy regimen in 82 patients diagnosed with unresectable gastric cancer. The overall response rate to chemotherapy in our series was 49% (40 of the 82 patients), which compares well to that achievable with other active chemotherapy regimens available (Findlay et al, 1994; Louvet et al, 2002). However, the most interesting data arising from our study is the curative resectability rate, which we obtained in this particularly difficult setting of patients: in fact, 45% (37 of the 82 patients) of all cases treated could undergo a radical resection, a procedure that was excluded at presentation. Moreover, the 4-year survival rate of the resected group was definitely higher (68%) compared to that achieved by the whole group (31%). These data seem to confirm that complete resection of all gross disease with negative margins on pathology examination represents the only potentially curative therapy for gastric cancer, and that a preoperative, effective, chemotherapy regimen might probably improve the outcome of patients, who would have been otherwise excluded from curative resection on the basis of initial findings. The chemotherapy combination we used also showed a favourable profile of toxicity, which was mild and quite acceptable. Overall, only two cases of grade 4 haematological toxicity (one case of leucopenia and one case of thrombocytopenia) were reported and no surgical complications were observed in those who underwent surgery. Other authors explored preoperative chemotherapy in locally advanced gastric cancer patients with contrasting results, basically depending on the patients’ population investigated (resectable or not resectable at presentation) and the chemotherapy regimen employed. The available data with the ECF regimen (epi-ADR, cisplatin and 5-FU) in this setting are disappointing. In a small trial by Melcher et al (1996), only one of 10 patients found to have locally advanced, unresectable, disease proceeded to radical surgery after ECF chemotherapy, and in a more recent study other authors substantially confirmed the findings previously reported by Melcher using the same regimen, as none of the four patients with initially unresectable disease was rendered resectable; moreover, none of them was alive at a median follow-up of 30 months (Geh et al, 2000). Even though it is possible that chemotherapy duration, 12 weeks as opposed to the 24 weeks of the Royal Marsden Hospital's experience, could have negatively affected results, these data do not seem encouraging for further studies in this group of patients. Interesting results have been initially reported with the use of the FAMTX regimen (5-FU, doxorubicin and methotrexate). In patients with high risk, but potentially curable, gastric tumours, 34 of 56 patients (61%) received a curative resection, but at the cost of substantial toxicity (mainly neutropenic fever) with one chemotherapy-related death (Kelsen et al, 1996). Nevertheless, data from a small randomised trial that compared the use of FAMTX as preoperative therapy before surgery vs surgery alone in operable gastric cancer could not demonstrate that the FAMTX regimen was suitable as neoadjuvant chemotherapy, and the authors concluded that more active regimens should be tested in further randomised studies (Songun et al, 1999). It should be noticed that in preoperatively unresectable patients, a combination chemotherapy containing methotrexate and 5-FU was reported by Plukker et al (1991) to allow 40% of curative resections. In a further trial, 34 patients with unresectable gastric cancer were treated with either of the two neoadjuvant chemotherapies: FEMTXP (5-FU, epirubicin, methotrexate, cisplatin) or THP-FLPM (pirarubicin, 5-FU, leucovorin, cisplatin, mitomycin C). Of 33 evaluable patients, only eight (24%) curative resections could be performed; interestingly, at multivariate analysis salvage surgery was found to be the only independent prognostic factor in this series (Yano et al, 2002). The EAP regimen (etoposide, doxorubicin and cisplatin) obtained more than 70% of curative resections in patients with high-risk, locally advanced gastric cancer. Nevertheless, toxicity was considerable and all cases were theoretically resectable at presentation (Schuhmacher et al, 2001). Results with the same regimen in not resectable cases are clearly less appealing and approached a 44% of resectability rate (Wilke et al, 1990). A major matter of debate in this area is also accurately defining preoperative staging procedures. Although a correct diagnosis of the extent of disease is of paramount importance in locally advanced gastric cancer, standard techniques are still to be defined. Direct vision by surgical exploration might represent the best initial assessment available, but would significantly contribute to increase treatment morbidity and might cause the patients to undergo an unnecessary laparotomy. Laparoscopy, EUS or a combination of these two techniques could complement traditional staging methods and provide clinical data not otherwise obtainable (Ajani et al, 1999). Demonstration exists that these procedures can improve staging of the primary tumour and detect unsuspected metastatic disease with interesting sensitivity and specificity, thus allowing a better patient selection and confrontation between different series. Particularly promising seemed data with regard to the use of EUS in preoperative staging of stomach tumours (Lightdale et al, 1989; Botet et al, 1991). Endoscopy and endoscopic ultrasonography showed an accuracy of 75–85% in predicting tumour stage before surgery, but its use in the evaluation of response to treatment in patients, who received preoperative chemotherapy, was disappointing and unreliable probably due to chemotherapy-induced changes in the physical pattern of the tumour (Kelsen et al, 1996; Ajani et al, 1999). Nevertheless, before a more widely diffusion of these methods occur, traditional procedures are to be applied in order to define surgical resectability. CT scan proved to possess an accuracy of 80–90% in defining local diffusion in gastric cancers. Clear CT scan signs of tumour extension to pancreas, aorta, omentum, oesophagus and liver, and the presence of bulky tumour (>7 cm) should discourage surgery, as initial treatment in these patients, as the probability to obtain a radical resection is very low (Sussman et al, 1988; Rougier et al, 1994). In our trial more than a half of the patients were considered not resectable by direct surgical exploration: in fact, 52 (63%) patients underwent laparotomy, as a part of a failed attempt at radical primary surgery, before study entry. In the remaining 30 (27%) patients, the diagnosis of locally advanced disease was confirmed by CT scan of the abdomen (23 patients) and EUS (seven patients). These data demonstrate that in our series preoperative tumour upstaging is unlikely to have occurred, thus making our findings fully interpretable.\n\nChemotherapy with weekly CDDP, epi-ADR, 5-FU, 6S-leucovorin, glutathione and bone marrow support (filgastrim) seemed to be highly effective in patients with locally advanced, unresectable, gastric cancer, as it allowed a potentially curative resection in 45% of the cases we observed. Moreover, even though the study design could not allow any definitive conclusion, the median survival and the 4-year survival time (68%) of the resected group were suggestive of a survival advantage in this subset of patients determined by the use of preoperative chemotherapy. These findings are even more interesting when we consider the favourable profile of toxicity and the short period of treatment requested (8 weeks as opposed to 12–24 weeks of other chemotherapy regimens). Taken together, the data obtained from the present study suggest that this intensive weekly regimen could represent a therapeutic option for patients with locally advanced, unresectable, gastric cancer, with the aim to allow a curative resection, and hopefully a prognostic improvement, in about half of all cases. According to these findings, the PELF weekly regimen has now become our standard ‘off-trial’ treatment for selected cases, showing clinical characteristics similar to those outlined in our protocol. However, in the daily clinical practice, this chemotherapy regimen should not always be considered a possible choice, especially for patients in poor general conditions, thus making this treatment unsuitable for approximately 15–20% of all cases. Further, well-designed randomised studies are clearly warranted in order to confirm our findings. 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"fulltext_license": "CC BY",
"issn_linking": "0007-0920",
"issue": "90(8)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D015251:Epirubicin; D005260:Female; D000069585:Filgrastim; D005472:Fluorouracil; D005978:Glutathione; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D002955:Leucovorin; D007970:Leukopenia; D058766:Levoleucovorin; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011994:Recombinant Proteins; D013274:Stomach Neoplasms; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1521-5",
"pmc": null,
"pmid": "15083179",
"pubdate": "2004-04-19",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": "10561303;10492627;11251943;12209246;12454110;3357941;2305269;1913116;1924784;8204531;7993836;8658222;8656250;8932350;9363860;9703289;10077040;10942336",
"title": "High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).",
"title_normalized": "high curative resection rate with weekly cisplatin 5 fluorouracil epidoxorubicin 6s leucovorin glutathione and filgastrim in patients with locally advanced unresectable gastric cancer a report from the italian group for the study of digestive tract cancer giscad"
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"abstract": "Epidermal growth factor receptor (EFGR) inhibitors are targeted chemotherapeutic agents that are effective in treating various epithelial cancers. Cutaneous adverse effects, most commonly acneiform/papulopustular eruption, can occur with these medications and limit their tolerability. In severe cases, patients may refuse treatment with EGFR inhibitors because of the significant impact on the quality of life and aesthetic discomfort. We present a 72-year-old-man with a history of EGFR+ non-small-cell lung carcinoma who developed a severe acneiform eruption secondary to afatinib that failed to improve with various traditional treatment modalities. The patient was treated with dapsone and his acneiform eruption resolved within two months of initiating therapy. Patient tolerated dapsone with no reported adverse effects and continues on low dose dapsone, as he will remain on afatinib indefinitely. Dapsone can be an effective therapy for refractory or severe cases of EGFR-induced acneiform eruptions. As in this case, dapsone may improve patient adherence to EGFR inhibitors, thereby allowing for effective therapy of underlying malignancy.",
"affiliations": "Department of Dermatology, University of Utah, Salt Lake City, UT. abram.beshay@hey.com.",
"authors": "Beshay|Abram|A|;Petersen|Marta|M|;Rhoads|Jamie L W|JLW|",
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"pmid": "34391331",
"pubdate": "2021-07-15",
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"title": "Severe EGFR inhibitor-induced acneiform eruption responding to dapsone.",
"title_normalized": "severe egfr inhibitor induced acneiform eruption responding to dapsone"
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"abstract": "An adult woman developed polymorphic post-transplant lymphoproliferative disorder (PTLD) 58 months after unrelated cord blood transplantation. She was treated successfully with chemotherapy and radiation therapy but presented with lymphadenopathy and splenomegaly 74 months after transplantation. A lymph node biopsy confirmed the diagnosis of nodular sclerosis type Hodgkin lymphoma (classical Hodgkin lymphoma [CHL]-type PTLD). After salvage therapy and hematopoietic stem cell harvesting, she was subsequently treated with consolidative high-dose chemotherapy with melphalan followed by stem cell rescue, which resulted in durable remission. High-dose chemotherapy using stem cell rescue has potential as a therapeutic option for subsequent CHL-type PTLD.",
"affiliations": "Department of Hematology, Nagasaki University Hospital, Japan.;Department of Hematology, Sasebo City General Medical Center, Japan.;Department of Hematology, Nagasaki University Hospital, Japan.;Department of Hematology, Sasebo City General Medical Center, Japan.;Department of Hematology, Sasebo City General Medical Center, Japan.;Department of Hematology, Nagasaki University Hospital, Japan.;Department of Internal Medicine, National Hospital Organization Nagasaki Medical Center, Japan.;Department of Pathology, School of Medicine, Kurume University, Japan.;Department of Hematology, Sasebo City General Medical Center, Japan.;Department of Pathology, School of Medicine, Kurume University, Japan.;Department of Hematology, Nagasaki University Hospital, Japan.",
"authors": "Itonaga|Hidehiro|H|;Kato|Takeharu|T|;Fujioka|Machiko|M|;Taguchi|Masataka|M|;Taniguchi|Hiroaki|H|;Imaizumi|Yoshitaka|Y|;Yoshida|Shinichiro|S|;Miyoshi|Hiroaki|H|;Moriuchi|Yukiyoshi|Y|;Ohshima|Koichi|K|;Miyazaki|Yasushi|Y|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2871708510.2169/internalmedicine.56.7938Case ReportHigh-dose Chemotherapy with Stem Cell Rescue Provided Durable Remission for Classical Hodgkin Lymphoma-type Post-transplant Lymphoproliferative Disorder after Unrelated Cord Blood Transplantation: A Case Report and Review of the Literature Itonaga Hidehiro 12Kato Takeharu 23Fujioka Machiko 12Taguchi Masataka 2Taniguchi Hiroaki 2Imaizumi Yoshitaka 1Yoshida Shinichiro 4Miyoshi Hiroaki 3Moriuchi Yukiyoshi 2Ohshima Koichi 3Miyazaki Yasushi 1\n1 Department of Hematology, Nagasaki University Hospital, Japan\n2 Department of Hematology, Sasebo City General Medical Center, \n3 Department of Pathology, School of Medicine, Kurume University, Japan\n4 Department of Internal Medicine, National Hospital Organization Nagasaki Medical Center, JapanCorrespondence to Dr. Hidehiro Itonaga, itonaga-ngs@umin.ac.jp\n\n15 7 2017 56 14 1873 1877 5 7 2016 7 11 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).An adult woman developed polymorphic post-transplant lymphoproliferative disorder (PTLD) 58 months after unrelated cord blood transplantation. She was treated successfully with chemotherapy and radiation therapy but presented with lymphadenopathy and splenomegaly 74 months after transplantation. A lymph node biopsy confirmed the diagnosis of nodular sclerosis type Hodgkin lymphoma (classical Hodgkin lymphoma [CHL]-type PTLD). After salvage therapy and hematopoietic stem cell harvesting, she was subsequently treated with consolidative high-dose chemotherapy with melphalan followed by stem cell rescue, which resulted in durable remission. High-dose chemotherapy using stem cell rescue has potential as a therapeutic option for subsequent CHL-type PTLD. \n\nClassical Hodgkin lymphomapost-transplant lymphoproliferative disorderunrelated cord blood transplantationhigh-dose chemotherapy\n==== Body\nIntroduction\nPost-transplant lymphoproliferative disorders (PTLDs) include histologically heterogeneous diseases from benign to malignant entities that develop in patients who have undergone organ transplantation or allogeneic hematopoietic stem cell transplantation (allo-HSCT). PTLDs have been divided into four subtypes according to the WHO classification: early lesions and polymorphic-, monomorphic-, and classical Hodgkin lymphoma types (1). Classical Hodgkin lymphoma-type PTLD (CHL-type PTLD) was previously reported to occur at the lowest frequency, approximately 0.043%, among allogeneic bone marrow transplant recipients (2). Therefore, the clinical course of CHL-type PTLD remains unclear.\n\nWe herein report a case of CHL-type PTLD that was successfully treated with high-dose chemotherapy using stem cell rescue derived from cord blood. Our results provide valuable insight into the management of CHL-type PTLD.\n\nCase Report\nA 59-year-old woman with secondary acute myeloid leukemia transformed from essential thrombocythemia underwent unrelated cord blood transplantation [total nucleated cell dose, 2.36×107 cells/kg; CD34-positive cell dose, 1.58×105 cells/kg; human leukocyte antigen (HLA) 2 loci mismatched (HLA-B and -DRB1 loci were serologically mismatched), from a male donor] in the non-remission stage after chemotherapy using reduced-intensity pre-transplant conditioning (fludarabine 150 mg/m2, melphalan 80 mg/m2, and total body irradiation 4 Gy). Tacrolimus was used as a single agent for graft-versus-host disease (GVHD) prophylaxis. Neutrophil and platelet counts in the peripheral blood reached >0.5×109/L on day +20 and >20×109/L, respectively, without transfusions on day +39. She achieved 100% donor chimerism, which was confirmed by an XY-fluorescence in situ hybridization (FISH) analysis of bone marrow cells. Limited-type chronic GVHD emerged after the discontinuation of tacrolimus on day +154. The patient presented with chest pain 58 months after transplantation, for which she had not received any immunosuppressants. Computed tomography (CT) revealed an anterior mediastinal mass (Fig. 1). A needle biopsy confirmed the diagnosis of polymorphic PTLD, which showed diffuse effacement of the nodal architecture with mixed cell proliferation including immunoblasts expressing CD20 and PAX5, plasma cells, a small number of CD20-negative Reed-Stenberg (RS)-like cells, and CD3-positive lymphocytes; however, these cells were negative for CD30 and Epstein-Barr virus (EBV) (Fig. 2). The biopsy samples were too small to evaluate the origin of polymorphic PTLD cells by an XY-FISH analysis. The use of rituximab for PTLD was not approved at that time in Japan. Furthermore, immunohistochemical staining revealed that polymorphic PTLD included CD20-positive immunoblasts and CD3-positive lymphocytes but CD20-negative RS-like cells, indicating that rituximab was less effective in treating this subtype of PTLD than other subtypes. Therefore, rituximab in combination with chemotherapy was not considered. Partial remission was achieved following 6 courses of chemotherapy (vincristine, cyclophosphamide, doxorubicin, and prednisone [CHOP]) and 40 Gy of radiation therapy.\n\nFigure 1. Computed tomography (CT) images showing an anterior mediastinal mass at the diagnosis of polymorphic post-transplant lymphoproliferative disorder (PTLD).\n\nFigure 2. The pathological diagnosis of polymorphic PTLD. A needle biopsy showed mixed cell infiltration (A: Hematoxylin and Eosin staining, ×600), including immunoblasts expressing CD20 (B: ×600) and PAX5 (C: ×600), CD3-positive lymphocytes (D: ×600), and no CD30-positive cells (E: ×600) or Epstein-Barr virus (EBV)-encoded small RNA (EBER)-positive cells (F: ×600).\n\nShe developed left hilar and left supraclavicular lymphadenopathies as well as splenomegaly without the use of immunosuppressants 74 months after transplantation. A biopsy specimen of the supraclavicular lymph node showed the presence of nodular sclerosis-type Hodgkin lymphoma with RS cells. Immunohistochemical staining revealed that the RS cells were positive for CD15, CD30, PAX5, Epstein-Barr encoding region (EBER), and EBV latent membrane protein 1 (LMP1) and negative for CD3, CD20, and EBV nuclear antigen 2 (EBNA2) (Fig. 3A-F), which indicated type 2 latency according to the EBV antigen expression pattern in infected memory B cells. A FISH analysis showed that the RS cells did not have the chromosome Y signal (e.g. one or two chromosome X signals), while small-sized lymphocytes in the background had chromosome X and Y signals (e.g. XY-type) (Fig. 3G and H). She received three courses of salvage chemotherapy (etoposide, cytarabine, cisplatin, and prednisone [ESHAP]), and peripheral blood hematopoietic stem cells (PBSCs) derived from cord blood were harvested using granulocyte colony-stimulating factor mobilization. Since the tumor regression was -33.5% in the sum of the product of greatest diameters (SPD) on CT after an additional 4 cycles of chemotherapy, she was judged to have achieved stable disease for CHL-type PTLD according to the established response criteria (3). High-dose melphalan treatment (180 mg/m2) was then initiated, followed by PBSC rescue (CD34-positive cells, 4.24×106 cells/kg). Neutrophil engraftment and platelet recovery were achieved on days +9 and +101, respectively. A FISH analysis of peripheral blood cells revealed that 99.8% had the XY signal. Partial remission was observed after engraftment, with a 63.6% reduction in the tumor SPD on CT (Fig. 4). Severe complications such as infection and organ failure did not occur after high-dose chemotherapy. There were no clear signs of GVHD without the use of immunosuppressive agents after PBSC rescue. Since a 72.3% reduction in the tumor SPD without the appearance of new lesions was observed on CT on day +777 after stem cell rescue, partial remission was deemed to have been maintained without any symptoms to indicate the relapse of PTLD.\n\nFigure 3. The pathological diagnosis of classical Hodgkin lymphoma-type PTLD (CHL-type PTLD). A supraclavicular lymph node biopsy revealed a polymorphous lymphoid infiltrate with a large number of Reed-Sternberg (RS) cells (A: Hematoxylin and Eosin staining, ×600), which showed specific positivity for CD30 (B: ×600) and negativity for CD20 (C: ×600);in situ hybridization revealed positivity for EBER (D: ×600) and EBV latent membrane protein 1 (LMP1) (E: ×600), and negativity for EBV nuclear antigen 2 (EBNA2) (F: ×600). An XY-fluorescencein situ hybridization analysis showed that RS cells had one (A: white arrow) or two (B: red arrow) red chromosome X signals, while small-sized lymphocytes had one red chromosome X signal and one green chromosome Y signal (A: green arrow) (G and H).\n\nFigure 4. A CT scan showing left-hilar lymphadenopathies and splenomegaly (spleen length 9.9 cm) at the diagnosis of CHL-type PTLD (A). A CT scan demonstrating the resolution of left-hilar lymphadenopathies and splenomegaly (spleen length 9.0 cm) before high-dose chemotherapy (B) and further resolution of stenosis of the trachea due to left-hilar lymphadenopathies and splenomegaly (spleen length 7.5 cm) after high-dose chemotherapy with stem cell rescue (C).\n\nDiscussion\nDifficulties were associated with confirming the origin of RS cells in the present case. In most cases of PTLDs after allo-HSCT, proliferative lymphocytes are of donor origin (4), while those of recipient origin are very rare (5). The results of the FISH analysis in this case suggested two possibilities: the RS cells were derived either from (i) recipient cells (female) or from (ii) donor cells (male) with the loss of the Y chromosome as a cytogenetic abnormality. Although it was not possible to identify the cell origin of the preceding polymorphic PTLD by an XY-FISH analysis, the origin of the CD20-negative RS-like cells is of interest. Since identifying the origins of the RS-like cells in polymorphic PTLD and CHL-type PTLD may be helpful for obtaining a clearer understanding of the development of these PTLDs, further analyses of more cases of CHL-type PTLD following polymorphic PTLD are needed.\n\nCHL-type PTLD was previously reported to develop in recipients with other preceding PTLD subtypes, mainly polymorphic-type PTLD (6); however, difficulties were associated with clarifying the relationship between preceding polymorphic-type and CHL-type PTLDs. In our case, although preceding polymorphic-type PTLD included a small number of large cells as immunoblasts with the expression of PAX5, the immunohistochemical examination did not reveal any expression of CD30 or EBER, indicating a less-common manifestation of these cells between polymorphic-type and CHL-type PTLDs. Based on the positive conversion of the EBV antigen on large cells in CHL-type PTLD, EBV infection in tumor cells appears to have promoted the transformation of PTLD in our case. To clarify the relationship between polymorphic-type and CHTL-type PTLDs, further molecular analyses on the nature of tumor cells in PTLDs are required. For example, the presence of immunoglobulin gene rearrangements in the tumor cells of these two PTLDs is of interest (7).\n\nBased on these findings in addition to the clinical course of the present case, a re-biopsy for subsequent PTLD was helpful in the selection of an appropriate salvage therapy, as rituximab may not be a feasible option for CD20-negative RS cells. However, optimum therapeutic strategies have not yet been established for subsequent PTLD after conventional chemotherapy (4). Only limited findings are available for high-dose chemotherapy using stem cell rescue for subsequent PTLD in recipients after organ transplant, as summarized in Table (8-10). Notably, the present case confirmed that an adequate number of granulocyte colony-stimulating factor-mobilized peripheral blood hematopoietic stem cells derived from the donor could indeed be obtained, even in recipients after allo-HSCT. The present case may support high-dose chemotherapy with stem cell rescue as a promising option for patients after allo-HSCT; however, concerns have been expressed regarding increases in the risk of treatment toxicity due to a previous history of intensive chemotherapies.\n\nTable. Summary of High-dose Chemotherapy Using Stem Cell Rescue for Post-transplant Lymphoproliferative Disorders.\n\nReference \ncase\tAge at \nPTLD \ndiagnosis\tGender\tAllograft \ntype\tPTLD type\tStatus of \nPTLD at \nASCT\tHigh-dose \nchemotherapy \nregimen\tResponse \nto ASCT\tSurvival\tPatient \nstatus\t\n6\t66\tM\tHeart\tMonomorphic type \n(DLBCL)\t2nd PR\tBEAC\tCR\tNot \nreported\tAlive\t\n7\t26\tM\tKidney\tMonomorphic type \n(DLBCL)\tRelapse\tMelphalan\tCR\t4 years\tAlive\t\n8\t4\tF\tLiver\tMonomorphic type \n(T-cell lymphoma)\t2nd PR\tBEAM\tCR\t3.5 years\tAlive\t\nPresent case\t59\tF\tCord blood\tCHL type\tSD\tMelphalan\tPR\t2.1 years \n(777 days)\tAlive\t\nDLBCL: diffuse large B-cell lymphoma, CHL: classical Hodgkin lymphoma, CR: complete remission, PR: partial remission, SD: stable disease, BEAC: carmustine, etoposide, cytarabine, and cyclophosphamide, BEAM: carmustine, etoposide, cytarabine, and melphalan\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nAuthor contributions: H.I.: Clinical management, data analysis/interpretation, and drafting the manuscript; T.K., H.M., and K.O.: Pathological evaluation and critical revision of the manuscript; M.F., M.T., H.T., and Y. Moriuchi: Clinical management and critical revision of the manuscript; Y.I. and S.Y.: data analysis/interpretation and critical revision of the manuscript; Y. Miyazaki: Critical revision and final approval of the manuscript.\n==== Refs\n1. \nSwerdlow SH , Campo E , Harris L , et al \nPost-transplant lymphoproliferative disorders . In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . Swerdlow S , Campos E , Harris L et al , Eds. IARC press, World Health Organization , Lyon, France , 2008 : 343 -349 .\n2. \nRowlings PA , Curtis RE , Passweg JR , et al \nIncreased incidence of Hodgkin's disease after allogeneic bone marrow transplantation . J Clin Oncol \n17 : 3122 -3127 , 1999 .10506608 \n3. \nCheson BD , Pfistner B , Juweid ME , et al \nRevised response criteria for malignant lymphoma . J Clin Oncol \n25 : 579 -586 , 2007 .17242396 \n4. \nHeslop HE \nHow I treat EBV lymphoproliferation . Blood \n114 : 4002 -4008 , 2009 .19724053 \n5. \nAu WY , Lie AK , Lee CK , et al \nLate onset post-transplantation lymphoproliferative disease of recipient origin following cytogenetic relapse and occult autologous haematopoietic regeneration after allogeneic bone marrow transplantation for acute myeloid leukaemia . Bone Marrow Transplant \n28 : 417 -419 , 2001 .11571518 \n6. \nBasso S , Zecca M , Calafiore L , et al \nSuccessful treatment of a classic Hodgkin lymphoma-type post-transplant lymphoproliferative disorder with tailored chemotherapy and Epstein-Barr virus-specific cytotoxic T lymphocytes in a pediatric heart transplant recipient . Pediatr Transplant \n17 : E168 -E173 , 2013 .23992468 \n7. \nMarafioti T , Hummel M , Foss HD , et al \nHodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription . Blood \n95 : 1443 -1450 , 2000 .10666223 \n8. \nMalhotra B , Rahal AK , Farhoud H , Moore DF Jr, Kallail KJ \nTreatment of recurrent posttransplant lymphoproliferative disorder with autologous blood stem cell transplant . Case Rep Transplant \n2015 : 801082 , 2015 .26688773 \n9. \nBobey NA , Stewart DA , Woodman RC \nSuccessful treatment of posttransplant lymphoproliferative disorder in a renal transplant patient by autologous peripheral blood stem cell transplantation . Leuk Lymphoma \n43 : 2421 -2423 , 2002 .12613536 \n10. \nWilliams KM , Higman MA , Chen AR , et al \nSuccessful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma . Pediatr Blood Cancer \n50 : 667 -670 , 2008 .17318876\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(14)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Classical Hodgkin lymphoma; high-dose chemotherapy; post-transplant lymphoproliferative disorder; unrelated cord blood transplantation",
"medline_ta": "Intern Med",
"mesh_terms": "D005260:Female; D005312:Fetal Blood; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D008232:Lymphoproliferative Disorders; D008558:Melphalan; D008875:Middle Aged; D016879:Salvage Therapy",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1873-1877",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11571518;17242396;19724053;10506608;26688773;23992468;17318876;10666223;12613536",
"title": "High-dose Chemotherapy with Stem Cell Rescue Provided Durable Remission for Classical Hodgkin Lymphoma-type Post-transplant Lymphoproliferative Disorder after Unrelated Cord Blood Transplantation: A Case Report and Review of the Literature.",
"title_normalized": "high dose chemotherapy with stem cell rescue provided durable remission for classical hodgkin lymphoma type post transplant lymphoproliferative disorder after unrelated cord blood transplantation a case report and review of the literature"
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"abstract": "Cladophialophora bantiana brain abscesses are rare, but are frequently and quickly lethal in transplanted patients. We report the case of a 63-year-old man who had undergone lung transplantation for chronic obstructive pulmonary disease and presented with headaches and a neurological deficit. Magnetic resonance imaging revealed multiple brain abscesses. C. bantiana was identified by DNA sequencing performed directly on cerebral tissue obtained by surgical biopsy. After 6 months of antifungal treatment, the brain abscesses were replaced by ischemic sequelae. The patient died suddenly 2 months later from a pulmonary bacterial infection. This is the second reported case of C. bantiana brain abscesses in a lung transplant recipient, to our knowledge, who experienced a long survival period with medical antifungal treatment alone. We review the literature and discuss our treatment.",
"affiliations": "Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Laboratoire de Parasitologie et Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Laboratoire de Parasitologie et Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Service de Radiologie B, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.;Service d'Hématologie et d'Oncologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Service de Pneumologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Fédération de Médecine Translationnelle (FMTS), Strasbourg, France.",
"authors": "Gschwend|Anthony|A|;Dégot|Tristan|T|;Denis|Julie|J|;Sabou|Alina M|AM|;Jeung|Mi Young|MY|;Zapata|Emilie|E|;Porzio|Michele|M|;Renaud-Picard|Benjamin|B|;Herbrecht|Raoul|R|;Kessler|Romain|R|http://orcid.org/0000-0002-5798-5715",
"chemical_list": "D000935:Antifungal Agents",
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"keywords": "\nCladophialophora bantiana\n; antifungal treatment; brain abscess; lung transplantation; survival",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000935:Antifungal Agents; D001203:Ascomycota; D001706:Biopsy; D001921:Brain; D001922:Brain Abscess; D020314:Central Nervous System Fungal Infections; D017809:Fatal Outcome; D006801:Humans; D025301:Hyphae; D016040:Lung Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D013997:Time Factors",
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"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Brain abscesses caused by Cladophialophora bantiana in a lung transplant patient: A case report and review of the literature.",
"title_normalized": "brain abscesses caused by cladophialophora bantiana in a lung transplant patient a case report and review of the literature"
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"abstract": "Chemotherapy is considered \"state of the art\" for the treatment of poorly differentiated neuroendocrine neoplasms. Unfortunately, there is no standard effective post-first-line treatment for relapsing high-grade gastroenteropancreatic neuroendocrine neoplasms. We report the case of a patient with a gastric neuroendocrine carcinoma stage IV, with massive gastrointestinal bleeding at diagnosis. After the first line of platin-based chemotherapy a major tumoral response was documented, but the patient relapsed after 4 months. A second line of chemotherapy treatment was given, with the FOLFOX regimen, and the patient has been free of progression for almost 2 years. There is no second-line standard treatment accepted for this type of carcinoma, but 5-fluorouracil combined with oxaliplatin showed interesting antitumor activity.",
"affiliations": "Centro Hospitalar S. João, Clinical Oncology Department. Porto, Portugal.;Hospital Universitário Ramón y Cajal, Clinical Oncology Department. Madrid, Spain.;Hospital Universitário Ramón y Cajal, Clinical Oncology Department. Madrid, Spain.;Hospital Universitário Ramón y Cajal, Clinical Oncology Department. Madrid, Spain.;Hospital Universitário Ramón y Cajal, Clinical Oncology Department. Madrid, Spain.;Hospital Universitário Ramón y Cajal, Pathology Department. Madrid, Spain.;Hospital Universitário Ramón y Cajal, Clinical Oncology Department. Madrid, Spain.",
"authors": "Ribeiro|Maria João Marques|MJM|;Alonso|Teresa|T|;Gajate|Pablo|P|;Molina|Javier|J|;Barquin|Arantzazu|A|;Perna|Cristian|C|;Grande|Enrique|E|",
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"fulltext": "\n==== Front\nAutops Case RepAutops Case RepAutopsy & Case Reports2236-1960São Paulo, SP: Universidade de São Paulo, Hospital Universitário 29515980autopsy-08-01-e201800510.4322/acr.2018.005Article / Clinical Case ReportHuge recurrent gastric neuroendocrine tumor: a second-line chemotherapeutic dilemma Huge recurrent gastric neuroendocrine tumor: a second-line chemotherapeutic dilemmaRibeiro MJM, Alonso T, Gajate P, et al.Ribeiro Maria João Marques aAlonso Teresa bGajate Pablo bMolina Javier bBarquin Arantzazu bPerna Cristian cGrande Enrique ba Centro Hospitalar S. João, Clinical Oncology Department. Porto, Portugal.b Hospital Universitário Ramón y Cajal, Clinical Oncology Department. Madrid, Spain.c Hospital Universitário Ramón y Cajal, Pathology Department. Madrid, Spain.Author contributions: All authors had equally contributed to the conception and design of the work, data collection and interpretation, drafting the article and final critical revision and approval of the final version to be published.\n\nConflict of interest: None\n\nCorrespondence\nMaria João Marques Ribeiro\nClinical Oncology Department - Centro Hospitalar S. João\nAlameda Prof. Hernâni Monteiro 4200-319 – Porto – Portugal\nPhone: +351 963171252\nmjmarquesribeiro@gmail.com27 2 2018 Jan-Mar 2018 8 1 e201800525 9 2017 21 12 2017 Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2018.2018Autopsy and Case ReportsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the article is properly cited.Chemotherapy is considered “state of the art” for the treatment of poorly differentiated neuroendocrine neoplasms. Unfortunately, there is no standard effective post-first-line treatment for relapsing high-grade gastroenteropancreatic neuroendocrine neoplasms. We report the case of a patient with a gastric neuroendocrine carcinoma stage IV, with massive gastrointestinal bleeding at diagnosis. After the first line of platin-based chemotherapy a major tumoral response was documented, but the patient relapsed after 4 months. A second line of chemotherapy treatment was given, with the FOLFOX regimen, and the patient has been free of progression for almost 2 years. There is no second-line standard treatment accepted for this type of carcinoma, but 5-fluorouracil combined with oxaliplatin showed interesting antitumor activity.\n\nKeywords\nCarcinoma, NeuroendocrineStomach NeoplasmsNeoplasm MetastasesMedical Oncology\n==== Body\nINTRODUCTION\nNeuroendocrine neoplasms (NENs), which arise from the gastroenteropancreatic (GEP) system, define a group of heterogeneous diseases with a growing incidence.1,2 According to histopathological characteristics, NENs can be classified in neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs usually show more aggressive behavior, and patients are usually diagnosed with metastatic disease.2,3 The European guidelines recommends that systemic chemotherapy should be the treatment of choice for metastatic poorly differentiated NECs.2,4 We present the case of a poorly differentiated gastric neuroendocrine carcinoma that had a sustained major response to a second line of chemotherapy with 5-fluorouracil (5-FU) combined with oxaliplatin.\n\nCASE REPORT\nA 63-year-old male with no previous significant medical history was admitted to our department after hemorrhagic shock. He complained of dysphagia and asthenia for 2 weeks followed by abdominal pain and melena over the past 3 days. On physical examination, he presented with pale skin, blood pressure of 99/69 mmHg and tachycardia of 110 bpm. There were no palpable masses on the abdomen. The laboratory tests showed a hemoglobin level of 6.8 g/dL (reference value [RV]: 14-17.5 g/dL), a hematocrit of 20.5% (RV: 40-54%), and a normal platelet count. The liver function tests, renal function tests, and coagulation results were normal. The electrocardiogram, and the chest and abdominal x-rays showed no abnormal findings. A gastroesophageal transit and an upper abdominal endoscopy were performed; an important ulcerated tumor was seen, which involved the esophagogastric junction and the gastric fundus with active bleeding (Figure 1A).\n\nFigure 1 A – Gastroesophageal transit showing a huge mass involving the esophagogastric junction and the gastric fundus; B – CT scan showing an exophytic mass in the lesser gastric curvature referring to the known gastric cancer (asterisk).\nA computed tomography (CT) scan (Figure 1B) was also performed and revealed extensive gastric wall thickening extending from the cardia through the minor curvature. Large masses in the gastrohepatic ligament and celiac trunk were also described, which were consistent with a conglomerate of lymph nodes. The size of the primary tumor was around 10.6 × 7.8 × 8.4 cm, and the left gastric artery was invaded. The CT also showed several enlarged lymph nodes in the retroperitoneum, a 20 mm mass in segment VII of the liver, nodules of 16 mm and 10 mm in the right adrenal gland, and 12 mm in the left adrenal gland, which were consistent with metastases.\n\nThe gastric tumor was biopsied. Microscopic examination showed malignant epithelial proliferation forming nests of large cells, with no glandular differentiation. Immunohistochemistry disclosed diffuse cytokeratin AE1/AE3 and diffuse synaptophisin staining, focal chromogranin positivity and Ki-67 proliferation index of 90%. Histopathological diagnosis was gastric carcinoma with neuroendocrine differentiation, grade 3.\n\n(Figure 2). As the biopsy was taken by endoscopy, the mitotic index could not be established in 10 high-power fields (HPF). However, in an isolated HPF, four mitotic figures were found.\n\nFigure 2 Photomicrography of the gastric biopsy. A – Nests of a poorly differentiated carcinoma stained with hematoxylin-eosin; B – Diffuse cytoplasmic synaptophysin immunostaining; C – High cell proliferation index, showing 90% of Ki-67 positive cells.\nThe extended laboratory blood work-up showed an elevated chromogranin A of 586 ng/mL (RV: <36.4 ng/mL) and enolase of 94.8 ng/mL (RV: ≤15 ng/mL).\n\nThe clinical staging was cT4N1M1, stage IV, according to the tumor, node, and metastasis (TNM) classification for gastric endocrine tumors (European Neuroendocrine Tumor Society).5-7 The case was presented at the hospital multidisciplinary tumor board and systemic treatment was initiated with carboplatin (AUC5, at day 1) and etoposide (100 mg/m2 at days 1, 2, and 3). The patient was discharged after the first cycle of chemotherapy; he was clinically steady, tolerating oral diet and without any signs of bleeding.\n\nAfter the end of six cycles of chemotherapy, a control CT scan (Figures 3A and 3B) revealed a partial tumoral response, with almost complete recovery of the gastric wall; however, a lymph node of 20 mm remained in the celiac axis.\n\nFigure 3 A and B – CT-scans revealing a major tumoral response, with almost complete recovery of the gastric wall (black arrow), but a lymph node of 20 mm remained in the celiac axis (white arrow).\nOn the fourth month of follow-up, a new CT scan (Figure 4A) showed a 70 mm mass in the gastrohepatic ligament.\n\nFigure 4 A – CT scan showing local relapse (asterisk); B – The sustained major tumoral response after the 44th cycle of chemotherapy (arrow).\nThe patient started second-line treatment with mFOLFOX6 (oxaliplatin 85 mg/m2; folinic acid 200 mg/m2; 5-FU 400 mg/m2; and an infusion of 2 400 mg/m2 for 46 hours), every 14 days. Tree months after, on re-evaluation of the first CT scan, there was a partial tumoral response. The patient presented with grade 3 neuropathy, which lead to the discontinuation of oxaliplatin on the 16th cycle, while the CT scans showed a sustained partial response, and continued with the De Gramont scheme ((folinic acid 200 mg/m2; 5-FU 400 mg/m2; and an infusion of 2 400 mg/m2 for 46 hours, every 14 days). The patient has been free of tumor progression for 24 months, on the 44th cycle of the De Gramont scheme and the last CT scan (Figure 4B) documented a sustained major tumoral response.\n\nThe patient signed an informed consent and the case report is in accordance with the institution’s ethics committee.\n\nDISCUSSION\nThe classification for GEP NENs was recently revised. The World Health Organization defines grade 3 GEP carcinomas according to a Ki-67 greater than 20% and/or mitosis greater than 20/HPF. The recommended therapeutic regimen for grade 3 neuroendocrine tumors is the systemic chemotherapy with platinum plus etoposide.2,4,8 Grade 3 carcinomas show diverse responses and outcomes to chemotherapy. Some studies have shown a correlation between Ki-67 and the response to a platinum-based chemotherapy, while others have shown longer survival rates with lower Ki-67 values.9-11 A new sub-classification, which was recently proposed by Fazio and Milione,12 uses the term “tumor” for morphological well-differentiated neoplasms, and “carcinoma” for poorly differentiated neoplasms, and classified GEP NENs according to the Ki67 index. In this setting, they suggest using an alkylating-based or oxaliplatin-based chemotherapy for poorly differentiated GEP NET G3, with a Ki-67 inferior to 55%, while the poorly-differentiated GEP NECs with a Ki-67 superior to 55% should be treated with cisplatin/carboplatin plus etoposide.12\n\nTreatment with first-line chemotherapy usually results in response rates around 42%; the median duration of response is approximately 9.2 months.11 However, our patient responded well to the platin-etoposide chemotherapeutic regimen, but relapsed within 4 months. There is no standard second-line therapy established for GEP tumors. The European Society for Medical Oncology guidelines refer to promising results regarding a fluoropyrimidine drug associated with oxaliplatin or irinotecan.2 The response rate with irinotecan is known to be around 31%, with disease stabilization also around 31%, and a median progression free survival (PFS) of 4 months.13 Alternatively, Hadoux et al.14 evaluated the antitumor activity of 5-FU and oxaliplatin (FOLFOX) chemotherapy in poorly differentiated grade 3 neuroendocrine carcinomas that relapsed after the cisplatin-based regimen. This French retrospective study revised 17 patients—all with distant metastases—in which 11 patients (64%) had a stable disease/partial response with FOLFOX; the median PFS was 4.5 months. An Italian Group15 also analyzed the response to the oxaliplatin-based scheme (n = 78) and documented a PFS of 8 months. After receiving 16 cycles (approximately 8 months) of FOLFOX, our patient is still on the De Gramont scheme with good tolerability, showing a PFS (until now) superior to the aforementioned studies.\n\nThe activity of other chemotherapy regimens has been evaluated only in small retrospective studies for poorly differentiated tumors. Welin et al.16 tested temozolomide alone or in combination with bevacizumab and capecitabine, in patients who had a platinum failure, achieving a median overall survival of 22 months. Other approaches, such as monotherapy docetaxel, or FOLFIRI, showed similar results.13,17\n\nCONCLUSION\nThe prognosis for grade 3 NECs is dismal.6,10 Evidence on what should be the second line of chemotherapy is still lacking. Our patient presents an excellent response to the FOLFOX regimen as a second line of chemotherapy; nevertheless, further larger, prospective studies and guidelines are needed to establish an optimal second-line treatment.\n\nHow to cite: Ribeiro MJM, Alonso T, Gajate P, et al. Huge recurrent gastric neuroendocrine tumor: a second-line chemotherapeutic dilemma. Autops Case Rep [Internet]. 2018;8(1):e2018005. http://dx.doi.org/10.4322/acr.2018.005\n\nFinancial support: None\n==== Refs\nREFERENCES\n1 Yao JC , Hassan M , Phan A , et al \nOne hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States . J Clin Oncol . 2008 ;26 (18 ):3063 -72 . http://dx.doi.org/10.1200/JCO.2007.15.4377. 18565894 \n2 Öberg K , Knigge U , Kwekkeboom D , Perren A \nNeuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol . 2012 ;23 (Suppl 7 ):vii124 -30 . 22997445 \n3 Frilling A , Modlin IM , Kidd M , et al \nRecommendations for management of patients with neuroendocrine liver metastases . Lancet Oncol . 2014 ;15 (1 ):e8 -21 . http://dx.doi.org/10.1016/S1470-2045(13)70362-0. 24384494 \n4 Delle Fave G , O′'Toole D , Sundin A , et al \nENETS Consensus Conference participants: ENETS consensus guidelines update for gastroduodenal neuroendocrine neoplasms . Neuroendocrinology . 2016 ;103 (2 ):119 -24 . http://dx.doi.org/10.1159/000443168. 26784901 \n5 Rindi G , Arnold R , Bosman FT , et al \nNomenclature and classification of neuroendocrine neoplasms of the digestive system In: Bosman FT , Carneiro F , Hruban RH , et al , editors. WHO classification of tumors of the digestive system . Lyon : IARC ; 2010 p. 13 -145 .\n6 Pape UF , Jann H , Muller-Nordhorn J , et al \nPrognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors . Cancer . 2008 ;113 (2 ):256 -65 . http://dx.doi.org/10.1002/cncr.23549. 18506737 \n7 Rockall AG , Reznek RH \nImaging of neuroendocrine tumours (CT/MR/US) . Best Pract Res Clin Endocrinol Metab . 2007 ;21 (1 ):43 -68 . http://dx.doi.org/10.1016/j.beem.2007.01.003. 17382265 \n8 Bongiovanni A , Riva N , Ricci M , et al \nFirst-line chemotherapy in patients with metastatic gastroenteropancreatic neuroendocrine carcinoma . Onco Targets Ther . 2015 ;8 :3613 -9 . http://dx.doi.org/10.2147/OTT.S91971. 26664145 \n9 Kim HK , Ha SY , Lee J , et al \nThe impact of pathologic differentiation (well/poorly) and the degree of Ki-67 index in patients with metastatic WHO grade 3 GEP-NECs . Oncotarget . 2017 ;8 (43 ):73974 -80 . 29088761 \n10 Sorbye H , Welin S , Langer SW , et al \nPredictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO grade 3): the NORDIC NEC study . Ann Oncol . 2013 ;24 (1 ):152 -60 . http://dx.doi.org/10.1093/annonc/mds276. 22967994 \n11 Mitry E , Baudin E , Ducreux M , et al \nTreatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin . Br J Cancer . 1999 ;81 (8 ):1351 -5 . http://dx.doi.org/10.1038/sj.bjc.6690325. 10604732 \n12 Fazio N , Milione M \nHeterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: new insights and treatment implications . Cancer Treat Rev . 2016 ;50 :61 -7 . http://dx.doi.org/10.1016/j.ctrv.2016.08.006. 27636009 \n13 Hentic O , Hammel P , Couvelard A , et al \nFOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3 . Endocr Relat Cancer . 2012 ;19 (6 ):751 -7 . http://dx.doi.org/10.1530/ERC-12-0002. 22940375 \n14 Hadoux J , Malka D , Planchard D , et al \nPost-first line FOLFOX chemotherapy in Grade 3 neuroendocrine carcinoma . Endocr Relat Cancer . 2015 ;22 (3 ):289 -98 . http://dx.doi.org/10.1530/ERC-15-0075. 25770151 \n15 Spada F , Antonuzzo L , Marconcini R , et al \nOxaliplatin-based chemotherapy in advanced neuroendocrine tumors: clinical outcomes and preliminary correlation with biological factors . Neuroendocrinology . 2016 ;103 (6 ):806 -14 . http://dx.doi.org/10.1159/000444087. 26789262 \n16 Welin S , Sorbye H , Sebjornsen S , Knappskog S , Busch C , Oberg K \nClinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy . Cancer . 2011 ;117 (20 ):4617 -22 . http://dx.doi.org/10.1002/cncr.26124. 21456005 \n17 Sorbye H , Strosberg J , Baudin E , Klimstra DS , Yao JC \nGastroenteropancreatic high-grade neuroendocrine carcinoma . Cancer . 2014 ;120 (18 ):2814 -23 . http://dx.doi.org/10.1002/cncr.28721. 24771552\n\n",
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"title": "Huge recurrent gastric neuroendocrine tumor: a second-line chemotherapeutic dilemma.",
"title_normalized": "huge recurrent gastric neuroendocrine tumor a second line chemotherapeutic dilemma"
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"abstract": "BACKGROUND\nPrimary biliary cholangitis (PBC) is a rare autoimmune chronic liver disease whose prevalence is increasing. Medical treatment is based on ursodeoxycholic acid. It association with autoimmune hepatitis defined the overlap syndrome (OS).\n\n\nOBJECTIVE\nIt was to determine therapeutic and evolving characteristics of PBC and to compare them to those in subjects having an overlap syndrome.\n\n\nMETHODS\nThis was a retrospective study of all the patients' files with PBC from hepato-gastroenterology department at Monastir hospital from April 1999 to November 2013.\n\n\nRESULTS\nForty six patients were included in our study: 43 women and 3 men with an average age of 55 years. OS was retained in 13 patients. Cirrhosis was retained in 21 patients. Thirty-eight patients were treated with ursodeoxycholic acid (UDCA) associated with corticosteroids and immunosuppressors in the case of OS. After an average follow-up of 50 months [13-169 months] the overall response rate to UDCA was 55%. This rate was comparable between the 2 groups isolated PBC and OS. It was lower in the cirrhosis group compared with non-cirrhotic patients (40% vs 65%, p=0,06). One patient underwent a liver transplantation. Three patients were died as a result of decompensated cirrhosis.\n\n\nCONCLUSIONS\nOur study highlights the frequency of cirrhosis at the time of PBC diagnosis, which may explain the low rate of response to UDCA. There is no difference in the therapeutic and evolving aspects between patients with isolated PBC and those with SC.",
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"authors": "Loghmari|Mohamed Hichem|MH|;Jemmali|Donia|D|;Ben Mansour|Wafa|W|;Guediche|Arwa|A|;Bouhlel|Wided|W|;Safer|Leila|L|",
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"title": "Primary biliary cholangitis : therapeutic and evolving aspects about 46 cases.",
"title_normalized": "primary biliary cholangitis therapeutic and evolving aspects about 46 cases"
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"abstract": "OBJECTIVE\nPatient injury claims data and insurance records provide detailed information on patient injuries. This study aimed to identify the errors and adverse events that led to patient injuries in vascular surgery for the treatments of abdominal aortic aneurysms (AAA) and iliac artery aneurysms (IAA) in Finland. The study also assessed the severity and preventability of the injuries.\n\n\nMETHODS\nA retrospective analysis of Finnish Patient Insurance Centre's insurance charts of compensated patient injuries in the treatment of AAA and IAA. Records of all compensated patient injury claims involving AAA and IAA between 2004 and 2017 inclusive were reviewed. Contributing factors to injury were identified and classified. The injuries were assessed for their preventability by using the WHO Surgical Safety Checklist correctly. The degree of harm was graded by Clavien-Dindo classification.\n\n\nRESULTS\nTwenty-six patient injury incidents were identified in the treatment of 23 patients. Typical injuries involved delays in diagnosis or treatment, errors in surgical technique or injuries to adjacent anatomic organs. Three (13.0%) patients died due to patient injury. Two deaths were caused by delays in diagnosis of ruptured abdominal aortic aneurysm (RAAA) and the third death was due to missed diagnosis of post-operative myocardial infarction. Retained foreign material caused injuries to two (8.7%) patients. One (4.3%) patient had a severe postoperative infection. Three (13.0%) patients experienced an injury to an adjacent organ. One patient had a bilateral and another a unilateral above-the-knee amputation due to patient injury. Three injuries were considered preventable. Most harms were grade IIIb Clavien-Dindo classification in which injured patients required a surgical intervention under general anesthesia.\n\n\nCONCLUSIONS\nCompensated patient injuries involving the treatment of AAA and IAA are rare, but are often serious. Injuries were identified during all stages of care. Most injuries involved open surgical procedures.",
"affiliations": "Department of Vascular Surgery, Kanta-Häme Central Hospital and University of Turku, Hämeenlinna, Finland. Electronic address: minna.laukkavirta@iki.fi.;HUS Joint Resources, Helsinki, Finland.;Centre for Vascular Surgery and Interventional Radiology, Tampere University Hospital and University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland.;Department of Vascular Surgery, Turku University Hospital and University of Turku, Turku, Finland.;Department of Vascular Surgery, Turku University Hospital and University of Turku, Turku, Finland.",
"authors": "Laukkavirta|Minna|M|;Blomgren|Karin|K|;Väärämäki|Suvi|S|;Nikulainen|Veikko|V|;Helmiö|Päivi|P|",
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"abstract": "Vedolizumab is a humanized monoclonal antibody that binds to the human a4β7 integrin and is approved for use in inflammatory bowel diseases. We describe a patient with severe, refractory erosive gingivostomatitis, which appeared a few days after the first dose of vedolizumab and resolved after discontinuation of the drug. We believe the gingivostomatitis to be a direct side effect of vedolizumab, rather than an extraintestinal manifestation of the underlying inflammatory bowel diseases. The clinicians need to be aware of this adverse event, which could be mistakenly considered as an extraintestinal manifestation of inflammatory bowel diseases.",
"affiliations": "Department of Dermatology, Amiens University hospital, Amiens. lucile.semeria28@gmail.com.",
"authors": "Semeria|L|L|;Dadban|A|A|;Brazier|F|F|;Fumery|M|M|;Ikoli|J F|JF|;Arnault|J P|JP|;Adas|A|A|;Dairi|M|M|;Lok|C|C|;Chaby|G|G|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab",
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"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003093:Colitis, Ulcerative; D005765:Gastrointestinal Agents; D005891:Gingivitis; D006801:Humans; D008297:Male; D009061:Mouth Mucosa; D013280:Stomatitis",
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"title": "Severe erosive gingivostomatitis in a patient treated by vedolizumab.",
"title_normalized": "severe erosive gingivostomatitis in a patient treated by vedolizumab"
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"abstract": "We present a patient who developed genital ulceration within hours following episiotomy procedure during a normal vaginal delivery. This was initially treated by the gynaecology and medical team as cellulitis with no improvement. A diagnosis of pyoderma gangrenosum (PG) was made by the dermatology team 12 days later. On further investigation, she was found to be hepatitis C positive. We report this case to highlight the phenomenon of pathergy and frequent misdiagnosis of PG by other medical teams. When a postsurgical wound is not healing despite relevant systemic treatment, the clinician should suspect PG as an early diagnosis and treatment is crucial.",
"affiliations": "Dermatology Department, Limerick University Hospital, Limerick, Ireland.;Dermatology Department, Limerick University Hospital, Limerick, Ireland.;Dermatology Department, Limerick University Hospital, Limerick, Ireland.;Dermatology Department, Limerick University Hospital, Limerick, Ireland.",
"authors": "Alani|Angela|A|;Sadlier|Muriel|M|;Ramsay|Bart|B|;Ahmad|Kashif|K|",
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"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D000897:Anti-Ulcer Agents; D002990:Clobetasol; D003622:Dapsone; D003937:Diagnosis, Differential; D004841:Episiotomy; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D009853:Omeprazole; D011239:Prednisolone; D017511:Pyoderma Gangrenosum; D016896:Treatment Outcome; D014945:Wound Healing",
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"pubdate": "2016-01-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9492798;10428135;9892972;23551965;19470075;21824126;17966539",
"title": "Pyoderma gangrenosum induced by episiotomy.",
"title_normalized": "pyoderma gangrenosum induced by episiotomy"
} | [
{
"companynumb": "IE-WATSON-2016-09894",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAppropriate treatment reduces the risk of stroke in patients with atrial fibrillation (AF). Despite the known benefits of warfarin, anticoagulation prescribing rates remain inadequate in high-risk patients. Over the last 6 years, 4 novel oral anticoagulants have been approved for use for stroke prophylaxis in non-valvular AF (NVAF), which may allow prescribers to tailor therapy for each NVAF patient.\n\n\nOBJECTIVE\nThe goal of this investigation was to determine the effect of dabigatran and rivaroxaban availability on the rate of anticoagulant prescribing at hospital discharge in patients with a principal diagnosis of NVAF.\n\n\nMETHODS\nA retrospective chart review of adult patients presenting with NVAF (CHADS2 score ≥2) was conducted using a historical control group of patients from 2009 compared to patients admitted in 2012 following formulary availability of dabigatran and rivaroxaban. In addition to antithrombotic therapy prescribed, subsequent hospitalizations during a 1-year period were reviewed for major bleeding and stroke events.\n\n\nRESULTS\nTwo hundred patients were enrolled in the study. The rate of anticoagulant prescribing in the 2009 and 2012 groups was 68.3% and 77.1%, respectively (p = .16). Of the patients in the 2012 group prescribed an anticoagulant, 58 (64%) received warfarin, 26 (28%) received dabigatran, and 7 (8%) received rivaroxaban. One patient (1.2%) in the 2009 group and 4 patients (4.4%) in the 2012 group had a major bleed (p = .4).\n\n\nCONCLUSIONS\nThere was no statistical difference in the rate of anticoagulant prescribing between the 2 groups. Despite the availability of additional anticoagulant options, the rate of prescribing remains suboptimal in this high-risk population.",
"affiliations": null,
"authors": "Marler|Jacob|J|;Usery|Justin B|JB|;Nolan|Shambria|S|;Oliphant|Carrie S|CS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1310/hpj5107-564",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "51(7)",
"journal": "Hospital pharmacy",
"keywords": "atrial fibrillation; dabigatran; rivaroxaban; stroke prophylaxis; warfarin",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "564-71",
"pmc": null,
"pmid": "27559189",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "18574273;24655711;24180541;26700008;24251359;22315271;24532967;9570191;24814537;20104933;22050392;21781237;18766100;23601912;21478739;24859719;25715385;21309657;24156648;19717844;15842354;1860198;11700158;17693178;21097765;10835435;24682348;24843316;24627401;22450212;21870978;16908781;21830957;22949490;23627576;19678723;11343485",
"title": "Antithrombotic Usage Patterns in the Era of New Oral Anticoagulant Options for Atrial Fibrillation.",
"title_normalized": "antithrombotic usage patterns in the era of new oral anticoagulant options for atrial fibrillation"
} | [
{
"companynumb": "US-TEVA-2019-US-1059289",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nBortezomib has shown significant activity in myeloma. In this multicenter trial, we assessed for the first time the combination of bortezomib, doxorubicin and low-dose dexamethasone (PAd) in the treatment of relapsed/refractory myeloma.\n\n\nMETHODS\nSixty-four patients were treated for a median of four 28-day cycles (1-6). Bortezomib was given at 1.3 mg/m(2) (days 1, 4, 8, 11) and dexamethasone at 40 mg (days 1-4); 34 patients receive doxorubicin at 20 mg/m(2) (days 1, 4) while 30 patients pegylated liposomal doxorubicin at 30 mg/m(2) (day 1).\n\n\nRESULTS\nFifty-eight percent of patients had undergone prior autologous transplantation, 70% prior anthracycline and 27% prior bortezomib-based regimens. Forty-three patients (67%) achieved at least a partial response including 16 (25%) with at least a very good partial response. One-year event-free survival was 34% after PAd and 31% after the previous line of therapy (hazard ratio 1.20, 95% confidence interval 0.76-1.90, P = 0.43). One-year overall survival from the start of PAd was 66%. Grade 3-4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%). Two patients had grade 3-4 cardiac heart failure.\n\n\nCONCLUSIONS\nPAd is an active salvage therapy with manageable toxicity in patients with relapsed/refractory myeloma.",
"affiliations": "Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy. appalumbo@yahoo.com",
"authors": "Palumbo|A|A|;Gay|F|F|;Bringhen|S|S|;Falcone|A|A|;Pescosta|N|N|;Callea|V|V|;Caravita|T|T|;Morabito|F|F|;Magarotto|V|V|;Ruggeri|M|M|;Avonto|I|I|;Musto|P|P|;Cascavilla|N|N|;Bruno|B|B|;Boccadoro|M|M|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdn018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "19(6)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D016879:Salvage Therapy",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1160-5",
"pmc": null,
"pmid": "18326520",
"pubdate": "2008-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma.",
"title_normalized": "bortezomib doxorubicin and dexamethasone in advanced multiple myeloma"
} | [
{
"companynumb": "IT-JNJFOC-20170720293",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
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"drugadditional": null,
... |
{
"abstract": "Interstitial lung disease (ILD) is a well-established common manifestation of idiopathic inflammatory myopathies. Yet, till now, the pathogenetic mechanisms are still poorly understood, classification is evolving and prognosis is variable. A refractory and rapidly progressive ILD (RPILD) that is associated with dermatomyositis (DM) with minimal muscle weakness and normal creatine kinase (termed clinically amyopathic DM) is increasingly being recognized, with more incidence in Asians. However, we are not aware of reports of the Arab region. Herein, we present a 38-year-old male with this condition that ended with a fatal outcome despite aggressive therapy, with a review of recent literature.",
"affiliations": "Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;Department of Laboratory Medicine and Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.",
"authors": "Mobeireek|Abdullah|A|;Conca|Walter|W|;Mohammed|Shamayel|S|;AlObaid|Fahad|F|;AlHajji|Mohammed|M|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/atm.atm_739_20",
"fulltext": "\n==== Front\nAnn Thorac Med\nAnn Thorac Med\nATM\nAnnals of Thoracic Medicine\n1817-1737\n1998-3557\nWolters Kluwer - Medknow India\n\nATM-16-294\n10.4103/atm.atm_739_20\nCase Report\nFatal rapidly progressive interstitial lung disease in a patient with amyopathic dermatomyositis\nMobeireek Abdullah 1\nConca Walter 1\nMohammed Shamayel 2\nAlObaid Fahad 1\nAlHajji Mohammed 1\n1 Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia\n2 Department of Laboratory Medicine and Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia\nAddress for correspondence: Prof. Abdullah Mobeireek, King Faisal Specialist Hospital and Research Centre, Department of Medicine, PO Box 3354 (MBC 46), Riyadh 11211, Saudi Arabia. E-mail: mobeireek@yahoo.com\nJul-Sep 2021\n20 7 2021\n16 3 294298\n19 12 2020\n08 4 2021\nCopyright: © 2021 Annals of Thoracic Medicine\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nInterstitial lung disease (ILD) is a well-established common manifestation of idiopathic inflammatory myopathies. Yet, till now, the pathogenetic mechanisms are still poorly understood, classification is evolving and prognosis is variable. A refractory and rapidly progressive ILD (RPILD) that is associated with dermatomyositis (DM) with minimal muscle weakness and normal creatine kinase (termed clinically amyopathic DM) is increasingly being recognized, with more incidence in Asians. However, we are not aware of reports of the Arab region. Herein, we present a 38-year-old male with this condition that ended with a fatal outcome despite aggressive therapy, with a review of recent literature.\n\nAmyopathic dermatomyositis\nconnective tissue disease\nidiopathic inflammatory myopathy\ninterstitial lung disease\n==== Body\nThe association of interstitial lung disease (ILD) with connective tissue disease (CTD) is quite common; up to two-thirds of ILD patients may have one form of CTD if a careful assessment and follow-up are performed.[1] Furthermore, classification is evolving as more knowledge is gained about the autoimmune mechanisms of the disease. More recently, terms such as “interstitial pneumonia with autoimmune features”[2] and “autoimmune ILD”[3] have been suggested to further discern this group and distinguish them from the idiopathic type, which has a different management strategy and prognosis. Although, in general, the prognosis of ILD associated with CTD is more favorable than the idiopathic type (typically idiopathic pulmonary fibrosis),[2] certain types can be fulminant and refractory to modern therapy. We present, for the first time from the Arab region, a patient with amyopathic dermatomyositis (DM) who succumbed because of rapidly progressive interstitial lung disease (RPILD) despite aggressive management.\n\nCase Report\n\nA previously healthy 38-year-old male was referred for the evaluation of worsening dyspnea. Two months prior to his presentation, he started to have low-grade fever associated with dry cough, generalized fatigability, arthralgia, and documented weight loss of 12 kg. He also developed skin rash, painless, and nonitchy at both elbows, knuckles, and eyebrows. Three weeks later, he was admitted to the intensive care unit (ICU) in another hospital after developing hypoxic respiratory failure and was treated with antibiotics and corticosteroids without any improvement. He has significant smoking history of pipe smoking for the past 15 years (three times/week). He was receiving prednisone 40 mg daily.\n\nOn examination, he was afebrile with respiratory rate of 24 breath/min, oxygen saturation was 94% on 4 L of oxygen by nasal canula. Erythematous scaly papules were noted over the elbows and knuckles as well as scattered scales over the eyebrows, nose, and beard area (xerosis). On auscultation, there were bilateral inspiratory fine crackles. Neurologically, he had no significant muscle weakness. His initial routine laboratory investigations, including autoimmune panel, are shown in Table 1. Of note, creatine kinase (CK) was within normal limits.\n\nTable 1 Laboratory investigations\n\nCategory\tParameter\tValue\t\nHematology\tWBC (total)\t4.9\t\n\tNeutrophils\t87%\t\n\tLymphocytes\t4%\t\n\tHb\t115 g/L\t\n\tPlatelets\t219\t\n\tESR\t81 mm/h\t\n\tBAL WBC\t215 (106/L)\t\n\t Neutrophils\t24%\t\n\t Lymphocytes\t12%\t\n\t Histocytes\t52%\t\nBiochemistry\tElectrolytes, urea and creatinine\tWNR\t\n\tCK\t75 u/L\t\n\tALT\t79 u/L\t\n\tAST\t56 u/L\t\n\tAP\t108 u/L\t\n\tFerritin\t3387 ug/L (30-400 ug/L)\t\nImmunologic tests\tCRP\t7.7 mg/L\t\n\tComplement (g/L)\t\t\n\t C3\t1.23\t\n\t C4\t0.33\t\n\tImmunoglobulins (A, G, M, E)\tWNR\t\n\tCryoglobulin\tNegative\t\n\tANA\t1: 180, speckled pattern\t\n\tRF\t7.3 u (negative)\t\n\tACCP\t<15.6 u (WNR)\t\n\tC-ANCA (PR3)\t4.3 u (WNR)\t\n\tP-ANCA (MPO)\t2.6 u (WNR)\t\n\tANCA (IF)\tNegative\t\n\tAnti-ds-DNA\t99.1 iu/mL (WNR)\t\n\tAnti SSA (Ro)\t10.6 u (WNR)\t\n\tAnti SSB (La)\t2.5 u (WNR)\t\n\tAnti-Smith\t4.8 u (WNR)\t\n\tAnti-smooth muscle\tNegative\t\n\tAnti-Scl-70\t3.3 u (WNR)\t\n\tAnti-Jo\t4.5 u (WNR)\t\n\tAnti-RNP\t12.8 u (WNR)\t\n\tAnti-phospholipid\tNegative\t\n\tPTT-LA screening\t35 s\t\n\tLupus anticoagulant\tNegative\t\n\tAnti-myositis panel\tN/A\t\n\tAnti-GBM\t4.3 u (WNR)\t\nMiscellaneous\tHIV serology\tNegative\t\n\tHepatitis B and C serology\tNonreactive\t\nWBC=White blood cells, Hb=Hemoglobin, ESR=Erythrocyte sedimentation rate, BAL=Bronchoalveolar lavage, CK=Creatine kinase, AST=Aspartate aminotransferase, ALT=Alanine aminotransferase, AP=Alkaline phosphatase, CRP=C-reactive protein, ANA=Antinuclear antibody, RF=Rheumatoid factor, ACCP=Anti-cyclic citrullinated peptide, MPO=Myeloperoxidase, PR3=Proteinase 3, ANCA=Antineutrophil cytoplasmic antibodies, C-ANCA=Cytoplasmic-ANCA, P-ANCA=Perinuclear-ANCA, IF=Immunofluorescence, Anti-ds-DNA=Anti-double stranded DNA, Anti-SSA=Anti- Sjögren’s-syndrome-related antigen A, Anti SSB=Anti Sjögren’s syndrome related antigen B, Anti-RNP=Anti-ribonucleoprotein, PTT-LA=Partial thromboplastin time-lupus anticoagulant, Anti-GBM=Anti-glomerular basement membrane, WNR=Within normal range, N/A=Not available\n\nInitial chest radiograph and computed tomography (CT) showed bilateral patchy ground-glass opacities/consolidations with interstitial septal thickening [Figure 1]. These changes were bilateral and predominantly peribronchial, and more pronounced at the lower lobes. Microbiological screening was unremarkable. Skin biopsy showed epidermal atrophy, altered keratin and serum crust. The dermis showedmild dermal telangiectasia and mild mucin deposition. These features were consistent with interface dermatitis. DM was suspected initially. Bronchoscopy did not show any endobronchial lesion and the transbronchial biopsies are discussed below.\n\nFigure 1 Initial chest radiograph and selected images of computed tomography of the chest\n\nHistology and immunohistochemistry\n\nHematoxylin and eosin (H&E) staining and immunohistochemistry on sections of lung tissue were performed order to determine the phenotype of infiltrating inflammatory cells [Figures 2 and 3]. The histomorphology revealed the characteristic features of organizing pneumonia and interstitial inflammation [Figure 2a]. Differentiation of the cellular components revealed the simultaneous presence of CD3+ T lymphocytes [Figure 2b], including CD4+ [Figure 2c], and CD8+ [Figure 2d] T cells, CD20+ B cells [Figure 2e] and CD68+ macrophages [Figure 2f]. While CD3+ T cells were sparsely distributed throughout the interstitium, some CD20+ B cells accumulated at the margins and some within the T cell-rich area. In contrast, most CD68+ macrophages formed clusters predominantly in the alveolar spaces [Figure 3a]. On higher magnification, macrophages were “lipid-laden” with multilocular droplets [Figure 3b] and showed faint Prussian blue staining of iron-containing microparticles in the cytoplasm [Figure 3c], suggesting that they represent a source of ferritin, now considered as the most prominent and clinically useful biomarker in RPILD.[4]\n\nFigure 2 Histomorphology and immunohistochemical characterization of inflammatory cells in dermatomyositis-associated RPILD. Transbronchial biopsy showing organizing pneumonia with interstitial inflammation (a). CD3+ T lymphocytes sparsely distributed throughout the interstitium (b), and encompassed CD4+ (c) and CD8+ T cells (d). CD20+ B cells infiltrating the interstitium (e). The majority of CD68+ macrophages concentrated as clusters in the alveolar spaces (f). Magnification: ×20, bar length: 50 μm\n\nFigure 3 Histomorphology, immunohistochemistry and Prussian blue staining of macrophages in dermatomyositis-associated RPILD. CD68+ macrophages forming conspicuous clusters in alveoli (a) and displayed the characteristic morphology of “lipid-laden” macrophages (b). A faint bluish discoloration of cytoplasmic particles observed after Prussian blue staining indicated the presence of iron-binding macromolecular structures (c). Magnification x60, bar length: 20 μm\n\nClinical course\n\nPrednisone was increased to 1 mg/kg daily. Five days later, there was no clinical improvement. Pulse steroids were started in the form of methylprednisolone 1 g intravenously for 3 days. Subsequently, tacrolimus 0.5 mg orally twice daily was added to the regimen. Despite this, his condition kept worsening, and he was transferred to ICU because of worsening hypoxemic respiratory failure. He was started on intravenous immunoglobulin 40 g daily for 3 days and then given cyclophosphamide 800 mg intravenously without response. However, he continued to deteriorate and required ventilatory support for worsening respiratory failure (acute respiratory distress syndrome). He was considered for lung transplantation but found not to be a suitable candidate because of high risk being on ventilatory support and the likelihood of disease recurrence. After discussion with the family, the patient was designated not for resuscitation and the patient expired 6 weeks after admission.\n\nDiscussion\n\nIdiopathic inflammatory myopathies (IIM), such as DM or polymyositis, are associated with a variety of respiratory manifestations including ILD, respiratory muscle weakness, pleural disease, aspiration, and infection.[5] Among those, ILD occurs in 65% of patients and is the most important complication that can cause significant morbidity and mortality.[56] In the Arab region, only one case series of IIM in adults was reported.[7] However, all patients had proximal muscle weakness and 90% had elevated CK. Interestingly, our patient had the DM variant without muscle involvement and normal CK called clinically amyopathic DM (CADM), which is more common in Asians and in which ILD is also much less frequent but more severe than the classical DM.[456891011]\n\nThe exact mechanisms of RPILD are complex and yet to be elucidated. However, a recent study identified a circulating CD4+ T-cell subset characterized by the presence of CXCR4, a surface receptor for CXCL12.[12] This newly described T-cell population could play a crucial role in the florid inflammatory phase of RPILD. We hypothesize that the newly discovered pathogenic T-cells were among the CD4+ T-cell population beside other cellular components of innate and adaptive immunity such as alveolar macrophages, CD8+ T-cells, and B-cells.\n\nAlthough it is generally stated that the prognosis is more favorable for ILD associate with CTD in comparison to their idiopathic counterparts,[39] specific groups in the former may have a catastrophic course. Among these, falls ILD associated with CADM, with a mortality exceeding 50%.[45910] Recent research showed considerable heterogeneity within the IIM group. Specific autoantibodies were associated with phenotypes with varying degrees of pulmonary and extrapulmonary manifestations.[56] Of note, RPILD in association with MDA5 autoantibodies is a predictor of poor prognosis.[45691013] Others, such as the anti-synthetase group, have lower incidence and milder ILD and more favorable prognosis.[569] Unfortunately, these assays were not available to us, but the clinical picture and biopsy findings of our patient were highly suggestive of the MDA5 type. In this group, disease is often refractory to steroids and other immunosuppressive therapy and ends up with a fatal outcome.[56910] Other autoantibodies may coexist, especially if there is an overlap with other CTDs such asSystemic lupus erythematosus(SLE) or systemic sclerosis.[56] Discovery of these autoantibodies may give insight to the pathogenesis of these diseases, which is believed to result from environmental factors (such as viruses) and genetic susceptibility, as indicated by racial variation and Human Leukocyte Antigen (HLA) predisposition.[5]\n\nGuidelines on therapy have been published recently, but there is still lack of controlled trials on the optimal regimen.[14] Although the initial lung biopsy of our patient showed organizing pneumonia, which is associated with a favorable prognosis, his disease progressed despite high-dose corticosteroid and different immunosuppressive regimens. It is likely that the pathology evolved to diffuse alveolar damage and interstitial fibrosis. Kwan et al. reported a 62-year-old Vietnamese lady with a similar condition who received corticosteroids and mycophenolate who survived for nearly a year, but she was still left with considerable morbidity.[9] Novel therapies that may have a potential therapeutic role in the future include tofacitinib, a Janus kinase inhibitor.[4]\n\nIn conclusion, although ILD associated with CTD in general has a more favorable prognosis compared with the idiopathic type, certain phenotypes, can have a fulminant form (RPILD) that is refractory to modern therapy. It is prudent to be vigilant to clinical and laboratory clues to identify the high-risk groups of the “autoimmune” ILD to allow early intervention. Liaison between pulmonologists and rheumatologists and more collaborative research with basic scientists is required for newer approaches and innovative therapies to improve the outcome.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained allappropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Hu Y Wang LS Wei YR Du SS Du YK He X Clinical characteristics of connective tissue disease – Associated interstitial lung disease in 1,044 Chinese patients Chest 2016 149 201 8 26447566\n2 Ahmad K Barba T Gamondes D Ginoux M Khouatra C Spagnolo P Interstitial pneumonia with autoimmune features: Clinical, radiologic and histological characteristics and outcome in a series of 57 patients Resp Med 2017 123 56 62\n3 Collins BF Spiekerman CF Shaw MA Ho LA Hayes J Spada CA Idiopathic interstitial pneumonia associated with autoantibodies: A large case series followed over 1 year Chest 2017 152 103 12 28300570\n4 Chen Z Wang X Ye S Tofacitinib in amyopathic dermatomyositis-associated interstitial lung disease N Engl J Med 2019 381 291 3 31314977\n5 Lega JC Reynaud Q Belot A Fabien N Durieu I Cottin V Idiopathic inflammatory myopathies and the lung Eur Respir Rev 2015 24 216 38 26028634\n6 Hallowell RW Ascherman DP Danoff SK Pulmonary manifestations of polymyositis/dermatomyositis Semin Respir Crit Care Med 2014 35 239 48 24668538\n7 Mustafa KN Dahbour SS Clinical characteristics and outcomes of patients with idiopathic inflammatory myopathies from Jordan 1996-2009 Clin Rheumatol 2010 29 1381 5 20407818\n8 Mukae H Ishimoto H Sakamoto N Hara S Kakugawa T Nakayama S Clinical differences between interstitial lung disease associated with clinically amyopathic dermatomyositis and classic dermatomyositis Chest 2009 136 1341 7 19581351\n9 Kwan C Melosevic S Benham H Scot IA A rare form of myositis associated with muscle weakness and normal creatin kinase level BMJ Case Rep 2020 13 e232260\n10 Fujisawa T Hozumi H Kono M Enomoto N Hashimoto D Nakamura Y Prognostic factors for myositis – Associated interstitial lung disease PLoS One 2014 9 e98824 24905449\n11 Ye S Chen XX Lu XY Wu MF Deng Y Huang WQ Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: A retrospective cohort study Clin Rheumatol 2007 26 1647 54 17308858\n12 Wang K Zhao J Chen Z Li T Tan X Zheng Y CD4+CXCR4+T cells as a novel prognostic biomarker in patients with idiopathic inflammatory myopathy-associated interstitial lung disease Rheumatology 2019 58 511 21 30508148\n13 Li Y Gao X Li Y Jia X Zhang X Xu Y Predictors and mortality of rapidly progressive interstitial lung disease in patients with idiopathic inflammatory myopathy: A series of 474 patients Front Med (Lausanne) 2020 7 363 32850886\n14 Vacchi C Sebastiani M Cassone G Cerri S Della Casa G Salvarani C Therapeutic options for the treatment of interstitial lung disease related to connective tissue diseases. A narrative review J Clin Med 2020 9 407\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1998-3557",
"issue": "16(3)",
"journal": "Annals of thoracic medicine",
"keywords": "Amyopathic dermatomyositis; connective tissue disease; idiopathic inflammatory myopathy; interstitial lung disease",
"medline_ta": "Ann Thorac Med",
"mesh_terms": null,
"nlm_unique_id": "101280721",
"other_id": null,
"pages": "294-298",
"pmc": null,
"pmid": "34484446",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30508148;26447566;28137497;24905449;32033996;31314977;28300570;17308858;19581351;32850886;20407818;32028635;26028634;24668538",
"title": "Fatal rapidly progressive interstitial lung disease in a patient with amyopathic dermatomyositis.",
"title_normalized": "fatal rapidly progressive interstitial lung disease in a patient with amyopathic dermatomyositis"
} | [
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"companynumb": "SA-LUPIN PHARMACEUTICALS INC.-2021-22021",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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{
"abstract": "BACKGROUND\nImmunoglobulin G4 (IgG4)-related disease is a chronic inflammatory disease that was recognized in 2011. Pleuritis associated with IgG4-related disease is rare and can be difficult to diagnose. Although there have been previous reports on pleuritis associated with IgG4-related disease by thoracoscopic findings, this is the first to observe pleuritis with IgG4-related disease from normal pleural thoracoscopic findings.\n\n\nMETHODS\nA 70-year-old Japanese female treated for breast cancer 33 years ago was referred to our hospital complaining of dyspnea on exertion. Chest computed tomography (CT) revealed left pleural effusion that was exudative and predominant with lymphocytes, elevated adenosine deaminase (ADA) and Class III cytology (malignancy suspected). Subsequently, thoracoscopic pleural biopsy was performed for definitive diagnosis. Although pleural macroscopic findings appeared normal, we performed pleural biopsy at random sites. This patient was negative for mycobacterium tuberculosis, and neither granulomas nor malignant cells were found in the collected specimens. An infiltration of inflammatory cells, mainly plasma cells and lymphocytes, was observed. Immunostaining revealed the number of IgG4-positive plasma cells was 102/high power field (HPF), and the percentage of IgG4 positive/immunoglobulin G (IgG)-positive cells was 41.4%. Since IgG4 serum levels were high and IgG4-related submandibular sialadenitis was also observed, a definitive diagnose of pleuritis associated with IgG4-related disease was confirmed.\n\n\nCONCLUSIONS\nWe diagnosed pleuritis associated with IgG4-related disease by thoracoscopic pleural biopsy samples taken from a visually normal pleura. Although exudative pleural effusion with high ADA and lymphocyte predominance is a characteristic of tuberculous pleuritis, other diseases might be present. Since thoracoscopy can increase the diagnostic yield, pleural biopsy should be considered even if thoracoscopic pleural findings are deemed normal.",
"affiliations": "Hirakata Kohsai Hospital, 1-2-1, Fujisakahigashimachi, Hirakata, Osaka, 573-0153, Japan.;Hirakata Kohsai Hospital, 1-2-1, Fujisakahigashimachi, Hirakata, Osaka, 573-0153, Japan. yklcab01kai02@gmail.com.;Hirakata Kohsai Hospital, 1-2-1, Fujisakahigashimachi, Hirakata, Osaka, 573-0153, Japan.;Hirakata Kohsai Hospital, 1-2-1, Fujisakahigashimachi, Hirakata, Osaka, 573-0153, Japan.;Hirakata Kohsai Hospital, 1-2-1, Fujisakahigashimachi, Hirakata, Osaka, 573-0153, Japan.;Department of Respiratory Medicine, Nara Medical University Hospital, 840 Shijocho, Kashihara, Nara, 634-8522, Japan.;Department of Diagnostic Pathology, Kyoto University Hospital, 54 Shougoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.",
"authors": "Shimada|Hiroki|H|;Kato|Yuto|Y|;Okuda|Miyuki|M|;Fukuda|Koji|K|;Tanaka|Nobuya|N|;Okuda|Yutaro|Y|;Yoshizawa|Akihiko|A|",
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"doi": "10.1186/s13256-021-02718-4",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2718\n10.1186/s13256-021-02718-4\nCase Report\nPleuritis associated with immunoglobulin G4-related disease under normal thoracoscopic findings: a case report\nShimada Hiroki hiro2453tkd@gmail.com\n\n1\nKato Yuto yklcab01kai02@gmail.com\n\n1\nOkuda Miyuki ryoheikunn@msf.biglobe.ne.jp\n\n1\nFukuda Koji k-fukuda@kkr-hirakoh.jp\n\n1\nTanaka Nobuya nobuya1125@gmail.com\n\n1\nOkuda Yutaro okudamoai@gmail.com\n\n2\nYoshizawa Akihiko akyoshi@kuhp.kyoto-u.ac.jp\n\n3\n1 Hirakata Kohsai Hospital, 1-2-1, Fujisakahigashimachi, Hirakata, Osaka 573-0153 Japan\n2 grid.474851.b 0000 0004 1773 1360 Department of Respiratory Medicine, Nara Medical University Hospital, 840 Shijocho, Kashihara, Nara 634-8522 Japan\n3 grid.411217.0 0000 0004 0531 2775 Department of Diagnostic Pathology, Kyoto University Hospital, 54 Shougoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507 Japan\n30 4 2021\n30 4 2021\n2021\n15 24119 7 2020\n3 2 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\nImmunoglobulin G4 (IgG4)-related disease is a chronic inflammatory disease that was recognized in 2011. Pleuritis associated with IgG4-related disease is rare and can be difficult to diagnose. Although there have been previous reports on pleuritis associated with IgG4-related disease by thoracoscopic findings, this is the first to observe pleuritis with IgG4-related disease from normal pleural thoracoscopic findings.\n\nCase presentation\n\nA 70-year-old Japanese female treated for breast cancer 33 years ago was referred to our hospital complaining of dyspnea on exertion. Chest computed tomography (CT) revealed left pleural effusion that was exudative and predominant with lymphocytes, elevated adenosine deaminase (ADA) and Class III cytology (malignancy suspected). Subsequently, thoracoscopic pleural biopsy was performed for definitive diagnosis. Although pleural macroscopic findings appeared normal, we performed pleural biopsy at random sites. This patient was negative for mycobacterium tuberculosis, and neither granulomas nor malignant cells were found in the collected specimens. An infiltration of inflammatory cells, mainly plasma cells and lymphocytes, was observed. Immunostaining revealed the number of IgG4-positive plasma cells was 102/high power field (HPF), and the percentage of IgG4 positive/immunoglobulin G (IgG)-positive cells was 41.4%. Since IgG4 serum levels were high and IgG4-related submandibular sialadenitis was also observed, a definitive diagnose of pleuritis associated with IgG4-related disease was confirmed.\n\nConclusions\n\nWe diagnosed pleuritis associated with IgG4-related disease by thoracoscopic pleural biopsy samples taken from a visually normal pleura. Although exudative pleural effusion with high ADA and lymphocyte predominance is a characteristic of tuberculous pleuritis, other diseases might be present. Since thoracoscopy can increase the diagnostic yield, pleural biopsy should be considered even if thoracoscopic pleural findings are deemed normal.\n\nKeywords\n\nIgG4-related disease\nMedical thoracoscopy\nPleuritis\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nImmunoglobulin G4 (IgG4)-related disease is a chronic inflammatory systemic disease that was recognized in 2011 [1]. IgG4-related disease, a multi-organ disease, is known to cause damage to the pancreas, bile duct, lacrimal gland, salivary gland, central nervous system, thyroid, lung, liver, digestive tract, kidney, prostate, retroperitoneum, artery, lymph node, skin, and mammary gland. Among these, lung lesions are particularly difficult to diagnose, requiring computed tomography (CT)-guided biopsy or thoracoscopy for diagnosis. On the other hand, reports of pleuritis associated with IgG4-related diseases are rare, and only around 20 cases have thus far been reported. Pleural findings such as pleural plaque, fibrous deposits, pleural thickening, and nodules are recognized as IgG4-related disease, but currently, there are no reports on IgG4-related disease from normal plural findings assessed by thoracoscopy.\n\nWe report a case of pleuritis associated with IgG4-related disease confirmed by randomly selected pleural biopsy sites after normal thoracoscopic findings.\n\nCase presentation\n\nA 70-year-old Japanese female complaining of dyspnea on exertion was admitted to our hospital after chest X-ray showed left pleural effusion. Her medical history included hypertension, dyslipidemia, paroxysmal atrial fibrillation, cerebral infarction, and left breast cancer. Her hypertension, dyslipidemia, and paroxysmal atrial fibrillation were well managed by medication, and she underwent total left mastectomy and remnant gauze removal surgery 33 and 13 years ago, respectively. She was a nonsmoker with no history of autoimmune diseases, multiple myeloma, tuberculosis, or exposure to asbestos. Her family history revealed that her father had liver cirrhosis, and her mother had been diagnosed with lung cancer. There was no family history of autoimmune disease or tuberculosis.\n\nOn admission, she was lucid, with heart rate of 74 beats/minute, blood pressure of 138/68 mmHg, peripheral oxygen saturation of 96%, and body temperature of 35.8 °C. Heart sounds were normal but with decreased breath sounds in the left lung field. No spontaneous pain or tenderness was present in the chest. Her abdomen was flat and soft, with no abdominal tenderness or bowel sounds. No pitting edema was observed in either her forearms or legs; however, bilateral submandibular gland enlargement was observed. She had no motor or sensory deficits in her extremities and no arthralgia or morning stiffness associated with rheumatoid arthritis.\n\nLaboratory findings\n\nInflammatory findings such as C reactive protein (CRP) and tumour makers were within the normal range (normal CRP, < 0.3 mg/dL). Autoantibodies were serologically negative. Serum immunoglobulin G (IgG) was 2001 mg/dL including 637 mg/dL for IgG4 (normal IgG 870–1700 mg/dL, normal IgG4 4–108 mg/dL). Chest X-ray and CT showed left pleural effusion without abnormal lung shadow and no pleural thickening (Fig. 1a, b). We performed pleural puncture and drained 1200 mL of pleural fluid. Pleural puncture revealed lymphocytes were dominant and adenosine deaminase (ADA) was high, but Mycobacterium tuberculosis was not detected (normal ADA 8.6–20.5 U/L). Elevated IgG and IgG4 levels were observed in the pleural effusion (IgG 1756 mg/dL; IgG4 684 mg/dL). Class III cells were identified from the pleural effusion, suggesting the possibility of breast cancer dissemination. Mycobacterium cultures for sputum, pleural fluid, and pleural biopsy samples were negative.Fig. 1. Radiological findings. Chest X-ray at admission showed pleural effusion (a). Chest CT scan showed no thickening, calcification, or nodules in the left pleura. No tumour nodules were suspected in the lungs (b)\n\nClinical progress\n\nThe results of pleural puncture suggested tuberculous pleuritis, pleuritis due to autoimmune disease, or carcinomatous pleuritis, but a definitive diagnosis could not be made. Thus, we performed thoracoscopic pleural biopsy. Under thoracoscopy, no obvious lesions, pleural thickening, nodules, or pleural-pulmonary adhesions were found for the left pleura. Although the pleura appeared normal, we randomly collected seven specimens at three locations (Fig. 2).Fig. 2. Thoracoscopic findings of left pleura. Thoracoscopically, there were no obvious mass lesions, pleural thickening, nodules, or pleural-pulmonary adhesions observed for the left pleura\n\nPathological examination revealed membranous tissue with superficial proliferation in the reactive mesothelium. We confirmed plasmacytoid, lymphocyte-dominated inflammatory cell infiltration. The formation of reactive lymphatic follicles was also present. Polymerase chain reaction for mycobacterium tuberculosis (TB-PCR) was negative, and no granulomas were found in the pleural specimens. There were no malignant epithelial lesions and immunostaining showed no deviation in IgG-k or IgG-λ chains. Epstein-Barr virus-encoded small Rino Nucleic Acid (RNA) and Congo red stain were also negative. IgG4-positive cells were 102/high power field (HPF), and the percentage of IgG4 positive/IgG positive cells was 41.4%, suggesting pleuritis associated IgG4-related disease (Fig. 3a, b).Fig. 3. Pathological findings of the left pleura. Biopsy specimens stained with hematoxylin and eosin stain (a) and IgG4 immunostaining (b). Plasmacytoid, lymphocyte-dominated inflammatory cell infiltration was present. The formation of reactive lymphatic follicles was also found\n\nWe then performed 2-deoxy-2-(18F]-fluoro-d-glucose (FDG) positron emission tomography (PET)-CT for systemic retrieval analysis. FDG PET-CT showed FDG accumulation within the bilateral submandibular glands of the left pleura. Subsequently, under ultrasound guidance, we collected biopsy samples from the right side of the submandibular gland. An infiltration of plasmacytes and lymphocytes around the adeno-atrial tissue was present; however, no malignant cells or granulomas were noted. Immunostaining confirmed IgG4-positive cells were 96/HPF and the percentage of IgG4 positive/IgG positive cells was 55.2%, confirming pleuritis-associated IgG4-related disease.\n\nWe have started treatment with prednisolone 30 mg/day because of increased pleural effusion after discharge from the hospital. The patient was followed for 10 months. The dose was reduced every month from 30 to 20 mg/day to 15 mg/day to 12.5 mg/day to 10 mg/day. Eventually, the dose was reduced to 7.5 mg/day 6 months after the start of treatment, and now the dose was continued at 7.5 mg/day. Since the prednisolone dose was reduced, the patient has progressed without relapse of pleuritis and submandibular gland swelling. Although some side effects of prednisolone such as lipid abnormalities and worsening of diabetes were observed, the treatment was successful without major side effects.\n\nDiscussion\n\nIn this case, a biopsy from a grossly normal pleura led to the diagnosis of pleuritis associated with IgG4-related disease, and remission was achieved with steroid therapy. Although papers on IgG4-related diseases have reported abnormal findings in the pleura [2–4], we were able to confirm a definitive diagnosis of pleuritis associated with IgG4-related disease by performing random biopsies of the pleura using thoracoscope. IgG4-related disease is a chronic inflammatory condition characterized by mass or hypertrophic lesion infiltration with lymphocytes and IgG4-secreting plasma cells with various degrees of fibrosis. The clinical diagnostic criteria for IgG4-related disease states: (1) clinical examination showing characteristic diffuse/localized swelling or masses in single/multiple organs; (2) hematological examination of elevated serum IgG4 concentrations (> 135 mg/dL); (3) histopathologic examination showing (a) marked lymphocyte and plasmacyte infiltration and fibrosis and (b) infiltration of IgG4-positive plasma cells: ratio of IgG4-positive/IgG positive cells > 40% and > 10 IgG4-positive plasma cells/HPF [5]. This present case satisfied all of the aforementioned criteria.\n\nAdditionally, the diagnostic criteria for IgG4-related respiratory disease were proposed as follows: (1) abnormal shadow on chest CT; (2) serum IgG4 level of > 135 mg/dL; (3) histopathologic features fulfilling the comprehensive diagnostic criteria; (4) presence of extrathoracic lesions [6]. IgG4-related diseases can cause interstitial pneumonia, inflammatory nodules, and airway inflammation, but pleuritis is uncommon.\n\nPleural effusion for heart and renal failures is often due to systemic diseases associated with leakage or bilateral pleural effusion. Pleural effusion due to IgG4-related disease is expected to be exudative pleural effusion due to inflammation and can take the form of either unilateral or bilateral pleural effusion patterns. Pleural effusion in pleuritis associated with IgG4-related disease has been reported to be lymphocyte-dominated exudative pleural effusion with high ADA [7]. To date, lymphocyte-dominated exudative pleural effusion with a high level of ADA has been considered an indication of tuberculous pleuritis. A report on ADA [8] showed a sensitivity of 100% and a specificity of 93.9% for tuberculous pleuritis if the cut-off value of ADA was set for 40.3 U/L, after which, many studies have shown the diagnostic accuracy of tuberculous pleuritis to be high [9, 10]. To diagnose tuberculous pleuritis, it is important to confirm by mycobacterium culture and TB-PCR. Other diagnostic tools are cell fractionation of the pleural fluid, pleural fluid ADA activity, QuantiFERON TB-2G (QFT-2G; Cellestis Ltd., Carnegie, Victoria, Australia), and purified protein derivative (PPD) reaction.\n\nHowever, Miyoshi et al. reported that only 1 of 32 cases of tuberculous pleuritis had a positive pleural fluid culture, and it is thought that the diagnosis based on pleural fluid examination alone is extremely difficult. Pleural biopsy, which was performed in this case, is said to be useful for diagnosis and has superior sensitivity and specificity compared to pleural fluid examination [11]. In tuberculous pleuritis, pleural gross findings often show nodular lesions and pleural thickening, and pathology proves butyric granulomas. Tuberculous pleuritis was considered negative since this case showed elevated ADA but no evidence of mycobacterium tuberculosis on pleural fluid culture or pleural biopsy sample, and the gross findings of pleura were normal. Pathology did not reveal butyric granulomas, and her TB-PCR was negative.\n\nOn the other hand, exudative pleural effusion with high ADA and lymphocyte-dominated pleural effusion is not a finding specific to tuberculous pleuritis since it is also found in primary effusion lymphoma, leukemia, pyothorax, rheumatic disease, and pleural effusion associated with malignant pleural mesothelioma. It has been reported that thoracoscopic pleural biopsy can provide a definitive diagnosis 90% of the time [12, 13]. Therefore, for our case, a diagnosis of pleuritis associated IgG4-related disease obtained from pleural biopsy is considered quite accurate.\n\nThus far, three patterns of thoracoscopic findings have been described for IgG4-associated pleuritis: (1) milky pleural plaques suggestive of hyalinized collagen fiber deposits; (2) diffuse inflammatory thickening of the pleura; (3) nodules on the parietal pleura [2]. In each of these cases, pleural biopsies showed an infiltration of IgG4-positive cells. However, in our case, the thoracoscopic findings were normal, but random biopsies led to a definitive diagnosis. Pleural biopsy is considered useful for diagnosis and should be performed even when thoracoscopic findings of the pleura appear normal.\n\nConclusions\n\nAlthough thoracoscopic findings of the pleura appeared normal in this case, we performed random pleural biopsies to confirm a diagnosis of pleuritis associated with IgG4-related disease. We suggest that thoracoscopic pleural biopsy should be considered even when pleural findings on thoracoscopy appear normal.\n\nAbbreviations\n\nIgG4 Immunoglobulin G4\n\nIgG Immunoglobulin G\n\nCT Computed tomography\n\nADA Adenosine deaminase\n\nFDG 2-Deoxy-2-[18F]-fluoro-d-glucose\n\nPET Positron emission tomography\n\nHPF High power field\n\nTB-PCR Polymerase chain reaction for Mycobacterium tuberculosis\n\nQFT-2G QuantiFERON TB-2G\n\nPPD Purified protein derivative\n\nAcknowledgements\n\nWe would like to thank our patient and her family.\n\nAuthors’ contributions\n\nThe manuscript was prepared by HS under the supervision of YK and MO. Pleural biopsy was performed by HS, YK and NT. Immunostaining was performed by AY. All authors read and approved the final manuscript.\n\nFunding\n\nThe authors declare that this study was not funded.\n\nAvailability data and materials\n\nThe authors declare that the data supporting the findings of this case report are available within the article and its additional information files.\n\nEthics approval and consent to participate\n\nThe Ethics Committee at Hirakata Kohsai Hospital waived the need for approval.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Stone JH Khosroshahi A Deshpande V Chan JKC Heathcote JG Aalberse R Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations Arthritis Rheum 2012 64 10 3061 3067 10.1002/art.34593 22736240\n2. Yasokawa N Shirai R Tanaka H Kurose K Oga T Oka M Thoracoscopic findings in IgG4-related pleuritis. The Japanese Society of Internal Medicine Intern Med 2020 59 2 257 260 10.2169/internalmedicine.3031-19 31554752\n3. Tong X Bai M Wang W Han Q Tian P Fan H IgG4-related disease involving polyserous effusions with elevated serum interleukin-6 levels: a case report and literature review Immunol Res 2017 65 4 944 950 10.1007/s12026-017-8934-y 28710703\n4. Ramponi S Gnetti L Marvisi M Lung manifestations of IgG4- related disease. A multifaceted disorder Sarcoidosis Vasc Diff 2018 35 1 74 80\n5. Umehara H Okazaki K Masaki Y Kawano M Yamamoto M Saeki T Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011 Mod Rheumatol 2012 22 1 21 30 10.3109/s10165-011-0571-z 22218969\n6. Matsui S Yamamoto H Minamoto S Waseda Y Mishima M Kubo K Proposed diagnostic criteria for IgG4 related respiratory disease Respir Investig 2016 54 2 130 132 10.1016/j.resinv.2015.09.002\n7. Nagayasu A Kubo S Nakano K Nakayamada S IgG4-related pleuritis with elevated adenosine deaminase in pleural effusion Intern Med 2018 57 15 2251 2257 10.2169/internalmedicine.0387-17 29526951\n8. Krenke R Safianowska A Paplinska M Krenke R Pleural fluid adenosine deaminase and interferon gamma as diagnostic tools in tuberculosis pleurisy J Physiol Pharmacol 2008 59 Suppl 6 349 360 19218659\n9. Ocana I Martinez-Vazquez JM Segura RM Fernandez-De-Sevilla T Capdevila JA Adenosine deaminase in pleural fluids. Test for diagnosis of tuberculous pleural effusion Chest 1983 84 1 51 53 10.1378/chest.84.1.51 6602695\n10. Valdes L Alvarez D San Jose E Tuberculous pleurisy: a study of 254 patients Arch Intern Med 1998 158 18 2017 2021 10.1001/archinte.158.18.2017 9778201\n11. Miyoshi M Fukushima F Takizawa H Usefulness of thoracoscopy under local anesthesia in tuberculous pleuritis Dokkyo J Med Sci 2012 39 3 193 199\n12. Blanc F Atassi K Bignon J Diagnostic value of medical thoracoscopy in pleural disease: a 6-year retrospective study Chest 2002 121 5 1677 1683 10.1378/chest.121.5.1677 12006460\n13. Sugiyama M Horiguchi T Ishibashi A Clinical utility and safety of diagnostic thoracoscopy Ann Jpn Respir Soc 2001 39 12 899 902\n\n",
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"keywords": "IgG4-related disease; Medical thoracoscopy; Pleuritis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D000077733:Immunoglobulin G4-Related Disease; D010994:Pleura; D010996:Pleural Effusion; D010998:Pleurisy; D014396:Tuberculosis, Pleural",
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"pubdate": "2021-04-30",
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"title": "Pleuritis associated with immunoglobulin G4-related disease under normal thoracoscopic findings: a case report.",
"title_normalized": "pleuritis associated with immunoglobulin g4 related disease under normal thoracoscopic findings a case report"
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"abstract": "In atypical hemolytic-uremic syndrome (aHUS), various defects of the complement system have been reported to explain pathophysiology. Therapeutic options for complement inhibition are well-recognized; however, the links between various immune-derived diseases and aHUS are unclear, and their interference with treatment efficacy during long-term complement-blocking therapy is scarcely known.\n\n\n\nWe present a pediatric patient who developed aHUS with acute kidney injury in parallel with the onset of Crohn's disease (CD), and who required long-term complement-blocking therapy with eculizumab (ECU). Unexpectedly, during the 6-year ECU treatment, an important intra-patient variation of the degree of complement inhibition was observed. In spite of continuous and stable doses of complement-blocking therapy, periods of incomplete blockade were observed in strong association with relapses of CD. When conventional and later biological therapy with adalimumab was introduced, with CD going into remission, complement blockade became complete again. Despite periodically low ECU levels and insufficient complement inhibition, no clinical or hematological signs of aHUS recurrence were detected during CD relapses.\n\n\n\nIn aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.",
"affiliations": "First Department of Pediatrics, Semmelweis University, HU, 1083, Budapest, Hungary.;First Department of Pediatrics, Semmelweis University, HU, 1083, Budapest, Hungary.;Research Laboratory, Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary.;First Department of Pediatrics, Semmelweis University, HU, 1083, Budapest, Hungary.;First Department of Pediatrics, Semmelweis University, HU, 1083, Budapest, Hungary.;First Department of Pediatrics, Semmelweis University, HU, 1083, Budapest, Hungary. reusz.gyorgy@med.semmelweis-univ.hu.",
"authors": "Horváth|Orsolya|O|0000-0002-3812-2711;Kelen|Kata|K|0000-0002-1011-1746;Prohászka|Zoltán|Z|0000-0003-1761-7982;Hosszú|Ádám|Á|0000-0002-8415-5637;Szabó|Attila J|AJ|0000-0001-7321-9861;Reusz|George S|GS|",
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"fulltext": "\n==== Front\nPediatr Nephrol\nPediatr Nephrol\nPediatric Nephrology (Berlin, Germany)\n0931-041X\n1432-198X\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n34328541\n5167\n10.1007/s00467-021-05167-9\nBrief Report\nAtypical HUS and Crohn’s disease—interference of intestinal disease activity with complement-blocking treatment\nhttps://orcid.org/0000-0002-3812-2711\nHorváth Orsolya 12\nhttps://orcid.org/0000-0002-1011-1746\nKelen Kata 1\nhttps://orcid.org/0000-0003-1761-7982\nProhászka Zoltán 3\nhttps://orcid.org/0000-0002-8415-5637\nHosszú Ádám 1\nhttps://orcid.org/0000-0001-7321-9861\nSzabó Attila J 1\nReusz George S reusz.gyorgy@med.semmelweis-univ.hu\n\n1\n1 grid.11804.3c 0000 0001 0942 9821 First Department of Pediatrics, Semmelweis University, HU 1083 Budapest, Hungary\n2 Pediatric Hematology and Stem Cell Transplantation Unit, Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, Budapest, Hungary\n3 grid.11804.3c 0000 0001 0942 9821 Research Laboratory, Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary\n30 7 2021\n30 7 2021\n2021\n36 10 32773280\n17 3 2021\n26 5 2021\n2 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This 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\nIn atypical hemolytic-uremic syndrome (aHUS), various defects of the complement system have been reported to explain pathophysiology. Therapeutic options for complement inhibition are well-recognized; however, the links between various immune-derived diseases and aHUS are unclear, and their interference with treatment efficacy during long-term complement-blocking therapy is scarcely known.\n\nCase-diagnosis/treatment\n\nWe present a pediatric patient who developed aHUS with acute kidney injury in parallel with the onset of Crohn’s disease (CD), and who required long-term complement-blocking therapy with eculizumab (ECU). Unexpectedly, during the 6-year ECU treatment, an important intra-patient variation of the degree of complement inhibition was observed. In spite of continuous and stable doses of complement-blocking therapy, periods of incomplete blockade were observed in strong association with relapses of CD. When conventional and later biological therapy with adalimumab was introduced, with CD going into remission, complement blockade became complete again. Despite periodically low ECU levels and insufficient complement inhibition, no clinical or hematological signs of aHUS recurrence were detected during CD relapses.\n\nConclusion\n\nIn aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.\n\nKeywords\n\nHemolytic-uremic syndrome (HUS)\nThrombotic microangiopathy (TMA)\nInflammatory bowel disease (IBD)\nCrohn’s disease (CD)\nTreatment\nhttp://dx.doi.org/10.13039/100003989 National Kidney Foundation of Iowa 124549 issue-copyright-statement© IPNA 2021\n==== Body\npmcIntroduction\n\nAtypical hemolytic-uremic syndrome (aHUS) is a severe condition. Early and appropriate diagnosis and treatment are needed to avoid chronic kidney injury [1]. Patients with a genetic susceptibility to aHUS are prone to thrombotic microangiopathy (TMA) recurrences and may require lifelong complement inhibition therapy [2]. Although various defects in the complement system explaining pathophysiology have been described, and therapeutic options for complement inhibition are well-recognized [3–6], the links between various immune-derived diseases and aHUS are unclear. We report a pediatric case in which the patient developed TMA during the first manifestations of Crohn’s disease (CD).\n\nCase report\n\nThe patient’s story\n\nHere we report the case of a girl followed between the ages of 13 and 18 years with CD and aHUS. The patient was born after an uneventful twin pregnancy. Her twin brother has severe CD with complications necessitating repeated surgery for abdominal abscesses and fistulas. The first symptoms in our patient started in 2014 at the age of 13 with recurrent diarrhea, mucus in the stool, weight loss, and anemia. Initial laboratory data suggested CD (no pathogens in the stool culture, stool calprotectin, and anti-Saccharomyces cerevisiae antibodies (ASCA) IgG were elevated (> 900 microgram/g and 149 U/L, respectively)). The parents did not agree to performing an endoscopy at this stage.\n\nIn parallel, the patient had anemia, normal thrombocytes, proteinuria—reaching nephrotic range—and hematuria, while serum creatinine started to increase rapidly (223 micromole/L). Abdominal ultrasound showed enlarged hyperechogenic kidneys. Kidney biopsy was performed. Two days after the kidney biopsy, the complete clinical picture of aHUS developed with thrombocytopenia, hemolytic anemia, low haptoglobin levels, acute kidney impairment (serum creatinine 263 micromole/L), and high lactate dehydrogenase levels. Indeed, kidney histology confirmed the presence of thrombotic microangiopathy.\n\nAfter Enterohemorrhagic E. coli (EHEC)–induced HUS diagnosis was ruled out, complement and genetic diagnostics were performed to establish the etiology of aHUS. Treatment of TMA was urgent due to rapidly decreasing kidney function (estimated glomerular filtration rate 23 mL/min/m2) and low thrombocyte levels before any knowledge of the patient’s genetic background. Transfusions of fresh frozen plasma (FFP, 18 times), therapeutic plasma exchange sessions (4 times), and intravenous steroid shots (250 mg each, 3 times) were performed to eliminate eventual anti-factor H antibodies.\n\nHemolysis was stopped before the initial treatment, and hematological response was reached; however, proteinuria, hematuria persisted, and serum creatinine remained high. To avoid chronic kidney failure, complement-blocking therapy was urgent. Six weeks after the diagnosis of aHUS, complement blockade with eculizumab (ECU) became available and was started with an initial dose of 900 mg (for her weight of 38 kg).\n\nComplement measurements (all pathway activities, complement activation products, and ADAMTS13 (a distintegrin and metalloprotease with thrombospondin-1-like domains, member 13)) were performed. Total classical (CH50, sheep red blood cell hemolytic titration, reference range: 48–103 CH50/mL) and alternative pathway (ALT, Wieslab Comp AP330 kit, 70-125%, Euro Diagnostica, Malmö, Sweden) activities and free serum ECU (in-house enzyme-linked immunosorbent assay from 2016 onward) levels were performed systematically directly before starting ECU infusion every 2 weeks. Fully suppressed CH50 and ALT activities were defined as an activity below 10%. Serum ECU concentrations of 50–100 microgram/mL were considered to achieve complete complement blockade [7].\n\nSigns of effective complement blockade were detected without delay. Classical and alternative pathway activities were depleted. Low C3 and C4 levels, as signs of severe complement consumption, normalized (to 1.1 mg/L and 0.56 mg/L, respectively). Lower ADAMTS13 activity values (54–77%), as a sign of secondary endothelial damage [8], returned to normal (99–111%). ECU treatment was continued and a satisfying nephrological response was reached; creatinine returned to normal, and proteinuria decreased gradually to the normal range. Other, supportive aHUS therapies (PE, FFP) were stopped.\n\nA thorough genetic study of the complement system was performed and revealed the presence of a previously undescribed “likely pathogenic” factor I variant (R339L). In silico prediction of variant pathogenicity was assessed, showing that the serine protease domain of human complement factor I was affected. In addition, CFH tgtgt and MCP ggaac aHUS risk haplotypes were detected. The twin brother carries the same factor I variant (R339L), the CFH tgtgt and MCP ggaac risk haplotypes. The mother bears the same CFI mutation and the MCP ggaac risk haplotype and is heterozygous for the CFH tgtgt risk haplotype. Family history was negative for aHUS despite this genetic background.\n\nEmerging problems\n\nECU therapy was started in 2014 and was continued systematically every 2 weeks during the entire study period. Maintenance ECU was initially 900 mg (every 2 weeks). Unexpectedly, a remarkable intra-patient variation of complement inhibition was observed. In spite of continuous complement-blocking therapy, peaks of complement pathway activities (CH50, ALT) were observed, the blockade was incomplete, and a strong association with the recurrence of bowel symptoms was found. In response, first the ECU dose was increased (to 1200 mg every 2 weeks, as the patient’s weight meanwhile had increased to 42 kg) assuming that the patient needed a higher dose due to weight gain. However, complement blockade was reduced even at higher doses during CD relapse. An ileum biopsy performed in April 2016 showed the typical histological picture of CD. Conventional treatment for CD (steroids, local steroids, and azathioprine) was started, with a rapid remission of CD. Non-compliance with conventional therapy resulted in CD recurrence in October 2017, coupled with the development of a perianal fistula. Biological treatment with adalimumab, a fully human, high-affinity, recombinant anti-tumor necrosis factor alpha monoclonal antibody [9], was introduced, which resulted in the remission of CD.\n\nFigure 1 shows the variation of complement activity with time (on day 14 after administering the prescribed dose and before the next dose) as a function of the course of intestinal disease. While CD was in remission, complete complement blockade was achieved, and CH50 and ALT pathway activities were below 10%. However, during CD recurrence, the efficacy of complement blockade decreased dramatically. Fig. 1 Complement classical and alternative pathway activities (from 2014 to 2020) and free eculizumab levels (from 2016 to 2020) (measured on day 14 after ECU infusion) during atypical hemolytic-uremic syndrome and Crohn’s disease treatment. Complete complement blockade is observed only during eculizumab and adalimumab therapy. Legend: aHUS, atypical hemolytic-uremic syndrome; ALT, alternative pathway activity; CH50, classical pathway activity; CD, Crohn’s disease; ECU, eculizumab; S ECU, serum free eculizumab level\n\nTo determine the cause of this intra-patient variability, other potential factors were analyzed. Proteinuria had not been detected since 2015, and intestinal bleeding was not significant. Free ECU serum levels were analyzed shortly before the next ECU dose from 2016 onward. Serum levels decreased to subtherapeutic concentrations (< 8–10 microgram/mL) despite regular dosing. As shown in Fig. 1, with stable doses of ECU (1200 mg every 2 weeks), therapeutic levels (> 50 microgram/mL) were reached shortly after the start of adalimumab therapy. Despite low ECU levels and incomplete complement inhibition, no clinical or hematological signs of TMA activity were observed during the recurrence of CD. The patient’s weight was stable (between 50 and 55 kg) from the age of 16. The patient remained in hematologic and renal remission throughout the study period. C3 (median (1.2 mg/L (IQR 0.99–1.37)), C4 (0.4 mg/L (IQR 0.28–0.45)), and ADAMTS13 activity (median 101% (IQR 91–115%)) values were within the normal range from the start of ECU therapy.\n\nDiscussion\n\nThis is a case of a pediatric patient who developed aHUS with acute kidney injury during an episode of CD, requiring long-term complement-blocking therapy. During long-term ECU treatment, a considerable intra-patient variability in the degree of complement blockade was observed along with incidents of CD. The ECU doses were adjusted for weight as recommended, but were too low for the patient with an ongoing inflammatory intestinal disease. Relapses and remissions induced characteristic fluctuations in the efficacy of complement blockade, with apparent ECU consumption during CD incidents. The temporary decrease in the effectiveness of the blockade was not associated with the return of the aHUS.\n\nECU is a humanized monoclonal antibody against complement C5 [1, 4]. A number of factors have been identified that can affect ECU clearance during long-term therapy, including substantial change in body weight, variable serum C5 levels during infections, or loss by proteinuria [10, 11]. In this case, the reason for decreased ECU activity is not clear. Possible explanations include local inflammation in the gut or intestinal ECU loss.\n\nIn addition, our patient had the same genetic background as her twin brother, both patients had CD, but only the girl developed aHUS. How far the likely pathogenic CFI variant had a role in the occurrence of aHUS in our patient with CD and in the remission of aHUS under ECU is uncertain.\n\nTo our knowledge, five aHUS cases associated with inflammatory bowel disease have been published in the literature [12–15]. Importantly, CD and colitis ulcerosa cases were also described with aHUS cases [12–15]. All five cases were treated with ECU successfully. To our knowledge, however, simultaneous serum-free ECU levels, CH50 and ALT activities, are described for the first time in our case. In two published cases considered secondary TMA, an attempt was made to stop ECU therapy. One patient had a simultaneous recurrence of aHUS and CD after discontinuation of ECU [12], and UC relapsed in another case after stopping ECU [14]. The pathomechanism of inflammatory bowel disease may hypothetically be analogous with stem cell transplantation–associated TMA with acute graft-versus-host disease. Higher and frequent doses of ECU are needed to resolve this secondary form of TMA; patients with intestinal involvement have the fastest ECU clearance [16]. Further studies are needed to clarify the mechanism of ECU consumption in the gut and the role of concurrent immune-mediated diseases during long-term complement-blocking therapy.\n\nIn conclusion, Crohn’s disease can be one of the possible causes of secondary aHUS in children. In aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.\n\nAcknowledgements\n\nThe authors thank Áron Cseh, gastroenterologist (First Department of Pediatrics, Semmelweis University) and Attila Fintha, pathologist (First Department of Pathology, Semmelweis University) for their parts in patient care.\n\nAvailability of data and material\n\nNot applicable.\n\nCode availability\n\nNot applicable.\n\nFunding\n\nOpen access funding provided by Semmelweis University. GSR was supported by NKFI grant 124549.\n\nDeclarations\n\nConflict of interest\n\nThe authors declare no competing interests.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nOrsolya Horváth and Kata Kelen contributed equally to this work.\n==== Refs\nReferences\n\n1. Schmidtko J Peine S El-Housseini Y Pascual M Meier P Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab Am J Kidney Dis 2013 61 289 299 10.1053/j.ajkd.2012.07.028 23141475\n2. Menne J Delmas Y Fakhouri F Licht C Lommelé Å Minetti EE Provôt F Rondeau E Sheerin NS Wang J Weekers LE Greenbaum LA Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study BMC Nephrol 2019 20 125 10.1186/s12882-019-1314-1 30971227\n3. Kavanagh D Goodship T Genetics and complement in atypical HUS Pediatr Nephrol 2010 25 2431 2442 10.1007/s00467-010-1555-5 20526633\n4. Licht C Greenbaum LA Muus P Babu S Bedrosian CL Cohen DJ Delmas Y Douglas K Furman RR Gaber OA Goodship T Herthelius M Hourmant M Legendre CM Remuzzi G Sheerin N Trivelli A Loirat C Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies Kidney Int 2015 87 1061 1073 10.1038/ki.2014.423 25651368\n5. Vilalta R Lara E Madrid A Chocron S Muñoz M Casquero A Nieto J Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome Pediatr Nephrol 2012 27 2323 2326 10.1007/s00467-012-2276-8 22890512\n6. Zhang T Lu J Liang S Chen D Zhang H Zeng C Liu Z Chen H Comprehensive analysis of complement genes in patients with atypical hemolytic uremic syndrome Am J Nephrol 2016 43 160 169 10.1159/000445127 27064621\n7. Sweep F Brüggemann RJ Wetzels J van de Kar N van den Heuvel L Eculizumab dosing regimen in atypical HUS: possibilities for individualized treatment Clin Pharmacol Ther 2017 102 671 678 10.1002/cpt.686 28295239\n8. Farkas P Csuka D Mikes B Sinkovits G Réti M Németh E Rácz K Madách K Gergely M Demeter J Prohászka Z Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies Immunobiology 2017 222 119 127 10.1016/j.imbio.2016.10.014 27771173\n9. Hyams JS Griffiths A Markowitz J Baldassano RN Faubion WA Jr Colletti RB Dubinsky M Kierkus J Rosh J Wang Y Huang B Bittle B Marshall M Lazar A Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children Gastroenterology 2012 143 365 374 10.1053/j.gastro.2012.04.046 22562021\n10. Bouwmeester RN Ter Avest M Wijnsma KL Duineveld C Ter Heine R Volokhina EB Van Den Heuvel LPWJ Wetzels JFM van de Kar NCAJ Case report: Variable pharmacokinetic profile of eculizumab in an aHUS patient Front Immunol 2021 11 612706 10.3389/fimmu.2020.612706 33519821\n11. Wijnsma KL Ter Heine R Moes DJAR Langemeijer S Schols SEM Volokhina EB van den Heuvel LP Wetzels JFM van de Kar NCAJ Brüggemann RJ Pharmacology, pharmacokinetics and pharmacodynamics of eculizumab, and possibilities for an individualized approach to eculizumab Clin Pharmacokinet 2019 58 859 874 10.1007/s40262-019-00742-8 30758736\n12. Hanna RM Merin N Burwick RM Abdelnour L Selamet U Yanny B Bui P Fouad M Kurtz I Successful use of eculizumab to treat atypical hemolytic uremic syndrome in patients with inflammatory bowel disease Thromb J 2019 17 18 10.1186/s12959-019-0207-7 31516395\n13. Green H Harari E Davidovits M Blickstein D Grossman A Gafter U Gafter-Gvili A Atypical HUS due to factor H antibodies in an adult patient successfully treated with eculizumab Ren Fail 2014 36 1119 1121 10.3109/0886022X.2014.917574 24828571\n14. Øzbay LA Eculizumab treatment of thrombotic microangiopathy in a patient with ulcerative colitis Clin J Gastroenterol 2020 13 344 348 10.1007/s12328-019-01052-z 31612381\n15. Webb TN Griffiths H Miyashita Y Bhatt R Jaffe R Moritz M Hofer J Swiatecka-Urban A Atypical hemolytic uremic syndrome and chronic ulcerative colitis treated with eculizumab Int J Med Pharm Case Reports 2015 4 105 112 10.9734/IJMPCR/2015/18771 27135055\n16. Jodele S Dandoy CE Lane A Laskin BL Teusink-Cross A Myers KC Wallace G Nelson A Bleesing J Chima RS Hirsch R Ryan TD Benoit S Mizuno K Warren M Davies SM Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab Blood 2020 135 1049 1057 10.1182/blood.2019004218 31932840\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0931-041X",
"issue": "36(10)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Crohn’s disease (CD); Hemolytic-uremic syndrome (HUS); Inflammatory bowel disease (IBD); Thrombotic microangiopathy (TMA); Treatment",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "3277-3280",
"pmc": null,
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"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Atypical HUS and Crohn's disease-interference of intestinal disease activity with complement-blocking treatment.",
"title_normalized": "atypical hus and crohn s disease interference of intestinal disease activity with complement blocking treatment"
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"abstract": "OBJECTIVE\nTo determine if aerosol granulocyte macrophage-colony-stimulating factor (GM-CSF) decreases the 2-year pulmonary metastasis rate for soft tissue sarcoma.\n\n\nMETHODS\nPatients with high-grade soft tissue sarcomas were treated with 2 cycles of ifosfamide, mitomycin, doxorubicin, and cisplatin plus GM-CSF subcutaneous followed by 45 Gy irradiation with concurrent 2 cycles of mitomycin, doxorubicin, and cisplatin followed by surgery +/- intraoperative radiation or brachytherapy. Aerosol GM-CSF (250 mcg twice a day) was administered for 1 week every other week 3× during neoadjuvant therapy and beginning 4 weeks postoperatively every other week 5×.\n\n\nRESULTS\nA total of 39 patients were enrolled between November 2001 and April 2006. The median age was 51 years (range, 19 to 65 y). The median lesion size was 9 cm (range, 2.3 to 26.7 cm). Seventy-six percent experienced grade 3-4 hematologic toxicity. Twenty-four of the first 35 evaluable patients (69%; 95% CI, 41%-84%) were free of pulmonary metastasis at 2 years. A total of 82% (95% CI, 70%-95%) of patients were still alive after 3 years, with a median follow-up of 5.5 years (range, 3.4 to 7.6 y). A total of 58% (95% CI, 44%-76%) of patients remained progression free after 3 years.\n\n\nCONCLUSIONS\nThe addition of aerosol GM-CSF to combined chemotherapy, irradiation, and surgery for soft tissue sarcomas did not achieve the study endpoint to decrease the 2-year pulmonary metastasis rate.",
"affiliations": "Departments of *Oncology †Radiation Oncology ‡Orthopedics §Biostatistics ∥Division of Hematology/Oncology, Mayo Clinic, Rochester, MN.",
"authors": "Okuno|Scott|S|;Petersen|Ivy|I|;Shives|Thomas|T|;Mahoney|Michelle|M|;Haddock|Michael|M|;Sim|Franklin|F|;O'Connor|Mary I|MI|;Markovic|Svetomir N|SN|;Maples|William|W|",
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"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003131:Combined Modality Therapy; D004317:Doxorubicin; D005121:Extremities; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D011184:Postoperative Period; D011878:Radiotherapy; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D055815:Young Adult",
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"references": "18521899;12095968;15542808;15852434;15310783;11230464;12871055;20572040;11857314;12103287;9400508;19351756;10499599;16446327;14528078;10655437;16446334;11432887;11230463;16107623;15578712",
"title": "Chemotherapy, Irradiation, and Surgery for Function-preserving Curative Therapy of Primary Extremity Soft Tissue Sarcomas: Initial Treatment With I-MAP and Inhalation GM-CSF During Preoperative Irradiation and Postoperatively.",
"title_normalized": "chemotherapy irradiation and surgery for function preserving curative therapy of primary extremity soft tissue sarcomas initial treatment with i map and inhalation gm csf during preoperative irradiation and postoperatively"
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"abstract": "BACKGROUND\nThere is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs).\n\n\nMETHODS\nWe conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL.\n\n\nRESULTS\nWith a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis.\n\n\nCONCLUSIONS\nMonthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).",
"affiliations": "Department of Hematology and Oncology.;Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences.;Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine.;Department of Hematology, National Cancer Center Hospital, Tokyo.;Department of Internal Medicine, Sapporo Hokuyu Hospital.;Department of Medical Oncology, Kanagawa Cancer Center, Yokohama.;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Saga University.;Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University.;Department of Hematology, Sasebo City General Hospital.;Divisions of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa.;Department of Hematology and Infectious Diseases, Kumamoto University School of Medicine.;Division of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka.;Department of Hematology and Oncology, Anjo Kosei Hospital.;Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Division of Hematology-Oncology, Chiba Cancer Center.;Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital.;Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo.;Department of Hematology and Medical Oncology, Fujita Health University School of Medicine, Toyoake.;Department of Oncology/Hematology, Shimane University Hospital, Izumo.;Division of Hematology and Oncology, Toyohashi Municipal Hospital.;Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai.;Department of Hematology, International Medical Center, Saitama Medical University, Hidaka.;Department of Hematology, National Hospital Organization Nagasaki Medical Center, Ohmura.;Department of Hematology, Yokohama City University Medical Center.;Department of Hematology and Oncology, Tokai University School of Medicine, Isehara.;Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine.;Department of Hematology and Oncology, Nagoya University Graduate School of Medicine.;Department of Hematology, National Cancer Center Hospital, Tokyo.;Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine.;Department of Medicine, Shinshu University School of Medicine, Matsumoto.;Department of Hematology and Oncology, Shiga Medical Center for Adults, Moriyama.;Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya.;Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital.;The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa.;Department of Tumor Immunology, Aichi Medical University School of Medicine, Japan.",
"authors": "Kusumoto|Shigeru|S|;Tanaka|Yasuhito|Y|;Suzuki|Ritsuro|R|;Watanabe|Takashi|T|;Nakata|Masanobu|M|;Takasaki|Hirotaka|H|;Fukushima|Noriyasu|N|;Fukushima|Takuya|T|;Moriuchi|Yukiyoshi|Y|;Itoh|Kuniaki|K|;Nosaka|Kisato|K|;Choi|Ilseung|I|;Sawa|Masashi|M|;Okamoto|Rumiko|R|;Tsujimura|Hideki|H|;Uchida|Toshiki|T|;Suzuki|Sachiko|S|;Okamoto|Masataka|M|;Takahashi|Tsutomu|T|;Sugiura|Isamu|I|;Onishi|Yasushi|Y|;Kohri|Mika|M|;Yoshida|Shinichiro|S|;Sakai|Rika|R|;Kojima|Minoru|M|;Takahashi|Hiroyuki|H|;Tomita|Akihiro|A|;Maruyama|Dai|D|;Atsuta|Yoshiko|Y|;Tanaka|Eiji|E|;Suzuki|Takayo|T|;Kinoshita|Tomohiro|T|;Ogura|Michinori|M|;Mizokami|Masashi|M|;Ueda|Ryuzo|R|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/civ344",
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"issn_linking": "1058-4838",
"issue": "61(5)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HBV DNA monitoring; HBV reactivation; preemptive antiviral therapy; resolved HBV infection; rituximab",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004279:DNA, Viral; D005260:Female; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
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"pages": "719-29",
"pmc": null,
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"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study.",
"title_normalized": "monitoring of hepatitis b virus hbv dna and risk of hbv reactivation in b cell lymphoma a prospective observational study"
} | [
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"companynumb": "JP-JNJFOC-20151005457",
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"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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{
"abstract": "Transthyretin amyloidosis is a multisystemic disease caused by the aggregation of amyloid fibrils, resulting in high morbidity and mortality in the presence of cardiac involvement. Patients often experience vague symptoms that make amyloidosis difficult to diagnose. Differential diagnosis for hand pain in a patient with systemic amyloidosis is broad. We present a patient with severe hand cramping and inability to perform activities of daily living. This preceded a new diagnosis of familial amyloid cardiomyopathy. The patient was a poor responder to systemic corticosteroids, anti-inflammatories and anticonvulsant therapy. Her unique presentation gives insight into a rare but debilitating disorder and the potential link between amyloidosis and other disease processes.",
"affiliations": "Rheumatology, Montefiore Hospital and Medical Center, Bronx, New York, USA snehap721@gmail.com.;Internal Medicine, Monmouth Medical Center, Long Branch, New Jersey, USA.;Pathology, Montefiore Hospital and Medical Center, Bronx, New York, USA.;Rheumatology, Montefiore Hospital and Medical Center, Bronx, New York, USA.",
"authors": "Patel|Sneha N|SN|http://orcid.org/0000-0001-6702-3352;Koyoda|Sai Krishna|SK|;Schwartz|Daniel|D|;Ayesha|Bibi|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229677",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "arrhythmias; heart failure; musculoskeletal syndromes; peripheral nerve disease; rheumatology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D028227:Amyloid Neuropathies, Familial; D002318:Cardiovascular Diseases; D005260:Female; D006225:Hand; D006801:Humans; D009120:Muscle Cramp; D010146:Pain",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31645392",
"pubdate": "2019-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27386770;3039062;25940564;27568874;20462364;19075702;9042284;27386769;30145929;3893430;18295611;29187090;12136908;24286442;23040361;25604431;8110786;10924339;11373684;23984729;6824506;14724437;20660862;22471980;17968927;10908156;9486653;3740997;20848114",
"title": "Severe hand pain as an extracardiac manifestation of transthyretin amyloidosis.",
"title_normalized": "severe hand pain as an extracardiac manifestation of transthyretin amyloidosis"
} | [
{
"companynumb": "NVSC2019US053676",
"fulfillexpeditecriteria": "2",
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"activesubstancename": "PREDNISONE"
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"abstract": "The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and its high virulence along with its variable presentation have generated a significant amount of interest within the medical community. The heterogeneous nature of the symptoms of the disease caused by SARS-CoV-2, coronavirus disease 2019 (COVID-19), ranging from being asymptomatic to severe acute respiratory distress syndrome (ARDS), has created significant interest in potential therapeutics. Given the lack of randomized controlled trials, most medications are experimental, and only anecdotal evidence is available so far regarding their efficacy. One medication that emerged as an early frontrunner as a promising therapeutic was hydroxychloroquine (HCQ), a common antimalarial and lupus drug. The adverse side effects that could result from its use did not gain much attention initially. We present the cases of two COVID-19-positive patients treated with HCQ at our institution, which showed adverse effects of the medication. While HCQ may have some therapeutic effect, it should be borne in mind that patients may experience more harm than benefit from its use.",
"affiliations": "Internal Medicine, Ocala Regional Medical Center/University of Central Florida College of Medicine, Ocala, USA.;Family Medicine, Ocala Regional Medical Center/University of Central Florida College of Medicine, Ocala, USA.;Internal Medicine, Ocala Regional Medical Center/University of Central Florida College of Medicine, Ocala, USA.;Internal Medicine, Ocala Regional Medical Center/University of Central Florida College of Medicine, Ocala, USA.;Internal Medicine, Ocala Regional Medical Center/University of Central Florida College of Medicine, Ocala, USA.",
"authors": "Patel|Jay|J|;Patel|Radhika|R|;Rodriguez|Lyd-Marie|LM|;Blanco|Anamarys|A|;Hamza|Alan|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.9151",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9151\nCardiology\nInternal Medicine\nInfectious Disease\nCardiovascular Considerations of Experimental Hydroxychloroquine Therapy on Patients Diagnosed With COVID-19: A Case Series Review\nMuacevic Alexander Adler John R Patel Jay 1 Patel Radhika 2 Rodriguez Lyd-Marie 1 Blanco Anamarys 1 Hamza Alan 1 \n1 \nInternal Medicine, Ocala Regional Medical Center/University of Central Florida College of Medicine, Ocala, USA \n\n2 \nFamily Medicine, Ocala Regional Medical Center/University of Central Florida College of Medicine, Ocala, USA \n\nJay Patel jay.patel5@hcahealthcare.com\n12 7 2020 \n7 2020 \n12 7 e915118 5 2020 12 7 2020 Copyright © 2020, Patel et al.2020Patel et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/33660-cardiovascular-considerations-of-experimental-hydroxychloroquine-therapy-on-patients-diagnosed-with-covid-19-a-case-series-reviewThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and its high virulence along with its variable presentation have generated a significant amount of interest within the medical community. The heterogeneous nature of the symptoms of the disease caused by SARS-CoV-2, coronavirus disease 2019 (COVID-19), ranging from being asymptomatic to severe acute respiratory distress syndrome (ARDS), has created significant interest in potential therapeutics. Given the lack of randomized controlled trials, most medications are experimental, and only anecdotal evidence is available so far regarding their efficacy. One medication that emerged as an early frontrunner as a promising therapeutic was hydroxychloroquine (HCQ), a common antimalarial and lupus drug. The adverse side effects that could result from its use did not gain much attention initially. We present the cases of two COVID-19-positive patients treated with HCQ at our institution, which showed adverse effects of the medication. While HCQ may have some therapeutic effect, it should be borne in mind that patients may experience more harm than benefit from its use.\n\ncovid 19sars-cov-2prolonged qtbradycardiarisk-benefitThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nThe ongoing coronavirus disease 2019 (COVID-19) pandemic has led to global panic regarding its highly infectious process. In the race to find novel treatment strategies for COVID-19, numerous pharmacological agents are being touted as the silver bullet. The unfortunate reality of the COVID-19 pandemic is that, as providers, we are dealing with a highly virulent, variable, and potentially aggressive pathogen as evidenced by a reported R-naught (R0) of 5.7 [1]. Hydroxychloroquine (HCQ), a common antimalarial and lupus drug, has been shown to potentially reduce viral carriage and the number of symptomatic days in COVID-19 patients according to an open-label non-randomized French case study of 36 patients [2]. However, the findings of a subsequent randomized controlled trial have led to the FDA revoking HCQ's emergency use authorization [3]. The purpose of this case series was to highlight some of the cardiovascular complications related to HCQ and to engage in a risk-benefit analysis of its use in mild/moderate presentations of COVID-19.\n\nCase presentation\nCase 1\n\nA 74-year-old female with a past medical history of coronary artery disease (CAD), chronic obstructive pulmonary disease, and autoimmune hepatitis on tacrolimus presented with a six-day history of fatigue, dry cough, shortness of breath, chest tightness, nausea, vomiting, and diarrhea. Her vitals were stable and the exam demonstrated bilateral decreased breath sounds and wheezing on admission. She was admitted initially for possible community-acquired pneumonia and started on empiric coverage of ceftriaxone and azithromycin (AZM). Ondansetron was also started due to her nausea. On day two of hospitalization, the patient's condition improved symptomatically, but she was subsequently found to be COVID-19- and influenza-B positive. HCQ and Tamiflu® (Roche Pharmaceuticals, Basel, Switzerland) were started while AZM was continued. Labs demonstrated troponin of 0.01 ng/ml (three sets), potassium (K) level of 3.2 mEq/L, magnesium (Mg) level of 1.8 mEq/L, and white blood cell (WBC) count of 3.4 thousand/mm3 at the time of initiation. On the morning of admission, the patient was found to have a QTc of 446 ms (Figure 1A). A chest X-ray demonstrated a left perihilar infiltrate (Figure 1B). Echocardiogram demonstrated left ventricular ejection fraction of 60% and no diastolic dysfunction. Clostridium difficile testing was negative. A repeat EKG on day five of hospitalization demonstrated prolongation of Qtc to 650 ms, and several premature ventricular contractions with R-on-T waves were noted (Figure 1C). She was asymptomatic at this time. HCQ, ondansetron, and AZM were subsequently discontinued. Furthermore, her electrolytes were optimized, specifically with Mg of >2.0 mEq/L and K of >4.0 mEq/L. By hospital day nine, the patient stated that her symptoms had improved. Her QTc was noted to be 458 ms on EKG on the same day (Figure 1D). She made an uneventful recovery and was discharged on hospital day 10.\n\nFigure 1 Case 1 examinations\nA) EKG on admission demonstrating sinus rhythm with occasional PVC (green arrow) and QTc of 446 ms. B) Chest X-Ray demonstrating left-sided (blue arrow) perihilar disease in the left lung field. C) EKG on hospital day five demonstrating prolonged QTc of 650 ms (blue double arrow) and frequent premature ventricular contractions with R-on-T wave phenomenon (red arrows). D) EKG on discharge; QTc at this point was 458 ms, and PVCs had resolved\n\nEKG: electrocardiogram; PVC: premature ventricular contraction\n\nCommentary\n\nThis patient had a moderate presentation of COVID-19 infection. Her case was complicated by co-infection with influenza B, radiographic evidence of perihilar infiltrate, and leukopenia. Given these combined findings, the initial benefit of HCQ seemed superior to the risk given the fear of rapid progression to severe acute respiratory distress syndrome (ARDS). However, after a day of supportive therapy, the patient's condition dramatically improved. It is important to note that her Tisdale score was 13 after HCQ, ondansetron, and AZM administration (high risk for QT prolongation) [4]. She was also having premature ventricular contractions (PVCs) throughout her hospitalization. Especially worrisome were R-on-T waves noted on her telemetry, which could be a forewarning for impending ventricular fibrillation, especially in the setting of acquired long QT and her history of CAD [5]. In this case, the patient’s hospital course was clearly complicated by HCQ in addition to the many QTc-prolonging agents she was prescribed; hence, the overall benefit seemed marginal.\n\nCase 2\n\nA 40-year-old female with no significant medical history presented with a one-day history of nausea, vomiting, and diarrhea. She stated that she had recently returned from Scotland and had begun experiencing symptoms of rhinorrhea starting in late January 2020. She was not tested immediately for COVID-19 due to a lack of fever. She was given a steroid dose-pack and a five-day course of AZM at that time. She improved initially but later relapsed one week prior to admission when she developed symptoms of shortness of breath and mild wheezing. After testing positive for COVID-19, two days prior to admission, her primary care physician started HCQ. While on this medication, she developed nausea, vomiting, and diarrhea within 48 hours and required admission for the administration of intravenous fluids. Her vitals demonstrated a temperature of 36.7 °C and a heart rate of 48 beats per minute (bpm). The exam demonstrated scattered bilateral wheezes and bradycardia. Lab values demonstrated point-of-care (POC) troponin of 0.02 ng/ml, brain natriuretic peptide (BNP) of 231 ng/L, K of 4.0 mEq/L, Mg of 1.8 mEq/L, and WBC of 17.3 thousand/mm3. Clostridium difficile testing was negative. Her EKG (Figure 2) noted marked sinus bradycardia with a ventricular rate of 44 bpm. The patient had no prior history of arrhythmias. It was believed that her symptoms of sudden diarrhea, nausea, and vomiting were secondary to HCQ as was the bradycardia. The medication was discontinued, and her symptoms resolved; her heart rate improved to 60 bpm, and she was uneventfully discharged on no antimicrobial medication.\n\nFigure 2 Case 2 EKG on admission demonstrating marked sinus bradycardia\nEKG: electrocardiogram\n\nCommentary\n\nThis case showed a mild incidence of COVID-19 in a patient who was at low risk for QT prolongation given a Tisdale score of 4. Given the low risk of adverse effects, it initially appeared reasonable that the patient’s primary care provider had started her on HCQ treatment. The marked sinus bradycardia was a worrisome finding that thankfully resolved with discontinuation of the medication. It should be noted that the patient’s baseline EKG was unknown. Providers should consider obtaining a baseline EKG, renal panel, and hepatic panel prior to the administration of HCQ in these patients. This case illustrates the fact that HCQ provided little benefit for such a mild presentation of COVID-19 as in this patient.\n\nDiscussion\nWhile HCQ was demonstrated to be effective in the French study by Gautret et al., it is not a proven treatment modality and it should be used with caution. The above two cases add to the ongoing discussion as to whether HCQ therapy in COVID-19 patients is beneficial for all, especially given how it was paired with another arrhythmogenic agent AZM. We believe these are among the first few cases illustrating adverse cardiovascular effects of the experimental five-day HCQ therapy in mild/moderate presentations of COVID-19.\n\nWhile the safety profile on HCQ is relatively favorable, the drug is a well-known arrhythmogenic medication that can lead to life-threatening ventricular arrhythmias, most commonly recognized as Torsades de Pointes (TdP) [6]. Admittedly, the relationship between QTc prolongation and TdP is not linear; nevertheless, clinicians are well aware of the risks of prolonged QTc. The Tisdale risk stratification scoring system was invented for predicting the risk of QT prolongation [4]. As shown in Table 1 with respect to our patients, the Tisdale score characterizes patients as low risk (score<4), moderate risk (score 4-11), and high risk (score >11). Case 1, which was considered as high risk, involved a patient with potentially lethal asymptomatic prolongation of the QTc segment. Additionally, the R-on-T phenomenon noted on telemetry was worrisome as this could have potentiated a polymorphic ventricular tachycardia (PVT) or even ventricular fibrillation [5]. These were clear complications of the HCQ and, subsequently, prolonged the patient’s hospital stay. Case 2, considered as low risk, demonstrated how HCQ therapy initiated in an outpatient resulted in an adverse outcome that led to hospital admission. The bradycardia was thankfully recognized early as this could have progressed to potential atrioventricular block had the patient continued the medication [7]. Both of these cases throw light on HCQ-related complications resulting in prolonged hospital stay/hospitalization that exposed these patients to potential hospital-acquired infections or even re-infection with COVID-19, which has only been sporadically reported [8].\n\nTable 1 Tisdale score for cases 1 and 2\nCase 1 was classified as high risk (76%) for developing QTc prolongation. Case 2 was classified as low risk (15%) for developing QTc prolongation\n\n \tPoints if Yes\tCase 1\tCase 2\t\nAge ≥68 years\t1\t1\t0\t\nFemale sex\t1\t1\t1\t\nLoop diuretic\t1\t0\t0\t\nSerum K+ <3.5 mEq/L\t2\t2\t0\t\nAdmission QTc ≥450 ms\t2\t0\t0\t\nAcute MI\t2\t0\t0\t\n≥2 QTc-prolonging drugs\t3\t3\t0\t\nSepsis\t3\t3\t0\t\nHeart failure\t3\t0\t0\t\n1 QTc-prolonging drug\t3\t3\t3\t\nTotal\t \t13\t4\t\nThe American College of Cardiology (ACC) has issued guidance on how to proceed in patients who could potentially receive HCQ for COVID-19 therapy. In the outpatient setting, a baseline assessment with EKG, renal function panel, and hepatic function panel should be completed and, if possible, the EKG should be assessed by an electrophysiologist [9]. Furthermore, other QTc-prolonging agents should be discontinued if possible [9]. Relative contraindications in these patients would include: 1) history of long QT syndrome, 2) QTc of >480 ms, and 3) Tisdale score of ≥11 [9]. For inpatients, the recommendations include the same as above plus: 1) placing patients on telemetry 2) obtaining serum potassium on a daily basis, and 3) obtaining EKG two to three hours after the second dose of HCQ. Guidance on QTc increases of >60 ms or overall Qtc of >500 ms seems to point towards the discontinuation of AZM and subsequent dose decrease of HCQ. If QTc does not improve, the ACC recommends complete discontinuation of HCQ [9].\n\nThe emergence of new data regarding HCQ's application in the early disease course of COVID-19 has called its use into question. In the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) trial conducted by the Petal Network, 479 patients were enrolled in a double-blinded, placebo-controlled randomized trial to determine if five-day therapy with HCQ led to more favorable outcomes [10]. The dosing regimen included HCQ sulfate 400 mg PO twice daily on day one followed by 200 mg twice daily doses on days two to five [10]. The initial results from the trial suggested that there was no benefit or harm from HCQ use, and the trial was subsequently halted in mid-June 2020 [11]. The data is still awaiting full analysis for submission to peer review [11]. In June 2020, the FDA officially revoked emergency use authorization for HCQ as there was no benefit demonstrated from the aforementioned trial [3]. Moreover, the agency has cautioned against its use in the outpatient setting given its potential cardiovascular complications and inability to closely monitor patients [3]. The trial data and FDA recommendations in their totality demonstrate that HCQ use likely is not beneficial in the early disease course of these patients. Regarding the lack of harm shown by the ORCHID trial, more subgroup analysis is warranted in these patients to fully determine if patients with cardiovascular disease burden suffered harm, despite the absence of mortality among patients.\n\nThe potential for arrhythmogenic effects of these medications, especially in patients with cardiovascular disease, should be seriously weighed against their benefit before administration. Based on the recent preliminary analysis of data from the ORCHID trial, there is no benefit from HCQ use. If HCQ is commenced by providers for the treatment of COVID-19 in patients with a cardiac history, it should be done at the guidance of an infectious disease physician in conjunction with a cardiologist. While the prospect of potential lifesaving therapeutics seems tempting, the long-standing principle of “Do No Harm” is of importance now more than ever.\n\nConclusions\nExperimental therapy with HCQ in mild/moderate presentations of COVID-19 should be balanced with considerations of the risk of potential cardiac complications in both inpatient and outpatient settings. This is especially the case as there have been no double-blinded randomized control trials with results demonstrating that the benefits of the therapy outweigh the risks.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study. HCA Institutional Review Board issued approval 2020-304. This research activity was determined to be exempt or excluded from the Institutional Review Board (IRB) oversight in accordance with current regulations and institutional policy. The internal reference number for this determination is 2020-304.\n==== Refs\nReferences\n1 High contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2 Emerg Infect Dis Sanche S Lin YT Xu C Romero-Severson E Hengartner N Ke R 1470 1477 26 2020 32255761 \n2 Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial (Epub ahead of print) Int J Antimicrob Agents Gautret P Lagier JC Parola P 105949 2020 32205204 \n3 FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems 6 2020 2020 https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or \n4 Development and validation of a risk score to predict QT interval prolongation in hospitalized patients Circ Cardiovasc Qual Outcomes Tisdale JE Jaynes HA Kingery JR Mourad NA Trujillo TN Overholser BR Kovacs RJ 479 487 6 2013 23716032 \n5 R-from-T as a common mechanism of arrhythmia initiation in long QT syndromes Circ Arrhythmia Electrophysiol Liu MB Vandersickel N Panfilov AV Qu Z 0 12 2019 \n6 WHO Malaria Policy Advisory Committee meeting: the cardiotoxicity of antimalarials 7 2020 World Health Organization- Malaria Policy Advisory Committee Meeting. Malaria Policy Advisory Committee 13 14 2016 https://www.who.int/malaria/mpac/mpac-mar2017-erg-cardiotoxicity-report-session2.pdf \n7 Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases Rheumatology (Oxford) Costedoat-Chalumeau N Hulot JS Amoura Z Leroux G Lechat P Funck-Brentano C Piette JC 808 810 46 2007 17202178 \n8 Recurrence of positive SARS-CoV-2 RNA in COVID-19: a case report Int J Infect Dis Chen D Xu W Lei Z Huang Z Liu J Gao Z Peng L 297 299 93 2020 32147538 \n9 Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19 Cardiol Mag Simpson TF Kovacs RJ Stecker EC 1 9 2 2020 https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19 \n10 Outcomes related to COVID-19 treated with hydroxychloroquine among in-patients with symptomatic disease (ORCHID) 6 2020 2020 https://clinicaltrials.gov/ct2/show/NCT04332991 \n11 ORCHID: outcomes related to COVID-19 treated with hydroxychloroquine among In-patients with symptomatic disease 6 2020 2020 https://petalnet.org/studies/public/orchid\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(7)",
"journal": "Cureus",
"keywords": "bradycardia; covid 19; prolonged qt; risk-benefit; sars-cov-2",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e9151",
"pmc": null,
"pmid": "32789088",
"pubdate": "2020-07-12",
"publication_types": "D002363:Case Reports",
"references": "17202178;32255761;32147538;23716032;31838916;32205204",
"title": "Cardiovascular Considerations of Experimental Hydroxychloroquine Therapy on Patients Diagnosed With COVID-19: A Case Series Review.",
"title_normalized": "cardiovascular considerations of experimental hydroxychloroquine therapy on patients diagnosed with covid 19 a case series review"
} | [
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"companynumb": "US-ACCORD-197255",
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"activesubstancename": "TACROLIMUS"
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{
"abstract": "OBJECTIVE\nTo evaluate patterns, predictors, and outcomes of postprocedure delayed hemorrhage (PPDH) following flow diversion therapy for intracranial aneurysm treatment.\n\n\nMETHODS\nFrom 2012 to 2016, 50 patients with 52 aneurysms were treated with the Pipeline embolization device. Device placement was performed as a standalone therapy or with adjunctive coil embolization. Patients underwent dual antiplatelet therapy for 6 months after treatment. Medical comorbidities; aneurysm traits; and treatment factors, including platelet function testing, were studied. Statistical analysis was performed using cross-tabulation.\n\n\nRESULTS\nSix PPDHs (12%) occurred 2-16 days (mean 6.8 days) after Pipeline placement, manifesting as 1 of 2 distinct patterns: convexity subarachnoid hemorrhage (cSAH) (n = 4) or lobar intraparenchymal hemorrhage (IPH) (n = 2). All PPDHs occurred ipsilateral to the device; 1 IPH occurred ipsilateral but in a different arterial territory. PPDH occurred in both treated anterior communicating artery aneurysms. Cases of PPDH demonstrated on average lower P2Y12 reaction unit values at the time of treatment. Platelet function testing at the time of hemorrhage was consistently hypertherapeutic. Patients with cSAH had only minimal worsening of modified Rankin Scale score at the time of discharge, whereas the 2 patients with IPH experienced significant deterioration.\n\n\nCONCLUSIONS\nPPDH is a poorly understood complication following flow diversion therapy that can result in significant morbidity. In our experience, nonaneurysmal cSAH does not result in poor clinical outcomes, whereas IPH leads to long-term deficits or death. As previously suggested, there appears to be a correlation between low P2Y12 reaction unit values and PPDH.",
"affiliations": "Department of Neurosurgery, University of Colorado Hospital, Aurora, Colorado, USA; Department of Radiology, University of Louisville, Louisville, Kentucky, USA.;Department of Neurosurgery, University of Colorado Hospital, Aurora, Colorado, USA; Department of Radiology, University of Colorado Hospital, Aurora, Colorado, USA.;Department of Neurosurgery, University of Colorado Hospital, Aurora, Colorado, USA.;Department of Neurosurgery, University of Colorado Hospital, Aurora, Colorado, USA.;Department of Neurosurgery, University of Colorado Hospital, Aurora, Colorado, USA. Electronic address: Joshua.Seinfeld@ucdenver.edu.",
"authors": "White|Andrew C|AC|;Kumpe|David A|DA|;Roark|Christopher D|CD|;Case|David E|DE|;Seinfeld|Joshua|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.03.190",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "115()",
"journal": "World neurosurgery",
"keywords": "Convexity subarachnoid hemorrhage; Endovascular; Flow diversion; Flow diverter; Hemorrhagic complications; Intracranial aneurysm; Intraparenchymal hemorrhage; Pipeline; Subarachnoid hemorrhage",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D000069322:Self Expandable Metallic Stents; D013345:Subarachnoid Hemorrhage; D016896:Treatment Outcome",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "e97-e104",
"pmc": null,
"pmid": "29626682",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patterns, Predictors, and Outcomes of Postprocedure Delayed Hemorrhage Following Flow Diversion for Intracranial Aneurysm Treatment.",
"title_normalized": "patterns predictors and outcomes of postprocedure delayed hemorrhage following flow diversion for intracranial aneurysm treatment"
} | [
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"companynumb": "US-BAYER-2018-102769",
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"activesubstancename": "ASPIRIN"
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"abstract": "For many years, Tourette syndrome (TS) was considered to be a rare disorder, but tics and TS are now recognized as fairly common childhood-onset conditions. Children and adolescents with TS are frequently treated with antipsychotics, either as monotherapy or in combination with psychostimulants, melatonin and selective serotonin reuptake inhibitors (SSRIs). Antipsychotics are most often used in schizophrenia and related psychotic disorders, and in these conditions hyperprolactinemia is one of the most common adverse effects associated with antipsychotics, occurring in 40-50% of patients. We describe two patients with TS who experienced antipsychotic-induced hyperprolactinemia. Treatment options generally consist of dose reduction or switching from typical to atypical antipsychotics. However, diminishing dosages can lead to exacerbations of tics. Also, not all atypical antipsychotics have the same pharmacologic properties required to normalize prolactin levels. The choice of treatment may also be affected by the patient's age and sex. These factors are discussed in relation to these cases, and illustrated by the results of therapeutic interventions over the years.",
"affiliations": "Department of Neurology, LangeLand Hospital, Toneellaan 1, 2725 NA Zoetermeer, The Netherlands.;Department of Pediatrics, Haga Teaching Hospital, The Hague, The Netherlands.;Department of Internal Medicine, Haga Teaching Hospital, The Hague, The Netherlands.;Department of Neurology, Haga Teaching Hospital, The Hague, The Netherlands.;Center for Human Drug Research, Leiden, The Netherlands.;Diabeter, Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam, The Netherlands.",
"authors": "Rath|Judith J G|JJG|;Deen|Marlies E J|MEJ|;van Houten|Hessel|H|;de Bruijn|Sebastiaan F T M|SFTM|;van Gerven|Joop|J|;Mul|Dick|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2045125317705012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-1253",
"issue": "7(6-7)",
"journal": "Therapeutic advances in psychopharmacology",
"keywords": "Tourette syndrome; antipsychotic drugs; hyperprolactinemia",
"medline_ta": "Ther Adv Psychopharmacol",
"mesh_terms": null,
"nlm_unique_id": "101555693",
"other_id": null,
"pages": "201-205",
"pmc": null,
"pmid": "28740637",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "23647135;23020880;22728760;2665687;17606657;22331262;20848326;19339912;21445724;18477626;24295625;10545742;22472310;20527996;22772923;15289815;11020104;16554257;15456328;16645024;24167704",
"title": "Antipsychotic-induced hyperprolactinemia in Tourette syndrome.",
"title_normalized": "antipsychotic induced hyperprolactinemia in tourette syndrome"
} | [
{
"companynumb": "NL-JNJFOC-20170723474",
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"activesubstancename": "SULPIRIDE"
},
"drugadditional": "1",
"d... |
{
"abstract": "To report the first case of Neodymium Yttrium Aluminum Garnet (Nd:YAG) laser use to recanalize a CyPass occluded with a clot in the early postoperative follow-up.\nA 66 year-old woman with primary open angle glaucoma and cataract received combined cataract surgery plus CyPass in the right eye. Surgery was uneventful, however, there was a small amount of hyphema related to bleeding around the site of Cypass insertion. Intraocular pressure (IOP) was between 6 and 7 mmHg in the first week on no glaucoma medications. At the second postoperative week, IOP jumped to 30 mmHg and a clot was observed obstructing the CyPass lumen. We disrupted the clot with a single shot from a Nd:YAG laser. Twenty minutes after the laser, the IOP was 8 mmHg. CyPass was recanalized without complications. IOP was 11 mmHg at 1 month postoperatively with timolol 0.5% twice a day.\nIt is important to perform gonioscopy to evaluate for CyPass obstruction in cases of IOP spike. Nd:YAG laser may be a useful approach to recanalize the CyPass in the early postoperative follow-up.",
"affiliations": "Department of Ophthalmology, San Francisco School of Medicine, University of California, San Francisco, CA, United States.;Department of Ophthalmology, San Francisco School of Medicine, University of California, San Francisco, CA, United States.;Department of Ophthalmology, San Francisco School of Medicine, University of California, San Francisco, CA, United States.;Department of Ophthalmology, San Francisco School of Medicine, University of California, San Francisco, CA, United States.",
"authors": "Perez|Claudio I|CI|;Chansangpetch|Sunee|S|;Hsia|Yen C|YC|;Lin|Shan C|SC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2018.02.011",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(17)30357-210.1016/j.ajoc.2018.02.011Case reportUse of Nd:YAG laser to recanalize occluded Cypass Micro-Stent in the early post-operative period Perez Claudio I. abChansangpetch Sunee acHsia Yen C. aLin Shan C. shan.lin@ucsf.edua∗a Department of Ophthalmology, San Francisco School of Medicine, University of California, San Francisco, CA, United Statesb Fundación Oftalmológica los Andes, Universidad de los Andes, Santiago, Chilec Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand∗ Corresponding author. 10 Koret Way, Room K301, San Francisco, CA, 94143-0730, USA. shan.lin@ucsf.edu15 2 2018 6 2018 15 2 2018 10 114 116 21 11 2017 12 2 2018 © 2018 The Authors. Published by Elsevier Inc.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report the first case of Neodymium Yttrium Aluminum Garnet (Nd:YAG) laser use to recanalize a CyPass occluded with a clot in the early postoperative follow-up.\n\nObservations\nA 66 year-old woman with primary open angle glaucoma and cataract received combined cataract surgery plus CyPass in the right eye. Surgery was uneventful, however, there was a small amount of hyphema related to bleeding around the site of Cypass insertion. Intraocular pressure (IOP) was between 6 and 7 mmHg in the first week on no glaucoma medications. At the second postoperative week, IOP jumped to 30 mmHg and a clot was observed obstructing the CyPass lumen. We disrupted the clot with a single shot from a Nd:YAG laser. Twenty minutes after the laser, the IOP was 8 mmHg. CyPass was recanalized without complications. IOP was 11 mmHg at 1 month postoperatively with timolol 0.5% twice a day.\n\nConclusions and importance\nIt is important to perform gonioscopy to evaluate for CyPass obstruction in cases of IOP spike. Nd:YAG laser may be a useful approach to recanalize the CyPass in the early postoperative follow-up.\n\nKeywords\nGlaucomaLasers solid-stateCataract extraction\n==== Body\n1 Introduction\nIn the last decade, the surgical glaucoma landscape has witnessed the emergence of numerous novel devices grouped within the classification of minimally invasive glaucoma surgery (MIGS). These techniques are mainly designed to treat primary open angle glaucoma (POAG) and aim to reduce intraocular pressure (IOP), usually with an ab-interno approach and minimization of tissue trauma and adverse events.1 An example of a recently approved MIGS is the CyPass Micro-Stent (Alcon, Fort Worth, Texas, USA), which is a polymide implant intended to create a new permanent conduit for additional outflow of aqueous humor from the anterior chamber to the suprachoroidal space.1\n\nCataract extraction alone produces IOP reduction in patients with POAG.2 Cypass is usually performed as an adjunctive procedure to phacoemulsification for achieving an additional IOP-lowering effect and/or a reduction in the burden of glaucoma medication use.3, 4, 5, 6 Although the CyPass Micro-Stent has an overall good safety profile, there are potential ocular adverse events reported such as intraoperative hyphema, cyclodialysis cleft, and stent obstruction, among others.3, 4, 5, 6 To our knowledge, this is the first report of the use of Nd:YAG laser for opening an early CyPass obstruction due to a clot.\n\n2 Case report\nA 66 year-old Caucasian female has been followed in our institution since 2016 for moderate POAG and was treated with latanoprost, timolol and brimonidine in both eyes. She had developed intolerance to her glaucoma medications and was forming visually significant cataracts. Preoperative IOP was 13 mmHg OU. After consultation with the patient, we elected to perform combined phacoemulsification + intraocular lens + CyPass surgery in the right eye to reduce the burden of glaucoma drops and achieve better IOP control. Patient was on 81mg aspirin and was discontinued one week prior to the surgery.\n\nPhacoemulsification and lens implantation were uneventful and the CyPass was implanted without significant tissue resistance; there was a small amount of blood reflux from the stent and around the site of insertion (Fig. 1). On the first postoperative day, IOP was 7 mmHg without glaucoma medications and there was a hyphema of 1 mm. At the third and fifth postoperative days, IOP was 6 mmHg without drops and the hyphema was unchanged. At the second postoperative week, patient presented acutely with eye pain and nausea. IOP was 30 mmHg without glaucoma medications and the hyphema had resolved. We applied topical timolol 0.5% and brinzolamide 1% in the surgical eye as well as 250 mg of oral acetazolamide. After 45 minutes, IOP was still 30 mmHg. We performed a gonioscopy exam and found that the CyPass Micro-Stent was occluded with a clot (Fig. 2). Using a laser gonioscopy lens, we performed one shot of 3mJ with a Nd:YAG laser to the CyPass lumen to disrupt the clot (Fig. 3). Twenty minutes after the procedure, IOP was 8 mmHg. IOP was 11 mmHg at 1 month postoperatively with Timolol 0.5% twice a day in the right eye.Fig. 1 Intraoperative view of the CyPass procedure after cataract surgery, demonstrating a small amount of blood reflux from the lumen.\n\nFig. 1Fig. 2 Postoperative gonioscopic view shows clot inside the CyPass lumen.\n\nNote: This picture is of the contralateral left eye that also received CyPass and developed a similar clot in the CyPass lumen (pre-laser picture of the right eye not available).\n\nFig. 2Fig. 3 CyPass device after Neodymium Yttrium Aluminum Garnet laser, showing resolution of the clot that was observed prior to laser treatment.\n\nFig. 3\n\nFig. 4 shows swept-source optical coherence tomography imaging which can be used to evaluate the flow through the CyPass. The superior circumferential lake in the suprachoroidal space was present in the early postoperative image. Then, due to the clot obstruction in the Micro-Stent lumen, there is almost no superior circumferential lake at 2 weeks. Finally, the superior circumferential lake is visible again when the Micro-Stent was recanalized and the CyPass remains in good position in the nasal quadrant (Fig. 4).Fig. 4 Swept-Source optical coherence tomography images showing CyPass device and supra choroidal lake before and after recanalization with the Neodymium Yttrium Aluminum Garnet laser. A) Right eye is scanned superiorly and nasally. B) Postoperative day 3, red arrow shows a circumferential lake superiorly and CyPass in good position with posterior lake nasally. C) Postoperative day 14, intraocular pressure was 30 mmHg prior to laser. Red arrow shows almost minimal or no superior circumferential lake due to clot obstruction of the CyPass. D) Postoperative day 15, 1 day after laser, intraocular pressure 16 mmHg without treatment. Red arrow shows return of the superior circumferential lake in the suprachoroidal space. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4\n\n3 Discussion\nTo our knowledge this is the first case report of the use of Nd:YAG laser to recanalize a CyPass Micro-Stent. As the number of MIGS procedures performed expands, it is increasingly important for the glaucoma surgeon to know what to expect in terms of efficacy and potential adverse events as well as how to manage these adverse events. Studies with at least 1 year of follow-up have shown IOP reduction of 32.0% and 34.7% with and without cataract surgery, respectively.6,7 In the COMPASS trial, phacoemulsification + CyPass achieved 30% IOP reduction and the control group of cataract surgery alone had a 21% IOP reduction, at 24 months of follow-up.7\n\nCyPass insertion has a good safety profile as an adjunctive glaucoma procedure to cataract surgery. Nevertheless, clinicians should be aware that there are significant adverse events that can occur related to the CyPass including corneal edema (0.6–3.5%), cyclodialysis cleft > 2 mm (1.9%), hyphema (1.1–6.2%), iritis (4.4–8.6%), transient hypotony (2.9–13.8%), IOP spike ≥10 mmHg over baseline (4.3–10.8%) and stent obstruction (2.1–5.4%).3,5, 6, 7 Device repositioning was needed in 0.5%.5 García-Feijoo et al. described formation of peripheral anterior synechiae and partial obstruction of the CyPass in 3.1%.7 They also described the use of Nd:YAG laser in one case to successfully clear the synechiae from the Micro-Stent orifice without complications.7 Overall, the vast majority of complications were transient and required only conservative management.\n\nAnother option to recanalize the CyPass Micro-Stent that is blocked by clot could be the use of tissue plasminogen activator (t-PA). In the past, the use of t-PA has been described for resolving clots and fibrinous tube obstructions of glaucoma drainage devices.8 This method has not yet been reported for dissolving clots causing CyPass obstruction. However, we think that the use of Nd:YAG laser should be a safer method, because it is not necessary to enter to the anterior chamber, avoiding risk of endophthalmitis, direct corneal trauma, etc.\n\nThere are two possible learning points that can be of clinical value in this case report. First, if the IOP is significantly rising during the early post-operative period, it is important to do a gonioscopy exam. As described above, IOP spikes can occur in 5–10% of cases. Common causes of early obstruction are blood and fibrin that may come from a hyphema or blood around the tube insertion. The most common cause of late obstruction is formation of peripheral anterior synechiae.3,5, 6, 7 The second lesson is that Nd:YAG laser may be used to resolve CyPass obstruction in the early postoperative follow up. Also we showed the potential utility of Swept-Source imaging in evaluating flow through the CyPass to the suprachoroidal space. Since the typical wound healing process is most exuberant within the first 1–2 weeks after surgery, we believe that performing this procedure after the second postoperative week is a safe alternative that would not produce migration of the Micro-Stent and can help to decrease the IOP immediately.\n\n4 Conclusions\nIt is important to perform gonioscopy to evaluate for CyPass obstruction in cases of IOP spike. Nd:YAG laser may be a useful and safe approach to disrupt a clot obstructing the CyPass lumen in the early postoperative follow-up.\n\nPatient consent\nPersonal identifying information has been removed from this report because consent to publish such information was not obtained.\n\nAcknowledgements and disclosures\nFunding\nNone.\n\nConflict of interest\nThe authors have no financial disclosures related to the topic.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Saheb H. Ahmed I.I.K. Micro-invasive glaucoma surgery: current perspectives and future directions Curr Opin Ophthalmol 23 2012 96 104 22249233 \n2 Masis M. Mineault P.J. Phan E. Lin S.C. The role of phacoemulsification in glaucoma therapy: a systematic review and meta-analysis Surv Ophthalmol 2017 sep 6 \n3 Hoeh H. Vold S.D. Ahmed I.K. Initial clinical experience with the CyPass Micro-Stent: safety and surgical outcomes of a novel supraciliary microstent J Glaucoma 25 2016 106 112 25304276 \n4 Höh H. Grisanti S. Grisanti S. Two-year clinical experience with the CyPass Micro-Stent: safety and surgical outcomes of a novel supraciliary micro-stent Klin Monbl Augenheilkd 231 2014 377 381 24771171 \n5 Hoeh H. Ahmed II Grisanti S. Early postoperative safety and surgical outcomes after implantation of a suprachoroidal micro-stent for the treatment of open-angle glaucoma concomitant with cataract surgery J Cataract Refract Surg 39 2013 431 437 23506920 \n6 Vold S. Ahmed I.K. Craven R. Two-year COMPASS trial results: supraciliary microstenting with phacoemulsification in patients with Open-Angle Glaucoma and Cataracts Ophthalmology 123 2016 2103 2112 27506486 \n7 García-Feijoo J. Rau M. Grisanti S. Supraciliary micro stent implantation for open-angle glaucoma failing topical therapy: 1 year results of a multicente study Am J Ophthalmol 159 6 2015 Jun 1075 1081 25747677 \n8 Sidoti P.A. Morinelli E.N. Heuer D.K. Tissue plasminogen activator and glaucoma drainage implants J Glaucoma 4 4 1995 258 262 19920683\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "10()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Cataract extraction; Glaucoma; Lasers solid-state",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "114-116",
"pmc": null,
"pmid": "29520377",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": "25304276;19920683;25747677;24771171;22249233;27506486;23506920;28887138",
"title": "Use of Nd:YAG laser to recanalize occluded Cypass Micro-Stent in the early post-operative period.",
"title_normalized": "use of nd yag laser to recanalize occluded cypass micro stent in the early post operative period"
} | [
{
"companynumb": "US-BAYER-2019-000477",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BRINZOLAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nClozapine, an evidence-based treatment of refractory schizophrenia, is associated with increased weight gain and metabolic dysregulation compared with most antipsychotics in short-term clinical trials. However, there are limited data describing comparative long-term metabolic risks. In this report, we examined whether short-term differences persist with long-term exposure to clozapine.\n\n\nMETHODS\nThe data of all patients in a university-based clinic with a psychotic illness or a mood disorder with psychotic features, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis, and treated with an antipsychotic in calendar year 2012 were examined. A total of 307 patients met the criteria; 96 patients were treated with clozapine and the remaining 211 patients were treated with 1 or more non-clozapine antipsychotics. Body mass index, type 2 diabetes, hypertension, dyslipidemia, and obesity were compared.\n\n\nRESULTS\nThe mean duration of the clozapine treatment was 7.6 years (range, 2 months to 21 y). On all metabolic measures, there were no statistically significant differences between the clozapine and non-clozapine groups (mean body mass index, 31 vs 32; type 2 diabetes, 17% vs 18%; dyslipidemia, 35% vs 38%; hypertension, 32% vs 39%; and obesity, 48% vs 54%). Removing the olanzapine-treated patients (n = 51) from the non-clozapine group did not change the findings.\n\n\nCONCLUSIONS\nIn this university-based clinic sample with a large number of clozapine-treated patients, we found no evidence of increased risk in any individual measure for those receiving clozapine. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time because multiple other variables likely also impact metabolic risk during the life span. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time due to the accumulated impact of other variables that also impact metabolic risk across the life span.",
"affiliations": "From the *Department of Psychiatry, and †North Carolina Psychiatric Research Center, University of North Carolina at Chapel Hill, Chapel Hill; and ‡North Carolina Division of State Operated Healthcare Facilities, Raleigh, NC.",
"authors": "Kelly|Anne C|AC|;Sheitman|Brian B|BB|;Hamer|Robert M|RM|;Rhyne|David C|DC|;Reed|Robin M|RM|;Graham|Karen A|KA|;Rau|Shane W|SW|;Gilmore|John H|JH|;Perkins|Diana O|DO|;Peebles|Susan Saik|SS|;VanderZwaag|Carol J|CJ|;Jarskog|Lars Fredrik|LF|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0000000000000159",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "34(4)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D003024:Clozapine; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D008297:Male; D008659:Metabolic Diseases; D008875:Middle Aged; D009765:Obesity; D011618:Psychotic Disorders; D012559:Schizophrenia; D015430:Weight Gain; D055815:Young Adult",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "441-5",
"pmc": null,
"pmid": "24943389",
"pubdate": "2014-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A naturalistic comparison of the long-term metabolic adverse effects of clozapine versus other antipsychotics for patients with psychotic illnesses.",
"title_normalized": "a naturalistic comparison of the long term metabolic adverse effects of clozapine versus other antipsychotics for patients with psychotic illnesses"
} | [
{
"companynumb": "US-JNJFOC-20140715476",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Objective The long-term clinical course and prognosis of patients with chronic eosinophilic pneumonia (CEP) including factors predictive of the relapse of CEP have not been fully investigated. The aim of the present study was to investigate these issues. Methods We retrospectively investigated the rate of relapse and prognosis in 73 patients diagnosed as having CEP. Results Systemic corticosteroid therapy was administered at a prednisolone dose of 29.4±7.6 mg/day. During a median follow-up period of 1,939 days, 27 patients suffered from relapse of CEP. Two patients developed steroid-induced diabetes mellitus, and 1 patient developed pulmonary nontuberculous mycobacteriosis. Five patients died; however, none died of CEP. A history of smoking was the only independent negative risk factor for relapse of CEP [hazard ratio, 0.37 (0.14-0.98)]. Conclusion Patients with CEP frequently relapse. During the follow-up, metabolic and infectious complications under prolonged corticosteroid therapy are problematic. A history of smoking was a negative factor for predicting the risk of CEP relapse.",
"affiliations": "Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.",
"authors": "Ishiguro|Takashi|T|;Takayanagi|Noboru|N|;Uozumi|Ryuji|R|;Tada|Mami|M|;Kagiyama|Naho|N|;Takaku|Yotaro|Y|;Shimizu|Yoshihiko|Y|;Sugita|Yutaka|Y|;Morita|Satoshi|S|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6765",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D002908:Chronic Disease; D003920:Diabetes Mellitus; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D011239:Prednisolone; D011379:Prognosis; D011657:Pulmonary Eosinophilia; D012008:Recurrence; D012189:Retrospective Studies; D012907:Smoking",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2373-7",
"pmc": null,
"pmid": "27580536",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Long-term Clinical Course of Chronic Eosinophilic Pneumonia.",
"title_normalized": "the long term clinical course of chronic eosinophilic pneumonia"
} | [
{
"companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-GSH201803-001052",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"dr... |
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