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"abstract": "The paper describes diagnostic criteria, clinical presentation and types of hallucinogen persisting perception disorder (HPPD), as well as current approaches to the treatment of this phenomenon using available scientific sources. Three case reports are also presented to demonstrate different types of this disorder. The first case report describes a 23-year old patient with a previous history of cannabis consumption who reported HPDD type I after the use of psilocybin mushrooms with small amounts of alcohol and hash. A month later, after cannabis use, the same visual and auditory distortions appeared again. During the following year, hallucinations recurred with the consumption of natural cannabinoids but not with alcohol intake. The symptoms have reduced within a year. Surprisingly, both other cases belonging to HPDD type II appeared in patients who consumed ecstasy, although MDMA is generally not considered a hallucinogen and hallucinations are not frequently reported after MDMA consumption. In both cases of HPPD type II after the use of ecstasy, the condition was very stressful and frightening. Both patients sought medical help and received tofisopam, lamotrigine and sertraline. After that, in both cases visual impairments have smoothed, but have not passed completely. Scientific sources suggest that HPPD may affect more than 50% of hallucinogen users and this disorder is often underdiagnosed. Therefore, patients suffering from HPPD can present in various clinical settings, and clinicians should be aware of this condition.",
"affiliations": "Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.;Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.;Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.;Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.",
"authors": "Skryabin|Valentin Yurievich|VY|http://orcid.org/0000-0002-4942-8556;Vinnikova|Maria|M|http://orcid.org/0000-0003-3289-8786;Nenastieva|Anna|A|;Alekseyuk|Vladislav|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/10550887.2019.1673655",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1055-0887",
"issue": "37(3-4)",
"journal": "Journal of addictive diseases",
"keywords": "HPPD; flashback; hallucinations; hallucinogen persisting perception disorder; hallucinogens",
"medline_ta": "J Addict Dis",
"mesh_terms": null,
"nlm_unique_id": "9107051",
"other_id": null,
"pages": "268-278",
"pmc": null,
"pmid": "31613183",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hallucinogen persisting perception disorder: A literature review and three case reports.",
"title_normalized": "hallucinogen persisting perception disorder a literature review and three case reports"
} | [
{
"companynumb": "RU-ALKEM LABORATORIES LIMITED-RU-ALKEM-2019-09524",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOFISOPAM"
},
"drugad... |
{
"abstract": "Severe COVID-19 infection management for a recipient of kidney transplant has debatable prognosis and treatment. We described the case of a COVID-19 infected 70 year old female, previously had renal transplantation in 2017. The patient took immunosuppressive agents as routine drugs for transplant recipient status and received lopinavir/ritonavir, hydroxychloroquine, and dexamethasone daily at the hospitalization. Specific question arises about renal transplant recipients being infected by COVID-19 - whether the infection will get worse compared to those without immunosuppresive agent. In this case, author decided to stop the immunosuppressive agent followed administration of combination lopinavir/ritonavir, hydroxychloroquine, and dexamethasone that gives a good clinical impact change to patient's condition after once getting worsened and mechanically ventilated. Nevertheless, the assessment of risk and benefit in continuing immunosuppressive drugs is concurrently essential due to the prevention of transplant rejection.",
"affiliations": "Department of Internal Medicine, Faculty of Medicine Airlangga University, Airlangga University Hospital, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, Airlangga University Hospital, Surabaya, Indonesia. mochthaha@fk.unair.ac.id.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Department of Internal Medicine, Faculty of Medicine Airlangga University, General Teaching Hospital Dr. Soetomo, Surabaya, Indonesia.;Premier Hospital Surabaya, Surabaya, Indonesia.;Premier Hospital Surabaya, Surabaya, Indonesia.;Premier Hospital Surabaya, Surabaya, Indonesia.;Premier Hospital Surabaya, Surabaya, Indonesia.;Premier Hospital Surabaya, Surabaya, Indonesia.;Premier Hospital Surabaya, Surabaya, Indonesia.;Premier Hospital Surabaya, Surabaya, Indonesia.",
"authors": "Suryantoro|Satriyo Dwi|SD|;Thaha|Mochammad|M|;Pranawa|||;Santoso|Djoko|D|;Mardiana|Nunuk|N|;Widodo|||;Aditiawardana|||;Tjempakasari|Artaria|A|;Ardhany|Ardityo Rahmat|AR|;Pramudya|Dana|D|;Hertanto|Decsa Medika|DM|;Febriane|Evy|E|;Meryana|||;Angela|Maria|M|;Muliono|Ari Christy|AC|;Tanuwidjaja|Handoko|H|;Setiawan|Philia|P|;Sugiarto|David|D|",
"chemical_list": "D004338:Drug Combinations; D007166:Immunosuppressive Agents; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D006886:Hydroxychloroquine; D003907:Dexamethasone; D019438:Ritonavir",
"country": "Italy",
"delete": false,
"doi": "10.3855/jidc.14952",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1972-2680",
"issue": "15(9)",
"journal": "Journal of infection in developing countries",
"keywords": "hydroxycholorquine; immunosupressive drugs; kidney transplant; lopinavir; ritonavir",
"medline_ta": "J Infect Dev Ctries",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D003907:Dexamethasone; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D061466:Lopinavir; D019438:Ritonavir; D066027:Transplant Recipients",
"nlm_unique_id": "101305410",
"other_id": null,
"pages": "1257-1262",
"pmc": null,
"pmid": "34669593",
"pubdate": "2021-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe COVID-19 infection in a kidney transplant recipient treated with lopinavir/ritonavir, hydroxychloroquine and dexamethasone.",
"title_normalized": "severe covid 19 infection in a kidney transplant recipient treated with lopinavir ritonavir hydroxychloroquine and dexamethasone"
} | [
{
"companynumb": "ID-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-320394",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drug... |
{
"abstract": "Objective: Decreasing the primary cesarean delivery rate and associated maternal and fetal complications is a priority for obstetric care providers. External cephalic version (ECV) is a procedure recommended for women with singleton pregnancies where the fetus is malpresenting to avoid vaginal breech delivery, which is inherently riskier than cesarean delivery. However, little is known about this procedure in the context of twin gestations. Scheduled cesarean delivery is instead recommended for women with twin gestations where the presenting twin is not cephalic. Our aim is to evaluate the safety and efficacy of ECV in the setting of twin pregnancy where the presenting twin is not cephalic. We also present two patients with twin pregnancy at our institution that attempted ECV.Data sources: A systematic review of the following electronic databases was performed, searching from their inception until September 2019: Pubmed, Ovid, Scopus, and clinicaltrials.gov.Study eligibility criteria: All reported cases of ECV for a non-cephalic presenting twin were included. Studies were excluded if patients had contraindications to vaginal delivery and if they described ECV of the second twin only. Maternal demographics, procedure details, and outcomes data were collected.Study appraisal and synthesis methods: The primary outcome was a successful version of the presenting twin to the cephalic presentation following ECV. Statistical analysis involved calculating means, standard deviations, frequencies and percentages as appropriate.Results: Two case reports and one case series, totaling 22 patients, met inclusion criteria. Two additional patients attempted ECV at our institution. One completed ECV (for a total of 23 patients) while the other did not. This patient consented for ECV as Twin A was noted to be breeched upon presentation to labor and delivery but after receiving regional anesthesia, twin A was cephalic. No randomized controlled trials were identified. All were dichorionic pregnancies. Successful ECV of twin A occurred in 57% (13/23) of women and 48% (11/23) had a successful vaginal delivery. The majority were performed using regional anesthesia and a uterine relaxant (20/23). No serious adverse events occurred in any of the reports.Conclusions: ECV is insufficiently studied in twin pregnancy. Based on very limited data, it appears feasible to turn the non-cephalic presenting twin. Additional randomized controlled trials are needed to further evaluate the safety and efficacy of this procedure for a non-cephalic presenting twin.",
"affiliations": "Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA.",
"authors": "Felder|Laura|L|;McCurdy|Rebekah|R|;Berghella|Vincenzo|V|http://orcid.org/0000-0003-2854-0239",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14767058.2020.1768237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": null,
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": "Twins; dichorionic pregnancy; external cephalic version; multiples; preventing cesarean",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": null,
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "32434414",
"pubdate": "2020-05-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "External cephalic version of the non-cephalic presenting twin: a systematic review.",
"title_normalized": "external cephalic version of the non cephalic presenting twin a systematic review"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-06775",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
},
"drugadditiona... |
{
"abstract": "Monoclonal gammopathy of renal significance (MGRS) is a new concept with evolving evidence for treatment. MGRS in the transplant kidney is a rare cause of renal transplant dysfunction that can lead to graft loss. Most cases of post-transplant MGRS are due to recurrent disease. Clone-specific chemotherapy is required to target the underlying clone, and this may improve graft survival; however, this can be challenging, as most patients are elderly with age-related comorbidities and may have complications associated with increasing immunosuppression. Here, we report 3 cases of renal allograft MGRS, and each case highlights different challenges in the diagnosis and management of this condition.",
"affiliations": "Department of Renal Medicine, University Hospitals Birmingham, Birmingham, United Kingdom. Electronic address: ritika.rana@uhb.nhs.uk.;Department of Renal Medicine, University Hospitals Birmingham, Birmingham, United Kingdom.;Department of Haematology, University Hospitals Birmingham, Birmingham, United Kingdom.;Department of Haematology, University Hospitals Birmingham, Birmingham, United Kingdom.;Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.;Department of Histopathology, University Hospitals Birmingham, Birmingham, United Kingdom.;Department of Histopathology, University Hospitals Birmingham, Birmingham, United Kingdom.;Department of Renal Medicine, University Hospitals Birmingham, Birmingham, United Kingdom.",
"authors": "Rana|Ritika|R|;Cockwell|Paul|P|;Pratt|Guy|G|;Cook|Mark|M|;Drayson|Mark|M|;Vydianath|Bindu|B|;Neil|Desley|D|;Pinney|Jennifer H|JH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.12.040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D007668:Kidney; D007674:Kidney Diseases; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias; D011183:Postoperative Complications",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "857-864",
"pmc": null,
"pmid": "32143865",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-transplant Monoclonal Gammopathy of Renal Significance: A Case Series.",
"title_normalized": "post transplant monoclonal gammopathy of renal significance a case series"
} | [
{
"companynumb": "GB-STRIDES ARCOLAB LIMITED-2020SP005415",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "Background. The diagnosis of neonatal hemolysis is an easy exercise. However, the diagnosis of its etiology can be very challenging especially in low ressources countries where laboratory capacities are limited. We report the case of hemolytic anemia episodes that started in the neonatal period, for which the trigger factor, infectious of paracetamol, is debatable.",
"affiliations": "Department of Medical Hematology, Brazzaville Teaching Hospital, 13 Avenue Auxence Ikonga, BP 32, Brazzaville, Congo.;Department of Medical Hematology, Brazzaville Teaching Hospital, 13 Avenue Auxence Ikonga, BP 32, Brazzaville, Congo.;Department of Pediatry, Brazzaville Blanche Gomes Hospital, Sassou Nguesso Boulevard, Brazzaville, Congo.;Department of laboratory, Brazzaville Teaching Hospital, 13 Avenue Auxence Ikonga, BP 32, Brazzaville, Congo.",
"authors": "Ngolet|Lydie Ocini|LO|https://orcid.org/0000-0001-8757-8136;Louokdom|Josue Simo|JS|;Guembo|Nelly|N|;Thibault|Ocko Ngokaba|ON|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/3247127",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/3247127\nCase Report\nAddressing the Challenges to Diagnose Neonatal Hemolytic Anemia's Aetiologies in Low Ressources Countries: A Case Report\nhttps://orcid.org/0000-0001-8757-8136Ngolet Lydie Ocini lngolet@yahoo.fr\n1\n Louokdom Josue Simo \n1\n Guembo Nelly \n2\n Thibault Ocko Ngokaba \n3\n \n1Department of Medical Hematology, Brazzaville Teaching Hospital, 13 Avenue Auxence Ikonga, BP 32, Brazzaville, Congo\n\n2Department of Pediatry, Brazzaville Blanche Gomes Hospital, Sassou Nguesso Boulevard, Brazzaville, Congo\n\n3Department of laboratory, Brazzaville Teaching Hospital, 13 Avenue Auxence Ikonga, BP 32, Brazzaville, Congo\nAcademic Editor: Håkon Reikvam\n\n\n2020 \n26 2 2020 \n2020 324712712 10 2019 4 1 2020 5 2 2020 Copyright © 2020 Lydie Ocini Ngolet et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. The diagnosis of neonatal hemolysis is an easy exercise. However, the diagnosis of its etiology can be very challenging especially in low ressources countries where laboratory capacities are limited. We report the case of hemolytic anemia episodes that started in the neonatal period, for which the trigger factor, infectious of paracetamol, is debatable.\n==== Body\n1. Case Presentation\nA 3-month-old and 2-day-old male infant was referred to the hematology department of the University Hospital for anemia.\n\nThe patient was the product on an uncomplicated full-term pregnancy. His medical history revealed neonatal jaundice at 5 days of life and 2 episodes of acute anemia following febrile runny nose, respectively, at 1 and 2 months. They required blood transfusion (80 mL each) and antipyretic (paracetamol 10 mg/Kg every 6 hours when needed) and empiric antibiotics for the second episode (amoxicillin 50 mg/kg every 12 hours during 5 days). The malaria smear was negative. The hemoglobin electrophoresis was also negative for the hemoglobin S. The rate of the hemoglobin F was 12%, which for the age of 1 monthwas normal.\n\nSince the hemolytic anemia reoccurred 32 days after the last episode, the infant was referred to the hematology clinic at the University Hospital (June 12, 2019).\n\nOn physical examination, the patient was in good health, dynamic, and reactive. His rectal temperature was 36.6°C. There was pallor but no jaundice. The blood pressure was 129/88 mmHg and pulse rate was 120 beats per min, with enlarged spleen but no hepatomegaly. The rest of the physical was unremarkable.\n\nAfter examination, we performed several blood tests (Table 1). The initial thin smear revealed at the microscopic inclusions in the red cells. Eleven percent of the patient's red cells were infected by parasites identified as Plasmodium falciparum. The malaria rapide test was positive for Plasmodium falciparum. We made the diagnosis of severe malaria based on the parasitemia and anemia. The mother tested also positive for Plasmodium falciparum. An antimalarial treatment with artesunate IV (3 mg/kg/j) was initiated for the mother and the baby for 3 days. The infant's smear was repeated after three days of antimalarial treatment. The results were still positive for Plasmodium falciparum (1% of the red cell infected). We decided to extend the antimalarial treatment for a total of 7 days. We requested additional laboratory studies to investigate the cause of the hemolytic anemia. The second hemoglobin electrophoresis was again negative for the hemoglobin S. The direct antiglobulin test was negative. The Glucose 6 Phosphate dehydrogenase level was low at 3.1 U/GHb (6.6 to 17.2). Table 1. We concluded that the patient was Glucose 6 Phosphate Dehydrogenase deficient (G6PD). The trigger factor of the hemolytic anemia was malaria.\n\nAt the follow-up visit (July 17, 2019), no improvement was noticed. The hemoglobin level was at 6.9 g/d, and the hemolysis was persistent (Table 1). The family denied any febrile episodes or drug intake. We reviewed carefully the environmental agents (as naphthalene ball) to which the infant was exposed and also the diet of the infant's mother and medication intake, since she was breastfeeding. The interview revealed that the mother had been self-medicating with paracetamol for a migraine condition since she was pregnant and she had presented two malaria episodes. We stopped the paracetamol and scheduled the infant for a follow-up.\n\nThe patient consulted 4 weeks and 3 days later. The hemoglobin rate was normal and, there were no biological signs of hemolysis.\n\n2. Discussion\nThis case demonstrates the difficulty in diagnosing neonatal hemolytic anemia's etiology in Sub-Saharian Africa. The difficulties were related to not only the limit of diagnosis capacities but also the complexity of the case.It was unclear to deduce if the patient developed congenital malaria or was infected in the postnatal period. Congenital malaria is defined as the presence of plasmodium asexual stages in newborn's cord or peripheral blood during the first week of life as a result of maternofetal transfer of parasites [1]. In areas endemic for malaria, symptomatic malaria infection is rare because of the effectiveness of the placenta as a barrier and the high level of maternal's antibodies and hemoglobin F [2, 3]. It is reported that it might take 3 to 4 weeks before congenitally-infected infants present symptoms [4]. Neonatal jaundice when related to malaria is usually associated with fever, irritability, and hepatosplenomegaly. Congenital malaria is characterized by low parasitemia, and the diagnosis is often missed because malaria smears, used in low ressources countries as a tool diagnosis, are often negative. The presence of Plasmodium falciparum in the blood of the mother and malaria history during the pregnancy concurred to the hypothesis of congenital malaria. The Polymerase Chain Reaction technique which is very sensitive in the detection of low parasite density, if available in the Congo, would have been helpful in the revision of our primary care but also our initial management. Repeated malaria smears turned out to be positive at the age of 3 months. The high density in Plasmodium falciparum may be the result of the progression of the disease or new contamination. Severe malaria is rare in the infant population and the population with G6PD deficiency [5]. An article from Mali examined the relationship between G6PD deficiency and severe malaria and reported that the G6PD deficiency confers highly significant protection against severe malaria in hemizygous males but not in heterozygous females [6].\n\nThe diagnosis of acquired hemolytic anemia triggered only by malaria was revised because the anemia was persistent despite the antimalarial treatment. The usual presentation of the X-linked disease is, in the Sub-Saharian African region, acute hemolytic anemia triggered by a factor. Between the crisis, the hemoglobin rate is usually back to normal [6]. The persistence of the anemia between crisis and absence of acute hemolytic anemia in the infant's male sibling contributed to delay in the diagnosis of G6PD deficiency. Since he got a femoral fracture during the delivery, the pediatrician assessed neonatal nonimmune hemolytic anemia due to trauma. The jaundice was related to the hematoma resorption. The repetition of the hemolysis episodes led to the diagnosis. A blood specimen sent to France helped in diagnosis of G6PD deficiency.\n\nThe nature of the triggered factor of the acute hemolysis anemia remains unclear. Despite the malaria treatment, the patient kept hemolyzing. Potential triggering factors were reviewed. There was no exposure to environmental factors as naphtalene balls or diet-related cause. The mother was exclusively breastfeeding. She reported paracetamol intake during her pregnancy. Paracetamol or acetaminophen is not an oxidant medication. It is not considered as a drug that can cause acute the hemolytic reaction. However, we found 2 case reports of hemolytic crisis following paracetamol ingestion through the database from Pubmed [7, 8]. Per the authors, the interindividual reaction to the drug intake in patients with G6PD deficient may explain that fact. The same agent may cause hemolysis to one patient and not to another one. Differences result not only from multiple factors such as genetics but also from maturation of liver enzymes [9]. It is not clear in our case to determine if the acute and prolonged anemia were associated with the mother's consumption of paracetamol. However, the hemolysis resolved since the mother stopped taking paracetamol.\n\n\n\nAt that stage, we can state the following:The anemia was hemolytic and regenerative, which excluded aplastic anemia.\n\nThe hemolytic anemia was prolonged which is not common in G6PD deficiency. A G6PD genotype investigation, if available, would have been helpful.\n\nThe hyperbilirubinemia initially hemolytic turned out to be progressively mixt without liver enzymes elevation which eliminated liver disease and conforted a chronic hemolytic anemia.\n\nThe repeated hemoglobin electrophoresis was normal.\n\n\n\nThis observation highlights three points:There is a need to build our diagnosis capacity but also to develop and implement a neonatal G6PD screening program in the Congo where the disease rate is theoretically high.\n\nThe need to establish guidelines for the diagnosis and management of neonatal jaundice and acute hemolytic anemia.\n\nCongenital malaria should be suspected in all neonates in the Congo, endemic for malaria, who present with fever. Malaria smears and the rapid malaria test in the absence of the PCR technique should be repeated. Early diagnosis could prevent unnecessary antibiotic usage and avert the progression of malaria.\n\n\n\n3. Conclusion\nG6PD deficiency is a condition frequently underdiagnosed among infants in the Congo when symptoms are atypical. G6PD deficiency should be considered as a differential diagnosis in male infants with neonatal jaundice or hemolytic anemia.\n\nAcknowledgments\nThe authors wish to thank Ms. Ngenyi Ousman for her help in translating and editing the manuscript.\n\nConsent\nWritten informed consent was obtained from the parents of the patient for publication of this case report.\n\nConflicts of Interest\nThe authors declare that they no have conflicts of interest.\n\nAuthors' Contributions\nLydie Ocini Ngolet drafted the paper. Josue Simo Luokdom, Nelly Guembo, and Thibault Oko helped in the diagnosis. All authors read and approved the final paper.\n\nTable 1 Results of blood work.\n\nAge\nDate\t5 days\n15-03-2019\t1 month ½\n15-04-2019\t2 months\n14-05-2019\t3 months\n12-06-2019\t4 months\n17-07-2019\t5 months\n20-08-2019\t\nLaboratory studies\t \t \t \t \t \t \t\nWhite cell count (G/L)\t6.4\t3.8\t8.5\t6.9\t8.58\t7.30\t\nDifferential count\t \t \t \t \t \t \t\n Neutrophils (%)\t38\t20\t27.4\t16.0\t15.3\t12.9\t\n Lymphocytes (%)\t54\t70.8\t60.9\t73.5\t76.9\t61.6\t\nHemoglobin (g/dL)\t9.6\t5.0\t8.6\t7.9\t6.9\t12.5\t\nHematocrit (%)\t28.9\t15.0\t28\t25.9\t27.5\t30.7\t\nPlatelets (109 g/L)\t172\t157\t207\t243\t381\t281\t\nReticulocyte count (G/L)\t156.3\t214\t175.9\t186.2\t192.3\t98.8\t\nSerum bilirubin total (mg/L)\t183.4\t \t \t21.2\t22\t6.2\t\nSerum bilirubin indirect (mg/L)\t172.9\t \t \t12.13\t12.7\t3.2\t\nALT (UI/L)\t \t \t \t \t17\t \t\nAST (UI/L)\t \t \t \t \t13\t \t\nFerritin (μg/L)\t \t \t \t1518.4\t \t390.4\t\nDirect Coombs test\t \tNegative\t \tNegative\t \t \t\nHemoglobin electrophoresis\t \tA1 : 88%\nF.12%\t \t \t \tA1 : 97.9%\nA2 : 2.1%\t\nG6PD level (U/GHb)\t \t \t \t3.1\t \t \n==== Refs\n1 D’Allessandro U. Ubber D. Homeed K. Malaria in infants aged less than six months-is-it an area of unmet medical need? Malaria Journal 2012 11 p. 4400 \n2 Menendez C. Mayor A. Congenital malaria: the least known consequence of malaria in pregnancy Seminars in Fetal and Neonatal Medicine 2007 12 3 207 213 10.1016/j.siny.2007.01.018 2-s2.0-34247648197 17483042 \n3 Uyoga S. Ndila C. M. Macharia A. W. Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study The Lancet Haematology 2015 2 10 e437 e444 10.1016/s2352-3026(15)00152-0 2-s2.0-84955695298 26686045 \n4 Stassijns J. Van Den Boogaard W. Pannus P. Prevalence and diagnosis of congenital malaria in rural Burundi: a cross-sectionnal study Malaria Journal 2016 15 443 1 6 10.1186/s12936-016-1478-0 2-s2.0-84984783310 26729363 \n5 Ouattara A. K. Yameogo P. Diarra B. BMC Medical Genetics 2017 18 2 8 10.1186/s12881-017-0496-2 2-s2.0-85035234730 28061824 \n6 Guindo A. Fairhust R. M. Doumbo O. K. X-linked G6PD deficiency protects hemizigous males but not heterozygous females against severe malaria PLoS Medecine March 2007 4 3 10.1371/journal.pmed.0040066 2-s2.0-33947697792 \n7 Dobbs K. R. Dent A. E. Plasmodium malaria and antimalarial antibodies in the first year of life Parasitology 2016 143 2 129 138 10.1017/s0031182015001626 2-s2.0-84958108423 26743626 \n8 Bartsocas C. S. Schulman J. D. Corash L. Can acetaminophen cause hemolysis in G6PD deficiency? Acta Haematologica 1982 67 3 p. 228 10.1159/000207064 2-s2.0-0020472276 \n9 Olivier M. Coton T. Badens C. Homozygous G6PD deficiency and propacetamol induced hemolysis Haematologica 2001 86 987 988 11532629\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2020()",
"journal": "Case reports in hematology",
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"medline_ta": "Case Rep Hematol",
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"nlm_unique_id": "101576456",
"other_id": null,
"pages": "3247127",
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"pmid": "32158566",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "27577552;6805216;23198986;26743626;17483042;17355169;26686045;29169341;11532629",
"title": "Addressing the Challenges to Diagnose Neonatal Hemolytic Anemia's Aetiologies in Low Ressources Countries: A Case Report.",
"title_normalized": "addressing the challenges to diagnose neonatal hemolytic anemia s aetiologies in low ressources countries a case report"
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"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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"abstract": "A young girl aged 13-years-old treated with montelukast, fluticasone/salmeterol, desloratadine, fluticasone furoate and salbutamol has presented numerous spontaneous bruises after that treatment with montelukast was substituted by the generic form. Stopping montelukast allow a significant improvement in bruises.",
"affiliations": "Centre régional de pharmacovigilance, Service de pharmacologie médicale, CHRU Lille, Lille, France.;Service pharmacie, Centre hospitalier de Valenciennes, Valenciennes, France.;Service pharmacie, Centre hospitalier de Valenciennes, Valenciennes, France.;Centre régional de pharmacovigilance, Service de pharmacologie médicale, CHRU Lille, Lille, France.;Service pharmacie, Centre hospitalier de Valenciennes, Valenciennes, France.;Service de pneumologie pédiatrique, Centre hospitalier de Valenciennes, Valenciennes, France.;Centre régional de pharmacovigilance, Service de pharmacologie médicale, CHRU Lille, Lille, France.",
"authors": "Béné|Johana|J|;Gantois|Emeline|E|;Landouzy|Marion|M|;Auffret|Marine|M|;Coupé|Patrick|P|;Courouble|Mélanie|M|;Gautier|Sophie|S|",
"chemical_list": "D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; C093875:montelukast",
"country": "France",
"delete": false,
"doi": "10.2515/therapie/2014058",
"fulltext": null,
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"issn_linking": "0040-5957",
"issue": "69(6)",
"journal": "Therapie",
"keywords": null,
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"mesh_terms": "D000085:Acetates; D000293:Adolescent; D018927:Anti-Asthmatic Agents; D001249:Asthma; D003521:Cyclopropanes; D004438:Ecchymosis; D005260:Female; D006801:Humans; D011804:Quinolines; D013440:Sulfides",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "517-8",
"pmc": null,
"pmid": "25270304",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Ecchymosis during montelukast therapy: about one case.",
"title_normalized": "ecchymosis during montelukast therapy about one case"
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"companynumb": "FR-ACCORD-026477",
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"abstract": "Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure in adults and a major cause of acute liver failure in children. Prompt treatment with N-acetylcysteine can mitigate hepatotoxicity and progression to liver failure. This article describes a 16-year-old girl who ingested a large dose of extra-strength acetaminophen, and how the 150 rule was used in her management.",
"affiliations": "William A. Nicholas practices emergency medicine with EmCare in the Baylor Health System in Dallas, Tex. He also serves as a physician assistant in the Texas Army National Guard. Randy Moore practices at Wellness Pointe Family Health in Longview, Tex. The authors have disclosed no potential conflicts of interest, financial or otherwise.",
"authors": "Nicholas|William A|WA|;Moore|Randy|R|",
"chemical_list": "D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "United States",
"delete": false,
"doi": "10.1097/01.JAA.0000554235.40113.c5",
"fulltext": null,
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"issn_linking": "0893-7400",
"issue": "32(4)",
"journal": "JAAPA : official journal of the American Academy of Physician Assistants",
"keywords": null,
"medline_ta": "JAAPA",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D003937:Diagnosis, Differential; D018450:Disease Progression; D062787:Drug Overdose; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute",
"nlm_unique_id": "9513102",
"other_id": null,
"pages": "51-53",
"pmc": null,
"pmid": "30913151",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Using the 150 rule to prevent hepatotoxicity from acetaminophen.",
"title_normalized": "using the 150 rule to prevent hepatotoxicity from acetaminophen"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-231822",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "BACKGROUND\nPatients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.\n\n\nMETHODS\nOn Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient's condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.\n\n\nCONCLUSIONS\nAfter extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.",
"affiliations": "Cancer Center and Departments of Cell Biology and Biochemistry, Pharmacology and Neuroscience, Pediatrics, and Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, STOP 9445 79430 Lubbock, TX, USA. min.kang@ttuhsc.edu.",
"authors": "Kang|Min H|MH|;Villablanca|Judith G|JG|;Glade Bender|Julia L|JL|;Matthay|Katherine K|KK|;Groshen|Susan|S|;Sposto|Richard|R|;Czarnecki|Scarlett|S|;Ames|Matthew M|MM|;Reynolds|C Patrick|CP|;Marachelian|Araz|A|;Maurer|Barry J|BJ|",
"chemical_list": "D017313:Fenretinide; D000082:Acetaminophen; D002443:Ceftriaxone",
"country": "England",
"delete": false,
"doi": "10.1186/1756-0500-7-256",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central 1756-0500-7-2562475547510.1186/1756-0500-7-256Case ReportProbable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study Kang Min H 1min.kang@ttuhsc.eduVillablanca Judith G 2jvillablanca@chla.usc.eduGlade Bender Julia L 3jg589@columbia.eduMatthay Katherine K 4matthayk@peds.ucsf.eduGroshen Susan 5groshen@usc.eduSposto Richard 2rsposto@chla.usc.eduCzarnecki Scarlett 6sczarnecki@chla.usc.eduAmes Matthew M 7ames.matthew@mayo.eduReynolds C Patrick 1patrick.reynolds@ttuhsc.eduMarachelian Araz 2amarachelian@chla.usc.eduMaurer Barry J 1barry.maurer@ttuhsc.edu1 Cancer Center and Departments of Cell Biology and Biochemistry, Pharmacology and Neuroscience, Pediatrics, and Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, STOP 9445 79430 Lubbock, TX, USA2 Department of Pediatrics, University of Southern California, 4650 Sunset Blvd, 90027 Los Angeles, CA, USA3 Department of Pediatric Hematology & Oncology, Columbia University, 161 Fort Washington Ave, 10032 New York, NY, USA4 Division of Pediatric Hematology-Oncology, University of California San Francisco, 505 Parnassus Ave M647, 94143 San Francisco, CA, USA5 Department of Biostatistics, School of Medicine, University of Southern California, 1441 Eastlake Ave, 90089 Los Angeles, CA, USA6 NANT Operations Center, Children’s Hospital Los Angeles, 4650 Sunset Blvd, 90027 Los Angeles, CA, USA7 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 17778 East North Shore Lane, Bayview, 83803 Idaho, USA2014 23 4 2014 7 256 256 19 3 2014 16 4 2014 Copyright © 2014 Kang et al.; licensee BioMed Central Ltd.2014Kang et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPatients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.\n\nCase presentation\nOn Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.\n\nConclusions\nAfter extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.\n\nCeftriaxoneFenretinideAcetaminophenDrug interactionBiliary sludgeFulminant hepatic failure\n==== Body\nBackground\nCeftriaxone is a widely-used, semi-synthetic third generation cephalosporin antibiotic noted for its broad activity spectrum, long plasma half-life, and relative paucity of side effects. However, the association of ceftriaxone and biliary ‘sludging’ (pseudolithiasis) is well documented. [1-4]. Ceftriaxone is present in bile at 20- to 150-fold higher concentrations than serum, is minimally metabolized, and is excreted as a divalent anion that is calcium sensitive [4]. It is speculated that the pseudolithiasis results from the combination of a hepatic effect, wherein the liver secretes a biochemically abnormal bile, and a gall-bladder effect, which provides the environment for anion precipitation [4]. With rapid onset and disappearance, ceftriaxone-calcium sludging is generally asymptomatic, but can result in frank cholelithiasis (i.e., gallstones) [4]. The incidence of biliary sludging from ceftriaxone ranges from 25% to 46%, serious complications rarely occur [3].\n\nLiver toxicity from acetaminophen, a common pediatric antipyretic/analgesic is the most common cause of acute liver failure in the USA [5]. Recommended pediatric acetaminophen dosing is 10–15 mg/kg every 4–6 hours with daily maximum dose of 4 grams. Under normal hepatic clearance, acetaminophen is principally conjugated to a nontoxic glucuronide or sulfate. However, under conditions of acetaminophen excess or disturbed metabolism, cytochrome P450 2E1 can generate a reactive acetaminophen intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which interacts with proteins and nucleic acids to damage the liver [6]. As NAPQI is conjugated to glutathione and renally excreted, acetaminophen overdose overwhelms hepatic glutathione capacity leading to accumulation of unconjugated NAPQI and hepatotoxicity [6]. Children appear to be less susceptible to acetaminophen toxicity than adults because they have less capacity for oxidative metabolism [7].\n\nFenretinide (N-(4-hydroxyphenyl)retinamide; 4-HPR) is a synthetic cytotoxic retinoid with chemopreventative activity in animal models [8], and cytotoxic activity in a variety of human cancer cell lines in vitro [9-11]. Oral capsular fenretinide has a plasma half-life of ~15-20 hours [12]. Fenretinide is hepatically cleared, at least in part, by cytochrome CYP3A4-dependent metabolism, and glucuronidation by uridine 5’-diphospho-glucoronylosyl transferases (UGTs). Three pediatric cancer clinical trials of the capsule formulation (largely in neuroblastoma) reported minimal toxicity [12,13]. Grade 3–4 hepatic toxicities included hypoalbuminemia, and elevations of AST, ALT, bilirubin, and alkaline phosphatase, which resolved without sequelae. One patient developed fatal hepatic failure determined on autopsy to be due to massive tumor infiltration of the liver and felt to be unrelated to fenretinide. However, tumor responses in these trials were limited, possibly due to poor bioavailability of the capsular formulation. Novel powder and intravenous formulations have demonstrated improved bioavailability as evidenced by higher plasma levels [14,15]. A phase I study of the LXS powdered formulation achieved plasma levels 2–6 fold higher than the capsular formulation and four complete responses [14]. Hepatic toxicity was limited to grade 3 AST/ALT and Grade 4 elevation of alkaline phosphatase which resolved without sequelae.\n\nThe New Approaches to Neuroblastoma Therapy (NANT) consortium conducted a Phase I trial of an intravenous fenretinide emulsion formulation (IND#: 70058). We report a case of fatal hepatic failure during course one of therapy. After a thorough review of the clinical course, concomitant medications, laboratory data, and fenretinide plasma levels, we conclude that the event likely derived from an unexpected multi-drug interaction between fenretinide and ceftriaxone and acetaminophen.\n\nCase presentation\nThe NANT 2004–03 Phase I study (ClinicalTrials.gov Identifier NCT00646230) escalated the dose of intravenous (IV) fenretinide (given for five days as a continuous infusion and repeated every 21 days) using a standard 3 + 3 design to determine the maximum tolerated dose (MTD). Toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. (http://ctep.cancer.gov). Eligible patients were ≤ 30 years of age with relapsed/refractory high risk neuroblastoma. Organ function required included bilirubin, AST, ALT, and creatinine ≤ 1.5 × normal. Plasma fenretinide levels were obtained at hours 0, 6, 12, 24, 36, 48, 72, 96, 120 (end of infusion), then +2 hours and +48 hours after the end of infusion, protected from light, immediately frozen, and analyzed using an HPLC method [16]. The study was terminated prior to determination of the MTD due to inadequate drug supply after the enrollment of 17 patients. Table 1 summarizes dose levels tested, dose limiting toxicities, and all hepatic toxicities.\n\nTable 1 Dose limiting toxicity and maximum grade of all hepatic toxicities for all 15 patients enrolled on NANT 2004–04\n\nTotal dose of IV fenretinide\t# patients enrolled (# evaluable for dose escalation)\tPatient Age at study entry (years)\tFenretinide peak level Course 1 (μM)\tDose Limiting Toxicity\tTotal number courses/Hepatic toxicities (maximum grade (Gr) across all courses received )\tCeftriaxone during or after fenretinide\tAcetaminophen during or after fenretinide\t\nLevel 1: 640 mg/m2/day\t3 (3)\t7.9\t30.5\tNone\t6 courses: Gr 2 AST, Gr 2 hypoalbuminemia, Gr 1 hyperbilirubinemia\t3 days during Course 6\t \t\n8.5\t17.2\tNone\t1 course: Gr 1 hypoalbuminemia, Gr 1 AST\t \t1 dose 2 days after Course 1\t\n24\t30.1\tNone\t2 courses; none\t \t \t\nLevel 2: 770 mg/m2/day\t3 (3)\t4.2\t40.7\tNone\t30 courses: Gr. 3 ALT, Gr 3 AST, Gr. 2 hypoalbuminemia, Gr 1 alkaline phosphatase. Got dose level 1 for courses 26–30 due to delayed platelet recovery course 25.\t \t20 doses starting after completion of Course 14\t\n4.4\t70.2\tNone\t4 courses; Grade 1 AST\t \t \t\n5\t39.4\tGr 3 hypoalbuminemia*\t1 course: Gr 3 AST, Gr 3 hypoalbuminemia*\t \t \t\nLevel 3: 925 mg/m2/day\t7 ( 6 )\t6.7\t36.3\tNone\t2 courses: Gr. 1 ALT, Gr 1 AST, Gr. 1 hypoalbuminemia\t \t4 doses during Course 3\t\n5.2\t38.4\tNone\t6 courses; Gr 1 AST, Gr 1 hypoalbuminemia, Gr 2 hyperbilirubinemia\t2 days during Course 1\t \t\n9.7\t60.7\tGr 4 hypertriglyceridemia due to error in drug infusion\t1 course: Not evaluable for dose escalation due to error in drug infusion with 24 hour dose given over 12 hours; Gr 1 hypoalbuminemia, Gr 2 hyperbilirubinemia\t \t \t\n11.4\t33.0\tPseudotumor cerebri\t1 course: Gr 3 ALT, Gr 2 AST\t \t \t\n11\t29.1\tNone\t1 course; Gr 1 ALT, Gr 2 AST, Gr 1 hypoalbuminemia\t \t \t\n5.3\t23.7\tNone\t2 courses: Gr 1 AST\t \t \t\n12.6\t45.0\tNone\t2 courses; Gr 1 ALT, Gr 2 AST\t \t \t\nLevel 4: 1110 mg/m2/day\t2 (2)\t5.5\t83.3\tGr 4 epistaxis related to multi organism non-neutropenic bacteremia during course 5\t5 courses: Gr 1 ALT, Gr 2 AST, Gr 2 hypoalbuminemia, Gr 1 alkaline phosphatase\t4 days starting 9 days after completion of Course 5\t \t\n7.2\t110.9\tFatal hepatic failure, renal failure, and hypotension**\t1 course (subject of this case report): Gr 5 liver dysfunction/failure (clinical), Gr 4 ALT, Gr 4 AST, Gr 4 hyperbilirubinemia; Gr 3 hypoalbuminemia; Gr 1 alkaline phosphatase\t3 days starting 4th day of the infusion\t9 doses starting 4th day of the infusion\t\nLevel 3a: 925 mg/m2/day\t2 (0)\t6.7\t14.17#\tNone\t2 courses: Gr 1 ALT/Gr 1 AST\t \t \t\n7.8\t21.93#\tNone\t5 courses:Gr 1 AST, Gr 1 hypalbuminemia, Gr 1 alkaline phosphatase\t \t \t\n*Patient enrolled with Grade 1 hypoalbuminemia, resolved from asymptomatic Grade 3 to Grade 2 by day 27 of course; Grade 1 by Day 31 (definition of DLT was resolution to Grade 1 by Day 28). Dose level not expanded since not considered clinically significant & protocol amended to exclude metabolic abnormalities as DLT. ** Subsequent Gr 4 acidosis, colitis, disseminated intravascular coagulation, enteritis, hypoxia, and hemorrhage; Gr 3 encephalitis as described in the text. # Both patients had course 1 infusion interrupted for hypertriglyceridemia and dose reduced by 50% to complete course 1 and for subsequent courses.\n\nThe patient was a seven year-old male diagnosed with stage 4 high-risk neuroblastoma in October 2007, who received induction according to the ANBL02P1 regimen (NCT00070200) which included cyclophosphamide, topotecan, cisplatin, etoposide, doxorubicin, and vincristine [17] followed by myeloablative therapy with I131-MIBG, carboplatin, etoposide, and melphalan with autologous purged hematopoietic stem cell transplant in May 2008 on NANT Protocol 2001–02 (NCT00253435). He received 2160 cGy local radiation to the right adrenal primary and distal femurs in July 2008, two courses of 3 F8 anti-GD2 antibody, nine courses of isotretinoin, and an additional 1440 cGy radiation to a single persistent skull metastasis in July 2009. He then received five courses of irinotecan and temozolomide for refractory bone metastases September-December, 2009. Bone marrow exam done January 2010 showed recurrent tumor, with no other relapse sites by CT or MIBG scans. No additional anti-cancer therapy was received until the intravenous fenretinide in February 2010 (assigned dose 1110 mg/m2/day as a continuous infusion for 120 hours).\n\nThe patient tolerated therapy without adverse events until Day 4 when he developed fever (38.2°C) without localizing symptoms. Acetaminophen (10 mg/kg) every 4 hours was initiated, and increased to 15 mg/kg beginning with second dose. After blood cultures, intravenous ceftriaxone was initiated. On the same day, temperature increased to 39.4°C, despite acetaminophen and cooling measures, with Grade 1 abdominal pain (had not stooled in five days) and Grade 2 headache. Abdominal exam was soft with normal bowel sounds. Neurologic exam was normal and fundi without papilledema. The headache was assessed as likely due to fever/dehydration but pseudotumor cerebri from fenretinide could not be ruled out, so infusion was stopped on Day 5 at Hour +119 of the scheduled 120 hour infusion. Intravenous fluids were given for poor oral intake and decreased urine output. Acetaminophen and one dose of ibuprofen were given for fever management. Two doses of ibuprofen were administered Day 5. On the night of Day 5, headache improved to Grade 1, but intermittent fever persisted and abdominal pain increased to Grade 3. Abdominal plain film was consistent with constipation.\n\nDay 4 lab studies included an elevated LDH of 1241 U/L (797 baseline), bilirubin 0.6 mg/dl (0.2 mg/dl baseline), AST 57 U/L (39 U/L baseline), ALT 25 U/L (17 U/L baseline). No labs were performed on the morning of Day 5. On Day 5, the patient became hypotensive despite fluid support and required pressor support (dopamine). Oxygen saturation was 90% on room air but normal on mask oxygen. Blood bacterial cultures from Days 4, 5, 6 and 7 and fungal cultures from Day 6 were negative. On Day 6, AST further elevated to 698 U/L, ALT elevated to 259 U/L, creatinine was elevated at 1.6 mg/dL; LDH further elevated to 4,231 U/L; and albumin was 2.6 g/dL. Day 6 abdominal ultrasound showed renal echogenicity consistent with a medical insult, and a gall stone with surrounding fluid. Ceftriaxone was replaced on Day 6 with meropenem and vancomycin; metronidazole was added Day 7. On Day 7, the patient’s course steadily deteriorated with increasing abdominal distention and pain requiring narcotics, with new onset epistaxis. Abdominal X-rays showed paucity of gas without free air. Mental status was diminished, but the patient was arousable and verbal. A non-contrast head CT was normal. Elective intubation was performed to maintain respiratory status. CT scan of the chest/abdomen/pelvis showed marked hepatomegaly, moderate periportal edema, large bilateral pleural effusions and bibasilar atelectasis without pulmonary infiltrates. Bilateral chest tubes were required for the pleural effusions. Epinephrine and vasopressin (stopped after 5 days) were added to dopamine. Fever resolved on Day 7. On Day 8, the patient developed anasarca and had paracentesis Days 8 and 10 (culture negative) for ascites. Laboratory results showed progressive hepatic failure on Day 9 with secondary severe metabolic acidosis and coagulopathy: ammonia 72 μM/L, PT 24.7 sec, PTT 50 sec, fibrinogen 131, positive D-Dimers, AST 8,289 U/L, ALT 1,588 U/L, bilirubin 3.5 mg/dL, albumin 2.8 g/dL, and elevated lactate (101 mg/dL) with serum pH 7.17. Direct bilirubin was elevated when evaluated (Days 13, 17–20), with maximum of 9.3 mg/dL (indirect 12.6 mg/dL, total bilirubin 22.8 mg/dL) on Day 17. Skin biopsy (Day 14) of an erythematous confluent macular rash progressing to desquamation (onset Day 10) showed superficial perivascular and spongiotic dermatitis with eosinophils, consistent with either drug eruption or viral exanthem. By Day 18, there was worsening mucosal bleeding with frank blood from the paracentesis site and chest tubes. The patient was anuric by Day 20. Despite aggressive supportive care, the patient expired Day 20. Of note, this patient previously received ceftriaxone without hepatic toxicity or adverse reaction. Other concomitant medications included montelukast and ondansetron. Infectious evaluation included Influenza virus A&B Rapid DAA (Day 5); negative quantitative PCR for Epstein-Barr virus and cytomegalovirus (Day 6); Clostridia difficile toxin A&B DAA, Escheria coli 0157 screen, and stool adenovirus DAA (Day 8); negative respiratory culture (Days 8,10), non-reactive Hepatitis A IgM, Hepatitis B Core antibody, Hepatitis B surface antigen and reactive Hepatitis A IgG/IgM and Hepatitis B surface antibodies (Day 13, had history of Hepatitis A and B vaccines);and negative Acid Fast Bacilli, bacterial, viral, and fungal cultures of ascites, urine, trachea, liver and spleen (post mortem).\n\nAutopsy showed extensive hepatocellular damage and diffuse abdominal bleeding without evidence of tumor, infection, or allergic reaction. Liver findings included complete destruction of liver architecture with extensive hemorrhagic necrosis of liver parenchyma, marked bile duct proliferation, abundant hemosiderin consistent with cholestasis; no viral inclusions and negative immunohistochemistry for Herpes Simples virus 1 and 2, and cytomegalovirus. Post mortem skin biopsy showed subepidermal bullae and extensive upper dermal acute hemorrhage, likely a drug eruption since no evidence of an infection. Left ventricular papillary muscle necrosis was noted, likely contributing to circulatory failure and organ congestion. The autopsy was consistent with drug-related hepatotoxicity as the primary fatality-inducing event. Hepatic function, and fenretinide administration with plasma pharmacokinetics are summarized in Figure 1. The death was considered definitely related to fenretinide, but it remains unclear whether this was related to fenretinide-alone (e.g. plasma levels or total drug exposure) or to an interaction with other drugs that may have affected the elimination of fenretinide or acetaminophen (i.e., a hepato-biliary effect of ceftriaxone). The onset of fever with elevated LDH and ALT on Day 4, prior to starting ceftriaxone and acetaminophen, suggests that some hepatocellular injury may have occurred with fenretinide alone, but was likely exacerbated by these concomitant medications. The clinical generalized capillary leakage seen in this patient has been reported with infection, drug injury, multi-organ failure, and rarely with other retinoids [18].\n\nFigure 1 Plasma concentrations of fenretinide and its metabolites, concomitant ceftriaxone and acetaminophen, and laboratory analysis in patient. A) Plasma concentrations of fenretinide (closed circle) and the metabolites (4-MPR: open circle and 4-oxo-4-HPR: filled triangle) versus time after the initiation of infusion (hr) is plotted. Each dose of ceftriaxone (750 mg/dose), and acetaminophen (10 mg/kg for the initial dose and 15 mg/kg for subsequent doses) is indicated. B) Liver function analysis, AST/ALT, bilirubin (maximum for that date), and PT, are plotted on the same time scale. Due to the differences in values, the left Y-axis was used for plotting AST and ALT, and right Y-axis was used for bilirubin and PT. A PT value at 40 hours was not available.\n\nWhile Grade 4 alkaline phosphatase elevations have occurred in children treated with fenretinide capsular and LXS oral power formulations, no alkaline phosphatase elevations occurred in the other patients on the NANT intravenous fenretinide study (Table 1). Grade 3 hypoalbuminemia in one patient receiving intravenous fenretinide and was reported in one patient receiving capsular fenretinide [13]. One fatal case of hepatic toxicity occurred in a seven year old female on the ANBL0321 capsular fenretinide phase II study at a dose of 2475 mg/m2/day for seven days, with onset 6 days after Course One, but extensive tumor infiltration in the liver on autopsy was considered to be the etiology. No other fatal hepatic toxicity has been reported on any other adult or pediatric fenretinide study using the capsule, oral LXS powder, or intravenous formulations [12,14,15].\n\nIn an adult intravenous fenretinide trial [15], several patients tolerated fenretinide plasma concentrations between 100–150 μM without hepatic toxicity. In this patient, fenretinide plasma concentrations gradually increased to ~60 μM at the end of Day 4. After acetaminophen and ceftriaxone were started on Day 5, fenretinide plasma concentrations increased steeply to ~110 μM (Figure 1A). Within two hours of stopping fenretinide, the fenretinide level dropped to ~80 μM and, after two days, was less than 20 μM (Figure 1A). Peak fenretinide concentrations in two other patients on this study were > 70 μM with minimal toxicity (Table 1). Considering the minimal hepatic toxicity in all fenretinide studies, and the tolerance of higher fenretinide plasma levels without hepatotoxicity, fenretinide alone may not be the cause of hepatic failure in the present case. Three other patients on the NANT 2004–03 study who received concomitant ceftriaxone all reported transient grade 1–2 hepatic toxicities during that course (Table 1). This may be due to inter-patient variation in biliary sludging of ceftriaxone. Three other N2004-03 patients received concomitant acetaminophen without hepatic toxicity; but no other patient received all three drugs concomitantly. Also, peak plasma levels were variable within a given dose, suggesting individual pharmacogenomics may play a role in the variation of plasma levels. . In the present case, the fenretinide plasma level increased sharply after ceftriaxone and acetaminophen were initiated. Retrospective attempts to measure acetaminophen levels in the fenretinide PK samples were not informative since the samples were beyond the stability duration of acetaminophen. Based on the abrupt decrease of fenretinide clearance, we hypothesize that acetaminophen clearance was also reduced due to the concurrent ceftriaxone. It is unclear whether acute liver failure would have been due to altered pharmacokinetics of acetaminophen or to hepatic glutathione depletion. Based on a previous report, intracellular glutathione levels are not related to fenretinide cellular cytotoxicity in vitro, suggesting that fenretinide may not affect intracellular glutathione [19]. In addition, N-(4-methoxyphenyl)retinamide (4-MPR) is the major metabolite of fenretinide and is a methylation (phase II metabolism) product eliminated without further modification. Therefore, it is less likely that acetaminophen and fenretinide competed for glutathione - competition for UGT-mediated glucuronidation is more likely. This case suggests that the biliary sludging effect of ceftriaxone may have interfered with the elimination of fenretinide and acetaminophen, resulting in an unexpected adverse and severe acetaminophen toxicity. However, ibuprofen-related hepatic failure cannot be ruled out as it is reported that therapeutic doses of ibuprofen as a single agent can result in acute liver failure [20].\n\nAfter this event, NANT 2004–03, and related adult trials, PhI-42 (NCT00104923) and PhI-54 (NCT00387504), were amended to prohibit ceftriaxone or acetaminophen for 24 hours prior to the fenretinide infusion and for 24 hours (ceftriaxone) or 48 hours (acetaminophen) after fenretinide infusion completion, with ibuprofen recommended (if needed) for fever during the fenretinide infusion. After enrolling two patients following this amendment, the NANT 2004–03 trial closed secondary to insufficient drug supply prior to determining an MTD.\n\nConclusion\nThis clinical case reports lethal hepatotoxicity in a patient concurrently receiving intravenous fenretinide, ceftriaxone, and acetaminophen. The event is suspected to result from an unexpected drug interaction between these three agents resulting in hepatic acetaminophen toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.\n\nConsent\nWritten informed consent was obtained from the patient’s guardian for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nNANT: New Approaches to Neuroblastoma Therapy; LDH: Lactate dehydrogenase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PT: Prothrombin time.\n\nCompeting interests\nThe Children’s Hospital Los Angeles (CHLA) holds patents and/or patent applications on intravenous fenretinide (the study drug). CHLA and co-inventors of the study drug, Drs. BJM and CPR, Texas Tech University Health Sciences Center, Lubbock, TX, may potentially benefit financially from the development and future use of the study drug. JGV and AM are on the medical staff at CHLA, and SC is a CHLA employee, and may indirectly benefit from the development of the study drug.\n\nAuthors’ contributions\nMHK analyzed pharmacokinetic samples of the patient and wrote the manuscript; JGV was the primary oncologist of the patient; KKM and JGB were co-chairs of NANT 2004–03; AM was on the study committee of NANT 2004–03; JGV, AM, KKM, SG, RS, MMA, CPR, and BJM provided substantial intellectual contributions to the study as clinical trialists, biostatisticians, or a pharmacologist. JGV, AM, KKM, SG, and SC were part of the NANT study monitoring committee for N2004-03; SC was the research nurse for N2004-03. JGV, BJM, and CPR participated in writing the manuscript. All authors read and approved the final manuscript.\n\nAuthors’ information\nMHK, pharmacologist: Associate Professor and Director of Clinical Pharmacology Laboratory, Cancer Center, TTUHSC, JGV, pediatric oncologist: primary care physician of the patient presented in this manuscript. JGB, pediatric oncologist: participating physician of the phase I study, Study chair for other clinical trials for COG and NANT. KKM, pediatric oncologist: Senior Editor of Clinical Cancer Research, SG, Biostatistician: COG, NANT, and California Cancer Consortium biostatistician. RS, biostatistician: COG and NANT biostatistician, SC, RN and CRA: for NANT operation center. MMA, PhD in pharmacologist: Director of Clinical Pharmacology Laboratory, Mayo Clinic, CPR, MD/PhD: Director of Cancer Center, TTUHSC, BJM, pediatric oncologist (MD/PhD): associate professor, TTUHSC.\n\nAcknowledgements\nThe work was supported by National Cancer Institute, grant numbers: R01 CA100895 and P01 CA81403; Cancer Prevention & Research Institute of Texas, grant number RP100762; The Children's Neuroblastoma Cancer Foundation; Alex's Lemonade Stand Foundation; Children's Neuroblastoma Cancer Foundation; Pediatric Cancer Research Group; Dougherty Family Foundation; Evan T. J. Dunbar Neuroblastoma Foundation; Douglas Michael Fuller Foundation; Neuroblastoma Children's Cancer Society. We thank Drs. Malcolm Smith and Nita Seibel at National Cancer Institute, NIH for helpful discussion on the case.\n==== Refs\nKo CW Sekijima JH Lee SP Biliary sludge Ann Intern Med 1999 130 301 311 10.7326/0003-4819-130-4-199902160-00016 10068389 \nBor O Dinleyici EC Kebapci M Aydogdu SD Ceftriaxone-associated biliary sludge and pseudocholelithiasis during childhood: a prospective study Pediatr Int 2004 46 322 324 10.1111/j.1328-0867.2004.01884.x 15151550 \nFamularo G Polchi S De SC Acute cholecystitis and pancreatitis in a patient with biliary sludge associated with the use of ceftriaxone: a rare but potentially severe complication Ann Ital Med Int 1999 14 202 204 10566187 \nKim YS Kestell MF Lee SP Gall-bladder sludge: lessons from ceftriaxone J Gastroenterol Hepatol 1992 7 618 621 10.1111/j.1440-1746.1992.tb01496.x 1486190 \nSchiodt FV Atillasoy E Shakil AO Schiff ER Caldwell C Kowdley KV Stribling R Crippin JS Flamm S Somberg KA Rosen H McCashland TM Hay JE Lee WM Etiology and outcome for 295 patients with acute liver failure in the United States Liver Transpl Surg 1999 5 29 34 10.1002/lt.500050102 9873089 \nDahlin DC Miwa GT Lu AY Nelson SD N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen Proc Natl Acad Sci U S A 1984 81 1327 1331 10.1073/pnas.81.5.1327 6424115 \nvan der Marel CD Anderson BJ van Lingen RA Holford NH Pluim MA Jansman FG van den Anker JN Tibboel D Paracetamol and metabolite pharmacokinetics in infants Eur J Clin Pharmacol 2003 59 243 251 10.1007/s00228-003-0608-0 12761605 \nMoon RC Thompson HJ Becci PJ Grubbs CJ Gander RJ Newton DL Smith JM Phillips SL Henderson WR Mullen LT Brown CC Sporn MB N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat Cancer Res 1979 39 1339 1346 421218 \nDelia D Aiello A Lombardi L Pelicci PG Grignani F Grignani F Formelli F Menard S Costa A Veronesi U N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid Cancer Res 1993 53 6036 6041 8261419 \nO'Donnell PH Guo WX Reynolds CP Maurer BJ N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes Leukemia 2002 16 902 910 10.1038/sj.leu.2402485 11986953 \nOridate N Lotan D Xu XC Hong WK Lotan R Differential induction of apoptosis by all-trans-retinoic acid and N-(4-hydroxyphenyl)retinamide in human head and neck squamous cell carcinoma cell lines Clin Cancer Res 1996 2 855 863 9816241 \nVillablanca JG London WB Naranjo A McGrady P Ames MM Reid JM McGovern RM Buhrow SA Jackson H Stranzinger E Kitchen BJ Sondel PM Parisi MT Shulkin B Yanik GA Cohn SL Reynolds CP Phase II Study of Oral Capsular 4-Hydroxyphenylretinamide (4-HPR/Fenretinide) in Pediatric Patients with Refractory or Recurrent Neuroblastoma: a Report from the Children's Oncology Group Clin Cancer Res 2011 17 6858 6866 10.1158/1078-0432.CCR-11-0995 21908574 \nVillablanca JG Krailo MD Ames MM Reid JM Reaman GH Reynolds CP Phase I trial of oral fenretinide in Children with high-risk solid tumors: a report from the Children's Oncology Group (CCG 09709) J Clin Oncol 2006 24 3423 3430 10.1200/JCO.2005.03.9271 16849757 \nMaurer BJ Kang MH Villablanca JG Janeba J Groshen S Matthay KK Sondel PM Maris JM Jackson HA Goodarzian F Shimada H Czarnecki S Hasenauer B Reynolds CP Marachelian A Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: A report from the new approaches to neuroblastoma therapy (NANT) consortium Pediatr Blood Cancer 2013 60 1801 1808 10.1002/pbc.24643 23813912 \nMohrbacher A Gutierrez M Murgo AJ Kummar S Reynolds CP Maurer BJ Groshen S Vergara L Yang AS Phase I trial of fenretinide (4-HPR) intravenous emulsion for hematologic malignancies Blood 2007 110 2851 \nCooper JP Hwang K Singh H Wang D Reynolds CP Curley RW JrWilliams SC Maurer BJ Kang MH Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure Br J Pharmacol 2011 163 1263 1275 10.1111/j.1476-5381.2011.01310.x 21391977 \nPark JR Scott JR Stewart CF London WB Naranjo A Santana VM Shaw PJ Cohn SL Matthay KK Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study J Clin Oncol 2011 29 4351 4357 10.1200/JCO.2010.34.3293 22010014 \nEstival JL Dupin M Kanitakis J Combemale P Capillary leak syndrome induced by acitretin Br J Dermatol 2004 150 150 152 10.1111/j.1365-2133.2004.05771.x 14746632 \nCooper JP Bang S Singh H Williams SC Kang MH Fenretinide cytotoxicity is independent of both constitutive and pharmacologically modulated glutathione levels in pediatric acute lymphoblastic leukemia cells cultured at hypoxia Pediatr Blood Cancer 2012 58 994 997 10.1002/pbc.23293 22532987 \nRodriguez-Gonzalez FJ Montero JL Puente J Fraga E Costan G Barrera P Muntane J De la Mata M Zambrana JL Orthotopic liver transplantation after subacute liver failure induced by therapeutic doses of ibuprofen Am J Gastroenterol 2002 97 2476 2477 10.1016/S0002-9270(02)04372-1 12358284\n\n",
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"mesh_terms": "D000082:Acetaminophen; D002443:Ceftriaxone; D002648:Child; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017809:Fatal Outcome; D017313:Fenretinide; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009447:Neuroblastoma; D011859:Radiography",
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"title": "Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study.",
"title_normalized": "probable fatal drug interaction between intravenous fenretinide ceftriaxone and acetaminophen a case report from a new approaches to neuroblastoma nant phase i study"
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"abstract": "Intracranial abscesses are rare complications of Streptococcus pneumoniae infections, and to our knowledge, there have been no case reports of post-infectious vasculitis developing in such patients. Here we describe the case of a 48-year-old post-splenectomy male who developed post-infectious vasculitis following S. pneumoniae otitis media complicated by mastoiditis, osteomyelitis, meningitis, and intracranial abscess. Clinicians ought to be aware of the possible adverse outcomes of invasive S. pneumoniae and the limitations of current treatment options.",
"affiliations": "Geisel School of Medicine at Dartmouth , Hanover, NH.;Department of Medicine, Dartmouth-Hitchcock Medical Center , Lebanon, NH.;Department of Hospital Medicine, Dartmouth-Hitchcock Medical Center , Lebanon, NH, USA.",
"authors": "Lucas|Alexandra|A|;Maung|Ko Ko|KK|;Ratts|Ryan|R|",
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"doi": "10.4081/idr.2016.6844",
"fulltext": "\n==== Front\nInfect Dis RepInfect Dis RepIDRInfectious Disease Reports2036-74302036-7449PAGEPress Publications, Pavia, Italy 10.4081/idr.2016.6844Case ReportStreptococcus Pneumoniae Intracranial Abscess and Post-Infectious Vasculitis Lucas Alexandra 1Maung Ko Ko 2Ratts Ryan 31 Geisel School of Medicine at Dartmouth, Hanover, NH2 Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH3 Department of Hospital Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA30 Wolf Road Apt 213, Lebanon, NH 03766, USA. +1.978.771.9665. alexandra.t.lucas.med@Dartmouth.eduContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n31 12 2016 31 12 2016 8 4 684422 8 2016 03 11 2016 02 12 2016 ©Copyright A. Lucas et al.2016Licensee PAGEPress, ItalyThis work is licensed under a Creative Commons Attribution NonCommercial 4.0 License (CC BY-NC 4.0).Intracranial abscesses are rare complications of Streptococcus pneumoniae infections, and to our knowledge, there have been no case reports of post-infectious vasculitis developing in such patients. Here we describe the case of a 48-year-old post-splenectomy male who developed post-infectious vasculitis following S. pneumoniae otitis media complicated by mastoiditis, osteomyelitis, meningitis, and intracranial abscess. Clinicians ought to be aware of the possible adverse outcomes of invasive S. pneumoniae and the limitations of current treatment options.\n\nKey words\nstreptococcus pneumoniaeintracranial abscesspost-infectious vasculitis\n==== Body\nIntroduction\nStreptococcus pneumoniae intracranial abscess is a rare complication of pneumococcal infections, with the majority of cases being reported in the pre-antibiotic era. Today, the survival rate and long-term outcome of these patients remains quite poor, with up to 35% mortality and 40% experiencing prolonged neurological deficits.1,2 Most infections occur as a result of contiguous infection, with paranasal sinus and the middle ear being the most common sources.3 Post-infectious vasculitis is an uncommon complication of S. pneumoniae, with arterial cerebrovascular complications occurring in up to 21.8% of S. pneumoniae meningitis.4 To our knowledge, no case report has identified post-infectious vasculitis occurring after S. pneumoniae abscess in an adult. Here, we report a case of a 48yo male who developed post-infectious vasculitis following S. pneumoniae otitis media, mastoiditis, osteomyelitis, meningitis and abscess.\n\nCase Report\nOur patient is a 48 year-old male patient with childhood splenectomy and no pneumococcal vaccine who initially presented to an outside emergency department (ED) with ear pain and headache. He was given amoxicillin and hydrocodone bitartrate plus acetaminophen and was discharged home. That night he developed altered mental status, becoming uncommunicative and unable to follow commands. He re-presented to the same ED and found to be hypertensive and febrile, with a Glascow coma scale (GCS) score of 13 without focal motor or sensory deficits. A complete blood count revealed leukocytosis with a white blood cell (WBC) count of 51×103/mcL (reference value 4.0-10.0×103/mcL). An MRI demonstrated a left 4×4×3 cm heterogenous multiloculated mass extending intracranially from the mastoid air cells, consistent with mastoid abscess and osteomyelitis (Figure 1A). An epidural abscess, sigmoid sinus and jugular thrombosis were also seen (Figure 1B). Lumbar puncture showed 2600 white blood cells per mcl (reference value 0-5/mcL), 250 red blood cells per mcL (reference value 0-5/mcL), total protein content of 924 mg/dL (reference value 15-45 mg/dL), glucose <1 mg/dL. Gram staining revealed neutrophils and grampositive diplococci. He was transferred to our hospital, where he was taken to the operating room for mastoidectomy, craniotomy, and CSF shunt placement with evacuation of intradiploic skull mass and epidural abscess. Pathology of skull mass demonstrated a benign epithelial inclusion cyst with lymphocytic infiltrate. Initial antibiotic regimen included IV vancomycin, ceftriaxone, and steroid regimen of IV dexamethasone. Mastoid fluid culture revealed S. pneumoniae resistant to penicillin and ceftriaxone (unusual in our institution) and ceftriaxone was changed to rifampin. His status improved over the next 8 days, and he was discharged on hospital day (HD) 8 with an ongoing headache well controlled with oxycodone, a Montreal Cognitive Assessment (MOCA) of 19/30, and a decreasing leukocytosis (white blood cell count 20.2×103/mcL). At discharge, he remained on IV vancomycin and PO rifampin for a planned six-week course, and a two week PO dexamethasone taper starting from 10mg PO bid.\n\nTwo days after discharge, he re-presented to the outside ED with worsening temporal headache. His neurological exam was normal, but he was febrile to 38.2 C. A complete blood cell count revealed 22.6×103/mcL white blood cells, platelets 900×103/mcL (reference 145-370×103/mcL), and a new anemia, with hemoglobin of 11.4 gm/dL (reference range 13.7-17.5 gm/dL). A CT head revealed persistent opacification of residual left mastoid. He was begun on levofloxacin in addition to his vancomycin and rifampin, and transferred to our hospital. An MRI obtained at our institution demonstrated increased meningeal enhancement and new left cerebellar enhancement that was consistent with either post-surgical change or cerebellitis. His LP was consistent with persistent signs of infection versus inflammation (WBC 846 cells per mcL, protein 168 mg/dL, and glucose 4 mg/dL). His IV dexamethasone was empirically increased to 10 mg IV. On HD2, he developed sudden-onset of slurred speech and right facial droop; a CT did not demonstrate any new infarcts. Over the next 3 days, he remained febrile, dysarthric, confused, and agitated. His dexamethasone was decreased to 6 mg and then 4 mg bid to allow for better penetration of antibiotics. Given his ongoing signs of infection, ceftaroline was added to his regimen and levofloxacin replaced by moxifloxacin. Multiple blood and CSF cultures demonstrated no growth. On HD10, a stroke alert was activated due to unresponsiveness to voice and sternal rub. A CT head demonstrated a subacute lacunar infarct of the left basal ganglia and corona radiate, and levetiracetam was begun for seizure prophylaxis. An MRI the following day showed several punctate areas of restricted diffusion, most likely small areas of infarct consistent with post-infectious vasculitis (Figure 2). His dexamethasone was increased to 8 mg IV q8h, and his obtundation improved the next day. No intravenous immunoglobulin (IVIG) was given. Over the course of the next 47 days, he had fluctuating mental status that gradually improved. Consulting services during admission included neurosurgery, ENT, infectious disease, and neurology. His course was complicated by thrush, red man syndrome, hyponatremia secondary to SIADH, and urinary retention. He was maintained on a prolonged steroid taper and completed an additional 4 week course of vancomycin, rifampin, ceftaroline, and moxifloxacin. On HD46, he underwent an interventional radiology-guided mastoid fluid drainage, which showed only few WBCs without organisms or growth. On HD57, he was discharged home following an MRI that showed evolution of his old infarcts and no new disease. Post-discharge, his cognition, memory and motor function continued to gradually improved. Unfortunately, he died a few months later as a passenger in a single motor vehicle accident before full neurological recovery was achieved.\n\nDiscussion\nThis complex case highlights the risk of vascular involvement in invasive pneumococcal infections. Patients with S. pneumoniae infections are at particular risk of such complications given the pro-inflammatory cascade triggered by the bacteria, regardless of initial antibiotic therapy.5 Markers of both neuronal, glial, and myelin destruction have been identified in S. pneumoniae meningitis patients, likely due to streptococcal cell wall induced cytokine toxicity.6\n\nOur patient was at higher risk of invasive S. pneumoniae infection given his history of splenectomy without pneumococcal vaccination and of benign epithelial inclusion cyst. Underlying chronic predispositions for infection are found in over 40% of patients, with chronic alcoholism, asplenia, diabetes mellitus, and malignancy being among the most common.4,7 The majority of patients present with an associated infection, mainly ear or sinus infections or pneumonias.4 Nonetheless, pneumococcal abscesses remain very rare, with the majority of reported cases occurring in the pre-antibiotic era.1\n\nGiven the rarity of post-infectious vasculitis, there is no consensus on treatment for S. pneumoniae cerebral vasculitis. Corticosteroids are effective in preventing complications of meningitis, e.g. sensorineural hearing loss, if given very early in the course of treatment (prior to or at the time of antibiotics). Although treatment is typically limited to less than four days, some reports have suggested a rebound inflammatory effect whereby steroid withdrawal can result in increased vascular inflammation.5 Our patient’s course adds to this growing body of literature, given his progression while on a prolonged taper of steroids. The role of IVIG is not well-established in this population, although it is used in isolated cases of non-infectious cerebral vasculitis. However, IVIG and glucocorticoids have been reported to be efficacious in patients with post-infectious vasculitis.6 Although our patient did not receive IVIG, this is a possible treatment option that ought to be considered.\n\nConclusions\nThis report highlights the post-infectious vascular complications of invasive pneumococcal disease in an at-risk patients. Clinicians should be aware of the severity of illness and the possible adverse outcomes of S. pneumoniae. More research needs to be done in order to establish the various roles of antibiotics, glucocorticoids, and IVIG treatments so that we can effectively manage these patients in the future.\n\nFigure 1. Patient MRA obtained on HD1 of first admission. A) T1-weighted precontrast imaging demonstrating a 3×4 cm area of high signal intensity extending posteriorly from the left mastoid, consistent with mastoid abscess versus osteomyelitis. B) MRV demonstrating sigmoid sinus and jugular thrombosis.\n\nFigure 2. T2-weighted MRI obtained on HD11 of second admission, demonstrating punctate areas of restricted diffusion, most likely small areas of infarct consistent with post-infectious vasculitis.\n==== Refs\nReferences\n1. Grigoriadis E Gold WL \nPyogenic brain abscess caused by streptococcus pneumonia: case report . Clin Infect Dis \n1997 ;25 :1108 -12 .9402366 \n2. Tseng JH Tseng MY \nBrain abscess in 142 patients: factors influencing outcome and mortality . Surg Neurol \n2006 ;65 :557 -562 .16720170 \n3. Carpenter J Stapleton S Holliman R. \nRetrospective analysis of 49 cases of brain abscess and review of the literature . Eur J Clin Microbiol Infect Dis \n2007 ;26 :1 -11 .17180609 \n4. Kastenbauer S Pfister HW \nPneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases . Brain \n2003 ;126 :1015 -25 .12690042 \n5. Ribeiro S Domingues V Faria RM Mendonça T. \nInvasive pneumococcal disease complicated by cerebral vasculitis, transient diabetes inspidus and spondylodiscitis . BMJ Case Rep \n2013 :bcr2013010336 .\n6. Jorens PG Parizel PM Demey HE \nMeningoencephalitis cased by streptococcus pneumoniae: a diagnostic and therapeutic challenge . Neuroradiology \n2005 ;47 :758 -64 .16151706 \n7. Rueda AM Serpa JA Matloobi M \nThe spectrum of invasive pneumonoccal disease at an adult tertiary care hospital in the early 21st century . Medicine \n2010 ;89 :331 .20827110 \n8. Lu CH Chang WN Lui CC \nStrategies for the management of bacterial brain abscess . J Clin Neurosci \n2006 ;13 :979 -85 .17056261 \n9. Xiao F Tseng MY Teng LJ \nBrain abscess: clinical experience and analysis of prognostic factors . Surg Neurol \n2005 ;63 :442 -50 .15883068 \n10. Hakan T Ceran N Erdem I \nBacterial brain abscesses: an evaluation of 96 cases . J Infect \n2006 ;52 :359 -66 .16183134\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-7430",
"issue": "8(4)",
"journal": "Infectious disease reports",
"keywords": "intracranial abscess; post-infectious vasculitis; streptococcus pneumoniae",
"medline_ta": "Infect Dis Rep",
"mesh_terms": null,
"nlm_unique_id": "101537203",
"other_id": null,
"pages": "6844",
"pmc": null,
"pmid": "28191299",
"pubdate": "2016-12-31",
"publication_types": "D002363:Case Reports",
"references": "16720170;20827110;17180609;12690042;23960149;17056261;16183134;15883068;9402366;16151706",
"title": "Streptococcus Pneumoniae Intracranial Abscess and Post-Infectious Vasculitis.",
"title_normalized": "streptococcus pneumoniae intracranial abscess and post infectious vasculitis"
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"abstract": "Stenotrophomonas maltophilia (Sm) pneumonia in immunocompromized hosts is an increasingly common nosocomial infection. Even though resistant to multiple antimicrobials, this gram-negative bacteria usually does not present with a fulminant course leading to a fatal hemorrhagic respiratory infection in neutropenic patients. We report here the case of a 63-year-old woman treated by intensive chemotherapy for acute myeloid leukemia (AML) who presented while severely neutropenic and thrombocytopenic a Sm pulmonary infection with hemoptysis leading to death in 48 h. The bronchoalveolar lavage (BAL) performed shortly before death was highly hemorrhagic and contained a striking amount of extra- and intra-cellular pathogens. Blood and BAL cultures grew S. maltophilia. Post-mortem examination revealed bilateral extensive intra-alveolar hemorrhage (IAH) associated with a great amount of microorganisms and severe bone marrow aplasia was observed without evidence of leukemia residual disease. Sm pneumonia usually does not evolve into such a devastating clinical picture although infections due to the bacteria are known to be associated with high morbidity and mortality. So far, the present observation is the fourth similar case reported in the literature. Even though an early diagnosis and an adequate antibiotic prescription may improve Sm infection prognosis, S. maltophilia proves difficult to eradicate due to a high resistance rate in part intrinsic but also in part acquired.",
"affiliations": "Department of Pathology, Hôtel-Dieu, AP-HP, 1 Place du Parvis Notre-Dame, 75181 Paris Cedex 04, France.",
"authors": "Rousseau|Audrey|A|;Morcos|Mohib|M|;Amrouche|Liliane|L|;Foïs|Elena|E|;Casetta|Anne|A|;Rio|Bernard|B|;Le Tourneaua|Agnès|A|;Molina|Thierry|T|;Rabbat|Antoine|A|;Marie|Jean-Pierre|JP|;Audouin|Josée|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428190310001638850",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "45(6)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000208:Acute Disease; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid; D017809:Fatal Outcome; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006470:Hemorrhage; D006801:Humans; D016867:Immunocompromised Host; D007951:Leukemia, Myeloid; D008171:Lung Diseases; D008875:Middle Aged; D018410:Pneumonia, Bacterial; D020615:Stenotrophomonas maltophilia",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1293-6",
"pmc": null,
"pmid": "15360016",
"pubdate": "2004-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lethal pulmonary hemorrhage caused by a fulminant Stenotrophomonas maltophilia respiratory infection in an acute myeloid leukemia patient.",
"title_normalized": "lethal pulmonary hemorrhage caused by a fulminant stenotrophomonas maltophilia respiratory infection in an acute myeloid leukemia patient"
} | [
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"companynumb": "FR-PFIZER INC-2018216152",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
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"abstract": "Nivolumab exerts therapeutic activity in patients with classic Hodgkin's lymphoma (CHL) but may cause several types of immune-related adverse events. Some rheumatoid arthritis (RA) patients develop CHL during methotrexate therapy (MTX-CHL); however, the efficacy and safety of nivolumab for these patients remain unclear. A 68-year-old woman was diagnosed with CHL after six years of MTX therapy for RA. The disease did not respond to any type of chemotherapy. Nivolumab was then initiated, and the patient was successfully treated without the reactivation of RA. The reactivation of RA always needs to be considered with the administration of nivolumab.",
"affiliations": "Department of Hematology, Yokosuka Kyosai Hospital, Japan.;Department of Hematology, Yokosuka Kyosai Hospital, Japan.;Department of Hematology, Yokosuka Kyosai Hospital, Japan.;Department of Hematology, Yokosuka Kyosai Hospital, Japan.",
"authors": "Tanaka|Keisuke|K|;Kuboki|Mai|M|;Koi|Satoshi|S|;Toyota|Shigeo|S|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D018501:Antirheumatic Agents; D000077594:Nivolumab; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.3772-19",
"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n31761888\n10.2169/internalmedicine.3772-19\nCase Report\nNivolumab for Methotrexate-associated Classic Hodgkin's Lymphoma in a Rheumatoid Arthritis Patient\nTanaka Keisuke 1 Kuboki Mai 1 Koi Satoshi 1 Toyota Shigeo 1 \n1 Department of Hematology, Yokosuka Kyosai Hospital, Japan\nCorrespondence to Dr. Keisuke Tanaka, keisukeaota@yahoo.co.jp\n\n\n22 11 2019 \n15 3 2020 \n59 6 829 833\n6 8 2019 10 10 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Nivolumab exerts therapeutic activity in patients with classic Hodgkin's lymphoma (CHL) but may cause several types of immune-related adverse events. Some rheumatoid arthritis (RA) patients develop CHL during methotrexate therapy (MTX-CHL); however, the efficacy and safety of nivolumab for these patients remain unclear. A 68-year-old woman was diagnosed with CHL after six years of MTX therapy for RA. The disease did not respond to any type of chemotherapy. Nivolumab was then initiated, and the patient was successfully treated without the reactivation of RA. The reactivation of RA always needs to be considered with the administration of nivolumab. \n\nclassic Hodgkin's lymphomamethotrexaterheumatoid arthritisnivolumab\n==== Body\nIntroduction\nThe efficacy of immune checkpoint inhibitors as cancer therapy has been demonstrated. Programmed cell death-1 (PD-1) is a protein expressed on activated T cells, and the pathway of PD-1 and its ligands (PD-L1/L2), expressed on antigen-presenting cells, induces peripheral immune tolerance (1,2). Some cancer cells also express PD-1 ligands and evade immune surveillance through this pathway, and the blockade of this pathway with anti-PD-L1 antibodies has been shown to enhance anti-tumor effects (3).\n\nNivolumab is a fully human IgG4 monoclonal antibody that targets PD-1 and exerts anti-tumor effects by blocking immune tolerance for cancer cells. It has already been approved in Japan for the treatment of melanoma, non-small cell lung cancer, and renal cell carcinoma based on its efficacy in the Japanese population (4-7). Its efficacy and safety for relapsed or refractory classic Hodgkin's lymphoma (CHL) were subsequently reported (8,9), and it was approved for the treatment of relapsed or refractory CHL in Japan in December 2016.\n\nHowever, nivolumab inhibits immune tolerance of not only cancer cells but also normal tissues and may cause several types of immune-related adverse events (irAEs) (10). Rheumatoid arthritis (RA) is an autoimmune disease, and patients treated with methotrexate (MTX) occasionally develop lymphoproliferative disorders (MTX-LPDs) several years after the initiation of its administration (11). The majority of MTX-LPDs are diffuse large B-cell lymphomas, among which CHL accounts for 10-30% (MTX-CHL) (12-15).\n\nSince MTX-CHL patients have been excluded from clinical trials on nivolumab, its efficacy and safety in these patients remain unclear. To our knowledge, MTX-HL patients have yet to be treated with nivolumab.\n\nCase Report\nA 68-year-old woman had been diagnosed with RA in her 20s and treated with MTX. Six years after the initiation of MTX therapy, she developed lymphadenopathy, and MTX was discontinued without the initiation of other therapies for RA. After the withdrawal of MTX, her lymphadenopathy temporarily diminished, but systemic lymphadenopathy and splenomegaly were detected after two years. She developed a fever and fatigue that progressively worsened. A cervical lymph node biopsy was performed, and she was diagnosed with CHL (mixed cellularity type).\n\nFigure 1. The initial lymph node biopsy of the patient. A: Hematoxylin and Eosin staining (400×). B: CD30 immunostaining (100×). C: EBER immunostaining (100×). D: PD-L1 immunostaining (400×). Tumor cells are positive for CD30, EBER, and PD-L1 (arrows).\n\nThe histopathological findings are shown in Fig. 1. Hematoxylin and Eosin staining revealed large tumor cells (Hodgkin's cells) that were positive for CD30, Epstein-Barr virus-encoded small RNA (EBER), and PD-L1 according to immunohistochemical staining. Between the cessation of MTX and diagnosis of CHL, RA flares were not observed despite the absence of any treatment.\n\nAt her diagnosis, the clinical stage was IIIB (systemic lymph node and spleen), the international prognostic score (IPS) was 4 (albumin <4 g/dL, hemoglobin <10.5 g/dL, age >65 years old, lymphocytes <8%), and the clinical disease activity index (CDAI) was 0. Serum lactate dehydrogenase (LDH) was 261 U/L (upper limit 229 U/L) and C-reactive protein (CRP) was 4.8 mg/dL (upper limit 0.3 mg/dL). She was treated with eight courses of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) but only had a partial response. Therefore, she was treated with ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), C-MOPP (cyclophosphamide, vincristine, procarbazine, and prednisolone), and GDP (gemcitabine, dexamethasone, and cisplatin) as salvage therapies but did not respond to any of these treatments. Brentuximab vedotin (BV, 1.8 mg/kg every 3 weeks) was initiated; however, after 7 courses, fluoro-deoxyglucose positron emission tomography (FDG-PET) showed the progression of mediastinal and abdominal lymph node and spleen lesions (Fig. 2A). Her performance status was not good (Eastern Cooperative Oncology Group performance status of 2) because of the subsequent complication of RA, and the patient refused to undergo allogeneic stem cell transplantation. Therefore, we decided to introduce nivolumab as a treatment for refractory CHL.\n\nFigure 2. FDG-PET. A: Before the introduction of nivolumab. B: After seven courses of nivolumab (3 mg/kg every 2 weeks). Solid arrows indicate lesions. The areas with an abnormal uptake (indicated with dotted arrows) are not lesions (proven by a biopsy).\n\nShe had no other remarkable medical history or comorbidity apart from RA. Although some finger joints were deformed at the beginning of the nivolumab treatment, there was no active arthritis or symptoms (joint pain) in the absence of therapy for RA (CDAI:0). Blood tests were negative for rheumatoid factor and anti-cyclic citrullinated peptide antibody (Table 1). Laboratory data showed hemoglobin 8.6 g/dL (lower limit 11.3 g/dL), LDH 277 U/L, and CRP 21.76 mg/dL (Table 1). The copy number of serum Epstein-Barr virus (EBV) had increased to 2,000 copies/mL (≤200 copies/mL is undetectable).\n\nTable 1. Laboratory Findings with the Initiation of Nivolumab.\n\n[Complete blood cell count]\t\t\t\nWhite blood cell\t12,700\t/µL\t\nNeutrophil\t87\t%\t\nLymphocyte\t5.5\t%\t\nEosinophil\t4\t%\t\nMonocyte\t3.5\t%\t\nBasophil\t0\t%\t\nRed blood cell\t314×104\t/µL\t\nHemoglobin\t10.2\tg/dL\t\nPlatelet\t19.6×104\t/µL\t\n[Biochemistry]\t\t\t\nLDH\t199\tU/L\t\nAST\t32\tU/L\t\nALT\t59\tU/L\t\nγ-GTP\t225\tU/L\t\nALP\t876\tU/L\t\nT-Bil\t0.5\tmg/dL\t\nBUN\t16\tmg/dL\t\nCre\t0.7\tmg/dL\t\nNa\t133\tmEq/L\t\nK\t4.0\tmEq/L\t\nCl\t97\tmEq/L\t\nAlbumin\t2.8\tg/dL\t\nAmylase\t154\tU/L\t\n[Serology]\t\t\t\nC-reactive protein\t28.4\tmg/dL\t\n[Autoantibody]\t\t\t\nRheumatoid factor\t<3\tIU/mL\t\nAnti-CCP antibody\t<0.6\tU/mL\t\nLDH: lactate dehydrogenase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, γ-GTP: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine\n\nAfter 2 courses of nivolumab (3 mg/kg every 2 weeks), an asymptomatic elevated serum amylase level appeared, and we diagnosed this event as a nivolumab-related irAE (16,17) (Fig. 3). Nivolumab was therefore discontinued, and we started treating the patient with prednisolone (PSL). The serum amylase levels decreased after the initiation of PSL (starting at 20 mg/day and reduced to 10 mg/day), so nivolumab was restarted (3 mg/kg every 2 weeks). The serum amylase levels did not increase after the resumption of nivolumab. Serum EBV was not detectable after four courses of nivolumab, and FDG-PET showed that the mediastinal and spleen lesions had disappeared while the abdominal lesion had diminished (partial response) after seven courses (Fig. 2B). Nivolumab exerted strong effects on heavily treated refractory CHL. In addition, no active arthritis or joint pain was observed during the nivolumab treatment courses. Seven months after treatment initiation, she has shown no symptoms and is tolerating nivolumab.\n\nFigure 3. Clinical course of nivolumab treatment. PET-1: before the introduction of treatment, PET-2: after seven cycles of treatment (shown in Figure 2A, B). Serum EBV-PCR was positive before the initiation of treatment and became negative after four cycles. RA flares were not observed during the clinical course. CDAI: clinical disease activity index, EBV: Epstein-Barr virus, PCR: polymerase chain reaction, PET: positron emission tomography, PSL: prednisolone (mg/day)\n\nDiscussion\nTo our knowledge, this is the first case report of nivolumab therapy for an MTX-HL patient with RA. Retrospective studies have assessed the safety of anti-PD-1/PD-L1 therapy for other types of cancers with pre-existing autoimmune diseases; the findings of three of these studies are shown in Table 2 (18-20). A total of 126 patients were included (melanoma: 71, non-small-cell lung cancer: 56), with 124 receiving anti-PD-1 therapy and only two being treated with anti-PD-L1 therapy. One of the pre-existing autoimmune diseases was RA, and approximately 50% of patients showed the reactivation of RA after the introduction of anti-PD-1/PD-L1 therapy. The activity of pre-existing autoimmune diseases was identified as a risk factor for flares in these studies, and patients with rheumatic diseases were more likely to show reactivation than those with gastrointestinal diseases and neurological disorders. The safety of anti-PD-1 therapy for patients with pre-existing autoimmune diseases has not been investigated in detail and remains controversial; however, most flares in patients with RA were not severe and were easily managed without the termination of anti-PD-1 therapy. In the present case, RA did not reactivate during nivolumab therapy, which was thus continued safely.\n\nTable 2. Findings of Three Studies on Patients with Pre-existing Autoimmune Diseases Treated with Anti-PD-1/PD-L1 Inhibitors.\n\nAutoimmune disease\tPatient, n\tFlare, n (%)\t\nRheumatologic\t\t\t\nRheumatoid arthritis\t26\t14 (53.8)\t\nOther arthritis\t10\t4 (40)\t\nMyositis\t1\t1 (100)\t\nVasculitis\t2\t0\t\nPolymyalgia rheumatica\t9\t7 (77.8)\t\nSarcoidosis\t5\t2 (40)\t\nSLE\t3\t1 (33.3)\t\nScleroderma\t4\t1 (25)\t\nSjögren’s syndrome\t3\t2 (66.7)\t\nDermatologic\t\t\t\nPsoriasis\t23\t9 (39.1)\t\nOthers\t4\t0\t\nGastrointestinal\t\t\t\nUlcerative colitis\t6\t0\t\nCrohn disease\t6\t0\t\nCeliac disease\t1\t0\t\nNeurologic\t\t\t\nGuillan-Barré syndrome\t3\t0\t\nMyasthenia gravis\t2\t0\t\nMultiple sclerosis\t3\t0\t\nOthers\t2\t0\t\nEndocrine (thyroiditis)\t19\t3 (15.8)\t\nRespiratory (asthma)\t2\t0\t\nHematologic (AIHA or ITP)\t3\t2 (66.7)\t\nSLE: systemic lupus erythematosus, AIHA: autoimmune hemolytic anemia, ITP: immune thrombocytopenic purpura\n\nRoemer et al. reported genomic alterations in PD-1 ligands (chromosome 9q24.1) in 108 CHL patients (21); 107 patients had genomic alterations, and a correlation was observed between the PD-L1 expression assessed by immunohistochemistry and relative genomic alterations. Amplification was associated with the stronger expression of PD-L1 than polysomy and copy gain, and the incidence of 9q24.1 amplifications was higher in advanced-stage CHL than in early-stage CHL. They also reported that the expression of PD-L1 was stronger in EBV-positive cases than in EBV-negative cases (shown in the appendix). These previous findings suggest that the tumor cells of advanced-stage EBV-positive HL may express PD-L1 more strongly than those of early-stage EBV-negative HL. In a phase II study of nivolumab for HL, a correlation was observed between the level of PD-L1 expressed on tumor cells and the efficacy of nivolumab (22). Since the majority of cases of MTX-CHL are positive for EBV (12-15,23), nivolumab may be more beneficial as a treatment option for advanced-stage MTX-HL due to the stronger expression of PD-L1, than for early-stage disease. Clinical trials on nivolumab for EBV-positive lymphomas are ongoing (NCT03258567, NCT02973113), and this issue may be clarified based on the findings obtained therein.\n\nConclusion\nWe successfully treated a patient with nivolumab without RA flares. Refractory MTX-CHL patients are sometimes unable to receive high-dose chemotherapy or stem cell transplantation because of a poor performance status and elderly age. Thus, the treatment of patients with low-invasive therapy is important. BV is also a tolerable regimen for MTX-CHL patients with RA and is an important treatment option to be considered (24). The majority of RA flares induced by nivolumab are low-severity and thus manageable, and EBV may suppress the antitumor immunity by the PD-1/PD-L1 pathway in MTX-CHL cases. Nivolumab may therefore be suitable for these patients.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nFrancisco LM , Sage PT , Sharpe AH \nThe PD-1 pathway in tolerance and autoimmunity\n. Immunol Rev \n236 : 219 -242\n, 2010 .20636820 \n2. \nBoussiotis VA , Chatterjee P , Li L \nBiochemical signaling of PD-1 on T cells and its functional implications\n. Cancer J \n20 : 265 -271\n, 2014 .25098287 \n3. \nIwai Y , Ishida M , Tanaka Y , Okazaki T , Honjo T , Minato N \nInvolvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade\n. Proc Natl Acad Sci USA \n99 : 12293 -12297\n, 2002 .12218188 \n4. \nYamazaki N , Kiyohara Y , Uhara H , et al \nEfficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: a phase II study\n. Cancer Sci \n108 : 1223 -1230\n, 2017 .28342215 \n5. \nHida T , Nishio M , Nogami N , et al \nEfficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer\n. Cancer Sci \n108 : 1000 -1006\n, 2017 .28266091 \n6. \nNishio M , Hida Y , Atagi S , et al \nMulticentre phase II study of nivolumab in Japanese patients with advanced or recurrent non-squamous non-small cell lung cancer\n. ESMO Open \n1 : e000108 , 2017 .28861280 \n7. \nTomita Y , Fukasawa S , Shinohara N , et al \nNivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study\n. Jpn J Clin Oncol \n47 : 639 -646\n, 2017 .28419248 \n8. \nAnsell SM , Lesokhin AM , Borrello I , et al \nPD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma\n. N Engl J Med \n372 : 311 -319\n, 2015 .25482239 \n9. \nMaruyama D , Hatake K , Kinoshita T , et al \nMulticenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin's lymphoma\n. Cancer Sci \n108 : 1007 -1012\n, 2017 .28267244 \n10. \nKumar V , Chaudhary N , Garg M , Floudas CS , Soni P , Chandra AB \nCurrent diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy\n. Front Pharmacol \n8 : 1 -14\n, 2017 .28149278 \n11. \nKamel OW , van de Rijn M , Weiss LM , et al \nBrief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis\n. N Engl J Med \n328 : 1317 -1321\n, 1993 .8385742 \n12. \nIchikawa A , Arakawa F , Kiyasu J , et al \nMethotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression\n. Eur J Hematol \n91 : 20 -28\n, 2013 .\n13. \nGion Y , Iwaki N , Takata K , et al \nClinicopathological analysis of methotrexate-associated lymphoproliferative disorders: comparison of diffuse large B-cell lymphoma and classical Hodgkin's lymphoma types\n. Cancer Sci \n108 : 1271 -1280\n, 2017 .28380678 \n14. \nTokuhira M , Saito S , Okuyama A , et al \nClinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression\n. Leuk Lymphoma \n59 : 1143 -1152\n, 2018 .28877615 \n15. \nKurita D , Miyoshi H , Ichikawa A , et al \nMethotrexate-associated lymphoproliferative disorders in patients with rheumatoid arthritis clinicopathologic features and prognostic factors\n. Am J Surg Pathol \n43 : 869 -884\n, 2019 .31116708 \n16. \nIkeuchi K , Okuma Y , Tabata T \nImmune-related pancreatitis secondary to nivolumab in a patient with recurrent lung adenocarcinoma: a case report\n. Lung Cancer \n99 : 148 -150\n, 2016 .27565931 \n17. \nFriedman CF , Clark V , Raikhel AV , et al \nThinking critically about classifying adverse events: incidence of pancreatitis in patients treated with nivolumab + ipilimumab\n. J Natl Cancer Inst \n109 : 1 -3\n, 2017 .\n18. \nGutzmer R , Koop A , Meier F , et al \nProgrammed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmune or ipilimumab-triggered autoimmunity\n. Eur J Cancer \n75 : 24 -32\n, 2017 .28214654 \n19. \nMenzies AM , Johnson DB , Ramanujam S , et al \nAnti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab\n. Ann Oncol \n28 : 368 -376\n, 2017 .27687304 \n20. \nLeonardi GC , Gainor JF , Altan M , et al \nSafety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders\n. J Clin Oncol \n36 : 1905 -1912\n, 2018 .29746230 \n21. \nRoemer MG , Advani RH , Ligon AH , et al \nPD-L1 and PD-L2 genetic alterations define classical Hodgkin's lymphoma and predict outcome\n. J Clin Oncol \n34 : 2690 -2697\n, 2016 .27069084 \n22. \nYounes A , Santoro A , Shipp M , et al \nNivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial\n. Lancet Oncol \n17 : 1283 -1294\n, 2016 .27451390 \n23. \nMariette X , Hatem DC , Warszawki J , Liote F , Balandraud N , Sibilia J \nLymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France\n. Blood \n99 : 3909 -3915\n, 2002 .12010788 \n24. \nNakazato T , Takanashi S , Hirano M , et al \nBrentuximab vedotin is effective for rheumatoid arthritis in a patient with relapsed methotrexate-associated Hodgkin's lymphoma\n. Ann Hematol \n97 : 1489 -1491\n, 2018 .29455236\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(6)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "classic Hodgkin's lymphoma; methotrexate; nivolumab; rheumatoid arthritis",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008727:Methotrexate; D000077594:Nivolumab",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "829-833",
"pmc": null,
"pmid": "31761888",
"pubdate": "2020-03-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29746230;8385742;28267244;28419248;25098287;27687304;28342215;28266091;28228726;28214654;23560463;27069084;27565931;25482239;27451390;12010788;31116708;12218188;28040701;28877615;28861280;28380678;20636820;29455236",
"title": "Nivolumab for Methotrexate-associated Classic Hodgkin's Lymphoma in a Rheumatoid Arthritis Patient.",
"title_normalized": "nivolumab for methotrexate associated classic hodgkin s lymphoma in a rheumatoid arthritis patient"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-243682",
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"activesubstancename": "VINCRISTINE SULFATE"
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"abstract": "A 21-year-old woman in the 16th week of pregnancy was admitted due to acute presentation of severe exertional dyspnea. She had undergone mitral valve replacement (MVR) with bioprosthetic valve for infective endocarditis 2 years ago. She developed congestive heart failure from mitral bioprosthetic valve stenosis due to early structural valve deterioration. She also had severe pulmonary hypertension and underwent a redo MVR using a mechanical valve prosthesis with good maternal outcome but fetal demise. This report brings up the debate about what type of valve should be used in women in reproductive age, and discusses the management of severe mitral stenosis and stenosis of a bioprosthetic valve during pregnancy. Surgical options can almost always be delayed until fetal maturity is achieved and a simultaneous cesarean section can be performed. However, under certain circumstances when the maternal welfare is in jeopardy the surgical intervention is mandatory even before the fetus reaches viability.",
"affiliations": "Department of Medicine, University of Miami/Jackson Memorial Hospital, 1611 NW 12th Avenue, Central Building, Room 600D, Miami, FL, 33136, USA. jersonmunozmendoza@gmail.com.;Department of Medicine, University of Miami/Jackson Memorial Hospital, 1611 NW 12th Avenue, Central Building, Room 600D, Miami, FL, 33136, USA.;Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.;Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.;Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.",
"authors": "Munoz-Mendoza|Jerson|J|;Pinto Miranda|Veronica|V|;Tanawuttiwat|Tanyanan|T|;Badiye|Amit|A|;Chaparro|Sandra V|SV|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s11748-013-0366-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1863-6705",
"issue": "64(1)",
"journal": "General thoracic and cardiovascular surgery",
"keywords": "Bioprosthesis; Mitral stenosis; Pregnancy; Redo mitral surgery",
"medline_ta": "Gen Thorac Cardiovasc Surg",
"mesh_terms": "D001705:Bioprosthesis; D002585:Cesarean Section; D004697:Endocarditis, Bacterial; D005260:Female; D006333:Heart Failure; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008943:Mitral Valve; D008946:Mitral Valve Stenosis; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011475:Prosthesis Failure; D012086:Reoperation; D055815:Young Adult",
"nlm_unique_id": "101303952",
"other_id": null,
"pages": "38-42",
"pmc": null,
"pmid": "24374988",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19106383;10647757;16524533;16880336;7646173;21873418;12840093;19935039;22945848;18488120;23180241;16053950;20605238;18728340;22155997",
"title": "Severe bioprosthetic mitral valve stenosis in pregnancy.",
"title_normalized": "severe bioprosthetic mitral valve stenosis in pregnancy"
} | [
{
"companynumb": "US-PFIZER INC-2016452468",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPreclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors.\n\n\nMETHODS\nThis was a multicenter, open-label, single-arm dose escalation study in which subjects with refractory solid tumors received 21-day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin.\n\n\nRESULTS\nTwenty-eight patients with a median age of 8.5 years (range, 1-21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m2/dose) experienced dose-limiting gastrointestinal toxicities requiring a dose de-escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m2/dose). Three of 6 subjects at the second dose level experienced dose-limiting gastrointestinal complications and bone marrow suppression. A further dose de-escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m2/dose resulted in dose-limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed.\n\n\nCONCLUSIONS\nThe recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m2/dayx10 days) given every 21 days.",
"affiliations": "Department of Pediatric Hematology/Oncology, Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, New York 10467, USA. adlevy@montefiore.org",
"authors": "Levy|Adam S|AS|;Meyers|Paul A|PA|;Wexler|Leonard H|LH|;Jakacki|Regina|R|;Angiolillo|Anne|A|;Ringuette|Sarah N|SN|;Cohen|Marvin B|MB|;Gorlick|Richard|R|",
"chemical_list": "D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.23992",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "115(1)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D016190:Carboplatin; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "207-16",
"pmc": null,
"pmid": "19090012",
"pubdate": "2009-01-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors.",
"title_normalized": "phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors"
} | [
{
"companynumb": "US-MYLANLABS-2016M1004738",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
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"drugadditional": null,
... |
{
"abstract": "Children with high-risk neuroblastoma are currently treated with a chimeric monoclonal antibody against GD2 ganglioside (chimeric 14.18). The treatment improves survival but causes transient neuropathic pain-like syndrome. We retrospectively studied 16 children with neuroblastoma receiving GD2 therapy. To manage pain, all patients received morphine via nurse-controlled analgesia or patient-controlled analgesia. Mean daily pain scores ranged from 0 to 5 and all children had a 0 pain score upon discharge. No major side effects were noted, suggesting morphine via nurse-controlled analgesia/patient-controlled analgesia is effective in controlling transient neuropathic pain in children receiving GD2 antibody therapy.",
"affiliations": "The George Washington University School of Medicine and Health Sciences.;Department of Anesthesiology, Hofstra-Northwell School of Medicine, Hempstead.;The George Washington University School of Medicine and Health Sciences.;The George Washington University School of Medicine and Health Sciences.",
"authors": "Ari|Pranathi|P|;Kars|Michelle|M|;Meany|Holly|H|;Pestieau|Sophie|S|",
"chemical_list": "D000701:Analgesics, Opioid; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D009020:Morphine; C112746:dinutuximab",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000889",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D016058:Analgesia, Patient-Controlled; D000701:Analgesics, Opioid; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009020:Morphine; D009437:Neuralgia; D009447:Neuroblastoma; D059408:Pain Management",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e113-e116",
"pmc": null,
"pmid": "28678088",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of Transient Peripheral Neuropathy During Chimeric 14.18 Antibody Therapy in Children With Neuroblastoma: A Case Series.",
"title_normalized": "treatment of transient peripheral neuropathy during chimeric 14 18 antibody therapy in children with neuroblastoma a case series"
} | [
{
"companynumb": "US-009507513-1804USA007671",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of a 57-year-old male with clinically diagnosed and autopsy-confirmed early onset Alzheimer's disease who completed suicide by gunshot wound to the chest. This case has several unique aspects that have not been discussed in previous case reports of completed suicide in Alzheimer's disease. In particular, our patient's death was highly planned with successful compensation for his cognitive deficits. After all firearms had been removed from the home as a safety precaution, he obtained a new weapon, hid it and left himself cues to find and use it. The case is discussed in the context of literature differentiating the neural circuitry propagating impulsive versus planned suicidal acts.",
"affiliations": "Department of Supportive Oncology, Levine Cancer Institute, Carolinas HealthCare System, NC 28202, USA.;Department of Psychiatry, Overlake Medical Center, WA 98004, USA.;Department of Pathology, West Virginia University School of Medicine, WV 26506, USA.;Department of Behavioral Medicine & Psychiatry, West Virginia University School of Medicine, WV 26505, USA.;Department of Neurology, West Virginia University School of Medicine, WV 26506, USA.",
"authors": "Hartzell|Jennifer Wiener|JW|;Geary|Richard|R|;Gyure|Kymberly|K|;Chivukula|Venkata Ravi|VR|;Haut|Marc W|MW|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/nmt-2017-0045",
"fulltext": "\n==== Front\nNeurodegener Dis ManagNeurodegener Dis ManagNMTNeurodegenerative Disease Management1758-20241758-2032Future Medicine Ltd London, UK 2931940610.2217/nmt-2017-0045Case ReportCompleted suicide in an autopsy-confirmed case of early onset Alzheimer’s disease Hartzell, Geary, Gyure, Chivukula & HautCompleted suicide in an autopsy-confirmed case of early onset Alzheimer’s diseaseHartzell Jennifer Wiener *\n1\n\n2\nGeary Richard \n3\nGyure Kymberly \n4\n\n5\n\n6\nChivukula Venkata Ravi \n7\nHaut Marc W \n5\n\n7\n\n8\n\n1 Department of Supportive Oncology, Levine Cancer Institute, Carolinas HealthCare System, NC 28202, USA\n2 Department of Neuropsychology & Psychology, Carolinas Rehabilitation, Carolinas HealthCare System, NC 28203, USA\n3 Department of Psychiatry, Overlake Medical Center, WA 98004, USA\n4 Department of Pathology, West Virginia University School of Medicine, WV 26506, USA\n5 Department of Neurology, West Virginia University School of Medicine, WV 26506, USA\n6 Department of Neurosurgery, West Virginia University School of Medicine, WV 26506, USA\n7 Department of Behavioral Medicine & Psychiatry, West Virginia University School of Medicine, WV 26505, USA\n8 Department of Radiology, West Virginia University School of Medicine, WV 26506, USA*Author for correspondence: jennifer.hartzell@carolinashealthcare.org4 2018 10 1 2018 10 1 2018 8 2 81 88 3 10 2017 18 12 2017 10 1 2018 © 2018 Jennifer W Hartzell2018This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License\nWe report a case of a 57-year-old male with clinically diagnosed and autopsy-confirmed early onset Alzheimer’s disease who completed suicide by gunshot wound to the chest. This case has several unique aspects that have not been discussed in previous case reports of completed suicide in Alzheimer’s disease. In particular, our patient’s death was highly planned with successful compensation for his cognitive deficits. After all firearms had been removed from the home as a safety precaution, he obtained a new weapon, hid it and left himself cues to find and use it. The case is discussed in the context of literature differentiating the neural circuitry propagating impulsive versus planned suicidal acts.\n\nKeywords: \nAlzheimer’s diseaseearly onsetsuicide\n==== Body\nWe present a case of a 57-year-old, right-handed Caucasian male clinically diagnosed with early onset Alzheimer’s disease (AD), which was confirmed on autopsy after he completed suicide in October 2014 by a self-inflicted gunshot wound to the chest. He originally presented to our medical school-based Memory Disorder Clinic in January 2013 with complaints of forgetfulness over the last 5 years. He was working full-time and performed all activities of daily living independently. In addition to slowly progressive memory concerns, he reported anhedonia, decreased energy, restless sleep, decreased appetite and unintentional weight loss, but did not endorse depressed mood. He had no suicidal ideation at initial presentation. His affect was noted to be constricted.\n\nMedical history was otherwise notable for gallbladder disease and mild sleep apnea. He had no history of head injury or concussive events. Computed tomography of the brain in 2011 was negative. Daily medications included baby aspirin and vitamin D. He did not use a continuous positive airway pressure ventilator. Substance use history was unremarkable.\n\nA few years prior to presenting for treatment in our setting, he was prescribed escitalopram for symptoms of anxiety and depression, but discontinued on his own after 2 weeks, and his symptoms resolved over time. He had also participated in marital counseling for a few months over the summer prior to his intake. Otherwise, psychiatric history was unremarkable and he had no history of self-harm or suicide attempts.\n\nFamily history, however, was quite relevant. The patient’s only brother died from Wilson’s disease in 1993. His father killed himself by gunshot in 1994, 1 year after receiving a diagnosis of terminal lung cancer and losing his son. He was 74 years old at the time, but did not have any reported memory problems. His mother was still alive, but in an assisted-living facility for an unspecified dementia syndrome. Her memory problems began at the age of 85. A maternal uncle was also reported to have late-life memory problems.\n\nAt intake, he scored 22/30 on the Mini Mental Status Examination (MMSE) [1]. Laboratory values, including thyroid stimulating hormone, rapid plasma regain, B12 and folate, were normal. Serum ceruloplasmin was negative for Wilson’s disease. Bupropion (100 mg) was prescribed and he was referred for neuropsychological evaluation, MRI and EEG.\n\nOne month later (February 2013), neuropsychological evaluation revealed a pattern of cognitive deficits suspicious for early onset AD with impairments in memory encoding and consolidation, verbal fluency, visual construction, attention, verbal reasoning and cognitive flexibility. He scored 18/30 on the MMSE at that point and was not fully oriented to time. He had functional deficits related to making change from a simulated purchase and writing a check, which is of note considering that he had a Bachelor’s degree in finance and worked as a banking executive. He was informed of the results and preliminary diagnosis at a feedback appointment with the neuropsychologist 2 weeks later and appeared to understand and accept the results, but demonstrated restricted affect and reduced insight.\n\nMRI of the brain from April 2013 revealed generalized atrophy considered to be advanced for his age. As shown in Figure 1A, there is hippocampal atrophy evident on the coronal T1-weighted image, but the atrophy of the hippocampus is not out of proportion to the atrophy elsewhere in the brain. Examination of the axial and sagittal T1 images (Figure 1B & C) suggests there may be more atrophy in the parietal cortex than the other lobes, as has been reported in the setting of early onset AD [2,3]. His EEG was normal.\n\nFigure 1. \nMRI of the brain.\n\n\n(A) Coronal T1-weighted image post contrast. (B) Axial T1-weighted image. (C) Sagittal T1-weighted image.\n\nWhen our patient returned to the Memory Disorder Clinic for follow-up in March 2013, he reported improved mood, energy and sleep with weight gain. He did not endorse hopelessness or suicidal ideation. His wife noted improved memory. Bupropion was increased to 300 mg. In June 2013, he reported continued benefit from bupropion and no overt depression. He was formally diagnosed with early onset AD after seeking a second opinion at another academic medical center. He was considering quitting his job and applying for disability based on his diagnosis. Donepezil (10 mg) was prescribed and he requested information about genetic testing for AD.\n\nBy August 2013, he retired and applied for disability. His mood had declined. Bupropion was maintained at 300 mg. He reported experiencing a single visual hallucination of a cat, but was not distressed by this occurrence. He returned to clinic in December 2013, at which time his depression had worsened with disturbances in sleep and appetite. He also reported increased anxiety. Prior medications were maintained and he was started on memantine (28 mg). He returned in January 2014 with improved mood, sleep, appetite and anxiety. He returned in May 2014 and was doing well, tolerating bupropion, donepezil and memantine.\n\nIn July 2014, he was seen for a repeat neuropsychological evaluation to monitor cognitive progression. He reported no depression or suicidal ideation. Family confirmed that he had no access to guns in the home, as they had been removed. He was no longer managing his finances or medications. He continued to drive short distances on his own, but his wife indicated that she was no longer comfortable as a passenger. He characterized his retirement as being ‘let go’, which was not accurate, and was now receiving disability. His MMSE was 16/30 and Geriatric Depression Scale 15-item (GDS-15) was 3/15, indicating minimal depression. The results of the neuropsychological re-evaluation revealed progressive decline across cognitive domains. He performed at the first percentile across measures of verbal and nonverbal memory, the second percentile on a confrontation naming task and the 16th percentile on an abstract reasoning task. He was unable to complete a visual sequencing task and could not comprehend the instructions for a measure of cognitive flexibility. His overall cognitive pattern and rate of progression were determined to be consistent with a moderately advanced early onset AD.\n\nHe returned to the Memory Disorder Clinic in October 2014. His depression had recurred, yet he only reported mild symptoms on the GDS-15 (6/15). He expressed ‘slipping’ cognitively. He found enjoyment in mowing the lawn and spending time with his grandson. He attributed his depressed mood to concern over his mother’s health, which had declined. He made no mention of suicidal ideation. No medication changes were made.\n\nHe presented to the emergency department at the end of October 2014 with a gunshot wound to his chest, which was ruled suicide. He died in the operating room. At autopsy, examination of the brain conducted by a board-certified neuropathologist revealed that the brain weighed 1440 g and exhibited mild, diffuse narrowing of the gyri with deepening of the sulci. Coronal sections demonstrated symmetric dilatation of the lateral ventricular system, including the temporal horns. Hematoxylin–eosin-stained microscopic sections including those from the medulla, pons, midbrain, cerebellar vermis, cerebellar dentate, bilateral hippocampi, basal ganglia, thalamus, middle frontal gyrus, inferior parietal lobule, occipital lobe, cingulate gyrus and superior and middle temporal gyri were evaluated. Selected sections were additionally stained with a Bielschowsky silver stain. Frequent neuritic amyloid plaques were identified in the hippocampi, the adjacent entorhinal cortices and all neocortical regions examined, including the primary visual cortex of the occipital lobe (Figure 2A). Frequent neurofibrillary tangles were also present in a similar distribution (Figure 2B). In addition, there was granulovacuolar degeneration of and Hirano bodies present within hippocampal pyramidal neurons (Figure 2C). No brainstem or cortical Lewy bodies or other abnormal inclusions were identified. Using modified National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of AD, the degree of AD neuropathologic change was considered sufficient to explain this patient’s dementia [4]. Staging of the neuropathology of the disease was not completed at the time of the autopsy.\n\nFigure 2. \nNeuropathology slides.\n\n\n(A) Neuritic amyloid plaques (arrows) were readily identified in all neocortical regions examined (hematoxylin–eosin, original magnification 200×). (B) Neuritic plaques (thick arrows) and neurofibrillary tangles (thin arrows) were highlighted with a Bielschowsky silver stain (original magnification 200×). (C) Hippocampal pyramidal neurons exhibited granulovacuolar degeneration (arrow) and contained Hirano bodies (hematoxylin–eosin, original magnification 400×).\n\nBackground\nPrevalence rates of suicide in AD vary, with reports ranging from less than 1% to as high as 11% [5–7]. Some assert that dementia and AD specifically confer a lower risk of suicidal behavior in light of cognitive compromise [8,9], while others contend there is at least a mild–moderate risk [10–13]. A prospective study out of Denmark examining all cases of hospital-diagnosed dementia based on national registry data over an 11-year span revealed an elevated risk of completed suicide in adults over 50 following dementia diagnoses. Risk was highest in the first 6 months following diagnosis, but the occurrence of suicide more than a decade later was also high. Furthermore, the association between dementia and suicide risk remained significant even after controlling for current and past mood disorders. The authors comment on how surprising it is that so many cognitively impaired individuals, by nature of their disease, are capable of planning and executing a successful suicide [14]. We agree and believe that our case, relative to previous case reports, uniquely highlights just how surprising, yet realistic and possible, suicide is in the context of progressive cognitive impairment.\n\nThere are a handful of previously published case reports of completed suicide in AD. Common features of these cases include relatively preserved insight and higher educational attainment. Early age of onset of the disease, defined as clinical onset before age 65, is present in three of eight cases of completed suicide [15].\n\nRohde, Peskind and Raskind [16] reported two cases of completed suicide from a university-affiliated Alzheimer’s program. Both cases were clinically diagnosed with probable AD and enrolled in clinical trials. The first case was a 54-year-old woman who visited Dr Jack Kevorkian for physician-assisted suicide. AD was confirmed at autopsy. The second case was an 80-year-old male who died of a self-inflicted gunshot wound. Autopsy was not performed. Both individuals were highly educated professionals in the early stages of the disease with intact insight into their prognoses.\n\nA second set of completed suicide cases came from a Phase III clinical trial with eptastigmine, a cholinesterase inhibitor [17]. The first case was a 57-year-old man who died of a self-inflicted gunshot wound, while the second was a 73-year-old divorced male who jumped to his death from a 19th-floor window. Both individuals were well-educated professionals who met clinical diagnostic criteria for probable AD. Pathology was not discussed.\n\nA third set of cases revealed preserved insight in highly educated males who were more advanced in age at the time of clinical diagnosis [18]. The first was an 87-year-old who attempted suicide twice by wrist slashing, but ultimately died of respiratory failure at the age of 91. The second case was an 82-year-old who died of a self-inflicted gunshot wound to the head. In both cases, AD was confirmed at autopsy.\n\nThere is a single case report of presumed AD in a 58-year-old, well-educated male who died by gas inhalation, but his disease was not confirmed by autopsy [19]. At last, there is one additional case in the literature that was part of a 1986 murder-suicide in which a 67-year-old man died of a self-inflicted gunshot wound to the head and autopsy revealed plaques and tangles in the frontal lobes and left temporal lobe. Retrospectively, it was reported that he demonstrated cognitive and behavioral changes in the 2 years preceding his death; however, he had not been clinically diagnosed with dementia or AD while living [20].\n\nDiscussion\nWhile our case of completed suicide in the setting of early onset AD has similarities to the cases discussed above, such as being a well-educated male with relative insight into his prognosis, there are unique aspects to this case that have not been reported previously, which we will highlight.\n\nFirst, our patient’s death was a highly planned event. Following his suicide, his wife reported that he had purchased a new gun, unknown to her, after all firearms had been removed from the home as instructed by his providers. Generalizing from the literature examining planned versus impulsive suicides, the behavior eventually leading to our patient’s death is consistent with the neuropathology of his disease. Specifically, as we detail below, planned or premeditated suicides are associated with alterations in cortical processes, whereas impulsive suicidal behavior reflects alterations in subcortical processes [21]. Thus, our patient’s planned act was more likely to be related to cortical brain dysfunction, as is seen in AD.\n\nSecond, he appears to have successfully compensated for his cognitive deficits by leaving himself cues. After his death, we learned that he hid a newly purchased gun in a lockbox in the garage, tied a ribbon around the lockbox, marked the key to the lockbox and put the key on his keychain. Thus, despite his disease being moderately advanced at the time of his death, he maintained a level of awareness of his prognosis and sufficient executive functions at this point in the course of his disease to design and implement a suicide plan. His ability to accomplish this act may indicate a higher level of cognitive reserve (CR). The concept of CR posits that individual differences in factors such as educational and occupational attainment offer neural resiliency and the ability to compensate for pathologic brain changes, such as those occurring in AD [22]. Considering our patient’s status as a college-educated bank executive, high CR may have moderated the relationship between his pathology and his behavior.\n\nThird, our patient never presented with the agitated or hopeless presentations of major depression that have traditionally been perceived as ‘risk factors’ for suicidal behavior [23–25]. Rather, his depression came and went. When it was present, his depression was generally characterized by apathy, anhedonia and constricted affect instead of frank dysphoria or overt emotional turmoil. While we ultimately do not know if there was a specific negative experience precipitating his suicide, his wife did not perceive a downward affective shift in the days preceding his death, nor was she aware of any event that could be perceived as a trigger. In addition, despite the GDS-15 having strong reliability as a depression screening instrument for adults 60 years of age and over, it may have underestimated the severity of depression in our 57-year-old patient [26].\n\nA fourth distinct feature of our case is the positive family history of completed suicide in the context of terminal illness. There is a substantial body of evidence based on family, twin and adoption studies supporting the notion that genetic factors play a significant role in the predisposition to both suicide attempts and completed suicide [27–29]. Neurobiological abnormalities in the brains of suicide victims, particularly within the serotonergic system, have also been identified and explored through molecular genetics research [30,31]. Previous case reports of suicidal behavior in AD have lacked this heritability aspect and, thus, we believe our case uniquely represents a possible example of genetic transmission of suicide potential in the context of AD.\n\nAt last and perhaps the most distinct, our case demonstrates that cognitive impairment does not necessarily preclude patients from executing detailed suicide plans. On the surface, it may appear that neuropsychological performances at the first and second percentiles would not be compatible with the type of advanced planning and decision making that our patient displayed. We assert, however, that this type of assumption is dangerous. It is important for other clinicians to be aware of this flaw in logic and not assume that patients with moderately advanced dementia are no longer capable of a planned suicide by nature of their disease.\n\nCurrent literature on suicidal behavior in older adults draws several distinctions between impulsive and planned acts. While our patient was not elderly, we believe this literature provides context for this case. Behavioral research with impulsive suicide attempters reveals impairments in decision making on neuropsychological tests characterized by a lower willingness to delay gratification, also referred to as ‘delay discounting’ [21,32,33]. Impulsive attempters tend to ignore, or discount, the prospect of future rewards and over-focus on negative feedback or past failures, resulting in impulsive decisions [32,34].\n\nPlanned and premeditated suicidal behavior, in contrast, has been linked to greater willingness to delay gratification for larger rewards [21,33]. Individuals who exhibit highly lethal or planned suicidal behaviors tend to have a higher threshold for acting on suicidal ideation, but demonstrate an inability to flexibly conceptualize their situation and alternative solutions [34]. Thus, impairments in decision making exist across clinical pathways to suicide, but may be differentially expressed.\n\nRecent studies examining variations in brain function in suicide attempters have shed light on the neural circuitry involved. Functional MRI studies implicate abnormalities in basal ganglia and paralimbic activation in poorly planned or impulsive acts, whereas disruptions in the lateral and ventromedial prefrontal cortical activation appear to underlie planned or premeditated acts [21,32,35].\n\nThese findings mirror what we have observed clinically in diverse neurodegenerative presentations. We previously reported a case of completed suicide in clinically diagnosed progressive supranuclear palsy, a primarily subcortical dementia syndrome that appeared to be an impulsive, unplanned act [36]. Abnormalities in the subcortical reward circuitry make sense in the context of that particular pathology. Our present case of completed suicide in a clinically diagnosed and autopsy-confirmed cortical dementia syndrome (AD), in contrast, was a much more planned and detailed act, which supports the literature pointing to predominant cortical dysfunction in well-planned versus impulsive acts.\n\nThere is some evidence that specific neuropsychological deficits may be associated with suicide potential [33,37,38]. A recent meta-analysis of 25 neuropsychological studies revealed that deficits in decision making, verbal fluency and response inhibition are associated with suicidal behavior in older adults [39]. Our patient, however, demonstrated substantial and diffuse deficits across domains of memory, language, construction and executive functions, with no specific cognitive skill or domain more pronounced or impaired relative to others. Thus, it may be true that certain neuropsychological deficits predispose individuals to risky or suicidal behavior, but not necessarily that those same deficits predict who is likely to complete suicide.\n\nThere is concern within the literature regarding the implications of an early diagnosis of AD on suicide risk in patients who have relatively intact cognition and awareness early in the course of the disease [18,40]. Since the advent of imaging biomarkers for AD and increased accessibility of amyloid PET scans in recent years, suicide risk in response to positive diagnostic test results has become a major ethical and societal consideration [11]. As we have learned from research with asymptomatic individuals with positive predictive test results for Huntington’s disease, serious psychiatric distress and increased suicide risk are plausible consequences [41–43]. Thus, if individuals receive an amyloid PET scan or any of the other emerging biomarker to confirm clinical diagnosis, should screening for depression and suicidal ideation be conducted before and after test results in the interest of risk detection and prevention? We are likely to revisit this question as diagnostic tests for neurodegenerative syndromes are further refined.\n\nAt last, one last area of concern is related to genetics and AD. It is worth noting that our patient requested information on genetic testing for AD prior to his death, but did not complete testing. Thus, although we know the patient’s mother developed an unspecified dementia syndrome later in life, we ultimately cannot speak to the possibility of autosomal dominant or familial AD and whether or not this may impact suicide potential. This is a limitation. Case and cohort studies exploring the psychological impact of predictive and susceptibility testing for AD have thus far failed to identify adverse outcomes [43–47]. Larger, long-term outcome studies, however, are needed.\n\nFuture perspective\nSuicide risk prevention is an ever-important topic in healthcare and within communities. For clinicians who treat and evaluate patients with neurodegenerative disorders, safety and risk assessment must become integral components of ongoing care. Exclusively assessing for the presence or absence of depression in this population, however, is not always likely to be sufficient in determining suicide risk. In addition to considering acute depression severity and other overt risk factors, such as a family history of suicidal behavior, we may be able to utilize functional imaging and neuropsychological test results in order to identify individuals with early dementia who may be at elevated risk for suicidal behavior, and thereby intervene before patients act. In addition, advanced cognitive deficits do not preclude the possibility of a planned suicidal act. It is clear from this case how challenging prevention can be despite the best intent of providers and family.\n\n\nFinancial & competing interests disclosure\n\n\nMW Haut has received funding from the Conrad N Hilton Foundation; West Virginia Stroke CoBRE (P20 GM109098); the National Institutes of Health (NIH 1R01NS090677-01); and the American College of Radiology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nEthical conduct of research\n\n\nThe authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.\n\n\nOpen access\n\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\n1 Folstein MF Folstein SE McHugh PR Mini Mental State: a practical method for grading the cognitive state of patients for clinicians J. Psychiatr. Res. 12 189 195 1975 1202204 \n2 Frisoni GB Pievani M Testa C The topography of grey matter involvement in early and late onset Alzheimer’s disease Brain 130 720 730 2007 17293358 \n3 Karas G Scheltens P Rombouts S Precuneus atrophy in early onset Alzheimer’s disease: a morphometric structural MRI study Neuroradiology 49 967 976 2007 17955233 \n4 Hyman BT Phelps CH Beach TG National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease Alzheimers Dement. 8 1 13 2012 22265587 \n5 Schneider B Maurer K Frölich L Dementia and suicide Fortschr. Neurol. Psychiatr. 69 164 169 2001 11386121 \n6 Grabbe L Demi A Camann MA Potter L The health status of elderly persons in the last year of life: a comparison of deaths by suicide, injury, and natural causes Am. J. Public Health 87 434 437 1997 9096548 \n7 Peisah C Snowden J Gorrie C Kril J Rodriguez M Investigation of Alzheimer’s disease-related pathology in community dwelling older subjects who committed suicide J. Affect. Disord. 99 127 132 2007 17011041 \n8 Harris EC Barraclough B Suicide as an outcome for mental disorders. A meta-analysis Br. J. Psychiatry 170 205 228 1997 9229027 \n9 Purandare N Voshaar RCO Rodway C Bickley H Burns A Kapur N Suicide in dementia: 9-year national clinical survey in England and Wales Br. J. Psychiatry 194 175 180 2009 19182182 \n10 Barak Y Aizenberg D Suicide among Alzheimer’s disease patients: a 10-year survey Dement. Geriatr. Cogn. Disorder. 14 101 103 2002 \n11 Draper B Peisah C Snowdon J Brodaty H Early dementia diagnosis and the risk of suicide and euthanasia Alzheimers Dement. 6 75 82 2010 20129322 \n12 Serafini G Calcagno P Lester D Girardi P Amore M Pompili M Suicide risk in Alzheimer’s disease: a systematic review Curr. Alzheimer Res. 13 1083 1099 2016 27449996 \n13 Rubio A Vestner AL Stewart JM Forbes NT Conwell Y Cox C Suicide and Alzheimer’s pathology in the elderly: a case–controlled study Biol. Psychiatry 49 137 145 2001 11164760 \n14 Erlangsen A Zarit SH Conwell Y Hospital-diagnosed dementia and suicide: a longitudinal study using prospective, nationwide register data Am. J. Geriat. Psychiatry 16 220 228 2008 \n15 Jacobs D Sano M Marder K Age at onset of Alzheimer’s disease: relation to pattern of cognitive dysfunction and rate of decline Neurology 44 1215 1215 1994 8035918 \n16 Rhode K Peskind ER Raskind MA Suicide in two patients with Alzheimer’s disease J. Am. Geriatr. Soc. 43 187 189 1995 7836647 \n17 Ferris SH Hofeldt GT Carbone G Masciandaro P Troetel WM Imbimbo BP Suicide in two patients with a diagnosis of probable Alzheimer disease Alzheimer Dis. Assoc. Disord. 13 88 90 1999 10372951 \n18 Lim WS Rubin EH Coats M Morris JC Early-stage Alzheimer’s disease represents increased suicidal risks in relation to later stages Alz. Dis. Assoc. Disord. 19 214 219 2005 \n19 Margo GM Finkel JA Early dementia as a risk factor for suicide Hosp. Community Psychiatry 41 676 678 1990 2361677 \n20 Lesco PA Murder-suicide in Alzheimer’s disease J. Am. Geriatr. Soc. 37 167 168 1989 2642936 \n21 Vanyukov PM Szanto K Hallquist MN Paralimbic and lateral prefrontal encoding of reward value during intertemporal choice in attempted suicide Psychol. Med. 46 381 391 2016 26446615 \n22 Stern Y Cognitive reserve in ageing and Alzheimer’s disease Lancet Neurol. 11 1006 1012 2012 23079557 \n23 Van Orden KA Witte TK Cukrowicz KC Braithwaite S Selby EA Joiner TE The interpersonal theory of suicide Psychol. Rev. 117 575 600 2010 20438238 \n24 Weishaar ME Beck AT Hopelessness and suicide Int. Rev. Psychiatry 4 177 184 1992 \n25 Beck AT Kovacs M Weissman A Hopelessness and suicidal behavior: an overview JAMA 234 1146 1149 1975 1242427 \n26 Almeida OP Almeida SA Short versions of the Geriatric Depression Scale: a study of their validity for the diagnosis of a major depressive episode according to ICD-10 and DSM-IV Int. J. Geriat. Psychiatry 14 858 865 1999 \n27 Roy A Nielsen D Rylander G Sarchiapone M Segal N Genetics of suicide in depression J. Clin. Psychiatry 60 12 17 1999 \n28 Baldessarini RJ Hennen J Genetics of suicide: an overview Harv. Rev. Psychiatry 12 1 13 2004 14965851 \n29 Brent DA Mann JJ Family genetic studies, suicide and suicidal behavior Am. J. Med. Genet. C. Semin. Med. Genet. 133 13 24 2005 \n30 Mann JJ The neurobiology of suicide Nat. Med. 4 25 30 1998 9427602 \n31 Mann JJ Currier DM Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression Eur. Psychiatry 25 268 271 2010 20451357 \n32 Dombrovski AY Szanto K Clark L Reynolds CF Siegle GJ Reward signals, attempted suicide and impulsivity in late-life depression JAMA Psychiatry 70 1020 1030 2013 \n33 Dombrovski AY Hallquist MN The decision neuroscience perspective on suicidal behavior: evidence and hypotheses Curr. Opin. Psychiatry 30 7 14 2017 27875379 \n34 Szanto K de Bruin WB Parker AM Hallquist MN Vanyukov PM Dombrovski AY Decision-making competence and attempted suicide J. Clin. Psychiatry 76 e1590 e1597 2015 26717535 \n35 Bartra O McGuire JT Kable JW The valuation system: a coordinate-based meta-analysis of BOLD fMRI experiments examining neural correlates of subjective value Neuroimage 76 412 427 2013 23507394 \n36 Wiener J Moran MT Haut MW Completed suicide in a case of clinically diagnosed progressive supranuclear palsy Neurodegener. Dis. Manag. 5 289 292 2015 26295722 \n37 Kasckow J Youk A Anderson SJ Trajectories of suicidal ideation in depressed older adults undergoing antidepressant treatment J. Psychiatr. Res. 73 96 101 2015 26708830 \n38 Richard-Devantoy S Szanto K Butters MA Kalkus J Dombrovski AY Cognitive inhibition in elderly high-lethality suicide attempters Int. J. Geriatr. Psychiatry 30 274 283 2015 24816626 \n39 Richard-Devantoy S Berlim MT Jollant F A meta-analysis of neuropsychological markers of vulnerability to suicidal behavior in mood disorders Psychol. Med. 44 1663 1673 2014 24016405 \n40 Mattsson N Brax D Zetterberg H To know or not to know: ethical issues related to early diagnosis of Alzheimer’s disease Int. J. Alzheimers Dis. 2010 841941 2010 20798843 \n41 Di Maio L Squitieri F Napolitano G Campanella G Trofatter JA Conneally PM Suicide risk in Huntington’s disease J. Med. Genet. 30 293 295 1993 8487273 \n42 Almqvist EW Block M Brinkman R Craufurd D Hayden MR A worldwide assessment of the frequency of suicide, suicide attempts or psychiatric hospitalization after predictive testing for Huntington’s disease Am. J. Hum. Genet. 64 1293 1304 1999 10205260 \n43 Steinbart EJ Smith CO Poorkaj P Bird TD Impact of DNA testing for early onset familial Alzheimer disease and frontotemporal dementia Arch. Neurol. 58 1828 1831 2001 11708991 \n44 Lannfelt L Axelman K Lilius L Basun H Genetic counseling in a Swedish Alzheimer family with amyloid precursor protein mutation Am. J. Hum. Genet. 56 332 335 1995 7825596 \n45 Green RC Roberts JS Cupples LA Disclosure of APOE genotype for risk of Alzheimer’s disease N. Engl. J. Med. 361 245 254 2009 19605829 \n46 Caselli RJ Marchant GE Hunt KS Predictive testing for Alzheiemr’s disease: suicidal ideation in healthy participants Alzheimer Dis Assoc Disord 29 252 254 2015 25984909 \n47 Paulsen JS Nance M Kim J A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases Prog. Neurobiol. 110 2 28 2013 24036231\n\n",
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"keywords": "Alzheimer’s disease; early onset; suicide",
"medline_ta": "Neurodegener Dis Manag",
"mesh_terms": "D000544:Alzheimer Disease; D001344:Autopsy; D001921:Brain; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D013405:Suicide",
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"title": "Completed suicide in an autopsy-confirmed case of early onset Alzheimer's disease.",
"title_normalized": "completed suicide in an autopsy confirmed case of early onset alzheimer s disease"
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"abstract": "Management of ischemic heart disease in pregnant women is still difficult, as there is little experience with many of the newer treatments such as clopidogrel. The safety of clopidogrel in pregnancy is unknown, especially in combination with aspirin. Its use during gestation has been described in a few case reports. We describe the case of a 36-year-old woman in her 9th week of pregnancy with a history of chronic hypertension, dyslipidemia and CAD, who required antiplatelet treatment. Clopidogrel and aspirin were administrated until one week before delivery and a healthy child was born at 36 weeks of pregnancy by caesarean section, without any complication.",
"affiliations": "Telefono Rosso-Teratology Information Service, Department of Obstetrics and Gynaecology, Università Cattolica del Sacro Cuore, Italy. marcodesantis@rm.unicatt.it",
"authors": "De Santis|Marco|M|;De Luca|Carmen|C|;Mappa|Ilenia|I|;Cesari|Elena|E|;Mazza|Andrea|A|;Quattrocchi|Tomasella|T|;Caruso|Alessandro|A|",
"chemical_list": "D000077144:Clopidogrel; D013988:Ticlopidine",
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"mesh_terms": "D000328:Adult; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D017202:Myocardial Ischemia; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D013988:Ticlopidine; D016896:Treatment Outcome",
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"title": "Clopidogrel treatment during pregnancy: a case report and a review of literature.",
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-03639",
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"abstract": "OBJECTIVE\nFOLFIRINOX (FFN), nab-paclitaxel plus gemcitabine (GN), and gemcitabine are three systemic therapies that provide clinically meaningful benefit to patients with unresectable pancreatic cancer (UPC). There are no clinical trials that directly compare the efficacy of all three regimens. In this study, we aim to examine and compare the real-world effectiveness of these treatments.\n\n\nMETHODS\nPatients diagnosed with UPC who initiated palliative chemotherapy from August 2014 to January 2016 at any one of six cancer centers in British Columbia were identified from the provincial pharmacy. Clinical, pathological, treatment, and outcome characteristics were compared.\n\n\nRESULTS\nTwo hundred twenty-five patients were included: 55% men, 68% Eastern Cooperative Oncology Group 0/1, 58% metastatic disease. Patients who received FFN were younger (p < 0.001) and in better performance status (p < 0.001). Patients treated with FFN or GN experienced significantly longer median overall survival (OS) when compared to those treated with gemcitabine (14.1 vs 10.5 vs 4.2 months, respectively, p < 0.001). Progression-free survival (PFS) was also longer among patients on FFN or GN in comparison to gemcitabine (FFN, HR 0.44, 95% CI 0.24 to 0.814, p = 0.008; GN, HR 0.30, 95% CI 0.19 to 0.47, p < 0.001). A significantly higher proportion of patients require two or more dose modifications on FFN (40%) compared to GN (14%) or gemcitabine (9%) (p < 0.001).\n\n\nCONCLUSIONS\nReceipt of modified FFN and GN portends a better prognosis than gemcitabine alone. In the absence of a randomized comparison of all three regimens, our population-based study reveals that the introduction of modified FFN and GN confers real-world effectiveness for UPC patients.",
"affiliations": "Division of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC, V5Z 4E6, Canada.;Faculty of Medicine, University of British Columbia, 2775 Laurel Street, 10th Floor, Vancouver, BC, V5Z 1M9, Canada.;Division of Medical Oncology, Tom Baker Cancer Centre, 1331 29 St NW, Calgary, AB, T2N 4N2, Canada. winson.cheung@ahs.ca.",
"authors": "Wang|Ying|Y|http://orcid.org/0000-0001-8087-459X;Camateros|Pierre|P|;Cheung|Winson Y|WY|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "United States",
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"doi": "10.1007/s12029-017-0028-5",
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"issue": "50(1)",
"journal": "Journal of gastrointestinal cancer",
"keywords": "Advanced; FOLFIRINOX; Gemcitabine; Pancreatic cancer; nab-Paclitaxel",
"medline_ta": "J Gastrointest Cancer",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101479627",
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"title": "A Real-World Comparison of FOLFIRINOX, Gemcitabine Plus nab-Paclitaxel, and Gemcitabine in Advanced Pancreatic Cancers.",
"title_normalized": "a real world comparison of folfirinox gemcitabine plus nab paclitaxel and gemcitabine in advanced pancreatic cancers"
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"abstract": "Bleomycin-induced pneumonitis (BIP) is a serious and potentially fatal adverse effect of bleomycin. Currently, BIP is treated on an empirical basis with high dose steroid. Pirfenidone is a new antifibrotic drug, which has been proven beneficial in idiopathic pulmonary fibrosis and is able to inhibit or reverse BIP in animal models. Here, the first two cases of human BIP treated with pirfenidone in addition to steroid therapy are presented. Unfortunately, both patients died, which may be explained by the initiation of therapy at a late stage. Therefore, studies of early or prophylactic treatment with pirfenidone in relation to bleomycin-containing chemotherapy regimens are needed.",
"affiliations": "Department of Respiratory Medicine and Allergology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark.;Department of Respiratory Medicine and Allergology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark.;Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark.;Department of Clinical Pharmacology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark.;Department of Respiratory Medicine and Allergology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark.",
"authors": "Bendstrup|Elisabeth|E|;Hyldgaard|Charlotte|C|;Agerbæk|Mads|M|;Andersen|Charlotte U|CU|;Hilberg|Ole|O|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(14)00015-X10.1016/j.rmcr.2013.12.010Case ReportNo effect of pirfenidone treatment in fulminant bleomycin-induced pneumonitis Bendstrup Elisabeth karbends@rm.dkkabend@rm.dka∗Hyldgaard Charlotte aAgerbæk Mads bAndersen Charlotte U. cHilberg Ole aa Department of Respiratory Medicine and Allergology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmarkb Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmarkc Department of Clinical Pharmacology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark∗ Corresponding author. Tel.: +45 7846 2201; fax: +45 78 46 21 20. karbends@rm.dkkabend@rm.dk02 5 2014 2014 02 5 2014 12 47 49 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Bleomycin-induced pneumonitis (BIP) is a serious and potentially fatal adverse effect of bleomycin. Currently, BIP is treated on an empirical basis with high dose steroid. Pirfenidone is a new antifibrotic drug, which has been proven beneficial in idiopathic pulmonary fibrosis and is able to inhibit or reverse BIP in animal models. Here, the first two cases of human BIP treated with pirfenidone in addition to steroid therapy are presented. Unfortunately, both patients died, which may be explained by the initiation of therapy at a late stage. Therefore, studies of early or prophylactic treatment with pirfenidone in relation to bleomycin-containing chemotherapy regimens are needed.\n\nKeywords\nBleomycinPneumonitisPirfenidone\n==== Body\nIntroduction\nBleomycin-induced pneumonitis (BIP) is a serious adverse effect of bleomycin, which is used in chemotherapy regimens in patients with testicular cancer or Hodgkin's lymphoma [1]. The incidence of BIP is 15–18% [2,3], and increasing age, low albumin level and the use of granulocyte colony-stimulating factor have been associated with the development of the condition [3]. BIP is diagnosed in the presence of a combination of worsening pulmonary symptoms, bilateral interstitial infiltrates on chest X-ray and/or computed tomography, or the presence of pulmonary fibrosis on transbronchial lung biopsy in the absence of infection [1]. Although similar 5-year overall survival rates have been found in BIP patients compared to unaffected patients, BIP has been associated with decreased survival in some studies [2,3], and the occurrence may necessitate cessation of potentially life-saving chemotherapy.\n\nThere are no large or randomized studies regarding the treatment of BIP, but traditionally, high-dose steroids have been used. In animal studies, oxygen therapy has been associated with worse outcome, and therefore, avoidance or at least minimization of oxygen therapy is recommended [1]. New pharmacological treatments are urgently needed.\n\nPirfenidone is a new anti-fibrotic agent which has been proven beneficial for idiopathic pulmonary fibrosis in humans [4]. It possesses both anti-inflammatory and anti-fibrotic properties and has been shown to slow or reverse bleomycin-induced pulmonary fibrosis in animals [5,6]. These characteristics suggest that pirfenidone could be beneficial for BIP in humans.\n\nHere, we report two patients with testicular cancer and bleomycin-induced fulminant pneumonitis in whom treatment with a combination of pirfenidone and high-dose steroids failed.\n\nPatient case 1\nA 19-year old male with Down's syndrome was diagnosed with a retroperitoneal germinal cell tumor in May 2012. At diagnosis, α-fetoprotein was increased to 1973 μg/l. Renal function was impaired with a glomerular filtration rate (GFR) of 36 ml/min due to ureteral compression. Pre-chemotherapy spirometry showed a forced expiratory volume in 1 s (FEV1) of 2.29 l (68% of predicted) and a forced vital capacity (FVC) 2.36 l (62%). The patient was treated with three series of bleomycin 30.000 IU on day 2, 9 and 16, etoposide 100 mg/m2 s.i.d. on day 1–5 and cisplatin 20 mg/m2 s.i.d. day 1–5. He was admitted to hospital with neutropenic fever after the first series, and started pegfilgatrim, a granulocyte-colony stimulating factor, after the 2nd and 3rd series. After the 3rd series, he was again admitted with neutropenic fever and severe desaturation. In spite of antibiotics and oxygen therapy, the patient deteriorated, and after 2 days mechanical ventilation was necessary. The chest X-ray showed bilateral consolidated infiltrates, and high dose Methylprednisolone 100 mg s.i.d. was initiated. C-reactive protein and α-fetoprotein were both normalized, indicating that the cancer had responded well to treatment. However, the patient's respiratory condition worsened, and one week after, pirfenidone 802 mg t.i.d was initiated. In spite of maximal treatment, the respiratory condition worsened and extra corporal membrane oxygenation (ECMO) was started. After 2 weeks of ECMO, 3 weeks of pirfenidone treatment and 4 weeks of high dose steroids in combination with weekly steroid pulse courses, the patient succumbed to BIP.\n\nPatient case 2\nA 42-year old mentally retarded male with schizophrenia was diagnosed with disseminated testicular cancer in December 2012. At diagnosis, α-fetoprotein was normal. The patient had impaired renal function due to compression of the ureteres by retroperitoneal tumor masses, and was treated with a nephrostomy catheter. He was treated with 4 series of bleomycin 30.000 IU on day 2, 9 and 16, etoposide 100 mg/m2 s.i.d on day 1–5, and cisplatin 20 mg/m2 s.i.d on day 1–5. A pulmonary function test prior to chemotherapy showed a slightly restrictive pattern with a mildly reduced diffusion capacity. Due to hospital admittance with a neutropenic fever after the first series, he was treated with pegfilgatrim after the remaining chemotherapy series. After the 4th series, routine positron emission tomography–computed tomography (PET–CT) showed interstitial pneumonitis compatible with bleomycin-induced pneumonitis, and it came forward that the patient had been experiencing progressive dyspnea and a dry cough for several weeks. He was able to walk 420 m on 6 min walk test with desaturation to 94%. High dose Methylprednisolone 100 mg s.i.d. was started, and pirfenidone treatment was considered, but abandoned at this time. After one month of steroid treatment the patient was admitted to hospital with a pulmonary infection and severe hypoxia; a CT scan showed no evidence of pulmonary embolism, but revealed interstitial changes (Fig. 1). The treatment was supplemented with pulse courses of steroid and pirfenidone 802 mg t.i.d. but in spite of this, the patient's condition deteriorated. Ventilator treatment was initiated and followed by ECMO, but the patient died from BIP two months after the diagnosis.\n\nDiscussion\nWe report here the first two cases of fulminant bleomycin-induced pneumonitis treated by pirfenidone. Disappointingly, pirfenidone did not seem to improve the clinical course.\n\nIn these two patients, treatment with granulocyte-colony stimulating factor, neglect of dyspnea and renal impairment may have contributed to the emergence of fatal BIP. The anti-inflammatory and anti-fibrotic actions of pirfenidone have been shown to slow or even reverse the effects of bleomycin in animal models [5,6]. In vitro, pirfenidone significantly reduced surrogate markers of fibrosis such as the expression of TGFβ-1 and proliferation in human lung fibroblasts in a dose dependent manner, and human synovial fibroblasts expressed less ICAM-1 in the presence of pirfenidone. Pirfenidone also reduces expression of other pro-fibrotic genes such as collagen III [7]. It has antioxidant effects and inhibits lipid peroxidation, and thus, pirfenidone may function as a scavenger of reactive oxygen species [8].\n\nThe anti-fibrotic action of pirfenidone has been compared with that of prednisolone in bleomycin-induced fibrosis in mice. Both drugs were administered daily for approximately 30 days. Only pirfenidone inhibited fibrosis and suppressed the increase in pulmonary levels of bFGF, TGFb1, stromal cell-derived factor 1a (SDF-1a), IL-18 and IFNg, while both drugs attenuated the increase in IL1b, IL-6, monocytes chemotactic protein (MCP)-1, and IL-12p40 (subunit of interleukin-12) [9,10]. The timing of pirfenidone treatment has been studied in animal models, and the effect of pirfenidone seems to be better when treatment is started prophylactically or early after bleomycin treatment [6].\n\nThe bleomycin lung fibrosis model in animals is widely used but has limitations. More than 200 drugs have been tried in the bleomycin mouse model but only pirfenidone have qualified for clinical use. Bleomycin causes inflammation by overproduction of free radicals and induction of pro-inflammatory cytokines and resembles more an acute lung injury in the early phases. The subsequent fibrosis is developed after about 7 days and is partly reversible. Thus, the slow and irreversible progressive of fibrosis seen in IPF is not reproduced in the bleomycin animal models, which may explain the disappointing success rate of translating results from the bleomycin model to IPF patients. It is also unclear whether the bleomycin model in rodents can be translated to human bleomycin-induced pneumonitis, although it may intuitively seem more plausible. Pirfenidone administered before or up to 7 days after bleomycin treatment will treat inflammation while pirfenidone administered more than 7 days after bleomycin targets the fibrotic pathways. Pirfenidone has shown beneficial effects with both scenarios although preventive treatment was the most efficient [6,11].\n\nTherefore, the lack of effect on BIP in our patients may be due to the initiation of therapy at a time when overt and fulminant BIP had already developed. Thus, studies of early or prophylactic pirfenidone treatment to clarify the role of pirfenidone in bleomycin-induced pneumonitis and fibrosis in humans are strongly needed.\n\nContribution to the study/Authorship\n1. Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: EB\n\n2. Drafting the article or revising it critically for important intellectual content: OH, EB, CH, MA, CUA\n\n3. Final approval of the version to be published: OH, EB, CH, MA, CUA.\n\n\n\nFig. 1 High resolution computed tomography (HRCT) of patient 2 at diagnosis of bleomycin-induced pneumonitis and 5 weeks later when pirfenidone was started. The first HRCT show consolidations and bronchiectasis and the second HRCT shows severe progression with development of diffuse ground glass opacities, consolidations and traction bronchiectasis.\n==== Refs\nReferences\n1 Sleijfer S. Bleomycin-induced pneumonitis Chest 120 2001 617 624 11502668 \n2 Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE, Ansell SM. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol;23:7614–20.\n3 Ngeow J. Tan I.B. Kanesvaran R. Tan H.C. Tao Quek R. Lim S.T. Prognostic impact of bleomycin-induced pneumonitis ion the outcome of Hodgkin's lymphoma Ann Hematol 90 2011 67 72 20676640 \n4 Hilberg O. Simonsen U. du Bois R. Bendstrup E. Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis Clin Respir J 6 2012 131 143 22697264 \n5 Iyer S.N. Margolin S.B. Hyde D.M. Giri S.N. Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model Exp Lung Res 24 1998 119 132 9457473 \n6 Schaefer C.J. Ruhrmund D.W. Pan L. Seiwert S.D. Kossen K. Antifibrotic activities of pirfenidone in animal models Eur Respir Rev 20 2011 85 97 21632796 \n7 Kaneko M. Inoue H. Nakazawa R. Azuma N. Suzuki M. Yamauchi S. Pirfenidone induces intercellular adhesion molecule-1 (ICAM-1) down-regulation on cultured human synovial fibroblasts Clin Exp Immunol 113 1998 727 736 \n8 Giri S.N. Leonard S. Shi X. Margolin S.B. Vallyathan V. Effects of pirfenidone on the generation of reactive oxygen species in vitro J Environ Pathol Toxicol Oncol 18 1999 169 177 15281229 \n9 Oku H. Shimizu T. Kawabata T. Nagira M. Hikita I. Ueyama A. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis Eur J Pharmacol 590 2008 400 408 18598692 \n10 McKane B.W. Fernandez F. Narayanan K. Marshbank S. Margolin S.B. Jendrisak M. Pirfenidone inhibits obliterative airway disease in a murine heterotopic tracheal transplant model Transplantation 77 2004 664 669 15021826 \n11 Moeller A. Ask K. Warburton D. Gauldie J. Kolb M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol 40 2008 362 382 17936056\n\n",
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"issue": "12()",
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"keywords": "Bleomycin; Pirfenidone; Pneumonitis",
"medline_ta": "Respir Med Case Rep",
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"title": "No effect of pirfenidone treatment in fulminant bleomycin-induced pneumonitis.",
"title_normalized": "no effect of pirfenidone treatment in fulminant bleomycin induced pneumonitis"
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"abstract": "Patients with human immunodeficiency virus (HIV) have increased risk of cardiovascular disease. Although evidence of subclinical atherosclerosis in perinatally acquired HIV (PHIV) is available, myocardial infarction has not been described in this population. We report a case of myocardial infarction in a patient with PHIV with a brief literature review.",
"affiliations": "Department of Medicine.;Department of Medicine.;Department of Medicine.;Department of Medicine.;Department of Medicine.;Department of Medicine.",
"authors": "Griffith|David C|DC|;Aronis|Konstantinos N|KN|;Orozco|Angela M|AM|;Traill|Thomas A|TA|;Manabe|Yukari C|YC|;Agwu|Allison L|AL|",
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"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n28480253\n10.1093/ofid/ofw260\nofw260\nBrief Report\nPremature Coronary Artery Disease and ST-Elevation Myocardial Infarction in a 24-Year-Old Man With Perinatally Acquired Human Immunodeficiency Virus: A Case Report\nGriffith David C. 12 Aronis Konstantinos N. 1 Orozco Angela M. 12 Traill Thomas A. 1 Manabe Yukari C. 1 Agwu Allison L. 12 1 \nDepartment of Medicine\n\n2 \nPediatrics, Johns Hopkins University, Baltimore, Maryland\nCorrespondence: D. C. Griffith, MD, 200 North Wolfe Street, Room 3150, Baltimore MD, 21287 (dgriff50@jhmi.edu).\n\n\nWinter 2017 \n10 2 2017 \n10 2 2017 \n4 1 ofw26030 9 2016 09 1 2017 © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nPatients with human immunodeficiency virus (HIV) have increased risk of cardiovascular disease. Although evidence of subclinical atherosclerosis in perinatally acquired HIV (PHIV) is available, myocardial infarction has not been described in this population. We report a case of myocardial infarction in a patient with PHIV with a brief literature review.\n\ncardiovascular diseaseHIVmyocardial infarctionperinatalNational Institutes of Health10.13039/100000002T32AI052071\n==== Body\nCASE PRESENTATION\nOur patient is a 24-year-old man with perinatally acquired human immunodeficiency virus (PHIV) who presented to his first visit at our hospital-based adult outpatient HIV clinic reporting fatigue and severe weight loss with worsening shortness of breath. Diagnosed with HIV shortly after birth, he initiated antiretroviral therapy at 5 years of age. His combination antiretroviral therapy (cART) history included multiple nucleoside reverse-transcriptase inhibitors (stavudine, lamivudine, didanosine, zidovudine, abacavir, emtricitabine), nonnucleoside reverse-transcriptase inhibitor (efavirenz), and protease inhibitors (nelfinavir, lopinavir, ritonavir, atazanvir), combined initially in dual and subsequently 3-drug regimens. He had periods of viral suppression from the age of 10 to 19, at which point he transferred care from the pediatric HIV program at our institution to another institution (see Supplementary data for treatment history). The patient reported difficulty engaging with the adult clinic and provider, had challenges with unstable housing, intermittent employment, and minimal family support. He therefore self-discontinued cART and had fallen out of care.\n\nHis interval medical history is significant for pneumocystis pneumonia and cryptococcal meningitis 2 years prior. He had been hospitalized at an outside hospital twice in the prior month for weakness in the setting of hypokalemia. He smoked approximately a half a pack of cigarettes daily for the past 8 years and has occasional marijuana use. From the age of 9–19 years, his calculated low-density lipoprotein (LDL-C) range was 79–136 mg/dL, triglyceride range was 76–255 mg/dL, and high-density lipoprotein (HDL) range was 29–82 mg/dL. He denied any other illicit drug use. He reported no known family history of diabetes, cardiovascular disease (CVD), or early cardiac death.\n\nHis initial vital signs were as follows: blood pressure 90/64 mmHg, heart rate 55 beats/minute, temperature 35.9°C, respiratory rate 18 breaths/minute, and body mass index 12.9 kg/m2. On exam, he was noted to be cachectic and frail, with the remainder of his exam normal, including heart with regular rate and rhythm without murmur, rub, or gallops. His initial laboratory tests were notable for hyponatremia (128 mEq/L), hypokalemia (2.3 mEq/L), hypophosphatemia (0.4 mg/dL), and a nonanion gap metabolic acidosis. Urine toxicology was negative. His CD4 count was 1 cell/mm3, and HIV-1 ribonucleic acid viral load was 43 642 copies/mL. Upon presentation, his electrocardiogram (ECG) showed normal sinus rhythm with left ventricular hypertrophy and prominent U waves in the precordial leads consistent with hypokalemia. His chest radiograph was normal.\n\nHe was admitted to our inpatient medicine ward for evaluation and management of his electrolyte derangements as well as nutritional assessment. His electrolyte abnormalities resolved; however, on hospital day 2, he suddenly developed new onset pressure-like chest pain that lasted for 20 minutes. The pain was severe in intensity, constant, and nonradiating. On exam, he was afebrile with a blood pressure of 94/62 mmHg and heart rate of 80 beats/minute. He was diaphoretic and mildly uncomfortable, but otherwise his physical examination was unchanged. An ECG showed prominent ST elevations in the anterior leads consistent with anterior wall ST elevation myocardial infarction (Figure 1a). Standard acute coronary syndrome treatment was promptly initiated. A transthoracic echocardiogram showed moderately reduced left ventricular systolic function with an ejection fraction of 30%–35% with severe hypokinesis of the mid anterior and anteroseptal wall as well as of the entire apex, consistent with ischemia in the left anterior descending (LAD) supply territory. His troponin I levels at the time of this event were 0.76 ng/mL (normal <0.04 ng/mL).\n\nFigure 1. (a) Electrocardiogram (ECG) during episode of chest pain showing prominent ST elevations in the anterior leads (8 mm in lead V3 and 5 mm in lead V4). The rhythm is normal sinus at a rate of 78 beats per minute. The right axis deviation and the left ventricular hypertrophy by voltage criteria are unchanged from the presenting ECG. Prominent U waves seen on initial ECG are no longer present. (b) Initial coronary angiogram: right anterior oblique caudal view of the left anterior descending coronary artery (LAD) showing a 95% long and hazy stenosis of the mid-LAD segment (arrow). The incomplete filling of the LAD on this static frame is due to thrombolysis in myocardial infarction (TIMI)-2 flow observed on cine. A 30%–40% stenosis of the left circumflex first obtuse marginal branch is also visualized. (c) Post- percutaneous coronary intervention coronary angiogram: the 95% mid-LAD stenosis is now converted to a 0% and TIMI-3 flow is restored.\n\nHe underwent emergent coronary angiography, which showed a long, hazy 95% stenosis at the mid segment of the LAD with thrombolysis in myocardial infarction (TIMI)-2 flow distally. The LAD first diagonal branch had a 40% proximal stenosis, the left circumflex obtuse marginal branch had a 30%–40% stenosis in the mid segment, and the dominant right coronary artery had a 30% stenosis in the mid segment. Notably, there were no significant coronary calcifications visualized on the angiogram. He underwent successful percutaneous coronary intervention of the proximal and mid LAD segments with 2 overlapping Vision bare metal stents converting the hazy 95% stenosis to 0% and restoring TIMI-3 antegrade flow (Figure 1b and c).\n\nHe was subsequently transferred to the cardiac care unit for observation. His ST elevations resolved. His troponin I levels peaked at 9.85 ng/mL, approximately 17 hours after the onset of his symptoms. The remainder of his laboratory tests revealed the following: total cholesterol 52 mg/dL, triglycerides 48 mg/dL, HDL 27 mg/dL, LDL-C 17 mg/dL, lipoprotein(a) levels <10 nmol/L, and C-reactive protein (CRP) <0.1 mg/dL. He was discharged on 81 mg of aspirin and 75 mg of clopidogrel. He was not prescribed a beta blocker because of hypotension. He was also restarted on cART.\n\nDISCUSSION\nThis case illustrates the development of premature atherosclerosis resulting in an acute coronary event in a young patient with PHIV. Cardiovascular disease is a major source of morbidity and mortality in patients with HIV with an estimated rate of 0.49 CVD events per 100 person years for virally suppressed patients and an adjusted hazard ratio of 2.1 (95% confidence interval, 1.7–2.6) for CVD event for every 10-year increase in age [1]. Large cohort studies have shown increased risk of acute myocardial infarction in HIV-infected adults, even after accounting for traditional CVD risk factors [2]. However, rates among individuals with PHIV are not captured or described in these studies, and as of yet there are no reports of myocardial infarction in PHIV.\n\nAlthough there are limited data on CVD events in youth, subclinical atherosclerosis has been described in HIV-infected youth through multiple imaging modalities. Ultrasound assessments of carotid artery intima media thickness (CIMT) was used in a in a multicohort study of HIV-infected patients and controls aged 6–75 years [3]. HIV-infected participants aged 6–29 years (n = 279) had increased CIMT compared with HIV-uninfected controls (n = 58) after adjusting for traditional CVD risk factors with strengthening of the association when the analysis was limited to PHIV. This difference was not seen in patients aged 30–49 (n = 738) and 50–75 years (n = 730), which suggests that in youth, HIV itself increases the risk of artery thickening, with an increasing role of traditional risk factors as patients age. Additional cohort studies support these findings with 1 cohort showing both cART-naive and virally suppressed HIV-infected children have increased CIMT compared with HIV-uninfected children [4]. Youth with early-acquired or PHIV (15–29 years old) had increased right coronary artery wall thickness, compared with HIV-uninfected controls in a study using coronary magnetic resonance imaging [5]. All identified plaques were noncalcified and not associated with significant luminal narrowing. These studies highlight that youth with PHIV have subclinical atherosclerosis, although there is lack of data that relates subclinical atherosclerosis to adverse clinical outcomes.\n\nThe increased risk of atherosclerosis in HIV-infected individuals is likely caused by several factors, including HIV-induced immune activation and monocyte/macrophage-mediated inflammation (regardless of cART use), direct vascular effects of HIV, and the adverse metabolic effects of antiretroviral therapy, in addition to traditional CVD risk factors [6]. Multivariable analysis of several cohorts of children and adolescents have shown that compared with controls, PHIV is associated with elevated markers of endothelial dysfunction, in particular soluble vascular cell adhesion molecule 1 (sVCAM) and soluble intracellular adhesion molecule 1 (sICAM) and markers of immune activation and inflammation, including monocyte chemoattractant protein-1 (MCP-1), interleukin-6, soluble CD14 (sCD14) and CRP, as well as fibrinogen, a marker of coagulant dysfunction [7, 8]. Higher HIV viral loads are associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM) [8]. However, sCD14 and sVCAM have been shown to be increased even in the setting of viral suppression [7]. Although based on small cohorts, these studies highlight the impact on early-acquired HIV on biomarkers associated with CVD.\n\nExposure to cART, in particular older protease inhibitor (PI) agents lopinavir and indinavir and potentially abacavir, has been associated with myocardial infarction; however, the data are not definitive [9]. More importantly, continuous cART has been shown to decrease the rate of CVD events compared with cART with treatment interruptions [10]. In children with PHIV, adverse structural and functional vascular changes (as measured by CIMT artery flow-mediated dilatation) have been associated with PI exposure [11]. Children and adolescents with PHIV have been shown to have higher rates of dyslipidemia compared with uninfected controls, with PI use being the strongest associated risk factor [12].\n\nOur patient’s CVD risk factors include prolonged periods of uncontrolled viral replication during the first 5 years of his life before he was started on cART and for the last 5 years when he was not taking cART. Moreover, he has a long history of cART, with exposure to agents potentially associated with CVD (lopinavir/ritonavir and abacavir). Finally, he is actively smoking, although with a limited pack-year history. He does not have a history of sustained hyperlipidemia, although his HDL was very low at the time of presentation.\n\nCONCLUSIONS\nAs shown in this case, an increased index of suspicion for CVD may be warranted in individuals with PHIV. Future studies on CVD risk assessment and optimization are needed, because there are currently no guidelines on CVD risk management in these patients. The role of statins is unclear, and individuals with PHIV do not meet the age inclusion criteria for the ongoing randomized trial to prevent vascular events in HIV (REPRIEVE) [13]. This case also highlights the importance of successful transition from pediatric to adult providers to minimize serious complications caused by lapses in care.\n\nSupplementary Data\nSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\nSupplementary Material\nofw260_suppl_ofid_case_supplement_figure Click here for additional data file.\n\n Acknowledgments\n\nFinancial support. This work was funded by the National Institutes of Health (Grant T32AI052071).\n\n\nPotential conflicts of interest. All authors: No reported conflicts.\n\nAll authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1 \nMiller CJ Baker JV Bormann AM et al. \nAdjudicated morbidity and mortality outcomes by age among individuals with HIV infection on suppressive antiretroviral therapy\n. PLoS One 2014 ; 9 :e95061\n.\n2 \nPaisible AL Chang CC So-Armah KA et al. \nHIV infection, cardiovascular disease risk factor profile, and risk for acute myocardial infarction\n. J Acquir Immune Defic Syndr 2015 ; 68 :209 –16\n.25588033 \n3 \nHanna DB Guo M Bůžková P et al. \nHIV infection and carotid artery intima-media thickness: pooled analyses across five cohorts of the NHLBI HIV-CVD Collaborative\n. Clin Infect Dis 2016 ; 1 –8\n.\n4 \nSainz T Álvarez-Fuente M Navarro ML et al. \nSubclinical atherosclerosis and markers of immune activation in HIV-infected children and adolescents\n. J Acquir Immune Defic Syndr 2014 ; 65 :42 –49\n.23982657 \n5 \nAbd-Elmoniem KZ Unsal AB Eshera S et al. \nIncreased coronary vessel wall thickness in HIV-infected young adults\n. Clin Infect Dis 2014 ; 59 :1779 –86\n.25159580 \n6 \nNou E Lo J Grinspoon SK \nInflammation, immune activation, and cardiovascular disease in HIV\n. AIDS 2016 ; 1495 –1509\n.27058351 \n7 \nSainz T Diaz L Navarro ML et al. \nCardiovascular biomarkers in vertically HIV-infected children without metabolic abnormalities\n. Atherosclerosis 2014 ; 233 :410 –4\n.24530771 \n8 \nMiller TI Borkowsky W DiMeglio LA et al. \nMetabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children\n. HIV Med 2012 ; 13 :264 –75\n.22136114 \n9 \nBavinger C Bendavid E Niehaus K et al. \nRisk of cardiovascular disease from antiretroviral therapy for HIV: a systematic review\n. PLoS One 2013 ; 8 :e59551\n.\n10 \nEl-Sadr W Lundgren JD Neaton JD et al. \nCD4+ count-guided interruption of antiretroviral treatment\n. N Engl J Med 2006 ; 355 :2283 –2296\n.17135583 \n11 \nCharakida M Donald AE Green H et al. \nEarly structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy\n. Circulation 2005 ; 112 :103 –9\n.15983247 \n12 \nFarley J Gona P Crain M et al. \nPrevalence of elevated cholesterol and associated risk factors among perinatally HIV-infected children (4-19 years old) in Pediatric AIDS Clinical Trials Group 219C\n. J Acquir Immune Defic Syndr 2005 ; 38 :480 –7\n.15764965 \n13 \nGilbert JM Fitch KV Grinspoon SK \nHIV-related cardiovascular disease, statins, and the REPRIEVE trial\n. Top Antivir Med 2015 ; 23 :146 –9\n.26713505\n\n",
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"keywords": "HIV; cardiovascular disease; myocardial infarction; perinatal",
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"title": "Premature Coronary Artery Disease and ST-Elevation Myocardial Infarction in a 24-Year-Old Man With Perinatally Acquired Human Immunodeficiency Virus: A Case Report.",
"title_normalized": "premature coronary artery disease and st elevation myocardial infarction in a 24 year old man with perinatally acquired human immunodeficiency virus a case report"
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"abstract": "Metronidazole desensitization is recommended in patients with trichomoniasis and history of an allergic reaction to metronidazole due to presumed cross reactivity with tinidazole and lack of reliably safe and effective alternative therapies. We report our experiences in a patient with persistent trichomoniasis who failed to complete metronidazole desensitization due to a burning sensation over her whole body and pruritus but was later successfully desensitized to tinidazole without experiencing any adverse effects.",
"affiliations": "College of Pharmacy, University of Illinois at Chicago, Rockford, IL, USA.;Department of Pharmacy, SwedishAmerican Hospital, Rockford, IL, USA.;Department of Pharmacy, SwedishAmerican Hospital, Rockford, IL, USA.;Division of Infectious Diseases, Department of Medicine, SwedishAmerican Hospital, Rockford, IL, USA.",
"authors": "Biagi|Mark|M|0000-0001-5190-0066;Slipke|Wendy|W|;Smalley|Alexa|A|;Tsaras|Geoffrey|G|",
"chemical_list": "D000994:Antitrichomonal Agents; D014011:Tinidazole; D008795:Metronidazole",
"country": "England",
"delete": false,
"doi": "10.1177/0956462420963912",
"fulltext": null,
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"issn_linking": "0956-4624",
"issue": "32(1)",
"journal": "International journal of STD & AIDS",
"keywords": "Desensitization; Trichomonas vaginalis; metronidazole; tinidazole; trichomoniasis",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000328:Adult; D000994:Antitrichomonal Agents; D004351:Drug Resistance; D005260:Female; D006801:Humans; D006967:Hypersensitivity; D008795:Metronidazole; D014011:Tinidazole; D016896:Treatment Outcome; D014245:Trichomonas Infections; D014246:Trichomonas vaginalis",
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"references": null,
"title": "Successful treatment of trichomoniasis with tinidazole following desensitization in a patient allergic to metronidazole.",
"title_normalized": "successful treatment of trichomoniasis with tinidazole following desensitization in a patient allergic to metronidazole"
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"abstract": "METHODS\nA 68-year-old male patient with psorias and a bullous pemphigoid as an underlying disease developed bilateral groundglass opacities on chest CT under longer-term, higher-dose immunosuppressive therapy with methylprednisolone with clinical symptoms of dry cough, progressive dyspnea and fever.\n\n\nMETHODS\nAfter the exclusion of COVID-19, Pneumocystis jirovecii pneumonia (PCP) was detected and a corresponding high-dose therapy with trimethoprim-sulfamethoxazole was initiated promptly.\n\n\nRESULTS\nNonetheless, a complicated course with bacterial superinfection and pulmonary aspergillosis as well as ARDS developed.\n\n\nCONCLUSIONS\nIn contrast to COVID-19, the typical course, diagnosis and therapy of Pneumocystitis jirovecii pneumonia are discussed. It is particularly emphasized that not all ground glass infiltrates in the CT chest image can be traced back to a COVID-19, even in a pandemic situation. Possible differential diagnoses should always be considered and taken into account in the diagnosis.",
"affiliations": "Bundeswehrzentralkrankenhaus Koblenz, Abteilung I - Klinik für Innere Medizin.;Bundeswehrzentralkrankenhaus Koblenz, Abteilung I - Klinik für Innere Medizin.;Bundeswehrzentralkrankenhaus Koblenz, Abteilung I - Klinik für Innere Medizin.",
"authors": "Schüßler|Meike|M|;Müller|Frank|F|;Rauschning|Dominic|D|",
"chemical_list": "D000935:Antifungal Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"delete": false,
"doi": "10.1055/a-1391-4403",
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"issue": "146(9)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
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"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D000086382:COVID-19; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "603-607",
"pmc": null,
"pmid": "33931838",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Not all cases of groundglas opacity are COVID-19 - Pneumocystis-jirovecii-pneumonia as a differential diagnosis.",
"title_normalized": "not all cases of groundglas opacity are covid 19 pneumocystis jirovecii pneumonia as a differential diagnosis"
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"abstract": "The pivotal LYM-3002 study compared frontline rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients for whom stem cell transplantation was not an option. This post hoc subanalysis of the VR-CAP data from LYM-3002 evaluated the effect of bortezomib dose intensity on OS in patients who completed ≥6 cycles of treatment. From the end of cycle 6, patients receiving ≥4.6 mg/m2/cycle of bortezomib had significantly longer OS (but not PFS) compared with those receiving <4.6 mg/m2/cycle by univariate analysis (HR 0.43 [95% CI: 0.23-0.80]; p = .0059). This association remained significant in multivariate analysis adjusting for baseline patient and disease characteristics (HR 0.40 [95% CI: 0.20-0.79]; p = .008]. Higher bortezomib dose intensity was the strongest predictor of OS in newly diagnosed MCL patients receiving VR-CAP. Clinicaltrials.gov identifier: NCT00722137.",
"affiliations": "a Copernicus Memorial Hospital , Medical University of Lodz , Lodz , Poland.;b Sun Yat-sen University Cancer Center , Guangzhou , Guangdong , China.;c The First Affiliated Hospital of Zhejiang University College of Medicine , Hangzhou , Zhejiang , China.;d Beijing Cancer Hospital , Beijing , China.;e West China Hospital of Sichuan University , Chengdu , Sichuan , China.;f Nizhniy Novgorod Region Clinical Hospital , Nizhniy Novgorod , Russian Federation.;g Cherkassy Regional Oncology Dispensary , Cherkassy , Ukraine.;h University Hospital Leuven , Leuven , Belgium.;i Siriraj Hospital , Mahidol University , Bangkok , Thailand.;j Cancer Research Center RAMS - N.N. Blokhin Academy of Medical Science , Moscow , Russian Federation.;k Hospital das Clinicas da Faculdade de Medicina da USP , São Paolo , Brazil.;l Faculty Hospital Brno , Brno , Czech Republic.;m Fudan University Shanghai Cancer Center , Shanghai , China.;n Department of Chemotherapy , Tokyo Metropolitan Cancer and Infectious Diseases Center , Komagome Hospital , Japan.;o Janssen Research and Development, LLC , Raritan , NJ , USA.;p Janssen Research & Development , High Wycombe , Buckinghamshire , UK.;q Millennium Pharmaceuticals, Inc. , Cambridge , MA , USA , a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.;r Oncology Institute of Southern Switzerland, Ospedale San Giovanni , Bellinzona , Ticino , Switzerland.",
"authors": "Robak|Tadeusz|T|;Huang|Huiqiang|H|;Jin|Jie|J|;Zhu|Jun|J|;Liu|Ting|T|;Samoilova|Olga|O|;Pylypenko|Halyna|H|;Verhoef|Gregor|G|;Siritanaratkul|Noppadol|N|;Osmanov|Evgenii|E|;Pereira|Juliana|J|;Mayer|Jiri|J|;Hong|Xiaonan|X|;Okamoto|Rumiko|R|;Pei|Lixia|L|;Rooney|Brendan|B|;van de Velde|Helgi|H|;Cavalli|Franco|F|",
"chemical_list": "D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2017.1321750",
"fulltext": null,
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"issn_linking": "1026-8022",
"issue": "60(1)",
"journal": "Leukemia & lymphoma",
"keywords": "LYM-3002; Mantle cell lymphoma; R-CHOP; VR-CAP; bortezomib; dose intensity",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D000077982:Progression-Free Survival; D016019:Survival Analysis",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "172-179",
"pmc": null,
"pmid": "28583031",
"pubdate": "2019-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Association between bortezomib dose intensity and overall survival in mantle cell lymphoma patients on frontline VR-CAP in the phase 3 LYM-3002 study.",
"title_normalized": "association between bortezomib dose intensity and overall survival in mantle cell lymphoma patients on frontline vr cap in the phase 3 lym 3002 study"
} | [
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"abstract": "BACKGROUND\nCorona virus disease (COVID-19) pandemic can cause myriad of ocular manifestations. We report a case of unilateral multi focal central serous retinopathy, post COVID-19 infection in an Asian Indian female.\n\n\nMETHODS\nA 42-year-old female presented to us with unilateral blurring, in the right eye (OD), 12 days after COVID-19 infection. She had fever, chills, shortness of breath and cough with tiredness and was COVID- RT PCR positive. She was administered intravenous and oral antibiotics with injection heparin/remdesivir, during her 7 day stay at the hospital. She was also on steroid inhalers. She had no systemic history of note. On ocular evaluation, her corrected distance visual acuity was 20/40 in OD and 20/20 in left eye (OS). Anterior segment was normal. Anterior vitreous was clear. Fundus examination of the OD showed central serous retinopathy (CSCR) with OS being normal.\n\n\nCONCLUSIONS\nCSCR can occur post COVID-19 due to steroid administration and physicians administering it should be aware of this and refer the patients to an ophthalmologist earlier.",
"affiliations": "Department of Uvea and Ocular Immunology, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India. sanjaygroup24@gmail.com.;Department of Retina, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India.;Chest and Maternity Centre, 878, 5th Block, Near Bashyam Circle, Rajaji Nagar Bengaluru, Karnataka, 560010, India.;Department of Uvea and Ocular Immunology, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India.;Department of Uvea and Ocular Immunology, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India.;Department of Uvea and Ocular Immunology, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India.;Department of Neuro-ophthalmology, Cornea and Refractive Surgery, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India.",
"authors": "Sanjay|Srinivasan|S|http://orcid.org/0000-0001-9756-1207;Gowda|Poornachandra B|PB|;Rao|Bhimasena|B|;Mutalik|Deepashri|D|;Mahendradas|Padmamalini|P|http://orcid.org/0000-0002-6137-8870;Kawali|Ankush|A|http://orcid.org/0000-0002-5536-8051;Shetty|Rohit|R|http://orcid.org/0000-0002-4556-1587",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s12348-021-00244-4",
"fulltext": "\n==== Front\nJ Ophthalmic Inflamm Infect\nJ Ophthalmic Inflamm Infect\nJournal of Ophthalmic Inflammation and Infection\n1869-5760\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n244\n10.1186/s12348-021-00244-4\nBrief Report\n“Old wine in a new bottle” - post COVID-19 infection, central serous chorioretinopathy and the steroids\nhttp://orcid.org/0000-0001-9756-1207\nSanjay Srinivasan sanjaygroup24@gmail.com\n\n1\nGowda Poornachandra B. 2\nRao Bhimasena 34\nMutalik Deepashri 1\nhttp://orcid.org/0000-0002-6137-8870\nMahendradas Padmamalini 1\nhttp://orcid.org/0000-0002-5536-8051\nKawali Ankush 1\nhttp://orcid.org/0000-0002-4556-1587\nShetty Rohit 5\n1 Department of Uvea and Ocular Immunology, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India\n2 Department of Retina, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India\n3 Chest and Maternity Centre, 878, 5th Block, Near Bashyam Circle, Rajaji Nagar Bengaluru, Karnataka 560010 India\n4 Vikram Hospital, Anne’s College, No.71/1, Millers Road, Bangalore, India\n5 Department of Neuro-ophthalmology, Cornea and Refractive Surgery, 121/C, Chord Road, Narayana Nethralaya, Bangalore, India\n14 5 2021\n14 5 2021\n2021\n11 1413 1 2021\n3 4 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/.\nIntroduction\n\nCorona virus disease (COVID-19) pandemic can cause myriad of ocular manifestations.\n\nWe report a case of unilateral multi focal central serous retinopathy, post COVID-19 infection in an Asian Indian female.\n\nCase presentation\n\nA 42-year-old female presented to us with unilateral blurring, in the right eye (OD), 12 days after COVID-19 infection. She had fever, chills, shortness of breath and cough with tiredness and was COVID- RT PCR positive. She was administered intravenous and oral antibiotics with injection heparin/remdesivir, during her 7 day stay at the hospital. She was also on steroid inhalers. She had no systemic history of note.\n\nOn ocular evaluation, her corrected distance visual acuity was 20/40 in OD and 20/20 in left eye (OS). Anterior segment was normal. Anterior vitreous was clear. Fundus examination of the OD showed central serous retinopathy (CSCR) with OS being normal.\n\nConclusion\n\nCSCR can occur post COVID-19 due to steroid administration and physicians administering it should be aware of this and refer the patients to an ophthalmologist earlier.\n\nKeywords\n\nCorona virus disease-19 (COVID-19)\nOphthalmic manifestations\nCentral serous chorioretinopathy\nSpectral Domain Optical Coherence Tomography (SD-OCT)\nInhalational steroids\nOral steroids\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nSevere acute respiratory syndrome virus 2 (SARS-CoV2) infection resulted in a global pandemic of Coronavirus disease 2019 (COVID-19). Wuhan in China was the first place of the outbreak in December 2019. As of 23 March 2021, there have been 123,419,065 confirmed cases of COVID-19, including 2,719,163 deaths, reported to WHO. As of 19 March 2021, a total of 397,950,709 vaccine doses have been administered [1]. Conjunctival involvement, cotton wool spots (CWS) and retinal hemorrhages, central retinal artery/vein occlusion, ophthalmic artery occlusion, panuveitis, papillophlebitis, multifocal chorioretinitis and Adie’s syndrome are the ophthalmic manifestations associated with COVID-19 infection [2–6].\n\nWe describe an unique case of unilateral multifocal central serous retinopathy (CSCR) in a patient who had just recovered from COVID-19 and had been treated with inhalational and oral steroids.\n\nCase presentation\n\nThe procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975 as revised in 1983. The patient’s written and informed consent was obtained and the study was approved by the hospital ethics committee.\n\nA 42-year-old Asian Indian female presented to us with unilateral blurring, in the right eye (OD), 12 days after COVID-19 infection. Prior to presentation to us, she had fever, chills, shortness of breath and cough with generalized fatigue. Her physician noted that she was afebrile, oxygen saturation was 97% with few crepitations in her lungs and heart rate was 132/min. Complete blood count (CBC) was within normal limits, erythrocyte sedimentation rate (ESR) 35 mm /hr., random blood sugar (RBS)-118 mg/dl, COVID-19 rapid antigen test was negative.\n\nInvestigations done at the local hospital a day later showed upper respiratory swab for COVID-19 using real time polymerase chain reaction (RT-PCR) was positive and B-beta (Corona virus) CoV specific target gene and severe acute respiratory syndrome- corona virus 2 (SARS-CoV2) specific target gene were detected, WIDAL test negative, urine analysis was within normal limits. Chest X ray of the lung showed bilateral ground glass opacities (Fig. 1). Based on the records that were available with the patient, we in Table 1 show the medications administered during her stay at a local hospital. Fig. 1 Chest X ray PA view of the lung showing bilateral ground glass opacities with left lung consolidation during her admission\n\nTable 1 Shows medications administered to the patient while she was admitted at the local hospital\n\nRoute\tDrug\tDose/duration\t\nIntravenous\tCefoperazone+ Sulbactam\t1000 mg + 1000 mg for 4 days\t\nSubcutaneous\tHeparin\t5000 units every 8 h for 3 days\t\nIntravenous\tRemdesivir\t200 mg loading dose, then 100 mg a day for 4 days\t\nOral\tDexamethasone\t6 mg daily for 7 days\t\nOral\tAzithromycin\t500 mg for 7 days\t\nOral\tDoxycycline\t100 mg twice daily for 7 days\t\nOral\tMontelukast and Levocetrizine combination\t(10 mg) and (5 mg) for 7 days\t\nOral\tVitamin C\t1 g for 7 days\t\nOral\tPantoprazole\t40 mg once daily for 7 days\t\nOral\tIvermectin\t12 mg once daily for 7 days\t\nInhalation\tOxygen\t2 litres/minute for 7 days\t\nInhalation\tFormoterol fumarate dehydrate and budesonide 200 combination\t(6 mcg) and 9200mcg) twice daily, which was continued even after discharge\t\nInhalation\tSalbutamol rotacaps\tfour times daily\t\nShe had no systemic history of note\n\nAt the time of discharge she was switched to oral steroids (methylprednisolone) 16 mg once daily till her presentation to us\n\nLegends: mg milligram; mcg microgram\n\nOn ophthalmic examination, her corrected distance visual acuity was 20/40 in OD and 20/20 in the left eye (OS). The intraocular pressure was 15 and 18 mmHg in OD/OS respectively. Examination of the anterior segment was normal in both eyes (BE). Fundus evaluation, OD showed absent foveal reflex with serous elevation of the retina with ring reflex at the macula. The OS was within normal limits.\n\nA spectral domain optical coherence tomography (SD-OCT) scan on the Spectralis™ (Heidelberg Engineering, Heidelberg, Germany) of the OD showed hyper-reflective dots in the posterior vitreous, altered foveal contour with serous detachment in the macula and with pigment epithelial detachment (Fig. 2 a). OS was normal (Fig. 2 b). Fundus fluoroscein angiography (Fig. 3a-e) showed an arm-retina time of 18 s with multiple hyperfluoroscent spots seen in the macula which increased in size and intensity in later films in an inkblot pattern characteristic of central serous retinopathy in OD. One of the lesion showed a mixed “smoke stack” and “ink blot” appearance (Fig 3e). Fig. 2 a shows a spectral domain optical coherence tomography scan across the macula of the OD. The white arrow points to a doom shaped elevation which is the serous retinopathy. Also in the scan is a smaller doom which represents retinal pigment epithelial detachment. b shows the normal scan of OS\n\nFig. 3 a-e fundus fluoroscein angiography (FFA) of the OD from early phases a,b to later phases c-e. The yellow arrows point to a pinpoint leak initially and increasing in size in later phases. The black arrow with yellow arrow head adjacent to optic disc shows a mixed inkblot and smoke stack pattern. f- shows normal left eye\n\nAt the time of ocular presentation, investigations showed serum Ferritin 87.90 U/L (females 11–307), Procalcitonin 0.032(< 0.5), mild leucocytosis 11,600 (4500–11,000), ESR-35 (< 20 mm/hr), CRP 10.7 mg/l(< 3), Immunoglobulin (Ig) G antibodies to nucleocapsid antigen of SARS-CoV2 were positive 4.41 (< 1.0 non reactive).\n\nBased on the clinical and imaging findings, a diagnosis of unilateral OD multifocal central serous chorioretinopathy (CSCR) was made. In consultation with chest physician the inhalational and oral steroids were stopped.\n\nOne month later, there was an improvement in her vision to 20/25 in OD, OCT showed reduction of the sub-retinal fluid and the hyper-reflective material and resolution of the pigment epithelial detachment (Fig. 4) Fig. 4 shows a spectral domain optical coherence tomography scan across the macula of the OD with reduction of the sub-retinal fluid and the pigment epithelial detachment a month later\n\nWe would like to report for the first time a case of a unilateral multifocal CSCR in an Asian Indian post COVID-19 treatment.\n\nPublished data show that SARS-CoV-2 binds to the host cells via the angiotensin converting-enzyme (ACE) 2 receptor [7]. Endothelial cells become vulnerable when the ACE 2 receptors are expressed and binding of SARS-CoV-2 may cause systemic endothelial dysfunction. All major organs like the lungs, heart, veins, and arteries have higher density ACE 2 receptors. Endothelial dysfunction leads to vasoconstriction, ischemia, tissue edema, and a procoagulant state secondary to endothelial alterations including endothelitis [7].\n\nThe exact pathophysiology of ocular transmission of the virus remains incompletely understood, although there is preliminary evidence of SARS-CoV-2 being detected in ocular secretions. The ocular tropism of the virus and its potential to cause localized ocular disease are worth considering [8].\n\nSteroids may be necessary to manage the post COVID-19 systemic manifestations including the cytokine storm.\n\nOur patient was administered oral and inhalational steroids during her stay at the local hospital. CSCR occurs or is aggravated by administration of corticosteroids irrespective of the route of administration. Steroids when used topically for skin conditions, intra-articular, intravenous, intramuscular, oral, epidural, intranasal and inhalation are all associated with CSCR [9, 10].\n\nIt is postulated that the blood retinal barrier may be damaged, with damage to retinal pigment epithelial pump and hyperpermeability of choriocapillaries leading to CSCR.\n\nCSCR can develop secondary to exogenous corticosteroids several years later.\n\nThere may be a temporal correlation between the use of a corticosteroid nasal spray and the development of CSCR. Posterior sub capsular cataract can occur after nasal/inhaled steroids.\n\nCessation of inhalational steroids can lead to resolution of CSCR, which also happened partially in our patient [11].\n\nThe choroid has extensive choriocapillaries whose role is to supply oxygen and nutrients to the outer retina which has no vascular network. Glucocorticoids possibly enhance the fibroblasts proliferation with compromised capillary function leading to their fragility. Corticosteroids may affect choroid, Bruch’s membrane, or the retinal pigment epithelium [12].\n\nPostulates on the mechanism of CSCR include vascular auto-regulation via increased transcription of adrenergic receptors or potentiation of vascular reactivity, effects from steroid-induced systemic hypertension, or a prothrombotic effect. Inhibition of collagen synthesis in Bruch’s membrane may be another mechanism. The barrier function of retinal pigment epithelium (RPE) may be compromised due to impaired ion and water transport. The role of the RPE in CSCR pathogenesis remains poorly understood. Increased tissue hydrostatic pressure in the choroid can cause the barrier function of the RPE to be compromised and lead to areas of fluid accumulation between the retina and the RPE which can also lead to pigment epithelial detachment(s) which also represent a form of RPE decompensation [13]\n\nSome refer to the pinpoint areas of leakage seen in acute CSCR as “micro-rips” or “blowouts”.\n\nCSCR is a self-limiting condition; various modalities of treatment have been described in the literature for the recurrent cases. One month after stopping steroids (inhalation and oral) there was a significant improvement in patient’s visual acuity and SD-OCT findings. Subsequently she was lost to follow up.\n\nConclusion\n\nWe hereby describe a patient with unilateral serous chorioretinopathy post COVID-19 infection, who developed ophthalmic manifestations 12 days after she was discharged from the hospital, after having tested negative for COVID-19. Patients with COVID-19 should be warned about possible ophthalmic sequelae even after their systemic recovery. Physicians treating COVID-19 should be aware of these important sequelae and refer the patient to an ophthalmologist for timely intervention.\n\nAbbreviations\n\nSARS-CoV2 Severe Acute Respiratory Syndrome Corona Virus 2\n\nCOVID-19 Coronavirus disease 2019\n\nCWS Cotton wool spots\n\nOD Right eye\n\nCBC Complete blood count\n\nESR Erythrocyte sedimentation rate\n\nRBS Random blood sugar\n\nRT-PCR Real time polymerase chain reaction\n\nOS Left eye\n\nSD-OCT Spectral domain optical coherence tomography\n\nCSCR Central serous chorioretinopathy\n\nIg Immunoglobulin\n\nACE Angiotensin converting-enzyme\n\nRPE Retinal pigment epithelium\n\nAcknowledgements\n\nDr. Nikhita Reddy, Department of Retina, Narayana Nethralaya, Bengaluru, India\n\nAuthors’ contributions\n\nDesign: S S, B R. Acquisition of data: SS, PBG, DM. Analysis and intrepretation: SS, PBG,PM, AK. Manuscript writing: SS, PBG, DM, PM, AK, RS. Manuscript editing: SS, PBG, PM,AK, RS. Intellectual content: SS, PBG, PM, AK, RS. The authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nAvailable on request\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was approved by the hospital ethics committee.\n\nThe study was approved by the Narayana Nethralaya Ethics committee, Vide approval number EC reference NO C/2020/09/09 (virtual). All tenets of the Helsinki declaration were adhered to.\n\nPatient's written and informed consent was obtained for inclusion in the study.\n\nConsent for publication\n\nThe patient’s written and informed consent was obtained.\n\nCompeting interests\n\nNone.\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. World Health Organisation (WHO), COVID-19 dashboard. https://covid19.who.int/. Accessed 24 Mar 2021.\n2. Acharya S Diamond M Anwar S Glaser A Tyagi P Unique case of central retinal artery occlusion secondary to COVID-19 disease IDCases. 2020 21 e00867 10.1016/j.idcr.2020.e00867 32572363\n3. Insausti-García A Reche-Sainz JA Ruiz-Arranz C López Vázquez Á Ferro-Osuna M Papillophlebitis in a COVID-19 patient: inflammation and hypercoagulable state [published online ahead of printJul 30] Eur J Ophthalmol 2020 2020 1120672120947591 10.1177/1120672120947591\n4. Ortiz-Seller A, Martínez Costa L, Hernández-Pons A, Valls Pascual E, Solves Alemany A, Albert-Fort M. (2020) Ophthalmic and neuro-ophthalmic manifestations of coronavirus disease 2019 (COVID-19). Ocul Immunol Inflamm 16; 28: 1285-1289. doi: 10.1080/09273948.2020.1817497. Epub 2020 Oct 6\n5. Sheth JU, Narayanan R, Goyal J, Goyal V (2020) Retinal vein occlusion in COVID-19: a novel entity. Indian J Ophthalmol 68:2291–2293. https://doi.org/10.4103/ijo.IJO238020\n6. Sanjay S, Srinivasan P, Jayadev C, Mahendradas P, Gupta A, Kawali A, Shetty R. Post COVID-19 Ophthalmic Manifestations in an Asian Indian Male. Ocul Immunol Inflamm. 2021: 1–6. doi: 10.1080/09273948.2020.1870147. Epub ahead of print)\n7. To KFLo AW Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2) J Pathol 2004 203 3 740 743 10.1002/path.1597 15221932\n8. Ho D, Low R, Tong L, Gupta V, Veeraraghavan A, Agrawal R. (2020) COVID-19 and the ocular surface: a review of transmission and manifestations. Ocul Immunol Inflamm;28:726–734. doi: 10.1080/09273948.2020.1772313. Epub 2020 Jun 16. PMID: 32543262, 5\n9. Haimovici R, Gragoudas ES, Duker JS, Sjaarda RN, Eliott D. (1997) Central serous chorioretinopathy associated with inhaled or intranasal corticosteroids. Ophthalmology. Oct;104(10):1653–1660. doi: 10.1016/s0161-6420(97)30082-7.\n10. Tittl MK Spaide RF Wong D Pilotto E Yannuzzi LA Fisher YL Freund B Guyer DR Slakter JS Sorenson JA Systemic findings associated with central serous chorioretinopathy Am J Ophthalmol 1999 128 1 63 68 10.1016/s0002-9394(99)00075-6 10482095\n11. Nakatsuka AS Khanamiri HN Lam QN El-Annan J Intranasal corticosteroids and central serous Chorioretinopathy: a report and review of the literature Hawaii J Med Public Health 2019 78 5 151 154 31049263\n12. Bouzas EA Karadimas P Pournaras CJ Central serous chorioretinopathy and glucocorticoids Surv Ophthalmol 2002 47 5 431 448 10.1016/S0039-6257(02)00338-7 12431693\n13. Nicholson B Noble J Forooghian F Meyerle C Central serous chorioretinopathy: update on pathophysiology and treatment Surv Ophthalmol 2013 58 2 103 126 10.1016/j.survophthal.2012.07.004 23410821\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1869-5760",
"issue": "11(1)",
"journal": "Journal of ophthalmic inflammation and infection",
"keywords": "Central serous chorioretinopathy; Corona virus disease-19 (COVID-19); Inhalational steroids; Ophthalmic manifestations; Oral steroids; Spectral Domain Optical Coherence Tomography (SD-OCT)",
"medline_ta": "J Ophthalmic Inflamm Infect",
"mesh_terms": null,
"nlm_unique_id": "101553216",
"other_id": null,
"pages": "14",
"pmc": null,
"pmid": "33987731",
"pubdate": "2021-05-14",
"publication_types": "D016428:Journal Article",
"references": "23410821;32543262;10482095;32735134;32971697;33733987;15221932;12431693;32572363;31049263;9331207",
"title": "\"Old wine in a new bottle\" - post COVID-19 infection, central serous chorioretinopathy and the steroids.",
"title_normalized": "old wine in a new bottle post covid 19 infection central serous chorioretinopathy and the steroids"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-300208",
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"activesubstance": {
"activesubstancename": "ALBUTEROL"
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{
"abstract": "Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.\n\n\n\nWe report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial.\n\n\n\nThe most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.\n\n\n\nDespite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.",
"affiliations": "Division of Pediatric Hematology-Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin. mmburke@mcw.edu.;Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.;Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.;Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado.;Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.;Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.;NCI, NIH, Bethesda, Maryland.;NCI, NIH, Bethesda, Maryland.;NCI, NIH, Bethesda, Maryland.;NCI, NIH, Bethesda, Maryland.;Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.;St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pediatrics, UCSF Medical Center-Mission Bay, San Francisco, California.;Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.;Department of Pediatrics, Children's Hospital of Orange County, Orange, California.;Department of Pediatrics, Primary Children's Hospital, University of Utah, Salt Lake City, Utah.;Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, Cook Children's Medical Center, Fort Worth, Texas.;Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio.;Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia.;Department of Pediatrics, UT Southwestern/Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas.;Department of Pediatrics, Carolinas Medical Center/Levine Cancer Institute, Charlotte, North Carolina.;Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.;Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, Carolinas Medical Center/Levine Cancer Institute, Charlotte, North Carolina.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.;Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.;Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.;Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.",
"authors": "Burke|Michael J|MJ|;Kostadinov|Rumen|R|0000-0002-8617-2836;Sposto|Richard|R|;Gore|Lia|L|;Kelley|Shannon M|SM|;Rabik|Cara|C|;Trepel|Jane B|JB|;Lee|Min-Jung|MJ|0000-0001-6011-151X;Yuno|Akira|A|;Lee|Sunmin|S|0000-0001-6011-151X;Bhojwani|Deepa|D|;Jeha|Sima|S|;Chang|Bill H|BH|0000-0003-3783-1820;Sulis|Maria Luisa|ML|;Hermiston|Michelle L|ML|;Gaynon|Paul|P|;Huynh|Van|V|;Verma|Anupam|A|0000-0001-6555-7924;Gardner|Rebecca|R|;Heym|Kenneth M|KM|;Dennis|Robyn M|RM|;Ziegler|David S|DS|;Laetsch|Theodore W|TW|0000-0002-8497-3138;Oesterheld|Javier E|JE|;Dubois|Steven G|SG|;Pollard|Jessica A|JA|;Glade-Bender|Julia|J|;Cooper|Todd M|TM|;Kaplan|Joel A|JA|;Farooqi|Midhat S|MS|0000-0002-5238-1349;Yoo|Byunggil|B|;Guest|Erin|E|0000-0003-2482-5608;Wayne|Alan S|AS|;Brown|Patrick A|PA|",
"chemical_list": "D011092:Polyethylene Glycols; D000077337:Vorinostat; D014750:Vincristine; D000069286:Bortezomib; D000077209:Decitabine; C042705:pegaspargase; D003907:Dexamethasone; D004317:Doxorubicin; D008942:Mitoxantrone; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-19-1251",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "26(10)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D000077209:Decitabine; D003907:Dexamethasone; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008942:Mitoxantrone; D009364:Neoplasm Recurrence, Local; D010865:Pilot Projects; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D014750:Vincristine; D000077337:Vorinostat; D055815:Young Adult",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "2297-2307",
"pmc": null,
"pmid": "31969338",
"pubdate": "2020-05-15",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19164206;16707479;24891274;28960845;28494518;20215641;16258094;21131038;16254255;14616997;7935682;19959380;10759711;15927669;17634552;12060634;20564122;29728694;29728402;27449971;23255467;12412576;25040094;20385996;19435910;19410540;24642620;19752007;17060944;23428641;17925355;18829512;11038037;9324340;12114423",
"title": "Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study.",
"title_normalized": "decitabine and vorinostat with chemotherapy in relapsed pediatric acute lymphoblastic leukemia a tacl pilot study"
} | [
{
"companynumb": "US-MYLANLABS-2020M1074014",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MITOXANTRONE HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nTo compare the characteristics of NMDR induced muscle paralysis in breast cancer patients with and without a history of recent chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) regimen.\n\n\nMETHODS\nThis is a non-randomized prospective cohort study.\n\n\nMETHODS\nOperating room of a university-affiliated teaching hospital.\n\n\nMETHODS\nOut of a total of 50 patients who had undergone mastectomy, 22 patients were allocated to the \"Chemo group\" and 28 patients to the \"Non-Chemo group\", based on a valid history of recent chemotherapy.\n\n\nMETHODS\nAfter induction of anesthesia with thiopental and cisatracurium, neuromuscular monitoring was started for all patients.\n\n\nMETHODS\nInitially the time to 100% single-twitch (ST) suppression was measured. Then, the time for the appearance of the first response to post-tetanic count (PTC) stimulation, Train-of-Four (TOF) stimulation, and TOF50% were measured consequently.\n\n\nRESULTS\nTime to get STzero was significantly longer in the Chemo group than in the Non-chemo group. Time for the appearance of the first response of PTC and TOF and TOF50% was significantly shorter in the Chemo group than the other group. The mean duration of intense block was 27.66 minutes in the Chemo group versus 42.47 minutes in the Non-chemo group.\n\n\nCONCLUSIONS\nThis research demonstrated that in patients having undergone chemotherapy, the effect of NDMRs starts with a longer lag time and finishes earlier too. Thus, these patients are ready for intubation after a longer time. Moreover, we have to repeat cisatracurium injections after shorter intervals to maintain the desired level of blockade.",
"affiliations": "Tehran University of Medical Sciences, Assistant Professor, Dept. of Anesthesia and Intensive Care, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran, 1419733141, Iran. Electronic address: p_zanjani@yahoo.com.;Tehran University of Medical Sciences, Assistant Professor, Dept. of Anesthesia and Intensive Care, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran, 1419733141, Iran. Electronic address: maziarmdaa@yahoo.com.;Tehran University of Medical Sciences, Assistant Professor, Dept. of Anesthesia and Intensive Care, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran, 1419733141, Iran. Electronic address: makaremj@yahoo.com.;Tehran University of Medical Sciences, Professor, Dept. of Anesthesia and Intensive Care, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran, 1419733141, Iran. Electronic address: farrokhnia1503@yahoo.com.;Tehran University of Medical Sciences, Dept. of Anesthesia and Intensive Care, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran, 1419733141, Iran. Electronic address: ghadikolahi@gmail.com.;Tehran University of Medical Sciences, Professor, Dept. of Anesthesia and Intensive Care, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran, 1419733141, Iran. Electronic address: Khanzh51@yahoo.com.",
"authors": "Zanjani|Amir Poya|AP|;Maghsoudloo|Maziar|M|;Makarem|Jalil|J|;Farokhnia|Fahimeh|F|;Fazli|Morteza|M|;Khan|Zahid Hussain|ZH|",
"chemical_list": "D003473:Neuromuscular Nondepolarizing Agents; D001279:Atracurium; D004317:Doxorubicin; D003520:Cyclophosphamide; C101584:cisatracurium; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jclinane.2016.10.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "36()",
"journal": "Journal of clinical anesthesia",
"keywords": "Chemotherapy; Cisatracurium; Doxorubicin; General anesthesia; Neuromuscular blocking agents",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D000971:Antineoplastic Combined Chemotherapy Protocols; D001279:Atracurium; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008408:Mastectomy; D008875:Middle Aged; D016343:Monitoring, Intraoperative; D020360:Neoadjuvant Therapy; D019148:Neuromuscular Blockade; D009469:Neuromuscular Junction; D003473:Neuromuscular Nondepolarizing Agents; D011446:Prospective Studies",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "84-87",
"pmc": null,
"pmid": "28183581",
"pubdate": "2017-02",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article",
"references": null,
"title": "Chemotherapy alters cisatracurium induced neuromuscular blockade characteristics: A prospective cohort study.",
"title_normalized": "chemotherapy alters cisatracurium induced neuromuscular blockade characteristics a prospective cohort study"
} | [
{
"companynumb": "IR-JNJFOC-20170110847",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SUFENTANIL"
},
"drugadditional": null,
... |
{
"abstract": "Melioidosis is an emerging infection in India. Seventeen cases of culture proven melioidosis are reported in this study. The isolation rate was high during the rainy season. Except one case, all the patients had diabetes mellitus as an underlying disease. Eleven patients improved with ceftazidime or combination therapy and maintenance therapy with doxycycline and Cotrimoxazole. The high prevalence of B. pseudomallei in this region is a matter for serious concern.",
"affiliations": "Department of Microbiology, Father Muller Medical College, Kankanady, India. beenafmmc@gmail.com",
"authors": "Antony|Beena|B|;Pinto|Hilda|H|;Dias|Meena|M|;Shetty|Anup Kumar|AK|;Scaria|Bibin|B|;Kuruvilla|Thomas|T|;Boloor|Rekha|R|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0125-1562",
"issue": "41(1)",
"journal": "The Southeast Asian journal of tropical medicine and public health",
"keywords": null,
"medline_ta": "Southeast Asian J Trop Med Public Health",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016957:Burkholderia pseudomallei; D048909:Diabetes Complications; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D007194:India; D008297:Male; D008554:Melioidosis; D008875:Middle Aged; D011891:Rain; D012621:Seasons; D012988:Soil Microbiology",
"nlm_unique_id": "0266303",
"other_id": null,
"pages": "169-74",
"pmc": null,
"pmid": "20578496",
"pubdate": "2010-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Spectrum of melioidosis in the suburbs of Mangalore, S West Coast of India.",
"title_normalized": "spectrum of melioidosis in the suburbs of mangalore s west coast of india"
} | [
{
"companynumb": "IN-PFIZER INC-2019548716",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": null,
... |
{
"abstract": "The use of monoclonal antibodies (mAbs) is increasing in various clinical fields. Although mAb safety must be demonstrated prior to approval, targeted pharmacovigilance is essential for the recognition and assessment of adverse reactions. The purpose of this study was to identify the major clinical features of adverse reactions to mAbs in Korea.\n\n\n\nSpontaneous reports of adverse reactions attributed to 18 mAbs from January 2005 to December 2014 were extracted from the Korea Adverse Event Reporting System. We analyzed these reports for information relating to patient characteristics and the types of adverse reactions.\n\n\n\nIn total, 11 492 adverse reactions were reported in 7569 patients. Almost 19% of total study population showed suspected hypersensitivity reactions. Leukocyte abnormalities were reported frequently (10.0%), as well as infections (9.5%), drug eruptions (7.5%), and pruritus (5.0%). Furthermore, 3716 of the adverse reactions in 2538 patients were classified as serious; these included severe infections (18.2%), neutropenia (12.1%), visual dysfunctions (6.6%), and anaphylaxis (4.8%). The mAbs with the highest number of adverse reaction reports were rituximab (27.6%), adalimumab (17.5%), cetuximab (11.9%), and infliximab (10.7%).\n\n\n\nHypersensitivity reactions were observed more frequently than expected, although no previously unrecognized reactions were observed. Adverse reactions occurred more frequently in children and in elderly patients. Close monitoring of adverse reactions to therapeutic mAbs is therefore warranted because these can potentially cause serious medical conditions or death. Copyright © 2016 John Wiley & Sons, Ltd.",
"affiliations": "Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Severance Hospital Regional Pharmacovigilance Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Severance Hospital Regional Pharmacovigilance Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Severance Hospital Regional Pharmacovigilance Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Severance Hospital Regional Pharmacovigilance Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Severance Hospital Regional Pharmacovigilance Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Severance Hospital Regional Pharmacovigilance Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Severance Hospital Regional Pharmacovigilance Center, Yonsei University College of Medicine, Seoul, Korea. jhleemd@yuhs.ac.",
"authors": "Sim|Da Woon|DW|0000-0002-9723-0720;Park|Kyung Hee|KH|;Park|Hye Jung|HJ|;Son|Young Woong|YW|;Lee|Sang Chul|SC|;Park|Jung-Won|JW|;Lee|Jae-Hyun|JH|",
"chemical_list": "D000911:Antibodies, Monoclonal",
"country": "England",
"delete": false,
"doi": "10.1002/pds.4049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "25(11)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "adverse reaction; hypersensitivity; monoclonal antibody; neutropenia; pharmacovigilance; preferred term",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D002648:Child; D002675:Child, Preschool; D003875:Drug Eruptions; D004342:Drug Hypersensitivity; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D056910:Republic of Korea; D012189:Retrospective Studies; D012720:Severity of Illness Index; D055815:Young Adult",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "1279-1286",
"pmc": null,
"pmid": "27364925",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical characteristics of adverse events associated with therapeutic monoclonal antibodies in Korea.",
"title_normalized": "clinical characteristics of adverse events associated with therapeutic monoclonal antibodies in korea"
} | [
{
"companynumb": "KR-JNJFOC-20161109926",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"d... |
{
"abstract": "Gogou M, Pavlidou E, Pavlou E, Papageorgiou T, Tragiannidis A, Giannopoulos A, Hatzipantelis E. Charcot-Marie -Tooth 1A concurrent with anaplastic ependymoma in a toddler: when an acute event unmasks a chronic condition. Turk J Pediatr 2019; 61: 428-430. We report a 14-month-old toddler admitted to the Pediatric Oncology Department after surgical resection of supratentorial anaplastic ependymoma. The child was treated with International Society of Pediatric Oncology Ependymoma II 2015 chemotherapy protocol (vincristine, carboplatin, cisplatin, cyclophosphamide and methotrexate). At the end of the first cycle the child presented with symptoms such as unsteadiness and ataxic gait along with decreased motor and sensory action potentials of the limbs. As the father of the child was diagnosed with Charcot-Marie-Tooth 1A disease, a genetic analysis of the PMP22 gene was performed confirming the diagnosis of Charcot- Marie-Tooth 1A in the child, too. This case gently reminds the possibility of vincristine-induced neurotoxicity and underscores the significance of an appropriate neurological assessment before vincristine initiation.",
"affiliations": "Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece.;Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece.;Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece.;Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece.;Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece.;Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece.;Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece.",
"authors": "Gogou|Maria|M|;Pavlidou|Efterpi|E|;Pavlou|Evangelos|E|;Papageorgiou|Theodotis|T|;Tragiannidis|Athanasios|A|;Giannopoulos|Andreas|A|;Hatzipantelis|Emmanuel|E|",
"chemical_list": "D009185:Myelin Proteins; C073687:PMP22 protein, human",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "61(3)",
"journal": "The Turkish journal of pediatrics",
"keywords": "Charcot-Marie-Tooth; ependymoma; neurooncology; neurotoxicity; vincristine",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000208:Acute Disease; D002607:Charcot-Marie-Tooth Disease; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D004806:Ependymoma; D005260:Female; D006801:Humans; D007223:Infant; D009154:Mutation; D009185:Myelin Proteins",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "428-430",
"pmc": null,
"pmid": "31916723",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Charcot-Marie-Tooth 1A concurrent with anaplastic ependymoma in a toddler: when an acute event unmasks a chronic condition.",
"title_normalized": "charcot marie tooth 1a concurrent with anaplastic ependymoma in a toddler when an acute event unmasks a chronic condition"
} | [
{
"companynumb": "GR-TEVA-2018-GR-952910",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "The clinical course of a case of infant botulism was characterized by several relapses despite therapy with amoxicillin and metronidazole. Botulism was confirmed by identification of botulinum toxin and Clostridium botulinum in stools. A C. botulinum A2 strain resistant to penicillins and with heterogeneous resistance to metronidazole was isolated from stool samples up to 110 days after onset. Antibiotic susceptibility was tested by disc agar diffusion and MICs were determined by Etest. Whole genome sequencing allowed detection of a gene cluster composed of blaCBP for a novel penicillinase, blaI for a regulator, and blaR1 for a membrane-bound penicillin receptor in the chromosome of the C. botulinum isolate. The purified recombinant penicillinase was assayed. Resistance to β-lactams was in agreement with the kinetic parameters of the enzyme. In addition, the β-lactamase gene cluster was found in three C. botulinum genomes in databanks and in two of 62 genomes of our collection, all the strains belonging to group I C. botulinum. This is the first report of a C. botulinum isolate resistant to penicillins. This stresses the importance of antibiotic susceptibility testing for adequate therapy of botulism.",
"affiliations": "Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, France.;Unité des Agents Antibactériens, Institut Pasteur, Paris, France.;Département de Microbiologie, Hôpital Charles Nicolle, Rouen, France.;Pédiatrie médicale, Hôpital Charles Nicolle, Rouen, France.;Pédiatrie néonatale et réanimation, Hôpital Charles Nicolle, Rouen, France.;AP-HP, Service de Pédiatrie-Réanimation, Pôle Pédiatrique, Hôpital R. Poincaré, Garches, Hôpitaux Universitaires Paris-Ile-de-France Ouest, France.;Unité des Agents Antibactériens, Institut Pasteur, Paris, France.;Pédiatrie médicale, Hôpital Charles Nicolle, Rouen, France.;Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, France.;Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, France.;Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, France.;Plateforme Genomique-Pôle Biomics, Institut Pasteur, Paris, France.;AP-HP, Service de Pédiatrie-Réanimation, Pôle Pédiatrique, Hôpital R. Poincaré, Garches, Hôpitaux Universitaires Paris-Ile-de-France Ouest, France; Centre de Référence des Maladies Neuromusculaires GNMH (FILNEMUS), France.;Département de Microbiologie, Hôpital Charles Nicolle, Rouen, France.;Unité des Agents Antibactériens, Institut Pasteur, Paris, France.;Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, France. Electronic address: michel-robert.popoff@pasteur.fr.",
"authors": "Mazuet|C|C|;Yoon|E-J|EJ|;Boyer|S|S|;Pignier|S|S|;Blanc|T|T|;Doehring|I|I|;Meziane-Cherif|D|D|;Dumant-Forest|C|C|;Sautereau|J|J|;Legeay|C|C|;Bouvet|P|P|;Bouchier|C|C|;Quijano-Roy|S|S|;Pestel-Caron|M|M|;Courvalin|P|P|;Popoff|M R|MR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D026901:Membrane Transport Proteins; D010406:Penicillins; D008795:Metronidazole; D001905:Botulinum Toxins; D010405:Penicillinase",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-743X",
"issue": "22(7)",
"journal": "Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases",
"keywords": "Antibiotic-resistance; Botulism; Clostridium botulinum; Infant botulism; Metronidazole; Penicillin",
"medline_ta": "Clin Microbiol Infect",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001905:Botulinum Toxins; D001906:Botulism; D003014:Clostridium botulinum; D024881:Drug Resistance, Bacterial; D005243:Feces; D005260:Female; D005809:Genes, Regulator; D016680:Genome, Bacterial; D006801:Humans; D007223:Infant; D026901:Membrane Transport Proteins; D008795:Metronidazole; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D010405:Penicillinase; D010406:Penicillins; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "9516420",
"other_id": null,
"pages": "644.e7-644.e12",
"pmc": null,
"pmid": "27108966",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A penicillin- and metronidazole-resistant Clostridium botulinum strain responsible for an infant botulism case.",
"title_normalized": "a penicillin and metronidazole resistant clostridium botulinum strain responsible for an infant botulism case"
} | [
{
"companynumb": "FR-BAUSCH-BL-2016-020828",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3",
... |
{
"abstract": "The implementation of the points-based driving license helps to change the drivers' behavior and is related to a reduction of traffic accidents and fatalities. In Spain, when a driver loses all points, the driving license is revoked, so the driver must enroll on a Driver Awareness and Re-education (DARE) course. However, at the moment offenders are not submitted to any test to confirm absence of alcohol or drugs of abuse consumption, even when 9% of Spanish drivers lose their driving license for driving under the influence (DUI). The objective of this pilot study was the comparison of the usefulness of psychological tests and hair analysis to identify those individuals with a chronic consumption of alcohol and drugs of abuse among drivers performing DARE courses. Volunteers were submitted to the AUDIT and DAST-10 tests. Also a hair sample was collected and analyzed for ethylglucuronide (EtG) (LOQ 5pg/mg) and 35 licit and illicit drugs (LOQ 5-50pg/mg) by LC-MS/MS. Sixty-one participants with a mean age of 37.2±11.6years, and mainly men (90.2%), were recruited and performed AUDIT and DAST-10 tests. All hair samples were analyzed for EtG and 17 samples for licit and illicit drugs. Mean AUDIT score was 9.6 (SD=7.5), showing a value ≥8 (indicator of hazardous and harmful alcohol use) in 52.4% of cases. Mean DAST-10 score was 2.9 (SD=3.3), but a score ≥6 was detected in 21.3% of cases (indicating drug abuse or dependence). Twenty-two samples were positive for EtG, 8 for drugs of abuse (8 cocaine, 2 opioids, 1 amphetamines, 1 cannabis), and 3 for medicines. EtG concentration (20.7-1254.1pg/mg) was higher than the Society of Hair Testing (SoHT) cut-off for chronic alcohol consumption (≥30pg/mg) in 21 cases. All positive cases for methadone and cannabis, and half of positive cases for opioids and cocaine presented higher concentrations than SoHT cut-offs for chronic consumption. Higher AUDIT score and higher EtG concentration in hair were statistically associated with declaration of alcohol consumption ≥4 times/month and with previous fine for DUI of alcohol. In addition, AUDIT scores and EtG concentration in hair had a moderate but significant Spearman correlation (r=0.331, p<0.05). The combination of psychological tests and hair analysis seems to be a promising tool to identify individuals with chronic and problematic consumption of alcohol and drugs of abuse. Moreover, their application during driving license regranting procedures could increase the effectiveness of DARE courses, reduce recidivism and improve road safety.",
"affiliations": "Sección de Toxicología, Instituto de Ciencias Forenses, Universidad de Santiago de Compostela, Spain; School of Pharmacy and Life Sciences, The Robert Gordon University, UK. Electronic address: elena.lendoiro@usc.es.;Sección de Toxicología, Instituto de Ciencias Forenses, Universidad de Santiago de Compostela, Spain.;Sección de Toxicología, Instituto de Ciencias Forenses, Universidad de Santiago de Compostela, Spain.;Departamento de Psicología Clínica y Psicobiología, Facultad de Psicología, Universidad de Santiago de Compostela, Spain.;Sección de Toxicología, Instituto de Ciencias Forenses, Universidad de Santiago de Compostela, Spain.;Sección de Toxicología, Instituto de Ciencias Forenses, Universidad de Santiago de Compostela, Spain.",
"authors": "Lendoiro|Elena|E|;de Castro|Ana|A|;Jiménez-Morigosa|Cristian|C|;Gomez-Fraguela|Xosé A|XA|;López-Rivadulla|Manuel|M|;Cruz|Angelines|A|",
"chemical_list": "D015415:Biomarkers; D005965:Glucuronates; D013287:Illicit Drugs; C093924:ethyl glucuronide",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2018.03.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "286()",
"journal": "Forensic science international",
"keywords": "AUDIT test; DAST-10 test; Driving license regranting; Drugs of abuse; EtG; Hair",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D001334:Automobile Driving; D015415:Biomarkers; D002853:Chromatography, Liquid; D000066448:Driving Under the Influence; D005260:Female; D005965:Glucuronates; D006197:Hair; D006801:Humans; D013287:Illicit Drugs; D008004:Licensure; D008297:Male; D013058:Mass Spectrometry; D010865:Pilot Projects; D011581:Psychological Tests; D013030:Spain; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "239-244",
"pmc": null,
"pmid": "29602151",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Usefulness of hair analysis and psychological tests for identification of alcohol and drugs of abuse consumption in driving license regranting.",
"title_normalized": "usefulness of hair analysis and psychological tests for identification of alcohol and drugs of abuse consumption in driving license regranting"
} | [
{
"companynumb": "ES-ALKEM LABORATORIES LIMITED-ES-ALKEM-2018-03281",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nTo report on efficacy and safety of intravenous immunoglobulin (IVIg) therapy in a case series of patients with COVID-19-related encephalopathy.\n\n\nMETHODS\nWe retrospectively collected data on all patients with COVID-19 hospitalized at two Italian hospitals who developed encephalopathy during disease course and were treated with IVIg.\n\n\nRESULTS\nFive patients (two females, mean age 66.8 years) developed encephalopathy after a mean of 12.6 days, since the onset of respiratory/constitutional symptoms related to COVID-19. Four patients suffered severe respiratory distress, three of which required invasive mechanical ventilation. Neurological manifestations included impaired consciousness, agitation, delirium, pyramidal and extrapyramidal signs. EEG demonstrated diffuse slowing in all patients. Brain MRI showed non-specific findings. CSF analysis revealed normal cell count and protein levels. In all subjects, RT-PCR for SARS-CoV-2 in CSF tested negative. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range: 19-55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range: 1-10 days). No adverse events related to IVIg were observed.\n\n\nCONCLUSIONS\nOur preliminary findings suggest that IVIg may represent a safe and effective treatment for COVID-19-associated encephalopathy. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities.",
"affiliations": "Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;Infermi Hospital, AUSL Romagna, Rimini, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.;IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;Karolinska Institutet, Stockholm, Sweden.;Infermi Hospital, AUSL Romagna, Rimini, Italy.;IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.;IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.;IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;Infermi Hospital, AUSL Romagna, Rimini, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy. francesca.bisulli@unibo.it.",
"authors": "Muccioli|Lorenzo|L|;Pensato|Umberto|U|;Bernabè|Giorgia|G|;Ferri|Lorenzo|L|;Tappatà|Maria|M|;Volpi|Lilia|L|;Cani|Ilaria|I|;Henry|Olivia J|OJ|;Ceccaroni|Francesca|F|;Cevoli|Sabina|S|;Stofella|Gloria|G|;Pasini|Elena|E|;Fornaro|Giacomo|G|;Tonon|Caterina|C|;Vidale|Simone|S|;Liguori|Rocco|R|;Tinuper|Paolo|P|;Michelucci|Roberto|R|;Cortelli|Pietro|P|;Bisulli|Francesca|F|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-020-10248-0",
"fulltext": "\n==== Front\nJ Neurol\nJ Neurol\nJournal of Neurology\n0340-5354\n1432-1459\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33030607\n10248\n10.1007/s00415-020-10248-0\nOriginal Communication\nIntravenous immunoglobulin therapy in COVID-19-related encephalopathy\nMuccioli Lorenzo 1\nPensato Umberto 1\nBernabè Giorgia 2\nFerri Lorenzo 1\nTappatà Maria 3\nVolpi Lilia 3\nCani Ilaria 1\nHenry Olivia J. 4\nCeccaroni Francesca 2\nCevoli Sabina 3\nStofella Gloria 3\nPasini Elena 3\nFornaro Giacomo 5\nTonon Caterina 13\nVidale Simone 2\nLiguori Rocco 13\nTinuper Paolo 13\nMichelucci Roberto 3\nCortelli Pietro 13\nBisulli Francesca francesca.bisulli@unibo.it\n\n13\n1 grid.6292.f 0000 0004 1757 1758 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy\n2 grid.414614.2 Infermi Hospital, AUSL Romagna, Rimini, Italy\n3 grid.492077.f IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy\n4 grid.4714.6 0000 0004 1937 0626 Karolinska Institutet, Stockholm, Sweden\n5 grid.6292.f 0000 0004 1757 1758 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy\n8 10 2020\n8 10 2020\n2021\n268 8 26712675\n9 9 2020\n17 9 2020\n19 9 2020\n© The Author(s) 2020\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/.\nObjective\n\nTo report on efficacy and safety of intravenous immunoglobulin (IVIg) therapy in a case series of patients with COVID-19-related encephalopathy.\n\nMethods\n\nWe retrospectively collected data on all patients with COVID-19 hospitalized at two Italian hospitals who developed encephalopathy during disease course and were treated with IVIg.\n\nResults\n\nFive patients (two females, mean age 66.8 years) developed encephalopathy after a mean of 12.6 days, since the onset of respiratory/constitutional symptoms related to COVID-19. Four patients suffered severe respiratory distress, three of which required invasive mechanical ventilation. Neurological manifestations included impaired consciousness, agitation, delirium, pyramidal and extrapyramidal signs. EEG demonstrated diffuse slowing in all patients. Brain MRI showed non-specific findings. CSF analysis revealed normal cell count and protein levels. In all subjects, RT-PCR for SARS-CoV-2 in CSF tested negative. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range: 19–55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range: 1–10 days). No adverse events related to IVIg were observed.\n\nConclusions\n\nOur preliminary findings suggest that IVIg may represent a safe and effective treatment for COVID-19-associated encephalopathy. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities.\n\nElectronic supplementary material\n\nThe online version of this article (10.1007/s00415-020-10248-0) contains supplementary material, which is available to authorized users.\n\nAlma Mater Studiorum - Università di BolognaOpen access funding provided by Alma Mater Studiorum - Università di Bologna within the CRUI-CARE Agreement.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nSevere acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease-2019 (COVID-19). While many individuals with SARS-CoV-2 infection are asymptomatic or develop only mild respiratory and constitutional symptoms, a subgroup of patients present with complications, including acute respiratory distress syndrome, disseminated intravascular coagulation and multiorgan dysfunction syndrome [1, 2].\n\nCytokine release syndrome (CRS) is a systemic hyperinflammatory condition presenting secondary to monocyte, macrophage and dendritic cell activation in severe COVID-19 infection and has been implicated in disease pathophysiology [3].\n\nNeuropsychiatric manifestations are increasingly being reported in association with COVID-19, including encephalopathy [4]. The pathophysiology underlying this presentation remains unclear; however, a role of cytokine-mediated neuroinflammation has been suggested [5−10]. COVID-19-associated encephalopathy has been described responsive to high-dose steroids and plasmapheresis, consistent with an immune-mediated pathogenesis [5, 11, 12].\n\nIntravenous immunoglobulin (IVIg) therapy has shown efficacy in treating systemic COVID-[13, 19] yet its role in the management of associated CNS manifestations remains to be determined.\n\nWe report five patients with COVID-19-related encephalopathy successfully treated with IVIg.\n\nMethods\n\nWe retrospectively collected data on all patients with COVID-19 hospitalized at Bellaria Hospital, Bologna, and Infermi Hospital, Rimini, Italy, from March 13, 2020, to May 27, 2020, who developed encephalopathy during disease course and were treated with IVIg. COVID-19 diagnosis was made on the basis of at least one positive SARS-CoV-2 real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasopharyngeal swab specimens and consistent clinical and/or radiological findings. IVIg therapy was prescribed by the treating neurologist based on the patient’s clinical profile and suspected immune-mediated/inflammatory encephalopathy, in accordance with institutional and international guidelines.\n\nResults\n\nFive patients (two females) with a mean age of 66.8 years (range: 54–75 years) were included in this retrospective study. Demographics, comorbidities, disease course, timing of IVIg and other immunotherapies are summarized in Table 1. Clinical, neuroradiological, EEG and CSF findings are summarized in Table 2. The illustrative case of the first patient is shown in Fig. 1.Table 1 Demographics, comorbidities and disease course\n\nPt\tAge (y),\nSex\tComorbidities\tCOVID-19 onset (day)a,b\tWorst P/F (day)a\tIVIg treatment\n(0.4 g/kg/d)\n(start, end)a\tClinical Response (initial, complete)a\tOther immunotherapies\n(start, end)a\tLast f.up (day)a\t\n1\t54, F\tNone\t− 5\t130 (+ 3)\t+ 18, + 21\t+ 19, + 21\tTocilizumab 400 mg (+ 0)\n\nLow-dose steroids (+ 3, + 17)\n\n\t+ 90\t\n2\t75, M\tType 2 DM, hypertension, ischemic heart disease,\n\nprevious stroke\n\n\t0\t114 (+ 12)\t+ 26, + 30\t+ 28, + 34\tTocilizumab 400 mg (+ 33)\n\nLow-dose steroids (+ 21, + 36)\n\n\t+ 115\t\n3\t69, F\tBipolar disorder, MCI, iatrogenic parkinsonism, type 2 DM\t− 15\t345 (+ 14)\t+ 28, + 32\t+ 30, + 38\tMP 1 g/die (+ 13, + 17)\t+ 86\t\n4\t69, M\tHypertensive cardiopathy\t− 23\t81\n\n(− 14)\n\n\t+ 22, + 27\t+ 24, + 28\t\t+ 70\t\n5\t67, M\tType 2 DM,\n\nhypertension\n\n\t− 20\t79\n\n(− 8)\n\n\t+ 55, + 60\t+ 65, + 75\tTocilizumab 400 mg (− 8)\t+ 105\t\nDM diabetes mellitus, MCI mild cognitive impairment, MP methylprednysolone\n\naWe referred to encephalopathy onset as day “0”, and to all events occurred previously or subsequently as minus or plus “day”, respectively\n\nbOnset of constitutional or respiratory symptoms such as fever, cough, dyspnea\n\nTable 2 Neurological clinical and investigative findings\n\nPt\tNeurological manifestations\tEEG (D)\tMRI (D)\tCSF (D)\t\n1\tIrritability, quadriparesis with pyramidal signs, akinetic mutism, agitated delirium, frontal release reflexes\tDiffuse slowing at 6–7 Hz\n\n(+ 15)\n\n\tFronto-parietal white matter hyperintensity\n\n(+ 16)\n\n\tCells: 0/μL\n\nProteins: 26 mg/dL\n\nQalb: 4\n\n(+ 17)\n\n\t\n2\tConfusion, disorientation, global memory deficits\tDiffuse slowing at 4–5 Hz\n\n(+ 21)\n\n\tPrevious right fronto-parietal stroke\n\n(+ 22)\n\n\tCells: 1 WBC/μL\n\nProteins: 60 mg/dL\n\nQalb: 17.8\n\n(+ 25)\n\n\t\n3\tApraxia, mixed delirium, pyramidal signs, frontal release reflexes, extrapyramidal signs (rigidity and bradykinesia)a\tDiffuse slowing at 6–7 Hz, frontal sharp waves\n\n(+ 13)\n\n\tParietal white matter hyperintensity, cerebral atrophy\n\n(+ 13)\n\n\tCells: 1 WBC/μL\n\nProteins: 32 mg/dL\n\nQalb: 3.8\n\n(+ 9)\n\n\t\n4\tDecreased level of consciousness, agitation, tonic muscle spasms\tDiffuse slowing at 5–6 Hz, FIRDA\n\n(+ 0)\n\n\tCerebral small vessel disease (chronic)\n\n(+ 2)\n\n\tCells: 6 WBC/μL\n\nProteins 35 mg/dL\n\n(+ 1)\n\n\t\n5\tDecreased level of consciousness, agitation, hemiparesis with pyramidal signs, extrapyramidal signs (rigidity and tremor), frontal release reflexes\tDiffuse slowing at 5–6 Hz\n\n(+ 2)\n\n\tCerebral small vessel disease (chronic)\n\n(+ 45)\n\n\tCells: 1 WBC/μL\n\nProteins: 29 mg/dL\n\n(+ 2)\n\n\t\nD number of days after encephalopathy onset, FIRDA frontal intermittent rhythmic delta activity, Qalb CSF/serum albumin quotient, WBC white blood cell\n\naExtrapyramidal signs were already present before COVID-19 due to drug-induced parkinsonism\n\nFig. 1 Disease course in patient 1. Neurological manifestations, respiratory distress, temperature, IL-6 levels, timing of immunomodulatory treatments and diagnostic investigations during disease course. Neurological status severity was evaluated by treating neurologists. On the 15th day after disease onset, neurological evaluation was performed during temporary weaning of sedatives (red dot). Temperature and SpO2/FiO2 ratio were measured at least daily during hospitalization. Crosses on the IL-6 line represent the actual measurements. EEG electroencephalography, EMG electromyography, ICU intensive care unit, IVIg intravenous immunoglobulin treatment, LP lumbar puncture, MRI magnetic resonance imaging, S/F SpO2/FiO2 ratio\n\nThree patients (1, 4, 5) were placed on invasive mechanical ventilation due to respiratory distress, while patient 2 was treated with non-invasive mechanical ventilation. Patient 3 had prior hospitalization in another facility for mild respiratory distress, where she was treated with low-flow oxygen therapy. She was subsequently re-admitted to our facility due to the subacute onset of neuropsychiatric symptoms. All patients developed encephalopathy, with a mean onset of 12.6 days (range 0–23 days) after the presentation of respiratory/constitutional symptoms related to SARS-CoV-2 infection. In patients 4 and 5, encephalopathy presented following sedation weaning as persisting impaired consciousness, whereas CNS symptoms developed in the other patients independently. Neurological manifestations were heterogeneous, including confusion, agitation, delirium, akinetic mutism, apraxia, pyramidal, extrapyramidal and frontal release signs. EEG demonstrated diffuse slowing in all patients, with frontal predominance in two cases. Brain MRI showed non-specific diffuse white-matter hyperintensities in two patients, while the others displayed chronic cerebrovascular findings. CSF analysis revealed ≤ 6 WBC and normal protein levels in each patient. In all subjects, RT-PCR for SARS-CoV-2 and for common neurotropic viruses in CSF, as well as a panel of CSF and serologic antibodies against neuronal intracellular and cell surface antigens, tested negative. Blood tests revealed elevated inflammatory markers, including IL-6 (Supplementary Appendix). Patient 3 developed hypernatremia (up to 164 mEq/L) and prerenal acute kidney injury during hospitalization, but their correction did not result in mental status improvement. With this exception, common causes of encephalopathy such as renal or hepatic failure, electrolyte imbalances, and hypoxemia were excluded in all cases. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range 19–55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range 1–10 days). No further neurological symptoms were observed at the last follow-up visit, which was performed after a mean of 54.8 days (range 30–81) since clinical recovery. In patient 1, a marked reduction of serum IL-6 levels was evident on the fourth IVIg infusion day (from 218 to 28 pg/mL), coinciding with clinical response. No adverse events related to IVIg were observed.\n\nDiscussion\n\nEncephalopathy is emerging as a recurrent complication of COVID-19, yet the best approach to management and treatment remains unknown. We described five patients with COVID-19-related encephalopathy, all of whom recovered following IVIg.\n\nIVIg is an efficient anti-inflammatory and immunomodulatory treatment for a growing number of neurological disorders; however, its mode of action is complex and not yet fully understood [15]. The pathophysiology underlying the diseases which respond to IVIg is highly heterogeneous, thus it is likely that IVIg acts on various disease-specific pathways.\n\nIn patients with COVID-19 and severe pulmonary involvement, treatment with IVIg led to a significant clinical improvement and concomitant reduction of serum inflammatory markers, observed as early as the first infusion day [13]. Correspondingly, our patients showed a prompt and dramatic improvement of neurological manifestations following IVIg. Similar results have been achieved in six other patients with COVID-19-related encephalopathy treated with high-dose corticosteroids [5, 11]. In our third case, steroid pulse therapy was ineffective, where subsequent IVIg was concomitant with clinical recovery. In support of our preliminary findings, IVIg led to improved neuropsychiatric symptoms in four COVID-19 patients with mixed central and peripheral neurological manifestations and to clinico-radiological recovery in a further patient with frontal status epilepticus and encephalopathy [16, 17].\n\nClinical course and investigative findings observed in the present case series, including negative RT-PCR for SARS-CoV-2 in CSF, absence of significant elevation of CSF cells and protein levels, non-specific MRI findings, and the dramatic response to immunotherapy, suggest an inflammatory/immune-mediated pathogenesis rather than CNS viral invasion. An autoantibody-mediated mechanism is unlikely to explain CNS involvement, based on the brief temporal interval between CNS and infection-related symptom onset, negative testing for anti-neuronal antibodies, and the prompt and sustained response to IVIg [15]. Cytokine-mediated neuroinflammation has been implicated in the underlying pathogenic mechanism of COVID-19-associated encephalopathy, and may have contributed to disease course in our patients [5–10]. Except the third case, all patients suffered acute respiratory distress secondary to CRS induced by SARS-CoV-2. Interestingly, case 3 is the only patient with previous cognitive impairment, a condition that possibly made her more susceptible to develop encephalopathy despite mild systemic inflammation, as in other reported geriatric patients [10]. In patient 1 and 4, we observed a delay between the rise of inflammatory markers in serum and the onset/peak of neurological manifestations, possibly due to a delayed rise of CSF cytokines with respect to serum levels. Unfortunately, we were not able to measure CSF cytokines.\n\nIVIg has anti-cytokine qualities, which appear important for its anti-inflammatory action. This may be related to the presence of anti-cytokine autoantibodies found in natural human immunoglobulin, including anti-TNF-α, anti-IL-1 and anti IL-8 [18]. Additionally, the natural IgG fraction inhibits the production of proinflammatory cytokines in a dose-dependent manner via the Fc portion [18]. Accordingly, IVIg therapy has been shown to significantly reduce circulating proinflammatory cytokines within 3 days [19], as observed in patient 1.\n\nCytokines may drive neuroinflammation even without severe CRS, possibly as a consequence of local CNS production [5, 6, 20]. The IVIg anti-cytokine effects documented peripherally may independently and directly act on the CNS. IVIg can cross an intact blood–brain-barrier and is bioavailable in sufficient concentrations to interact with the therapeutic targets, with the maximum concentration reached in the CNS 24 h after administration in a murine model [1, 2].\n\nNone of our patients experienced adverse events related to IVIg. Adverse reactions to IVIg therapy are usually minor and occur in less than 10% of patients [15]. However, as both COVID-19 and IVIg may predispose to thromboembolic events such as stroke and pulmonary embolism [2, 15], prophylactic anticoagulation should be considered. In patients with evidence of coagulopathy, an alternate immunotherapy such as high-dose corticosteroids should be preferred. However, since the likelihood of thromboembolic disease in COVID-19 might be secondary to CRS, the global thromboembolic risk may be partially compensated by the anti-inflammatory action of IVIg [1, 16].\n\nConclusions\n\nIVIg was a safe and effective treatment for COVID-19-related encephalopathy in our case series. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities. Our preliminary observation needs to be confirmed with larger clinical studies. However, considering the emerging evidence supporting an inflammatory-mediated pathogenesis in a subgroup of patients with COVID-19-related encephalopathy, we believe that immunotherapy with IVIg or other agents might be considered to hasten clinical recovery and prevent potential long-term neurological sequelae.\n\nElectronic supplementary material\n\nBelow is the link to the electronic supplementary material.Supplementary material 1 (DOCX 22 kb)\n\nAcknowledgements\n\nWe thank all the colleagues working at the COVID-19 units of Bellaria and Infermi hospitals, especially L. Guerra, S. Zaccaroni, L.L. Gramegna, P. Riguzzi, C. Calabrò, E. Fileccia, G. Fornaro, F. Volpato, L. Bussini. We also thank Prof. R. Lodi, Prof. P. Affanni, Prof. M.C. Re, G. Bordin, I. Bon, G. Rossini.\n\nAuthor contributions\n\nLM, UP, GB and FB contributed to conception and design of the study; all authors contributed to the acquisition and/or analysis of data; LM and UP drafted the manuscript; IC prepared the figure; FB supervised the study.\n\nFunding\n\nOpen access funding provided by Alma Mater Studiorum - Università di Bologna within the CRUI-CARE Agreement.\n\nCompliance with ethical standards\n\nConflicts of interest\n\nNothing to report.\n\nEthical approval\n\nAll investigations were carried out according to the Declaration of Helsinki.\n\nLorenzo Muccioli and Umberto Pensato have contributed equally to this work.\n==== Refs\nReferences\n\n1. Guan WJ Νi ZY Hu Y Clinical characteristics of Coronavirus Disease 2019 in China N Engl J Med 2020 382 18 1708 1720 10.1056/NEJMoa2002032 32109013\n2. Al-Ani F Chehade S Lazo-Langner A Thrombosis risk associated with COVID-19 infection. A scoping review Thromb Res 2020 192 152 160 10.1016/j.thromres.2020.05.039 32485418\n3. Moore JB June CH Cytokine release syndrome in severe COVID-19 Science 2020 368 6490 473 474 10.1126/science.abb8925 32303591\n4. Koralnik IJ Tyler KL COVID-19: a global threat to the nervous system Ann Neurol 2020 88 1 1 11 10.1002/ana.25807 32506549\n5. Pilotto A Odolini S Masciocchi S Steroid-responsive encephalitis in coronavirus disease 2019 Ann Neurol 2020 10.1002/ana.25783 33016374\n6. Muccioli L Pensato U Cani I COVID-19-associated encephalopathy and cytokine-mediated neuroinflammation Ann Neurol 2020 10.1002/ana.25855 32715524\n7. Cani I Barone V D’Angelo R Frontal encephalopathy related to hyperinflammation in COVID-19 J Neurol 2020 10.1007/s00415-020-10057-5 33030607\n8. Farhadian S Glick LR Vogels CBF Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19 BMC Neurol 2020 20 1 248 10.1186/s12883-020-01812-2 32552792\n9. Benameur K Agarwal A Auld SC Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020 Emerg Infect Dis 2020 10.3201/eid2609.202122 32857691\n10. Beach SR Praschan NC Hogan C Delirium in COVID-19: a case series and exploration of potential mechanisms for central nervous system involvement Gen Hosp Psychiatry 2020 65 47 53 10.1016/j.genhosppsych.2020.05.008 32470824\n11. Pugin D Vargas MI Thieffry C COVID-19-related encephalopathy responsive to high doses glucocorticoids Neurology 2020 10.1212/WNL.0000000000010354 32680950\n12. Dogan L Kaya D Sarikaya T Plasmapheresis treatment in COVID-19-related autoimmune meningoencephalitis: case series Brain Behav Immun 2020 87 155 158 10.1016/j.bbi.2020.05.022 32389697\n13. Cao W Liu X Bai T High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019 Open Forum Infect Dis 2020 7 3 102 10.1093/ofid/ofaa102\n14. Liu X Cao W Li T High-dose intravenous immunoglobulins in the treatment of severe acute viral pneumonia: the known mechanisms and clinical effects Front Immunol 2020 11 1660 10.3389/fimmu.2020.01660 32760407\n15. Lünemann JD Nimmerjahn F Dalakas MC Intravenous immunoglobulin in neurology–mode of action and clinical efficacy Nat Rev Neurol 2015 11 2 80 89 10.1038/nrneurol.2014.253 25561275\n16. Chaumont H San-Galli A Martino F Mixed central and peripheral nervous system disorders in severe SARS-CoV-2 infection J Neurol 2020 10.1007/s00415-020-09986-y 32533322\n17. Le Guennec L Devianne J Jalin L Orbitofrontal involvement in a neuroCOVID-19 patient Epilepsia 2020 10.1111/epi.16612 32589794\n18. Abe Y Horiuchi A Miyake M Kimura S Anti-cytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy Immunol Rev 1994 139 5 19 10.1111/j.1600-065X.1994.tb00854.x 7927413\n19. Sharief MK Ingram DA Swash M Thompson EJ I.v. Immunoglobulin reduces circulating proinflammatory cytokines in Guillain-Barre syndrome Neurology 1999 52 9 1833 1838 10.1212/WNL.52.9.1833 10371531\n20. Santomasso BD Park JH Salloum D Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia Cancer Discov 2018 8 8 958 971 10.1158/2159-8290.CD-17-1319 29880584\n21. St-Amour I Pare I Alata W Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier J Cereb Blood Flow Metab 2013 33 12 1983 1992 10.1038/jcbfm.2013.160 24045402\n\n",
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"mesh_terms": "D000368:Aged; D001927:Brain Diseases; D000086382:COVID-19; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D012189:Retrospective Studies; D000086402:SARS-CoV-2",
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"title": "Intravenous immunoglobulin therapy in COVID-19-related encephalopathy.",
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"abstract": "OBJECTIVE\nRetinal toxicity associated with antimalarial drug use in inflammatory conditions is well described and may be more common than previously recognized. Antimalarial drugs bind to melanin in ocular tissues, particularly the retinal pigment epithelium, but the mechanism of toxicity and its relation to light is unclear.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 62-year-old white woman with erosive rheumatoid arthritis developed hydroxychloroquine toxicity in her phakic eye, with her aphakic fellow eye only mildly affected.\n\n\nCONCLUSIONS\nWe report the clinical evaluation of this rare case of asymmetrical hydroxychloroquine retinopathy and present a hypothesis regarding the mechanism of drug toxicity.",
"affiliations": "Department of Ophthalmology, Melbourne Health, Victoria, Australia.;Royal Victorian Eye and Ear Hospital, Victoria, Australia.;Department of Ophthalmology, Melbourne Health, Victoria, Australia.;Centre for Eye Research Australia, University of Melbourne, Victoria, Australia.",
"authors": "Mack|Heather G|HG|;Fuzzard|Dujon R W|DRW|;Symons|R C Andrew|RCA|;Heriot|Wilson J|WJ|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
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"mesh_terms": "D018501:Antirheumatic Agents; D001036:Aphakia, Postcataract; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D007908:Lens, Crystalline; D008875:Middle Aged; D012160:Retina; D012164:Retinal Diseases; D041623:Tomography, Optical Coherence; D058609:Visual Field Tests; D014794:Visual Fields",
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"title": "ASYMMETRIC HYDROXYCHLOROQUINE MACULAR TOXICITY WITH APHAKIC FELLOW EYE.",
"title_normalized": "asymmetric hydroxychloroquine macular toxicity with aphakic fellow eye"
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"abstract": "The safety and feasibility of oral fluoroquinolone monotherapy in patients with low-risk febrile neutropenia (FN) were demonstrated in recent studies. Levofloxacin (LVFX) is a commonly prescribed antibiotic; however, evidence for its efficacy against FN is limited. Therefore, in this study, we retrospectively investigated the efficacy of LVFX against low-risk FN in patients with malignant lymphoma at our institution. Treatment success was defined as recovery from fever and neutropenia without alteration of the initial regimen. We recruited 29 patients between January 2013 and December 2018. The median age of the cohort was 64 (range: 21-87) years; 13 (44.8%) were aged over 65 years. In total, 22 patients had diffuse large B-cell lymphoma (DLBCL). Therapy was successful in 24 (82.8%) patients, whereas 5 had treatment failure requiring a change from LVFX to intravenous broad-spectrum antibacterial agents. No deaths related to FN were observed. Two patients required FN-related chemotherapy dose reduction in subsequent cycles. Although this cohort comprised many elderly patients, our study confirmed the efficacy of LVFX in patients with low-risk FN. This may improve the treatment of low-risk FN and malignant lymphoma.",
"affiliations": "Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.;Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.;Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.;Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.;Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.;Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.;Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.;Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.",
"authors": "Mogi|Ai|A|;Sasaki|Hidenori|H|;Nakashima|Yuta|Y|;Chinen|Shotaro|S|;Ishizu|Masanao|M|;Tanaka|Toshihiro|T|;Takata|Tohru|T|;Takamatsu|Yasushi|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014750:Vincristine; D064704:Levofloxacin; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
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"doi": "10.3960/jslrt.20008",
"fulltext": "\n==== Front\nJ Clin Exp Hematop\nJ Clin Exp Hematop\njslrt\nJournal of Clinical and Experimental Hematopathology : JCEH\n1346-4280 1880-9952 JSLRT \n\n32779614\n20008\n10.3960/jslrt.20008\nOriginal Article\nEfficacy of oral levofloxacin monotherapy against low-risk FN in patients with malignant lymphoma who received chemotherapy using the CHOP regimen\nMogi Ai Sasaki Hidenori Nakashima Yuta Chinen Shotaro Ishizu Masanao Tanaka Toshihiro Takata Tohru Takamatsu Yasushi Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, Fukuoka, Japan\nCorresponding author: Ai Mogi, Division of Medical Oncology, Hematology and Infection Disease, Department of Internal Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: amogi@fukuoka-u.ac.jp\n08 8 2020 \n9 2020 \n60 3 73 77\n03 3 2020 14 5 2020 01 6 2020 © 2020 by The Japanese Society for Lymphoreticular Tissue Research2020The Japanese Society for Lymphoreticular Tissue\nResearchThis is an open-access article distributed under the terms of the\nCreative Commons Attribution ShareAlike (CC BY-NC-SA) 4.0 License.The safety and feasibility of oral fluoroquinolone monotherapy in patients with low-risk febrile neutropenia (FN) were demonstrated in recent studies. Levofloxacin (LVFX) is a commonly prescribed antibiotic; however, evidence for its efficacy against FN is limited. Therefore, in this study, we retrospectively investigated the efficacy of LVFX against low-risk FN in patients with malignant lymphoma at our institution. Treatment success was defined as recovery from fever and neutropenia without alteration of the initial regimen. We recruited 29 patients between January 2013 and December 2018. The median age of the cohort was 64 (range: 21–87) years; 13 (44.8%) were aged over 65 years. In total, 22 patients had diffuse large B-cell lymphoma (DLBCL). Therapy was successful in 24 (82.8%) patients, whereas 5 had treatment failure requiring a change from LVFX to intravenous broad-spectrum antibacterial agents. No deaths related to FN were observed. Two patients required FN-related chemotherapy dose reduction in subsequent cycles. Although this cohort comprised many elderly patients, our study confirmed the efficacy of LVFX in patients with low-risk FN. This may improve the treatment of low-risk FN and malignant lymphoma.\n\nKeywords: \nfebrile neutropenialevofloxacinmalignant lymphomaCHOP\n==== Body\nINTRODUCTION\nCombination chemotherapy using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is the standard treatment regimen for malignant lymphoma.1-3 CHOP-induced neutropenia is a common clinical complication that often develops into life-threatening febrile neutropenia (FN). This may necessitate treatment interruptions and delays, which reduce the administered doses of chemotherapy, significantly deteriorating survival outcomes and the quality of life.4-6 Therefore, the prompt initiation of intravenous broad-spectrum antibiotics is necessary in such cases.7\n\nHowever, a subset of FN patients with a low risk for medical complications was identified. Controlled trials comparing oral and intravenous antibiotics in patients with low-risk FN reported equivalence in terms of safety and efficacy.8 Several guidelines recommend oral ciprofloxacin as initial empiric therapy with amoxicillin/clavulanate for low-risk FN.7,9\n\nRecent studies demonstrated the safety and feasibility of oral fluoroquinolones in patients with low-risk FN.10,11 Levofloxacin (LVFX) is a commonly prescribed fluoroquinolone antibiotic;12 however, evidence for its efficacy is limited. We therefore retrospectively investigated the efficacy of oral LVFX monotherapy in against low-risk FN in patients with malignant lymphoma who received chemotherapy using the CHOP regimen at our institution.\n\nMATERIALS AND METHODS\nStudy design\nThis was a single-center retrospective study and the protocol was approved by the institutional review board of the Fukuoka University Hospital. As it was based exclusively on existing data from medical records, the requirement for informed consent was waived.\n\nPatients\nWe reviewed the medical records of patients with malignant lymphoma who received CHOP therapy between January 2013 and December 2018 at the Fukuoka University Hospital. The data of patients who developed FN and were treated using 500 mg of LVFX orally per day were extracted. Patients received LVFX for at least 5 days if they did not need to change from LVFX to another antibiotic. In patients who received LVFX more than once, the second and subsequent treatments were excluded from analysis.\n\nAssessments\nThe data obtained from the records included the age, sex, Eastern Cooperative Oncology Group Performance status (ECOG PS), lymphoma subtype, rituximab administration, complications (heart failure, chronic obstructive pulmonary disease [COPD], and cerebral hemorrhage/infarction), infection, prophylactic interventions (antibiotics and granulocyte-colony stimulating factor; G-CSF), magnesium oxide administration, previous LVFX administration within 3 months, previous hospitalization within 3 months, blood tests, fever duration, and outcomes of therapy.\n\nDefinitions\nFN is defined as an axillary temperature of ≥37.5°C and an absolute neutrophil count of <500 cells/mm3 or that is expected to decrease to <500 cells/mm3 during the next 48 h. Low-risk patients were identified based on a Multinational Association of Supportive Care in Cancer (MASCC) risk-index score of ≥ 21.13 The predictive factors were: a burden of illness suggesting the absence of symptoms or mild symptoms (weight, 5) or moderate symptoms (weight, 3); absence of hypotension (weight, 5); absence of chronic obstructive pulmonary disease (weight, 4); presence of solid tumor or absence of previous fungal infection in patients with hematological malignancies (weight, 4); outpatient status (weight, 3); absence of dehydration (weight, 3); and age less than 60 years (weight, 2).\n\nTreatment success was defined as recovery from fever and neutropenia without alteration of the initial regimen, i.e., LVFX.\n\nIn cases where a pathogen was isolated from a blood sample, an infection site, or both, the infection was considered to be microbiologically documented. In cases of clinical signs and symptoms of infection without isolation of pathogens from the infection site, the infection was considered to be clinically documented. Fever of unknown origin was diagnosed in cases where fever was the only clinical sign of infection.\n\nRESULTS\nPatients\nIn total, 182 patients received CHOP therapy for malignant lymphoma. FN developed in 60 (33.0%) patients in 80 (8.6%) of 933 cycles of CHOP therapy administered in total. We assessed only the first FN event for each patient in the following analysis. Eighteen (30.0%) patients had high-risk FN and received intravenous antibiotics on admission. Thirty-five (58.3%) patients had low-risk FN, among whom 29 required oral LVFX, 4 required intravenous broad-spectrum antibacterial therapy, and 2 required oral antibiotics other than LVFX (ciprofloxacin plus amoxicillin/clavulanate and ciprofloxacin alone). The MASCC score was undetermined in 7 (11.7%) patients.\n\nThe characteristics of the 29 patients at the start of CHOP therapy are shown in Table 1. The median age was 64 (range: 21–87) years and 13 (44.8%) patients were aged over 65 years. The ECOG PS was 0-1 in 27 patients and 2 in 2. The subtype of lymphoma was diffuse large B-cell lymphoma (DLBCL) in 22, follicular lymphoma in 3, Adult-T cell leukemia/lymphoma in 2, and peripheral T-cell lymphoma not otherwise specified in 2. A total of 24 patients received rituximab. None of the patients had a medical history of heart failure, COPD, or cerebral hemorrhage/infarction. We did not evaluate whether our patients were positive for HIV.\n\nTable 1 Baseline patient characteristics (n=29)\nCharacteristics\tNo. (%)\t\nAge, years\t\t\nMedian (range)\t64 (21-87)\t\nSex\t\t\nMale\t13 (44.8)\t\nFemale\t16 (55.2)\t\nECOG PS\t\t\n0-1\t27 (93.1)\t\n2\t2 (6.9)\t\nMalignancy\t\t\nDLBCL\t22 (75.9)\t\nFL\t3 (10.3)\t\nATLL\t2 (6.9)\t\nPTCL-NOS\t2 (6.9)\t\nRituximab\t24 (82.8)\t\nComorbidity\t\t\nHeart failure\t0 (0.0)\t\nChronic obstructive pulmonary disease\t0 (0.0)\t\nCerebral hemorrhage/infarction\t0 (0.0)\t\nECOG PS: Eastern Cooperative Oncology Group Performance Status, DLBCL: diffuse large B-cell lymphoma, FL: follicular lymphoma, ATLL: adult-T-cell leukemia/lymphoma, PTCL-NOS: peripheral T-cell lymphoma-not otherwise specified\n\nClinical features of FN\nWe next investigated the clinical features of the 29 patients when they developed FN. Twenty-eight (96.6%) patients had an ECOG PS of 1 and 1 had an ECOG PS of 2 (Table 2). No patient had non-hematological toxicity, including renal and hepatic function of at least Common Terminology Criteria for Adverse Events grade 1. Five patients (17.2%) were diagnosed with clinical documented infection, among whom 3 had gingivitis and 2 had pharyngitis. G-CSF was administered for FN prophylaxis to 13 (44.8%) patients. Magnesium oxide was administered as a laxative to 18 (62.1%) patients. Three (10.3%) patients had a history of LVFX administration and 18 (62.1%) had been hospitalized within 3 months.\n\nTable 2 Clinical features of 29 patients with FN (n=29)\nCharacteristics\tNo. (%)\t\nECOG PS\t\t\n1\t28 (96.6)\t\n2\t1 (3.4)\t\nType of infection\t\t\nMicrobiologically documented\t0 (0.0)\t\nClinically documented\t5 (17.2)\t\nFever of unknown origin\t24 (82.8)\t\nProphylactic antibiotics\t0 (0.0)\t\nProphylactic G-CSF\t13 (44.8)\t\nMagnesium oxide\t18 (62.1)\t\nPrevious LVFX within 3 months\t3 (10.3)\t\nPrevious hospitalization within 3 months\t18 (62.1)\t\nBlood parameters (median)\t\t\nWhite blood cells\t0.80×109/L\t\nNeutrophils\t0.26×109/L\t\nHemoglobin\t10.6 g/dL\t\nPlatelets\t130×109/L\t\nAlbumin\t3.6 g/dL\t\nCreatinine\t0.8 mg/dL\t\nTotal bilirubin\t0.7 mg/dL\t\nAspartate aminotransferase\t21 U/L\t\nAlanine aminotransferase\t25 U/L\t\nLactate dehydrogenase\t178 U/L\t\nGlucose\t112 mg/dL\t\nC-reactive protein\t0.8 mg/dL\t\nECOG PS: Eastern Cooperative Oncology Group Performance Status, G-CSF: granulocyte-colony stimulating factor, LVFX: levofloxacin\n\nOutcomes of FN therapy\nFN was improved by oral LVFX treatment in 24 (82.8%) patients (Table 3). Seventeen of 24 patients became afebrile within 72 hours and 3 patients in whom fever persisted for longer than 72 hours continued to receive oral LVFX because their conditions were clinically stable, leading to normalization of their body temperature with neutrophil recovery. In four patients with treatment success, we were unable to follow the fever duration. The remaining 5 (17.2%) patients changed from LVFX to intravenous broads-spectrum antibacterial therapy because 1 developed new signs and symptoms of infection, 1 became hemodynamically unstable, and 3 had persistent fever. Following the alteration of antibacterial therapy, all 5 patients recovered from fever and neutropenia. No patient discontinued LVFX due to side effects and no FN-related death was observed in this cohort.\n\nTable 3 Treatment and outcomes (n=29)\nCharacteristics\tNo. (%)\t\nOutcome of therapy\t\t\nSuccess\t24 (82.8)\t\nFailure\t5 (17.2)\t\nDeath\t0 (0.0)\t\nFever duration in successfully treated patients\t\t\n≤72 hours\t17 (70.8)\t\n>72 hours\t3 (12.5)\t\nUnknown\t4 (16.2)\t\nSubsequent cycles\t\t\nDose reduction\t2 (6.9)\t\nAlthough treatment for FN was successful, 2 patients required FN-related chemotherapy dose reduction in the subsequent cycles. In 1 patient, the dose reduction was based on the criteria of clinical trials, whereas the other patient was 87 years old and required dose reduction due to PS deterioration.\n\nDISCUSSION\nIn this study, LVFX therapy was successful in 82.8% of the patients with malignant lymphoma who developed low-risk FN following CHOP therapy. The use of oral monotherapy with fluoroquinolones has been investigated for low-risk FN. Prior studies demonstrated equivalent efficacy between moxifloxacin and oral ciprofloxacin with amoxicillin/clavulanate,10 and ceftriaxone in patients with low-risk FN.11 Furthermore, ofloxacin and gatifloxacin were previously reported to be effective in patients with FN.14-16 LVFX is one of the most frequently prescribed antibiotics. Cornely et al. evaluated the efficacy of once-daily oral LVFX in comparison with intravenous piperacillin/tazobactam 3 times a day for 34 patients with low risk-FN following chemotherapy in a prospective, randomized, controlled multicenter trial.17 Although the planned number of patients was not enrolled, resulting in premature cessation of the trial, they demonstrated LVFX treatment to be successful in 13/17 (76.5%) of FN cases after 72 hours of treatment and found it to have equivalent efficacy to piperacillin/tazobactam. Lixian et al. also reported LVFX to be effective in 97.6% of patients with low-risk FN 7 days after the initiation of therapy in a pilot study.18 Thus, LVFX may be effective in patients with low-risk FN and our findings are consistent with those of previous studies.\n\nOf note, our cohort had 13 (44.8%) patients aged 65 or older and the median age was 64 years. Thirteen patients aged over 65 years received CHOP therapy at a median dose of 100% (75-100%) when they developed FN and the median number of cycles of CHOP therapy was 6 (2-8). Among them, FN was successfully treated in 11 (84.6%).\n\nOlder age was found to be one of the risk factors for the development of complications in patients with FN by the MASCC risk index.13 Gómez H et al. reported infections to be the most common cause for chemotherapy-related mortality in elderly patients with aggressive non-Hodgkin’s lymphoma,19 and infection was the cause of death in 29/35 (82.9%) patients. Therefore, further studies are needed to establish the optimal treatment approach in elderly patients with FN.\n\nHowever, the evidence for the efficacy of antibiotics in elderly patients with FN is limited. Yasuda et al. evaluated the efficacy of CFPM in patients with FN whose median age was 61 in a randomized controlled trial, and efficacy was noted in 19/25 (76.0%).20 Regarding oral fluoroquinolone monotherapy, Chamilos et al. demonstrated that moxifloxacin was effective for 50/55 (91%) outpatients with a median age of 62 years.21 However, many other reports describing the efficacy of oral single-agent broad-spectrum fluoroquinolones in patients with low-risk FN were of studies on children16,22,23 or on adults with median ages of 40-50;10,11,14,15,20,24 our adult patient cohort was older by 10 years.\n\nPrevious reports suggested that a poor PS (2-4) is also an important poor prognostic factor for chemotherapy–related mortality.19 However, in our study, almost all (96.6%) patients had a PS of 1 when they developed FN. Furthermore, the presence of comorbidities is also known to be an independent risk factor for a poorer OS in patients with DLBCL treated using rituximab-CHOP.25 In this study, we evaluated the presence of heart failure, cerebral infarction/hemorrhage, and COPD based on the Charlson comorbidity index,26 which is an indicator of comorbidity. However, the patients in our cohort did not have these diseases. Therefore, if selected appropriately, LVFX is effective in patients with low-risk FN, irrespective of age.\n\nLVFX is a concentration-dependent antibacterial drug; therefore, it is important to attain a high Cmax for therapeutic effects. However, concurrent administration of antacids, including magnesium and aluminum compounds, is known to reduce the bioavailability of LVFX by 15-52%.27 As such, pharmacists usually instruct patients not to take magnesium within a 2-hour period before or after LVFX administration. In our study, 62.1% of patients were receiving magnesium as a laxative when they developed FN. Satisfactory therapeutic effects were noted in this cohort despite this factor.\n\nThis study had several limitations. It was a retrospective cohort study performed at a single institution and there were few events. We also non-uniformly recruited patients with both B-cell and T-cell lymphoma undergoing CHOP therapy with or without rituximab.\n\nIn conclusion, our study suggests that oral LVFX is effective for treating patients with low-risk FN. This may improve the treatment of low-risk FN and malignant lymphoma. However, careful consideration is required for elderly patients. Further prospective studies on larger cohorts are needed to confirm our findings.\n\nCONFLICT OF INTEREST\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1 Feugier P Van Hoof A Sebban C \nLong-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte.\n\nJ Clin Oncol . 2005 ; 23 : 4117 -4126\n.15867204 \n2 Pfreundschuh M Trümper L Österborg A \nMabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group.\n\nLancet Oncol . 2006 ; 7 : 379 -391\n.16648042 \n3 Miyazaki K \nTreatment of diffuse large B-cell lymphoma.\n\nJ Clin Exp Hematop . 2016 ; 56 : 79 -88\n.27980306 \n4 Lalami Y Klastersky J \nImpact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: an overview about well-established and recently emerging clinical data.\n\nCrit Rev Oncol Hematol . 2017 ; 120 : 163 -179\n.29198330 \n5 Pettengell R Schwenkglenks M Bosly A \nAssociation of reduced relative dose intensity and survival in lymphoma patients receiving CHOP-21 chemotherapy.\n\nAnn Hematol . 2008 ; 87 : 429 -430\n.18299833 \n6 Yamaguchi H Hirakawa T Inokuchi K \nImportance of relative dose intensity in chemotherapy for diffuse large B-cell lymphoma.\n\nJ Clin Exp Hematop . 2011 ; 51 : 1 -5\n.21628854 \n7 Japanese Society of Medical Oncology. Guidelines for the management of febrile neutropenia. 2nd ed, Tokyo, Nanzan-do. 2017; pp. 30-33.\n8 Freifeld A Marchigiani D Walsh T \nA double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy.\n\nN Engl J Med . 1999 ; 341 : 305 -311\n.10423464 \n9 Taplitz RA Kennedy EB Bow EJ \nOutpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update.\n\nJ Clin Oncol . 2018 ; 36 : 1443 -1453\n.29461916 \n10 Kern WV Marchetti O Drgona L \nOral antibiotics for fever in low-risk neutropenic patients with cancer: a double-blind, randomized, multicenter trial comparing single daily moxifloxacin with twice daily ciprofloxacin plus amoxicillin/clavulanic acid combination therapy—EORTC infectious diseases group trial XV.\n\nJ Clin Oncol . 2013 ; 31 : 1149 -1156\n.23358983 \n11 Sebban C Dussart S Fuhrmann C \nOral moxifloxacin or intravenous ceftriaxone for the treatment of low-risk neutropenic fever in cancer patients suitable for early hospital discharge.\n\nSupport Care Cancer . 2008 ; 16 : 1017 -1023\n.18197434 \n12 Freifeld A Sankaranarayanan J Ullrich F Sun J \nClinical practice patterns of managing low-risk adult febrile neutropenia during cancer chemotherapy in the USA.\n\nSupport Care Cancer . 2008 ; 16 : 181 -191\n.17943327 \n13 Klastersky J Paesmans M Rubenstein EB \nThe Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients.\n\nJ Clin Oncol . 2000 ; 18 : 3038 -3051\n.10944139 \n14 Malik IA Abbas Z Karim M Malik IA \nRandomised comparison of oral ofloxacin alone with combination of parenteral antibiotics in neutropenic febrile patients.\n\nLancet . 1992 ; 339 : 1092 -1096\n.1349112 \n15 Rolston KVI Manzullo EF Elting LS \nOnce daily, oral, outpatient quinolone monotherapy for low-risk cancer patients with fever and neutropenia: a pilot study of 40 patients based on validated risk-prediction rules.\n\nCancer . 2006 ; 106 : 2489 -2494\n.16628654 \n16 Petrilli A Carlesse FA Pereira CAP \nOral gatifloxacin in the outpatient treatment of children with cancer fever and neutropenia.\n\nPediatr Blood Cancer . 2007 ; 49 : 682 -686\n.17253640 \n17 Cornely OA Wicke T Seifert H \nOnce-daily oral levofloxacin monotherapy versus piperacillin/tazobactam three times a day: a randomized controlled multicenter trial in patients with febrile neutropenia.\n\nInt J Hematol . 2004 ; 79 : 74 -78\n.14979482 \n18 He L Zhou C Zhao S Weng H Yang G \nOnce-daily, oral levofloxacin monotherapy for low-risk neutropenic fever in cancer patients: a pilot study in China.\n\nAnticancer Drugs . 2015 ; 26 : 359 -362\n.25486597 \n19 Gómez H Hidalgo M Casanova L \nRisk factors for treatment-related death in elderly patients with aggressive non-Hodgkin’s lymphoma: results of a multivariate analysis.\n\nJ Clin Oncol . 1998 ; 16 : 2065 -2069\n.9626205 \n20 Yasuda T Suzuki R Ishikawa Y \nRandomized controlled trial comparing ciprofloxacin and cefepime in febrile neutropenic patients with hematological malignancies.\n\nInt J Infect Dis . 2013 ; 17 : e385 -e390\n.23317527 \n21 Chamilos G Bamias A Efstathiou E \nOutpatient treatment of low-risk neutropenic fever in cancer patients using oral moxifloxacin.\n\nCancer . 2005 ; 103 : 2629 -2635\n.15856427 \n22 Petrilli AS Dantas LS Campos MC \nOral ciprofloxacin vs. intravenous ceftriaxone administered in an outpatient setting for fever and neutropenia in low-risk pediatric oncology patients: randomized prospective trial.\n\nMed Pediatr Oncol . 2000 ; 34 : 87 -91\n.10657866 \n23 Aquino VM Herrera L Sandler ES Buchanan GR \nFeasibility of oral ciprofloxacin for the outpatient management of febrile neutropenia in selected children with cancer.\n\nCancer . 2000 ; 88 : 1710 -1714\n.10738231 \n24 Rolston KVI Frisbee-Hume SE Patel S Manzullo EF Benjamin RS \nOral moxifloxacin for outpatient treatment of low-risk, febrile neutropenic patients.\n\nSupport Care Cancer . 2010 ; 18 : 89 -94\n.19387695 \n25 Wieringa A Boslooper K Hoogendoorn M \nComorbidity is an independent prognostic factor in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP: a population-based cohort study.\n\nBr J Haematol . 2014 ; 165 : 489 -496\n.24754632 \n26 Quan H Li B Couris CM \nUpdating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.\n\nAm J Epidemiol . 2011 ; 173 : 676 -682\n.21330339 \n27 Tanigawara Y Nomura H Kagimoto N Okumura K Hori R \nPremarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases.\n\nBiol Pharm Bull . 1995 ; 18 : 315 -320\n.7742805\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "60(3)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": "CHOP; febrile neutropenia; levofloxacin; malignant lymphoma",
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005334:Fever; D006801:Humans; D064704:Levofloxacin; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011241:Prednisone; D012189:Retrospective Studies; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "73-77",
"pmc": null,
"pmid": "32779614",
"pubdate": "2020-09-25",
"publication_types": "D016428:Journal Article",
"references": "15856427;23317527;14979482;21628854;10944139;16648042;16628654;18197434;9626205;10738231;7742805;1349112;24754632;29198330;10657866;25486597;29461916;15867204;21330339;17253640;10423464;27980306;17943327;18299833;19387695;23358983",
"title": "Efficacy of oral levofloxacin monotherapy against low-risk FN in patients with malignant lymphoma who received chemotherapy using the CHOP regimen.",
"title_normalized": "efficacy of oral levofloxacin monotherapy against low risk fn in patients with malignant lymphoma who received chemotherapy using the chop regimen"
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"abstract": "Candida utilis and Stenotrophomonas maltophilia co-infections connected to meningitis are uncommon. We describe a patient who developed C. utilis and S. maltophilia after undergoing neurosurgery and received effective nosocomial meningitis treatment. Multiple neurosurgeries were required for a 16-year-old girl due to complications. For probable nosocomial meningitis, she was treated with cefepime with vancomycin. Meropenem and liposomal amphotericin B were prescribed after her seizure and positive CSF culture for Candida utilis. Consequently, S. maltophilia was discovered in the CSF, and ceftazidime and trimethoprim-sulfamethoxazole were prescribed. The patient has been hemodynamically stable for the past two months, and consecutive CSF cultures have been negative. To the best of our knowledge, this is the first case of C. utilis and S. maltophilia co-infection that has been successfully handled.",
"affiliations": "Pharmacy Care Division, Clinical Pharmacy Section, King Saud Medical City, Riyadh, Saudi Arabia. Electronic address: yali2016@hotmail.com.;Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.;Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, 13713, Riyadh, Saudi Arabia. Electronic address: sasdag@mcst.edu.sa.;Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.;Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia; Pharmaceutical Care Division, Clinical Pharmacy Section, King Saud Medical City, Riyadh, Saudi Arabia.;Pharmaceutical Care Division, Clinical Pharmacy Section, King Saud Medical City, Riyadh, Saudi Arabia.;Department of Infectious Diseases, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.;Department of Infectious Diseases, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia; Department of Infectious Diseases, Al-Moosa Specialist Hospital, Al-Ahsa, Saudi Arabia.",
"authors": "Mohzari|Yahya|Y|;Al Musawa|Mohammed|M|;Asdaq|Syed Mohammed Basheerin|SMB|;Alattas|Majda|M|;Qutub|Mohammed|M|;Bamogaddam|Reem Faisal|RF|;Yamani|Amani|A|;Aldabbagh|Yasser|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.jiph.2021.10.004",
"fulltext": null,
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"issn_linking": "1876-0341",
"issue": "14(11)",
"journal": "Journal of infection and public health",
"keywords": "Candida utilis; Co-infection; Neurological surgeries; Nosocomial meningitis; Stenotrophomonas maltophilia",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D002175:Candida; D060085:Coinfection; D003428:Cross Infection; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008581:Meningitis; D020615:Stenotrophomonas maltophilia",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "1715-1719",
"pmc": null,
"pmid": "34700290",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Candida utilis and Stenotrophomonas maltophilia causing nosocomial meningitis following a neurosurgical procedure: A rare co-infection.",
"title_normalized": "candida utilis and stenotrophomonas maltophilia causing nosocomial meningitis following a neurosurgical procedure a rare co infection"
} | [
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"companynumb": "SA-LUPIN PHARMACEUTICALS INC.-2022-01304",
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"activesubstancename": "VANCOMYCIN"
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"abstract": "BACKGROUND\nAlthough numerous studies have shown that anticoagulation of nonvalvular atrial fibrillation (AF) significantly decreases the risk of stroke, anticoagulating critically ill patients in the intensive care unit (ICU) poses many challenges and the benefits have not been determined.\n\n\nOBJECTIVE\nTo assess the safety and efficacy of anticoagulation in AF patients with sepsis. Ascertaining the incidence of complications associated with anticoagulation therapy, such as bleeding, can optimize patient care.\n\n\nMETHODS\nThis was a retrospective observational study to assess the incidence of stroke and anticoagulation-related complications (eg, bleeding, heparin-induced thrombocytopenia) in AF patients with severe sepsis. This study was undertaken in a surgical/medical ICU of a teaching, community-based hospital. A total of 115 patients with AF who were admitted with a diagnosis of sepsis were included in the study.\n\n\nRESULTS\nAmong 115 patients (mean age 81 ± 9.5 years and CHADS2 [congestive heart failure, hypertension, age >75 years, diabetes mellitus, stroke] score 3.17 ± 1.20), 80 (69.6%) did not receive anticoagulation treatment during their hospitalization and none of these patients developed a stroke. Anticoagulation-related complications occurred more often in the group who received anticoagulation (8.6% [3/35] vs 0%, P = .008). In the anticoagulated group, a majority of the patients were within therapeutic range less than 50% of the time during their ICU stay. There was no statistically significant difference in survival rates during their hospitalization (66.2% [53/80] for the non-anticoagulated group vs 74.3% [26/35] in the anticoagulated group, P = .392).\n\n\nCONCLUSIONS\nAdministration of anticoagulation for elderly patients with a CHADS2 score at 2 or more in the setting of sepsis can be associated with an increased risk of anticoagulation-related complications (eg, bleeding, heparin-induced thrombocytopenia). Managing and targeting a therapeutic goal with warfarin therapy in critically ill patients with sepsis is challenging. Further studies are necessary to provide appropriate recommendations in this setting.",
"affiliations": "University of California Irvine, Irvine, CA, USA.",
"authors": "Darwish|Omar S|OS|;Strube|Sarah|S|;Nguyen|Huan Mark|HM|;Tanios|Maged A|MA|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D014859:Warfarin; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028013500938",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "47(10)",
"journal": "The Annals of pharmacotherapy",
"keywords": "anticoagulation; atrial fibrillation; sepsis; stroke",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017984:Enoxaparin; D005260:Female; D006493:Heparin; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D018805:Sepsis; D020521:Stroke; D014859:Warfarin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1266-71",
"pmc": null,
"pmid": "24259690",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Challenges of anticoagulation for atrial fibrillation in patients with severe sepsis.",
"title_normalized": "challenges of anticoagulation for atrial fibrillation in patients with severe sepsis"
} | [
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"activesubstancename": "WARFARIN"
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"druga... |
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"abstract": "To investigate the outcome of rifam- picin (RFP) monotherapy for latent tuberculosis infection (LTBI) and the incidence of RFP-induced liver toxicity. [Method] We conducted a retrospective chart review of patients who received RFP monotherapy as LTBI treatment at the Daiichi Dispensary Clinic. [Result] Of 61 patients who received RFP monotherapy, the treatment completion rate was 88.5%, self-termination rate was 3.3%, abandonment rate due to adverse drug effects was 8.2% (5 cases: 3 cases of skin eruption and 2 cases of liver dysfunction). Among the 2 cases of liver dysfunction, I was not associated with abnormal alkaline phosphatase (ALP) or gamma-glutamyl transferase (y GTP) levels. Among patients with liver dysfunction who did not discontinue RFP mono- therapy, no cases-of severely abnormal ALP and/or y GTP levels were reported. [Conclusion] The incidence of liver toxicity due to RFP is lower than that observed with isoniazid, and liver dysfunction due to RFP was not always associated with abnormal of ALP and/or yGTP levels.",
"affiliations": null,
"authors": "Ito|Kunihiko|K|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D012293:Rifampin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9776",
"issue": "91(5)",
"journal": "Kekkaku : [Tuberculosis]",
"keywords": null,
"medline_ta": "Kekkaku",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000904:Antibiotics, Antitubercular; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012293:Rifampin; D055815:Young Adult",
"nlm_unique_id": "0422132",
"other_id": null,
"pages": "509-513",
"pmc": null,
"pmid": "28661592",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "LIVER TOXICITY DUE TO RIFAMPICIN MONOTHERAPY IN LATENT TUBERCULOSIS INFECTION.",
"title_normalized": "liver toxicity due to rifampicin monotherapy in latent tuberculosis infection"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2017-07160",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "RIFAMPIN"
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"abstract": "Pregnancy and membranous nephropathy (MN) can occur concurrently with nephrotic syndrome. However, the pathophysiology of MN associated with pregnancy remains unclear, including the involvement of anti-M-type phospholipase A2 receptor (PLA2R) antibody, the major antigen of idiopathic MN (iMN). A treatment for the condition is also not established. We present the case of a 43-year-old pregnant female with incidental proteinuria and hypoalbuminemia. We made a diagnosis of nephrotic syndrome at 11 week gestation. Renal biopsy revealed iMN using predominant granular staining of IgG4 along the glomerular basement membrane. No secondary cause was identified. Oral glucocorticoid therapy was started from 17 week gestation and induced complete remission at 28 week gestation. A healthy infant was born at 38 week gestation. Glucocorticoid therapy was stopped postpartum without MN relapse. Anti-PLA2R antibody was later found to be positive using serum reserved from before treatment. In conclusion, we presented the case of a pregnant woman with iMN and anti-PLA2R antibodies, whose nephrotic syndrome was successfully controlled with oral glucocorticoids to reach complete remission, even after tapering off the medication. Pregnancy per se might be associated with iMN onset.",
"affiliations": "Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. euchino@kuhp.kyoto-u.ac.jp.;Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.",
"authors": "Uchino|Eiichiro|E|http://orcid.org/0000-0002-3148-0858;Takada|Daisuke|D|;Mogami|Haruta|H|;Matsubara|Takeshi|T|;Tsukamoto|Tatsuo|T|;Yanagita|Motoko|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-018-0304-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "7(1)",
"journal": "CEN case reports",
"keywords": "Anti-phospholipase A2 receptor antibody; Case report; Membranous nephropathy; Pregnancy",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "101-106",
"pmc": null,
"pmid": "29349731",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "3308231;26744127;25613900;20337545;23320849;15086481;26090644;19571279;22882219;22358611;7924014;21474589;23516008;23065496;26793398;24926082;25412738;16963391;25766536;20705965;21940842",
"title": "Membranous nephropathy associated with pregnancy: an anti-phospholipase A2 receptor antibody-positive case report.",
"title_normalized": "membranous nephropathy associated with pregnancy an anti phospholipase a2 receptor antibody positive case report"
} | [
{
"companynumb": "JP-TEVA-2018-JP-891862",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "This study retrospectively evaluated overall survival (OS) by treatment of recurrent or metastatic uterine adenosarcoma including surgery, radiation, chemotherapy, and hormonal therapy and evaluated OS and progression-free survival (PFS) after 1st line systemic chemotherapy.\n78 patients with recurrent or metastatic adenosarcoma comprised the study population. The Kaplan-Meier method was used to estimate OS and PFS. The log-rank test was performed to test the difference in survival between groups.\nMedian OS from diagnosis of recurrent or metastatic disease was 1.8 yrs. OS was influenced by pathology on recurrence, p=0.035. Median OS differed by surgery for 1st recurrence 26.3 months versus 15.1 months. OS was not influenced by chemotherapy, p=0.58, palliative radiation, p=0.58, or hormonal therapy, p=0.15. The response rate (CR + PR) per RECIST 1.1 for chemotherapy was 31.2% for doxorubicin-based regimens and 14.3% for gemcitabine/docetaxel. OS since 1st line chemotherapy was not significantly different among chemotherapy regimens. However, the median PFS was superior for doxorubicin/ifosfamide (15.4 months) compared to gemcitabine/docetaxel (5.0 months), platinum-based regimens (5.7 mo), or other doxorubicin-based regimens (6.5 months).\nThese results suggest that surgery is an important treatment modality for recurrent or metastatic uterine adenosarcoma, and the most effective chemotherapeutics are doxorubicin/ifosfamide and gemcitabine/docetaxel.",
"affiliations": "Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA.;Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 450, Houston, TX 77030, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 450, Houston, TX 77030, USA.;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 450, Houston, TX 77030, USA.;Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 450, Houston, TX 77030, USA.",
"authors": "Nathenson|Michael J|MJ|0000-0002-8888-4482;Conley|Anthony P|AP|;Lin|Heather|H|;Fleming|Nicole|N|;Ravi|Vinod|V|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2017/4680273",
"fulltext": "\n==== Front\nSarcomaSarcomaSARCOMASarcoma1357-714X1369-1643Hindawi 10.1155/2017/4680273Research ArticleTreatment of Recurrent or Metastatic Uterine Adenosarcoma http://orcid.org/0000-0002-8888-4482Nathenson Michael J. michaelj_nathenson@dfci.harvard.edu\n1\nConley Anthony P. \n2\nLin Heather \n3\nFleming Nicole \n4\nRavi Vinod \n2\n\n1Dana–Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA\n2Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 450, Houston, TX 77030, USA\n3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 450, Houston, TX 77030, USA\n4Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 450, Houston, TX 77030, USAAcademic Editor: Quincy Chu\n\n2017 28 12 2017 2017 46802736 9 2017 7 11 2017 Copyright © 2017 Michael J. Nathenson et al.2017This 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.Purpose\n This study retrospectively evaluated overall survival (OS) by treatment of recurrent or metastatic uterine adenosarcoma including surgery, radiation, chemotherapy, and hormonal therapy and evaluated OS and progression-free survival (PFS) after 1st line systemic chemotherapy. \n\nMethods\n 78 patients with recurrent or metastatic adenosarcoma comprised the study population. The Kaplan-Meier method was used to estimate OS and PFS. The log-rank test was performed to test the difference in survival between groups. \n\nResults\n Median OS from diagnosis of recurrent or metastatic disease was 1.8 yrs. OS was influenced by pathology on recurrence, p=0.035. Median OS differed by surgery for 1st recurrence 26.3 months versus 15.1 months. OS was not influenced by chemotherapy, p=0.58, palliative radiation, p=0.58, or hormonal therapy, p=0.15. The response rate (CR + PR) per RECIST 1.1 for chemotherapy was 31.2% for doxorubicin-based regimens and 14.3% for gemcitabine/docetaxel. OS since 1st line chemotherapy was not significantly different among chemotherapy regimens. However, the median PFS was superior for doxorubicin/ifosfamide (15.4 months) compared to gemcitabine/docetaxel (5.0 months), platinum-based regimens (5.7 mo), or other doxorubicin-based regimens (6.5 months). \n\nConclusion\n These results suggest that surgery is an important treatment modality for recurrent or metastatic uterine adenosarcoma, and the most effective chemotherapeutics are doxorubicin/ifosfamide and gemcitabine/docetaxel.\n\nWWWW Foundation, Inc.Amschwand Sarcoma Cancer Foundation\n==== Body\n1. Introduction\nUterine adenosarcoma is an extremely rare subtype of uterine sarcoma, which represents only 5.5 to 9% of all uterine sarcomas [1, 2]. Uterine adenosarcoma was first described by Dr. Phillip B. Clement and Dr. Robert E. Scully in 1974 [3]. This tumor is composed of a malignant mesenchymal component and a benign epithelial component [4, 5]. This biphasic cellular differentiation is characteristic of adenosarcomas and required for the diagnosis of this tumor. Adenosarcomas can arise from the uterus but have also been noted to arise from the ovaries, vagina, cervix, and pelvis usually in the setting of prior endometriosis [6–9].\n\nThere is a specific FIGO uterine adenosarcoma staging system which divides between stage Ia, Ib, and Ic by the presence and extent of myometrial invasion [10]. The majority of adenosarcoma patients (70 to 80%) will present with stage I disease [11–13]. Despite this, many patients, even with stage I disease, will develop recurrent or metastatic disease. Survival varies with the presence and extent of myometrial invasion and sarcomatous overgrowth [12–15].\n\nUnfortunately, given the rarity of adenosarcoma, there are limited data to guide treatment decisions in the recurrent or metastatic setting. There is no standard treatment for recurrent or metastatic disease, though surgery is often preformed [12]. A recent review suggests that uterine adenosarcomas can respond to doxorubicin/ifosfamide and gemcitabine/docetaxel chemotherapy [16]. Furthermore, the role of hormonal therapy in recurrent or metastatic disease is limited to case reports and case series.\n\nThe purpose of this study was to examine the role of surgery, radiation, and hormonal therapy in the recurrent or metastatic setting. Furthermore, this is the first study to report response rates, overall survival, and progression-free survival of adenosarcoma patients treated with chemotherapy for recurrent or metastatic disease.\n\n2. Patients and Methods\nWith approval by the MD Anderson Cancer Center Institutional Review Board, a search was conducted of the Institutional Tumor Registry. Seventy-eight patients treated at the MD Anderson Cancer Center from August 1982 to December 2014 with recurrent or metastatic uterine or extrauterine adenosarcoma were identified. The diagnosis of uterine adenosarcoma was confirmed by MD Anderson sarcoma or gynecologic pathologists. Demographic, clinicopathologic, and treatment characteristics were abstracted from the patients' medical records. Then, a deidentified database was constructed of all adenosarcoma patients. The stage was assigned using the International Federation of Gynecology and Obstetrics 2009 uterine adenosarcoma staging system [10].\n\nPatients' demographic and clinical characteristics were analyzed, with categorical variables summarized in frequency tables while continuous variables summarized using mean (±S.D.) and median (range). The product limit method of Kaplan and Meier was used to estimate overall survival (OS) and progression-free survival (PFS) [17]. OS was determined from the date of first recurrent or metastatic disease diagnosis to the date of death or date of last contact. OS since the start of chemotherapy for recurrent or metastatic disease was determined from the date of initiation of 1st line chemotherapy for recurrent or metastatic disease to the date of death or date of last contact. Progression-free survival was determined from the date of initiation of chemotherapy for recurrent or metastatic disease to the date of progression or death. Complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) were determined by RECIST 1.1 [18]. The log-rank test was performed to test the difference in survival between groups [19]. Regression analyses of survival data utilized the Cox proportional hazards model [20].\n\n3. Results\n3.1. Patient Characteristics\nSeventy-eight patients with recurrent or metastatic uterine or extrauterine adenosarcoma who received treatment at the MD Anderson Cancer Center were identified from a retrospective review of the Institutional Tumor Registry and were included in this study. The median follow-up time since recurrent or metastatic disease was 8.2 years. The demographic and clinical characteristics for all patients included in this study are summarized in Table 1. The median age at diagnosis was 55 years (range 27 to 79 years). The majority of patients were Caucasian (80.8%). The most common presenting symptom was abnormal uterine bleeding (44.9%), and the second most common presenting symptom was pelvic pain (16.7%). Thirty-nine patients had stage I primary tumor (50.1%). Thirty-six patients had stage II–IV primary tumor (46.2%). The primary tumor location was the uterine corpus in the majority of patients (74.4%). At last follow-up, 24 patients were alive, and 54 have died. Local recurrences occurred within the abdomen and pelvis in seventy-two patients, and sixteen patients developed distant metastasis. Patients who had local and distant recurrences commonly developed the local recurrence first. Sites of distant disease included the lung (14 pts), bone (4 pts), liver (3 pts), brain (1 pt), and subcutaneous tissue (4 pts).\n\n3.2. Treatment Characteristics for Recurrent or Metastatic Disease\nTreatment on recurrence varied greatly and was influenced by the location and extent of recurrence. Table 2 describes the treatments that patients received on 1st and 2nd recurrence including surgery, palliative radiation, chemotherapy, and hormonal therapy. First-line chemotherapy for recurrent or metastatic disease was given to 59 patients, at 1st recurrence in 40 pts, at 2nd recurrence in 10 pts, at 3rd recurrence in 2 pts, and at 4th recurrence in 2 pts. Three additional patients had residual disease after primary treatment, and upon progression, they received 1st line chemotherapy (Table 2). One patient had 7 prior surgeries and hormonal therapy prior to receiving chemotherapy, and another patient received chemotherapy for 1st recurrence, though documentation regarding the specific chemotherapy regimen was lacking. The specific chemotherapy regimens utilized greatly differed as well. Table 2 lists the specific chemotherapy regimens that patients received for 1st, 2nd, and 3rd line chemotherapy, as well as the number of patients that received surgery, radiation therapy, or hormonal therapy either before or after their chemotherapy as part of their treatment for recurrent or metastatic disease.\n\n3.3. Pathology on Recurrence\nOn recurrence, 58 patients had a biopsy available for review: high-grade sarcoma in 36 patients and mixed epithelial and mesenchymal components in 22 patients. Median overall survival differed by the pathology of recurrence. Patients with high-grade sarcoma on recurrence had a median overall survival of 17.6 months versus 33.5 months in patients with mixed histology, p=0.035, HR = 0.47 (95% CI 0.23–0.96) (Figure 1(a) and Table 3).\n\n3.4. Surgery for Recurrent or Metastatic Disease\nForty-five patients underwent surgery for recurrence or metastatic disease.\n\nForty-one patients underwent resection of recurrence within the abdomen and pelvis. Twenty-five patients underwent one resection, eight patients had two resections, four patients had three resections, three patients had four resections, and one patient had nine resections. Four patients underwent thoracotomies for resection of metastatic disease to the lung. Median overall survival was improved in those patients who underwent resection for recurrent or metastatic disease, for 1st recurrence 26.3 months versus 15.1 months, p=0.54 (Figure 1(b) and Table 3).\n\n3.5. Chemotherapy for Recurrent or Metastatic Disease\n3.5.1. Response Rates\nOf the fifty-nine patients that received 1st line chemotherapy for recurrent or metastatic disease, 9 received chemotherapy after surgical resection to obtain no evidence of disease, so response rate per RECIST 1.1 could not be calculated. Four patients received only 1 cycle of chemotherapy and were excluded. Imaging was not accessible for review in another twenty-five patients. Twenty-one patients with chemotherapy for 1st line recurrent or metastatic disease were evaluable for response per RECIST 1.1 (Table 4). The complete response (CR) + partial response (PR) rate for doxorubicin-based 1st line chemotherapy was 40% versus 25% for gemcitabine/docetaxel. Another 14 patients received 2nd or 3rd line chemotherapy and were evaluable for response per RECIST 1.1. The CR + PR rate for doxorubicin-based 1st, 2nd, and 3rd line chemotherapy was 31.2% versus 14.3% for gemcitabine/docetaxel (Table 3). The majority of the responses with doxorubicin-based regimens were seen in patients receiving the combination of doxorubicin and ifosfamide (4/5 pts) or doxorubicin and dacarbazine (1/5 pts). The rate of CR + PR + stable disease (SD) was 87.5% for doxorubicin-based regimens and only 42.9% for gemcitabine/docetaxel. Only five patients with a platinum-based regimen were evaluable for RECIST 1.1, 80% had SD, and the one patient with a partial response, also, received ifosfamide.\n\n3.6. Survival Analysis\n3.6.1. Overall Survival and Progression-Free Survival\nThe median overall survival after 1st recurrence was 1.8 yrs. Table 3 shows the median overall survival and progression-free survival from the beginning of 1st line chemotherapy for patients receiving 1st line chemotherapy for recurrent or metastatic disease. Thirty-seven patients were evaluable for time-to-event outcomes. Nine patients received only one cycle of chemotherapy and were excluded from these analyses. The median overall survival from the beginning of 1st line chemotherapy was 16.6 months. Median overall survival differed by the chemotherapy regimen (Figure 2(a)). Median overall survival was worse for all doxorubicin-based regimens, 14.9 months, when compared to gemcitabine/docetaxel, 24.9 months, or platinum-based chemotherapy, 24.3 months. The median overall survival for doxorubicin/ifosfamide (AI) was 22.5 months, not statistically different from gemcitabine/docetaxel (p=0.99) or platinum-based regimens (0.49). The median overall survival for doxorubicin-based regimens, other than AI, was 13.1 months. Additionally, patients who received AI had improved PFS (15.4 months) compared to other doxorubicin-based regimens (6.5 months), gemcitabine/docetaxel (5.0 mo), and platinum-based regimens (5.7 months) (Figure 2(b)). This difference trended toward statistical significance when comparing AI to other doxorubicin-based regimens p=0.083 or to platinum-based regimens p=0.06.\n\nPatients were analyzed for other factors which may have influenced the effectiveness of their chemotherapeutic regimens, such as chemotherapy dosing, # of chemotherapy cycles, presence of sarcomatous overgrowth (SO), point in their disease course when they received chemotherapy, and time to recurrence prior to initiation of chemotherapy, a potential indicator of the aggressiveness of their disease. Patients did not significantly differ in terms of chemotherapy dosing, # of chemotherapy cycles, presence of SO, or point in their disease course when they received chemotherapy. The median time to recurrence prior to initiation of 1st line chemotherapy was 10.1 months for all doxorubicin-based regimens, 12.9 months for AI, 9.6 months for other doxorubicin-based regimens, 8.1 months for platinum-based regimens, and 21.7 months for gemcitabine/docetaxel, indicating a possible physician bias for treating patients with doxorubicin-based regimens in patients with quicker relapses, so more aggressive disease.\n\n3.7. Hormonal Therapy for Recurrent or Metastatic Disease\nTwenty-eight patients received hormonal therapy at some point during their treatment course. Seven patients received more than 1 line of hormonal therapy. Initial hormonal therapies included GnRH agonists (leuprolide, 9 pts), progesterones (megestrol acetate, 7 pts), SERMs (tamoxifen 3 pts and raloxifene 1 pt), and aromatase inhibitors (anastrozole 3 pts and letrozole 1 pt). The medial overall survival for patients with recurrent disease who received hormonal therapy was 34.7 months compared to 17.6 months, a trend toward improved outcomes that was not statistically significant, p=0.15.\n\nOut of these twenty-eight patients, there were four that derived several years of benefit from hormonal therapy. Two patients treated with leuprolide had disease control for >2 years. Their tumors were not stained for the estrogen receptor (ER) or progesterone receptor (PR). A third patient was placed on leuprolide after surgical resection with the development of progression after two years. This patient was then placed on megestrol acetate without response and then on anastrozole with a complete response lasting for eight years. This patient developed a 2nd malignancy. She was taken off anastrozole at the time of surgery for her cholangiocarcinoma. Shortly after completing adjuvant chemotherapy for her cholangiocarcinoma, she developed recurrence of her adenosarcoma, biopsy proven. She was placed back on anastrozole with response lasting for another five years. More recently, she developed progression and is now on systemic chemotherapy with trabectedin. This patient's tumor stained for ER 80% and PR 40%. The mesenchymal portion of her initial tumor was described as endometrial stromal sarcoma, though she did have sarcomatous overgrowth noted as well. A fourth elderly patient with locally advanced unresectable disease was treated with leuprolide and carboplatin for seven cycles leading to a partial response. Her leuprolide was continued after chemotherapy resulting in a complete response after five years with resolution of her pelvic mass and remaining subcentimeter pelvic lymphadenopathy. She continued leuprolide for 14 years, at which point her leuprolide was stopped. She then developed radiographic recurrence within the abdomen and was restarted on leuprolide with stable disease until her death at age 95. The ER/PR status and SO status of her tumor are unknown.\n\n4. Discussion\nIn this study, we report the largest single-institution experience with recurrent or metastatic uterine and extrauterine adenosarcoma. There is no standard treatment for patients with local recurrence or metastatic uterine adenosarcoma. Treatment options include surgery, radiation, chemotherapy, and hormonal therapy. This study is the first to show that the pathology on recurrence influences outcomes. Specifically, those patients that present with a recurrence that is purely high-grade sarcoma have significantly worse outcomes than those patients who present with a recurrent tumor with mixed epithelial and mesenchymal components. This may represent selective clonal evolution of these tumors such that patients with a recurrence of pure high-grade sarcoma have a more clinically aggressive course.\n\nThe majority of uterine adenosarcomas recur locally, suggesting that resection of a local recurrence may improve overall survival and time to next recurrence. Previous reports have indicated a benefit for secondary cytoreduction of recurrent adenosarcoma in terms of overall survival and time to next recurrence [12, 21]. Our study shows an improvement in overall survival for those patients that underwent surgery for 1st recurrence, though this was not statistically significant. There is a selection bias in this result, in that patients able to undergo surgery likely had better functional status at the time of surgery, less medical comorbidities, and recurrence amenable to surgical resection. However, given the improvement in overall survival, it may be worth considering surgical resection of a recurrence, for those patients amenable to surgery.\n\nThis is the first retrospective report to examine the use of systemic chemotherapy in a large population of recurrent uterine adenosarcoma. Case reports and case series have described responses in adenosarcoma with the use of doxorubicin-based regimens [21–26], gemcitabine/docetaxel [21, 27], trabectedin [28], or platinum-based regimens [21]. This report shows that active agents in uterine adenosarcoma are doxorubicin/ifosfamide (AI), doxorubicin/dacarbazine (ADIC), and gemcitabine/docetaxel. The most effective agents for adenosarcoma in terms of response per RECIST 1.1 were the combination of doxorubicin and ifosfamide. All three are reasonable chemotherapeutic choices for recurrent or metastatic uterine adenosarcoma. The dosing of chemotherapy in this retrospective study varied greatly; however, the patients that received gemcitabine/docetaxel received 675 to 900 mg/m2 of gemcitabine and 75 to 100 mg/m2 of docetaxel; the patients that received doxorubicin-based regimens received 60 to 75 mg/m2 of doxorubicin, 7.5 to 10 gm/m2 of ifosfamide, and 750 to 1000 mg/m2 of dacarbazine. This is standard sarcoma chemotherapy dosing.\n\nThe OS after 1st line chemotherapy for recurrent or metastatic disease was not statistically different between AI, gem/doc, or platinum-based regimens. However, OS may be affected by subsequent therapies such as surgery, hormonal therapy, or further chemotherapy. Additionally, there was a trend toward worse survival for patients that received other doxorubicin-based regimens excluding AI, suggesting that ifosfamide is required to obtain the higher response rate and clinical benefit. However, whether this effective is limited to ifosfamide alone or a result of synergy between doxorubicin/ifosfamide, as noted in soft tissue sarcomas, is undetermined [29].\n\nPFS may be a better measure of benefit from systemic chemotherapy. Patients who received AI had the longest PFS (15.4 months), with a trend toward statistical significance when compared to patients who received doxorubicin alone or in combination with a 2nd agent or platinum-based regimens. If the goal of therapy is to produce reduction in tumor size prior to surgical resection of recurrent disease, AI chemotherapy may have advantages over gemcitabine/docetaxel. If patients are older with poor function status and multiple medical comorbidities, they are not a doxorubicin/ifosfamide candidate; then gemcitabine/docetaxel may be the preferred regimen. Cisplatin- and carboplatin-based regimens appear to be the least effective in uterine adenosarcomas and should not be recommended for treatment of recurrent or metastatic disease. Further study is required to evaluate the role of trabectedin in the treatment of uterine adenosarcomas.\n\nIt should be noted that there was likely a physician bias in choosing treatment with doxorubicin-based regimens over gemcitabine/docetaxel. There was a shorter median time to recurrence prior to the start of 1st line chemotherapy with AI (12.9 months) or other doxorubicin-based regimens (9.6 months) compared to gemcitabine/docetaxel (21.7 months), indicating that physicians were more likely to treat with doxorubicin-based regimens than with gemcitabine/docetaxel for patients that had quicker relapses, or more aggressive disease. This suggests a benefit of doxorubicin/ifosfamide over gemcitabine/docetaxel in the treatment of uterine adenosarcomas, despite similar median OS, as patients with more aggressive disease would be expected to have worse survival.\n\nEvidence for the use of hormonal therapy in uterine adenosarcoma is even more limited than evidence for the use of chemotherapy. Case reports or case series have noted responses to hormonal therapy lasting 10 months to 7 years [12, 30–33]. Agents used include GnRH agonists, progesterones, selective estrogen receptor modulators, or aromatase inhibitors. Responses have been occasionally correlated with the presence of estrogen receptor (ER) and progesterone receptor (PR) staining. Loss of ER and PR expressions has been associated with sarcomatous overgrowth [34]. Furthermore, loss of response to hormonal therapy was associated with reduced ER/PR expression in one case report [33]. This suggests ER and PR as possible predictors of response to hormonal therapy in uterine adenosarcomas, though this has not been studied in a systematic manner. In this study, the majority of patients (86%) did not receive benefit from hormonal therapy, though there were 4 patients that derived benefit in terms of stable disease and improved survival from leuprolide or anastrozole for 2 to 15 years, suggesting that select patients may have a benefit from hormonally targeted therapy. Unfortunately, we are currently unable to determine which patients will receive such a large benefit from hormonal therapy.\n\nThis study is limited by its retrospective nature and small sample size, though this is the largest single-institution recurrent or metastatic uterine or extrauterine adenosarcoma series to date. Overall, uterine adenosarcoma is a rare disease with limited evidence-based data to determine treatment recommendations. Treatment of recurrence or metastatic disease can consist of surgery, chemotherapy, preferable with doxorubicin/ifosfamide or gemcitabine/docetaxel, or hormonal therapy in select patients.\n\nAcknowledgments\nThis study was funded by the WWWW Foundation, Inc. (QuadW), and Amschwand Sarcoma Cancer Foundation.\n\nConflicts of Interest\nThere are no conflicts of interest to report.\n\nFigure 1 (a). Overall survival by pathology on recurrence. (b) Overall survival by surgery on recurrence.\n\nFigure 2 (a) and (b) Overall survival and progression-free survival for 1st line chemotherapy for recurrent or metastatic disease.\n\nTable 1 Patient characteristics.\n\nVariable\tPatients with recurrence, no. of patients (%)\t\nAge, median (range)\t55 years (27 to 79 years)\t\nRace\t\n Caucasian\t63 (80.8%)\t\n African American\t10 (12.8%)\t\n Hispanic\t5 (6.4%)\t\nECOG performance status\t\n 0\t17 (21.8%)\t\n 1\t30 (38.5%)\t\n Unknown\t31 (39.7%)\t\nPresenting symptoms\t\n Abnormal uterine bleeding\t35 (44.9%)\t\n Pelvic pain\t13 (16.7%)\t\n Incidental finding\t4 (5.1%)\t\n Other\t6 (7.7%)\t\n Unknown\t20 (25.6%)\t\nSize, median (range)\t7.1 cm (0.4 to 25 cm)\t\n ≤5 cm\t14 (17.9%)\t\n >5 cm\t36 (46.2%)\t\n Unknown\t28 (35.9%)\t\nMyometrial invasion\t\n No myometrial invasion\t12 (15.4%)\t\n ≤½ of myometrium\t26 (33.3%)\t\n >½ of myometrium\t8 (10.3%)\t\n Unknown\t32 (41.0%)\t\nSarcomatous overgrowth\t\n Absent\t15 (19.2%)\t\n Present\t58 (74.4%)\t\n Unknown\t5 (6.4%)\t\nLymph node involvement\t\n None\t34 (43.6%)\t\n Present\t1 (1.3%)\t\n No lymph node sampling\t39 (50.0%)\t\n Unknown\t4 (5.1%)\t\nUterine adenosarcoma FIGO stage at diagnosis\t\n Ia\t7 (9.0%)\t\n Ib\t19 (24.4%)\t\n Ic\t4 (5.1%)\t\n I (nos.)\t9 (11.6%)\t\n IIa\t7 (9.0%)\t\n IIb\t12 (15.4%)\t\n IIIa\t7 (9.0%)\t\n IIIb\t4 (5.1%)\t\n IIIc\t1 (1.3%)\t\n IVa\t4 (5.1%)\t\n IVb\t1 (1.3%)\t\n Unknown\t3 (3.8%)\t\nTumor location\t\n Uterine corpus\t58 (74.4%)\t\n Ovary\t5 (6.4%)\t\n Cervix\t2 (2.6%)\t\n Pelvic primary\t11 (14.1%)\t\n Vagina\t1 (1.3%)\t\n Unknown\t1 (1.3%)\t\nInitial treatment strategy\t\n Surgery alone\t45 (57.7%)\t\n Surgery + radiation (adjuvant or neoadjuvant)\t22 (28.2%)\t\n Surgery + chemotherapy (adjuvant or neoadjuvant)\t6 (7.7%)\t\n Surgery + radiation + chemotherapy\t4 (5.1%)\t\n Surgery + hormonal therapy\t1 (1.3%)\t\nBilateral salpingo-oophorectomy\t\n Yes\t55 (70.5%)\t\n No\t13 (16.7%)\t\n History of prior BSO\t9 (11.5%)\t\n Unknown\t1 (1.3%)\t\nLymphadenectomy\t\n Yes\t31 (39.7%)\t\n No\t43 (55.1%)\t\n Unknown\t4 (5.1%)\t\nVital status\t\n Alive\t24 (30.8%)\t\n Dead\t54 (69.2%)\t\nRecurrence\t\n Any recurrence\t78\t\n Local (abdomen/pelvis)\t61 (78.2%)\t\n Local and distant\t11 (14.1%)\t\n Distant\t5 (6.4%)\t\n Unknown\t1 (1.3%)\t\nMedian follow-up\t8.2 years\t\nThis table described patient demographics (age and race), presenting symptoms, performance status, tumor pathologic characteristics (size, myometrial invasion, sarcomatous overgrowth, and lymph node involvement), tumor stage, tumor location, initial treatments (surgery, radiation, chemotherapy, BSO, and lymphadenectomy), vital status (alive versus dead), and recurrence location for patients with recurrence.\n\nTable 2 Treatment characteristics on recurrence with 1st, 2nd, and 3rd line chemotherapy for recurrent or metastatic disease.\n\nTreatment on 1st recurrence\t\n Surgery alone\t13 (16.7%)\t\n Surgery + radiation\t8 (10.3%)\t\n Radiation alone\t1 (1.3%)\t\n Surgery + chemotherapy\t19 (24.3%)\t\n Chemotherapy alone\t18 (23.1%)\t\n Surgery + chemotherapy + radiation\t5 (6.4%)\t\n Chemotherapy + radiation\t1 (1.3%)\t\n Hormonal therapy alone\t3 (3.8%)\t\n None\t1 (1.3%)\t\n Unknown\t9 (11.6%)\t\nTreatment on 2nd recurrence\t\n Surgery alone\t11 (14.1%)\t\n Surgery + radiation\t2 (2.6%)\t\n Surgery + chemotherapy\t6 (7.7%)\t\n Chemotherapy alone\t11 (14.1%)\t\n Chemotherapy + radiation\t2 (2.6%)\t\n Unknown\t17 (21.8%)\t\n Did not obtain NED after 1st recurrence\t29 (37.2%)\t\n1st line chemotherapy additional treatments\t\n Chemotherapy alone\t30 (50.9%)\t\n Chemotherapy + surgery\t20 (33.9%)\t\n Chemotherapy + radiation\t2 (3.4%)\t\n Chemotherapy + radiation + surgery\t4 (6.8%)\t\n Chemotherapy + hormonal therapy\t1 (1.7%)\t\n Chemotherapy + surgery + hormonal therapy\t2 (3.4%)\t\n Chemotherapy given for residual disease after initial treatment\t3 (5.1%)\t\n Chemotherapy given for 1st recurrence\t40 (67.8%)\t\n Chemotherapy given for 2nd recurrence\t10 (16.9%)\t\n Chemotherapy given for 3rd recurrence\t2 (3.4%)\t\n Chemotherapy given for 4th recurrence\t2 (3.4%)\t\n Chemotherapy given for >4th recurrence\t1 (1.7%)\t\n Recurrence chemotherapy given for unknown\t1 (1.7%)\t\n1st line chemotherapy regimens\t\n Doxorubicin based\t28 (47.5%)\t\n Doxorubicin alone+\t4\t\n AI (doxorubicin/ifosfamide)\t9\t\n VAI (vincristine/doxorubicin/ifosfamide)\t1\t\n ADIC (doxorubicin/dacarbazine)\t3\t\n MAID (doxorubicin/ifosfamide/dacarbazine)\t1\t\n Other doxorubicin based∗\t10\t\n Gemcitabine/docetaxel\t14 (23.7%)\t\n Platinum based∗∗\t12 (20.3%)\t\n Other (ifosfamide/paclitaxel (2), paclitaxel, gemcitabine)\t4 (6.8%)\t\n Unknown\t1 (1.7%)\t\n2nd line chemotherapy regimens\t\n Doxorubicin based\t6 (25.0%)\t\n Doxorubicin alone+\t3\t\n AI (doxorubicin/ifosfamide)\t3\t\n Gemcitabine/docetaxel\t9 (37.5%)\t\n Platinum based (cisplatin/ifosfamide in one patient)∗∗∗\t4 (16.7%)\t\n Other (ifosfamide, paclitaxel, paclitaxel/bevacizumab, irinotecan/dacarbazine, trabectedin)\t5 (20.8%)\t\n3rd line chemotherapy regimens\t\n Doxorubicin based\t4 (36.4%)\t\n Doxorubicin alone\t2\t\n AI (doxorubicin/ifosfamide)\t1\t\n ADIC (doxorubicin/dacarbazine)\t1\t\n Platinum based∗∗∗∗\t2 (18.2%)\t\n Other (ifosfamide (2), paclitaxel, I/E++, TMZ+++)\t5 (45.5%)\t\nChemotherapy dosing: gemcitabine 675 to 900 mg/m2, docetaxel 75 to 100 mg/m2, vincristine 2 mg, doxorubicin 60 to 75 mg/m2, ifosfamide 7.5 to 10 gm/m2, and dacarbazine 750 to 1000 mg/m2; ∗doxorubicin/cyclophosphamide/cisplatin (1), low-dose doxorubicin/ifosfamide (50 mg/m2, 2.4 gm/m2) (1), doxorubicin/cisplatin (1), vincristine/doxorubicin/cyclophosphamide (1), doxorubicin/cisplatin/paclitaxel (1), doxorubicin/dacarbazine/cyclophosphamide (3), doxorubicin/carboplatin (1), and vincristine/doxorubicin/cyclophosphamide/dacarbazine (1); ∗∗carboplatin/docetaxel (2), bleomycin/etoposide/cisplatin (2), carboplatin/paclitaxel (4), cisplatin with weekly radiation (2), carboplatin/paclitaxel/bevacizumab (1), and carboplatin/cyclophosphamide (1); ∗∗∗carboplatin/docetaxel (1), carboplatin/paclitaxel (1), cisplatin/ifosfamide (1), and carboplatin/gemcitabine (1); ∗∗∗∗carboplatin/gemcitabine (1) and cisplatin/gemcitabine (1); +one patient had liposomal doxorubicin; ++ifosfamide/etoposide; +++temozolomide.\n\nTable 3 Treatment outcomes on recurrence with chemotherapy for recurrent or metastatic disease.\n\n \tMedian survival\t\np value\tHR\t95% CI\t\nOS by pathology on recurrence\t\n High-grade sarcomatous component only\t17.6 mo\t \t \t \t\n Similar to initial pathology\t33.5 mo\t0.035\t0.47\t0.23–0.96\t\n1st line chemotherapy\t\n OS\t\n All patients\t16.6 mo\t—\t \t \t\n Doxorubicin-based regimen\t14.9 mo\t—\t \t \t\n Doxorubicin/ifosfamide\t22.5 mo\tref\t \t \t\n Other doxorubicin-based regimens\t13.1 mo\t0.18\t2.18\t0.69–6.88\t\n Gemcitabine/docetaxel\t24.9 mo\t0.99\t0.99\t0.30–3.38\t\n Platinum-based regimen\t24.3 mo\t0.49\t0.60\t0.14–2.53\t\n PFS\t\n All patients\t7.0 mo\t—\t \t \t\n Doxorubicin-based regimen\t8.5 mo\t—\t \t \t\n Doxorubicin/ifosfamide\t15.4 mo\tref\t \t \t\n Other doxorubicin-based regimens\t6.5 mo\t0.083\t2.65\t0.88–7.98\t\n Gemcitabine/docetaxel\t5.0 mo\t0.27\t1.87\t0.62–5.63\t\n Platinum-based regimen\t5.7 mo\t0.06\t3.08\t0.95–9.93\t\n1st line chemotherapy additional treatments\t\n OS\t\n Surgery\t21.6 mo\t \t \t \t\n No surgery\t11.9 mo\t0.12\t1.36\t0.73–2.53\t\n PFS\t\n Surgery\t12.0 mo\t \t \t \t\n No surgery\t3.6 mo\t0.02\t2.04\t1.10–3.77\t\nOS by hormonal therapy for patients with recurrence\t\n Received hormonal therapy\t34.7 mo\t \t \t \t\n No hormonal therapy\t17.6 mo\t0.15\t1.58\t0.85–2.95\t\nOS therapy for 1st recurrence\t21.8 mo\t \t \t \t\nSurgery\t26.3 mo\t \t \t \t\n No surgery\t15.1 mo\t0.54\t1.21\t0.66–2.24\t\n Radiation\t16.5 mo\t \t \t \t\n No radiation\t23.4 mo\t0.58\t0.83\t0.42–1.63\t\n Chemotherapy\t18.6 mo\t \t \t \t\n No chemotherapy\t27.6 mo\t0.58\t0.85\t0.47–1.53\t\n Chemotherapy + surgery\t23.4 mo\t \t \t \t\n No chemotherapy + surgery\t16.5 mo\t0.97\t1.01\t0.55–1.85\t\nOS, overall survival; PFS, progression-free survival; TTP, time to progression.\n\nTable 4 Response rates with chemotherapy for recurrent or metastatic disease.\n\n \t1st line chemotherapy\tAll lines of chemotherapy (1, 2, 3)\t\nDoxorubicin-based regimens\t\n CR\t2 (20%)\t3 (18.7%) (AI (2), ADIC)\t\n PR\t2 (20%)\t2 (12.5%) (AI, VAI)\t\n (CR + PR)\t4 (40%)\t5 (31.2%)\t\n SD\t5 (50%)\t9 (56.3%) (AI (4), ADIC, Dox (3), CyA)\t\n (CR + PR + SD)\t9 (90%)\t14 (87.5%)\t\n PD\t1 (10%)\t2 (12.5%) (AI, Dox)\t\n Total patients\t10\t16\t\nGemcitabine/docetaxel\t\n CR\t1 (12.5%)\t1 (7.1%)\t\n PR\t1 (12.5%)\t1 (7.1%)\t\n (CR + PR)\t2 (25%)\t2 (14.3%)\t\n SD\t3 (37.5%)\t6 (42.9%)\t\n (CR + PR + SD)\t5 (62.5%)\t8 (57.1%)\t\n PD\t3 (37.5%)\t6 (42.9%)\t\n Total patients\t8\t14\t\nPlatinum-based regimens\t\n CR\t0\t0\t\n PR\t0\t1 (20%) (Cis/Ifos)\t\n (CR + PR)\t0\t1 (20%)\t\n SD\t3 (100%)\t4 (80%) (Cis/Gem, Cis + XRT, carbo/taxol (2))\t\n (CR + PR + SD)\t3 (100%)\t5 (100%)\t\n PD\t0\t0\t\n Total patients\t3\t5\t\nCR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; AI, doxorubicin/ifosfamide; ADIC, doxorubicin/dacarbazine; VAI, vincristine/doxorubicin/ifosfamide; Dox, doxorubicin; CyA, doxorubicin/cyclophosphamide; Cis, cisplatin; Ifos, ifosfamide; Gem, gemcitabine; carbo, carboplatin; XRT, radiation; taxol, paclitaxel.\n==== Refs\n1 Abeler V. M. Royne O. Thoresen S. Danielsen H. E. Nesland J. M. Kristensen G. B. Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients Histopathology 2009 54 3 355 364 10.1111/j.1365-2559.2009.03231.x 2-s2.0-60349124586 19236512 \n2 Benito V. Lubrano A. Arencibia O. Clinicopathologic analysis of uterine sarcomas from a single institution in the Canary Islands International Journal of Gynaecology and Obstetrics 2009 107 1 44 49 10.1016/j.ijgo.2009.05.020 2-s2.0-70249119959 19555952 \n3 Clement P. B. Scully R. E. Müllerian adenosarcoma of the uterus. A clinicopathologic analysis of ten cases of a distinctive type of Müllerian mixed tumor Cancer 1974 34 4 1138 1149 10.1002/1097-0142(197410)34:4<1138::aid-cncr2820340425>3.0.co;2-9 4371193 \n4 Clement P. B. Scully R. E. Müllerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature Human Pathology 1990 21 4 363 381 10.1016/0046-8177(90)90198-e 2-s2.0-0025267174 2156771 \n5 Kaku T. Silverberg S. G. Major F. J. Miller A. Fetter B. Blessing J. A. Adenosarcoma of the uterus: a gynecologic oncology group clinicopathologic study of 31 cases International Journal of Gynecological Pathology 1992 11 2 75 88 10.1097/00004347-199204000-00001 1316323 \n6 Eichhorn J. H. Young R. H. Clement P. B. Scully R. E. Mesodermal (müllerian) adenosarcoma of the ovary: a clinicopathologic analysis of 40 cases and a review of the literature American Journal of Surgical Pathology 2002 26 10 1243 1258 10.1097/00000478-200210000-00001 2-s2.0-0036787387 12360039 \n7 Jones M. W. Lefkowitz M. Adenosarcoma of the uterine cervix: a clinicopathological study of 12 cases International Journal of Gynecological Pathology 1995 14 3 223 229 10.1097/00004347-199507000-00005 8600073 \n8 Wang Y. Huang Y. W. Li Y. F. Primary vaginal sarcoma: experience of a regional cancer center in China Journal of Obstetrics and Gynaecology Research 2015 41 9 1463 1468 10.1111/jog.12746 2-s2.0-84941022632 26111799 \n9 Clement P. B. Scully R. E. Extrauterine mesodermal (müllerian) adenosarcoma: a clinicopathologic analysis of five cases American Journal of Clinical Pathology 1978 69 3 276 283 10.1093/ajcp/69.1.276 205129 \n10 Prat J. FIGO staging for uterine sarcomas International Journal of Gynecology and Obstetrics 2009 104 3 177 178 10.1016/j.ijgo.2008.12.008 2-s2.0-66549090700 19135669 \n11 Brooks S. E. Zhan M. Cote T. Baquet C. R. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999 Gynecologic Oncology 2004 93 1 204 208 10.1016/j.ygyno.2003.12.029 2-s2.0-1842425382 15047237 \n12 Carroll A. Ramirez P. T. Westin S. N. Uterine adenosarcoma: an analysis on management, outcomes, and risk factors for recurrence Gynecologic Oncology 2014 135 3 455 461 10.1016/j.ygyno.2014.10.022 2-s2.0-84920719228 25449308 \n13 Bernard B. Clarke B. A. Malowany J. I. Uterine adenosarcomas: a dual-institution update on staging, prognosis and survival Gynecologic Oncology 2013 131 3 634 639 10.1016/j.ygyno.2013.09.011 2-s2.0-84888290418 24135678 \n14 Arend R. Bagaria M. Lewin S. N. Long-term outcome and natural history of uterine adenosarcomas Gynecologic Oncology 2010 119 2 305 308 10.1016/j.ygyno.2010.07.001 2-s2.0-77957755222 20688363 \n15 Blom R. Guerrieri C. Adenosarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53 and mdm-2 analysis of 11 cases International Journal of Gynecological Cancer 1999 9 1 37 43 10.1046/j.1525-1438.1999.09885.x 2-s2.0-0033012128 11240741 \n16 Nathenson M. J. Ravi V. Fleming N. Wang W.-L. Conley A. Uterine adenosarcoma: a review Current Oncology Reports 2016 18 11 p. 68 10.1007/s11912-016-0552-7 2-s2.0-84990932675 \n17 Kaplan E. L. Meier P. Nonparametric estimator from incomplete observations Journal of the American Statistical Association 1958 53 282 457 481 10.1080/01621459.1958.10501452 2-s2.0-33845382806 \n18 Eisenhauer E. A. Therasse P. Bogaerts J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) European Journal of Cancer 2009 45 2 228 247 10.1016/j.ejca.2008.10.026 2-s2.0-57849117384 19097774 \n19 Mantel N. 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Matsumoto Y. Activity of pegylated liposomal doxorubicin for extragenital müllerian adenosarcoma with sarcomatous overgrowth: a case report and a review of the literature European Journal of Gynaecological Oncology 2011 32 5 542 546 22053671 \n25 Huang G. S. Arend R. C. Sakaris A. Hebert T. M. Goldberg G. L. Extragenital adenosarcoma: a case report, review of the literature, and management discussion Gynecologic Oncology 2009 115 3 472 475 10.1016/j.ygyno.2009.07.033 2-s2.0-70350774060 19712965 \n26 Roman L. D. Mitchell M. F. Tornos C. Glover A. Kavanagh J. J. Dedifferentiated extrauterine adenosarcoma responsive to chemotherapy Gynecologic Oncology 1993 49 3 389 394 10.1006/gyno.1993.1146 2-s2.0-0027178049 8390963 \n27 Verschraegen C. F. Arias-Pulido H. Lee S. J. Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen Annals of Oncology 2012 23 3 785 790 10.1093/annonc/mdr299 2-s2.0-84863238741 21746804 \n28 Schroeder B. A. Rodler E. T. Loggers E. T. Pollack S. M. Jones R. L. Clinical benefit of trabectedin in uterine adenosarcoma Medical Oncology 2013 30 2 p. 501 10.1007/s12032-013-0501-3 2-s2.0-84874345950 \n29 Edmonson J. H. Ryan L. M. Blum R. H. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas Journal of Clinical Oncology 1993 11 7 1269 1275 10.1200/jco.1993.11.7.1269 8315424 \n30 Hines B. J. Porges R. F. Mittal K. Use of medroxyprogesterone acetate in the treatment of müllerian adenosarcoma: a case report Gynecologic Oncology 2002 85 1 192 195 10.1006/gyno.2002.6585 2-s2.0-0036229114 11925144 \n31 Lee SJ. Bae JH. Kim DC. Park J. S. Namkoong S. E. Oral progesterone treatment in a young woman with müllerian adenosarcoma whose ovary was preserved: a case report International Journal of Gynecological Cancer 2010 20 7 1222 1224 10.1111/igc.0b013e3181a84062 2-s2.0-79960668268 21495235 \n32 Gruber T. J. Fabiano A. J. Deeb G. Lele S. B. Fenstermaker R. A. Intracranial meningiomas in patients with uterine sarcoma treated with long-term megestrol acetate therapy World Neurosurgery 2011 76 5 477.e16 477.e20 10.1016/j.wneu.2011.03.035 2-s2.0-82955220199 \n33 Tasaka N. Matsumoto K. Satoh T. Therapeutic effect of dienogest on adenosarcoma arising from endometriosis: a case report SpringerPlus 2013 2 1 p. 618 10.1186/2193-1801-2-618 2-s2.0-84891467372 \n34 Soslow R. A. Ali A. Oliva E. Müllerian adenosarcomas: an immunophenotypic analysis of 35 cases American Journal of Surgical Pathology 2008 32 7 1013 1021 10.1097/PAS.0b013e318161d1be 2-s2.0-47249160307 18469708\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1357-714X",
"issue": "2017()",
"journal": "Sarcoma",
"keywords": null,
"medline_ta": "Sarcoma",
"mesh_terms": null,
"nlm_unique_id": "9709257",
"other_id": null,
"pages": "4680273",
"pmc": null,
"pmid": "29445312",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "4371193;27718181;11925144;23283300;1316323;26111799;22053671;205129;19712965;24135678;11240741;2156771;19097774;21495235;8600073;18469708;21746804;5910392;24940501;24324925;12648604;15047237;19555952;12360039;22152580;20688363;19236512;19135669;8390963;23456619;8315424;25449308",
"title": "Treatment of Recurrent or Metastatic Uterine Adenosarcoma.",
"title_normalized": "treatment of recurrent or metastatic uterine adenosarcoma"
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"companynumb": "US-CIPLA LTD.-2018US13327",
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"occurcountry": "US",
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"abstract": "A 29-year old man was admitted to the intensive care unit after losing consciousness. On physical examination, a loud systolic murmur over the heart was found. Echocardiography revealed narrowing of pulmonary artery with high pressure gradient. Computed tomography of the chest revealed the presence of large tumour localised in the upper anterior mediastinum. Due to the risk of total closure of the pulmonary artery, interventional mediastinotomy was performed and diagnosis of carcinoma embryonale was established. Subsequent chemotherapy (BEP regimen) has brought regression of tumour and significant improvement in haemodynamic parameters (relief of pressure gradient in pulmonary artery). During the second surgery, the resection of all accessible tumour mass together with marginal resection of the right upper lobe was performed. No signs of cardiac or great vessels infiltration was found. Histopathologic examination revealed the necrotic masses and neoplastic foci diagnosed as teratoma immaturum. In a four-month follow-up the patient's condition remained good. The patient is still under the care of both oncological and cardiological specialists. Thus far he has not required further chemotherapy. Holter ECG monitoring revealed no arrhythmia, but the patient is still treated with mexiletine. The patient is planning to return to work.",
"affiliations": "Cardiopulmonary Intensive Care Unit, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland. f.grzegorczyk@igichp.edu.pl.",
"authors": "Grzegorczyk|Franciszek|F|;Dybowska|Małgorzata|M|;Kuca|Paweł|P|;Czajka|Cezary|C|;Burakowski|Janusz|J|;Langfort|Renata|R|;Orłowski|Tadeusz|T|;Tomkowski|Witold|W|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D008801:Mexiletine",
"country": "Poland",
"delete": false,
"doi": "10.5603/PiAP.2015.0024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0867-7077",
"issue": "83(2)",
"journal": "Pneumonologia i alergologia polska",
"keywords": null,
"medline_ta": "Pneumonol Alergol Pol",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D018236:Carcinoma, Embryonal; D004452:Echocardiography; D006337:Heart Murmurs; D006801:Humans; D008297:Male; D008479:Mediastinal Neoplasms; D008482:Mediastinum; D008801:Mexiletine; D000071079:Stenosis, Pulmonary Artery; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9302892",
"other_id": null,
"pages": "151-6",
"pmc": null,
"pmid": "25754058",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary artery stenosis due to embryonal carcinoma with primary mediastinal location.",
"title_normalized": "pulmonary artery stenosis due to embryonal carcinoma with primary mediastinal location"
} | [
{
"companynumb": "PL-ACCORD-029779",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Intestinal tuberculosis (TB) was recognized as the most common complication with a high frequency of active pulmonary TB during the TB epidemic period. However, intestinal TB has become a rare disease, and intestinal perforation due to intestinal TB is extremely rare. We herein report two cases of tuberculous intestinal perforation.\n\n\nMETHODS\nA 41-year-old man was admitted to our hospital complaining of persistent cough and anorexia. He was in poor nutritional condition, and his body mass index (BMI) and prognostic nutrition index (PNI) were 13.4 and 36.4, respectively. He was diagnosed with pulmonary TB and received anti-TB therapy. On the 51st day of hospitalization, he developed intestinal perforation. Pathologically caseating epithelioid granulomas were noted at the ulcer lesion.\n\n\nMETHODS\nA 61-year-old man was admitted to our hospital due to miliary TB caused by intestinal TB. He had taken oral immunosuppressive drugs and steroids for dermatomyositis over the previous eight years and had a poor nutritional condition, with a BMI of 13.4 and a PNI of 14.4. While receiving anti-TB therapy, he developed intestinal perforation on the 97th day of hospitalization. The patient's poor nutritional condition and immune reconstitution may have contributed to the intestinal perforation.",
"affiliations": null,
"authors": "Saitou|Miwako|M|;Suzuki|Tomoko|T|;Niitsuma|Katsunao|K|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9776",
"issue": "90(9)",
"journal": "Kekkaku : [Tuberculosis]",
"keywords": null,
"medline_ta": "Kekkaku",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000995:Antitubercular Agents; D006801:Humans; D007416:Intestinal Perforation; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014385:Tuberculosis, Gastrointestinal; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "0422132",
"other_id": null,
"pages": "631-4",
"pmc": null,
"pmid": "26761995",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "PULMONARY AND INTESTINAL TUBERCULOSIS DEVELOPING ACUTE TUBERCULOUS PERFORATION OF THE INTESTINE DURING ANTITUBERCULOSIS THERAPY.",
"title_normalized": "pulmonary and intestinal tuberculosis developing acute tuberculous perforation of the intestine during antituberculosis therapy"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201604286",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN.\n\n\n\nWe collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate.\n\n\n\nThirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m2 3-6 months later (p<0.001). After 3-6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/min/1.73 m2), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80% of patients received corticosteroid therapy. Median eGFR after 3-6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil.\n\n\n\nDespite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3-6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.",
"affiliations": "Department of Pediatric Nephrology, MHH, Hannover, Germany.;Department of Pediatric Nephrology, Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moskva, Russian Federation.;Department of Pediatric Nephrology, Temple Street Children's University Hospital, Dublin, Ireland.;Department of Pediatric Nephrology, Cipto Mangunkusumo Hospital, Faculty of Medicine, University of Indonesia, Central Jakarta, Indonesia.;Department of Pediatric Nephrology, Meyer Children's Hospital, Florence, Italy.;Department of Pediatric Nephrology, Bambino Gesù Children's Hospital, Roma, Italy.;Department of Pediatric Nephrology, Montpellier University, Arnaud de Villeneuve Hospital, Montpellier, France.;Department of Pediatric Nephrology, Dona Estefânia Hospital, Lisboa, Portugal.;Department of Pediatric Nephrology, Faculty of Medicine, Marmara University, Istanbul, Turkey.;Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.;KfH Centre of Pediatric Nephrology, Clementine Kinderhospital, Frankfurt am Main, Germany.;Department of Pediatric Nephrology and Transplantation, New Children's Hospital and Helsinki University Hospital, Helsinki, Finland.;Department of Pediatric Nephrology, Nationwide Children's Hospital, Columbus, Ohio, USA.;Department of Pediatric Nephrology, Aarhus University Hospital, Aarhus, Denmark.;Department of Pediatric Nephrology, Connecticut Children's Medical Center, Hartford, Connecticut, USA.;Department of Pediatric Nephrology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Pediatric Nephrology, Azienda Ospedaliero-Universitaria di Bologna, Ospedale S. Orsola-Malpighi, Bologna, Italy.;Department of Pediatric Nephrology, Karolinska University Hospital, Stockholm, Sweden.;Department of Pediatric Nephrology, Temple Street Children's University Hospital, Dublin, Ireland.;Department of Pediatric Nephrology, University Children's Hospital, Ljubljana, Slovenia.;Department of Pediatric Nephrology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.;Department of Pediatric Nephrology, Dr Behcet Uz Children Hospital, Izmir, Turkey.;Department of Pediatric Nephrology, Faculty of Medicine, Ege University, Izmir, Turkey.;Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.;Department of Pediatric Nephrology, University Hospital of Padova, Padova, Italy.;Department of Pediatric Nephrology, Stony Brook Children's Hospital, Stony Brook, New York, USA.;Department of Pediatric Nephrology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.;Department of Pediatric Nephrology, 2nf Faculty of Medicine, University Hospital Motol, Charles University, Praha, Czech Republic.;Department of Pediatrics II, University Hospital Essen, Essen, Germany lars.pape@uk-essen.de.",
"authors": "Wente-Schulz|Sarah|S|;Aksenova|Marina|M|;Awan|Atif|A|;Ambarsari|Cahyani Gita|CG|;Becherucci|Francesca|F|;Emma|Francesco|F|;Fila|Marc|M|0000-0001-8857-7100;Francisco|Telma|T|;Gokce|Ibrahim|I|;Gülhan|Bora|B|;Hansen|Matthias|M|;Jahnukainen|Timo|T|;Kallash|Mahmoud|M|;Kamperis|Konstantinos|K|;Mason|Sherene|S|;Mastrangelo|Antonio|A|;Mencarelli|Francesca|F|;Niwinska-Faryna|Bogna|B|;Riordan|Michael|M|;Rus|Rina R|RR|;Saygili|Seha|S|;Serdaroglu|Erkin|E|;Taner|Sevgin|S|;Topaloglu|Rezan|R|;Vidal|Enrico|E|;Woroniecki|Robert|R|;Yel|Sibel|S|;Zieg|Jakub|J|;Pape|Lars|L|0000-0002-3635-6418;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bmjopen-2020-047059",
"fulltext": "\n==== Front\nBMJ Open\nBMJ Open\nbmjopen\nbmjopen\nBMJ Open\n2044-6055\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34049919\nbmjopen-2020-047059\n10.1136/bmjopen-2020-047059\nPaediatrics\n1506\n1719\nOriginal researchAetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients: a cross-sectional web-based survey\nWente-Schulz Sarah 1\nAksenova Marina 2\nAwan Atif 3\nAmbarsari Cahyani Gita 4\nBecherucci Francesca 5\nEmma Francesco 6\nhttp://orcid.org/0000-0001-8857-7100\nFila Marc 7\nFrancisco Telma 8\nGokce Ibrahim 9\nGülhan Bora 10\nHansen Matthias 11\nJahnukainen Timo 12\nKallash Mahmoud 13\nKamperis Konstantinos 14\nMason Sherene 15\nMastrangelo Antonio 16\nMencarelli Francesca 17\nNiwinska-Faryna Bogna 18\nRiordan Michael 3\nRus Rina R 19\nSaygili Seha 20\nSerdaroglu Erkin 21\nTaner Sevgin 22\nTopaloglu Rezan 10\nVidal Enrico 23\nWoroniecki Robert 24\nYel Sibel 25\nZieg Jakub 26\nhttp://orcid.org/0000-0002-3635-6418\nPape Lars 27\nThe international TIN study group Boyer Olivia\nBuder Kathrin\nBulut İpek Kaplan\nCornelissen Elisabeth AM\nHernández Maria del Mar Espino\nHooman Nakysa\nKemper Markus\nMaquet Julie\nSantos Fernando\nWalden Ulrike\n\n1 Department of Pediatric Nephrology, MHH, Hannover, Germany\n2 Department of Pediatric Nephrology, Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moskva, Russian Federation\n3 Department of Pediatric Nephrology, Temple Street Children’s University Hospital, Dublin, Ireland\n4 Department of Pediatric Nephrology, Cipto Mangunkusumo Hospital, Faculty of Medicine, University of Indonesia, Central Jakarta, Indonesia\n5 Department of Pediatric Nephrology, Meyer Children's Hospital, Florence, Italy\n6 Department of Pediatric Nephrology, Bambino Gesù Children's Hospital, Roma, Italy\n7 Department of Pediatric Nephrology, Montpellier University, Arnaud de Villeneuve Hospital, Montpellier, France\n8 Department of Pediatric Nephrology, Dona Estefânia Hospital, Lisboa, Portugal\n9 Department of Pediatric Nephrology, Faculty of Medicine, Marmara University, Istanbul, Turkey\n10 Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey\n11 KfH Centre of Pediatric Nephrology, Clementine Kinderhospital, Frankfurt am Main, Germany\n12 Department of Pediatric Nephrology and Transplantation, New Children's Hospital and Helsinki University Hospital, Helsinki, Finland\n13 Department of Pediatric Nephrology, Nationwide Children’s Hospital, Columbus, Ohio, USA\n14 Department of Pediatric Nephrology, Aarhus University Hospital, Aarhus, Denmark\n15 Department of Pediatric Nephrology, Connecticut Children’s Medical Center, Hartford, Connecticut, USA\n16 Department of Pediatric Nephrology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy\n17 Department of Pediatric Nephrology, Azienda Ospedaliero-Universitaria di Bologna, Ospedale S. Orsola-Malpighi, Bologna, Italy\n18 Department of Pediatric Nephrology, Karolinska University Hospital, Stockholm, Sweden\n19 Department of Pediatric Nephrology, University Children's Hospital, Ljubljana, Slovenia\n20 Department of Pediatric Nephrology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey\n21 Department of Pediatric Nephrology, Dr Behcet Uz Children Hospital, Izmir, Turkey\n22 Department of Pediatric Nephrology, Faculty of Medicine, Ege University, Izmir, Turkey\n23 Department of Pediatric Nephrology, University Hospital of Padova, Padova, Italy\n24 Department of Pediatric Nephrology, Stony Brook Children's Hospital, Stony Brook, New York, USA\n25 Department of Pediatric Nephrology, Faculty of Medicine, Erciyes University, Kayseri, Turkey\n26 Department of Pediatric Nephrology, 2nf Faculty of Medicine, University Hospital Motol, Charles University, Praha, Czech Republic\n27 Department of Pediatrics II, University Hospital Essen, Essen, Germany\nCorrespondence to Professor Lars Pape; lars.pape@uk-essen.de\n2021\n28 5 2021\n11 5 e04705919 11 2020\n13 5 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nBackground\n\nAcute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN.\n\nPatients, design and setting\n\nWe collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate.\n\nResults\n\nThirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m2 3–6 months later (p<0.001). After 3–6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/min/1.73 m2), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80% of patients received corticosteroid therapy. Median eGFR after 3–6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil.\n\nConclusions\n\nDespite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3–6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.\n\npaediatrics\npaediatric nephrology\nacute renal failure\nspecial-featureunlocked\n==== Body\nStrengths and limitations of this study\n\nLargest study on children with tubulointerstitial nephritis.\n\nPatients from all parts of the word included as a joint project of the most important societies for paediatric nephrology.\n\nRetrospective data collected in a survey.\n\nShort follow-up period.\n\nDetailed results of renal biopsy were not available.\n\nIntroduction\n\nAcute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. TIN accounts for approximately 2%–3% of native renal biopsies.1–3 In biopsies to evaluate acute renal failure of unknown origin, TIN represents about 13% of cases in adult patients.2 3 Reliable data on the incidence and prevalence of paediatric TIN are lacking.\n\nRenal histopathology in TIN is characterised by interstitial cellular infiltrates and oedema, but vessels and glomeruli are typically spared.4 The inflammatory process may eventually lead to interstitial fibrosis and chronic kidney disease.5\n\nNumerous causes of TIN are known, with drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), being the trigger in 60%–70% of cases6; however, the identity of the causative agent in cases of TIN is usually speculative. Other cases of TIN are related to infections or systemic diseases. In some cases, renal disease can be accompanied by uveal inflammation (tubulointerstitial nephritis with uveitis (TINU)).7 8 Other TIN cases are presumed to be idiopathic.4 Despite the different aetiologies of TIN, a common immune-mediated pathogenic mechanism is assumed. Antigen-mediated cellular immune responses seem to play a key role in the pathogenesis of TIN.3 9 It is also important to note that this is a very heterogeneous group of patients. While histopathology is similar, TIN due to sarcoidosis is probably biologically distinct entity from that due to antibiotics, recreational drugs, NSAIDS and infectious agents. Clinical symptoms of TIN are often non-specific and therefore may lead to delayed diagnosis and treatment.4 10\n\nCorticosteroids are well established in the treatment of severe TIN, although prospective randomised controlled clinical trials assessing the indications and efficacy of corticosteroid treatment are not available. In adult patients, retrospective data indicated beneficial effects of corticosteroids on renal function recovery in drug-induced TIN.11–14 However, results of other retrospective studies did not support the routine administration of corticosteroid therapy.1 15 Results from a small prospective paediatric study showed an accelerated renal recovery with corticosteroid treatment.16 There is very limited experience of the use of other immunosuppressive agents (eg, mycophenolate mofetil (MMF)) in patients with TIN. Moreover, there is no consensus on a standard therapeutic regimen (eg, intravenous vs oral administration, dosage and duration of therapy) in either children or adults.\n\nIn this study, we assessed the aetiology, therapy and clinical course of TIN in a large paediatric cohort with manifestation of acute TIN between 2007 and 2018. Data were collected retrospectively via a survey circulated to members of the German Society of Pediatric Nephrology (GPN), European Society of Pediatric Nephrology (ESPN), European Network of Rare Kidney Diseases (ERKnet) and Pediatric Nephrology Research Consortium (PNRC) based in the USA.\n\nPatients and methods\n\nMembers of GPN, ESPN, ERKNet and PNRC were invited to participate in the online survey. An email invitation with a summary of the project and a link to an online questionnaire service provider (https://www.google.de/intl/de/forms/about/) was sent to all mailing list contacts of GPN, ESPN, ERKNet and PNRC. The survey was launched in April 2018 and was closed in June 2019.\n\nThe data collection was retrospective and fully anonymised. Only patients with biopsy-proven TIN were included in the study. Further inclusion criteria were age between 0 and 18 years, and presentation of disease was between 2007 and 2018.\n\nThe questionnaire comprised 57 items. Answers were given as multiple choice or short free texts assessing the incidence, aetiology and course of acute TIN in children. ‘Yes’, ‘no’ and ‘not assessed’ were given as answer options for disease symptoms, urinary findings and biopsy results. Free-text answers were required for precise causative factors for TIN (eg, drug name, pathogen, underlying systemic disease). The questionnaire is provided in the online supplemental material.\n\n10.1136/bmjopen-2020-047059.supp1 Supplementary data\n\nCreatinine-based ‘Bedside Schwartz’ formula (estimated glomerular filtration rate (eGFR)=0.413 × (height/Scr)) was used for eGFR.17\n\nThe responses were automatically collected in a database provided by the survey administration app. All statistical data analyses were performed in GraphPad Prism V.8 (https://www.graphpad.com). Continuous variables were expressed as median, and range as no normal distribution was assumed. Three different non-parametric tests were used for analysis of non-normally distributed variables: Mann-Whitney U test and Kruskal-Wallis test were used, respectively, to compare medians of two groups and three or more groups of variables not normally distributed; one sample Wilcoxon test was conducted for comparison of paired data. Statistical significance of dichotomous variables was measured by using the χ2 test. P<0.05 was considered statistically significant.\n\nEthics approval\n\nThe study was approved by the council of the ESPN, GPN, ERKNet and PNRC. Requests for authorisation by the ethics committees of the other centres were not considered necessary because this was a survey that simply collected the experience and practices of the physicians, and it did not involve approaching patients directly or seeking any patient-specific data.\n\nPatient and public involvement\n\nPatients and public were not involved in the design and conduct of this study.\n\nResults\n\nThirty-nine clinicians from 18 countries participated in the survey. One hundred and seventy-one patient cases were included in the final analysis. Patients originated from Northern Europe (n=41), Southern Europe (n=38), Western Europe (n=25), Eastern Europe (n=8), Western Asia (n=31), Southern Asia (n=1), Southeastern Asia (n=5) and Northern America (n=22).\n\nGender distribution was equal with 93 (54%) females and 78 males (46%). The median age (range) was 13 (1–17) years at diagnosis with the following age distribution: 1–5 years: 9% (16/171); 6–12 years: 38% (64/171); 13–18 years: 53% (91/171) (see figure 1).\n\nFigure 1 Age distribution of 171 patients with acute tubulointerstitial nephritis. TINU, tubulointerstitial nephritis with uveitis.\n\nAtiology\n\nAbout one-third of TIN cases was drug related or induced by a toxic agent (30%, 52/171). TINU syndrome accounts for another third of included cases (31%, 53/171). Twenty-eight per cent (48/171) of cases were presumed to be idiopathic. Systemic diseases (7%, 11/171) and infections (4%, 7/171) were rare causes of acute interstitial nephritis (see figure 2). Infectious causes were most prevalent in patients aged 6–12 years. TIN from other causes was predominant in teenage patients (13–18 years) (see figure 1).\n\nFigure 2 Aetiology of acute tubulointerstitial nephritis in 171 paediatric patients. TINU, tubulointerstitial nephritis with uveitis.\n\nDrug-induced TIN\n\nNSAIDs and antimicrobials were identified as the most common causative drugs and represented 79% (41/52) of drug-induced TIN cases. NSAIDs alone accounted for 48% (25/52) of drug-induced cases, while 10% (5/52) of patients received a combination of NSAIDs and antibiotics. Twenty-one per cent (11/52) of drug-induced cases were based on the administration of antimicrobial therapy (antiviral or antibacterial) without comedication. Other less frequent substances were identified in 21% (11/52) (see table 1).\n\nTable 1 Drugs and toxic agents as causes of tubulointerstitial nephritis (TIN) in 52 patients with acute TIN\n\nNSAIDs (without comedication)\t25\t48%\t\nIbuprofen\t6\t\t\nFlurbiprofen\t3\t\t\nMorniflumate\t3\t\t\nKetoprofen\t1\t\t\nUnspecified\t12\t\t\nAntimicrobials\t11\t21%\t\nAcyclovir\t1\t\t\nAmoxicillin±clavulanic acid\t3\t\t\nTrimethoprim/sulfamethoxazole\t1\t\t\nMidecamycin\t1\t\t\nPenicillin\t2\t\t\nUnspecified\t1\t\t\nCombination of antibiotics\t2\t\t\nNSAIDs+antimicrobials\t5\t10%\t\nOthers\t11\t21%\t\nBee venom\t2\t\t\nHerbal medicines\t3\t\t\nMesalazine\t2\t\t\nLevetiracetam+oxcarbazepine\t1\t\t\nParacetamol+chlorphenamine maleate\t1\t\t\nHydrochlorothiazide\t1\t\t\nSmoking\t1\t\t\nNSAIDs, non-steroidal anti-inflammatory drugs.\n\nMedian age (13 years, range 1–17) and gender distribution (24/52=46% male, 28/52=54% female) did not differ from the total group.\n\nTINU syndrome\n\nTINU syndrome showed a slight predominance in females (58%=31/53 female, 42%=22/53 male) without statistical significance. Median age of onset was equal to the total group (13 years) with an age range between 5 and 17 years.\n\nIdiopathic TIN\n\nIn 28% (48/171) of cases no acute TIN trigger could be identified. Median age (range) was 13 years (3–16) with a balanced gender distribution of 50% (24/48) males and 50% (24/48) females.\n\nTIN associated with systemic diseases\n\nMedian age (range) of onset was 14 years (1–17). Sixty-four per cent (7/11) were female and 36% (4/11) male patients. For a complete list of diagnoses see box 1.\n\nBox 1 List of diagnoses in patients with systemic diseases as causes of acute tubulointerstitial nephritis (TIN). Two patients were diagnosed with Sjögren’s syndrome, all other diagnoses were made in one patient each\n\nSarcoidosis.\n\nSjögren’s syndrome.\n\nAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy type 1.\n\nAtypic haemolytic syndrome.\n\nMicroscopic polyangiitis.\n\nFamilial Mediterranean fever.\n\nMetabolic disease (undefined).\n\nChronic osteomyelitis.\n\nJuvenile rheumatoid arthritis.\n\nB cell lymphoma.\n\nTIN associated with infections\n\nMedian age (range) was 11 years (1–15), and included four male (57%, 4/7) and three female patients (43%, 3/7). Adenovirus, BK polyoma virus, hepatitis C virus and rhinovirus were reported in one patient each. Three patients showed symptoms of upper respiratory tract infection without pathogen identification.\n\nClinical and urinary features\n\nClinical and urinary features in the patient cohort are summarised in table 2. The most frequent clinical symptom at presentation of disease was fatigue in 70% (119/171) of patients, followed by vomiting or nausea in 49% (83/169; no data=2) and fever in 43% (73/171) of patients. Fourteen per cent (24/169; no data=2) of patients showed ocular symptoms at manifestation of disease, consistent with the diagnosis of TINU syndrome. In 22 of 24 patients with ocular symptoms TINU was diagnosed, and vice versa, 58% (31/53) of TINU patients had no ocular symptoms at onset of renal disease.\n\nTable 2 Clinical and urinary features at presentation in patients with acute tubulointerstitial nephritis (TIN)\n\nFeatures\t\tNumber of patients\tNo data\t\nClinical features\t\t\t\t\nFatigue\t70%\t119/171\t0\t\nVomiting/nausea\t49%\t83/169\t2\t\nFever\t43%\t73/171\t0\t\nFlank pain\t33%\t56/168\t3\t\nArterial hypertension\t22%\t38/171\t0\t\nOliguria/anuria\t20%\t35/171\t0\t\nOcular symptoms\t14%\t24/169\t2\t\nJoint pain\t14%\t24/169\t2\t\nExanthema\t6%\t11/171\t0\t\nUrinary features\t\t\t\t\nTubular proteinuria\t72%\t79/109\t62\t\nGlucosuria\t56%\t80/143\t28\t\nGlomerular proteinuria, non-nephrotic range (<1000 mg/m2 BSA/day in 24 hours urine collection or <2 g/g creatinine in spot urine sample)\t53%\t90/171\t0\t\nMicroscopic haematuria\t39%\t66/170\t1\t\nLeukocyturia\t29%\t49/170\t1\t\nGlomerular proteinuria, nephrotic-range (>1000 mg/m2 BSA/day in 24 hours urine collection or >2 g/g creatinine in spot urine sample)\t11%\t19/171\t0\t\nUrinary eosinophilia\t9%\t7/78\t93\t\nMacroscopic haematuria\t8%\t14/169\t2\t\n\nPolyuria, nocturia or enuresis (12 patients), weight loss (10 patients) and headache (seven patients) were the most frequent additional symptoms given in free-text answers.\n\nHistological findings\n\nThe most frequent histological findings were interstitial infiltration in 95% (162/170; no data=1) and interstitial oedema in 63% (106/167; no data=4) of patients. Interstitial granulomas were reported in 6% (11/171) of patients, among them drug-induced (four patients), idiopathic (four patients) and TINU cases (two patients) and one patient with sarcoidosis.\n\nInterstitial fibrosis and tubular atrophy as markers of chronic renal damage were seen in 38% (64/170; no data=1) and 38% (65/171), respectively, whereas glomerulosclerosis was present in only 7% (12/171) of patients. Anonymised copies of original biopsy results were available in seven cases.\n\nTreatment\n\nCorticosteroids\n\nEighty per cent of patients (137/171) were treated with corticosteroids (intravenous and/or oral); 20% (34/171) did not receive any corticosteroids. Forty per cent of patients received a combination of intravenous steroids followed by oral steroids. Details of corticosteroid treatment in the patient group are summarised in table 3.\n\nTable 3 Details of corticosteroid treatment in 137 patients\n\nCorticosteroid-treated patients\tn=137 (≙ 100%)\tMedian dosage and range (in mg/kg/day)\t\nRoute of administration\t\t\t\n Oral CS, no intravenous CS\t56%\t\t\n Intravenous CS, no oral CS\t4%\t\t\n Oral+intravenous CS\t40%\t\t\nSubstance\t\t\t\n Oral prednisone\t31%\t1.03 (0.40–2.33)\t\n Oral prednisolone\t56%\t1.00 (0.35–2.00)\t\n Oral methlyprednisolone\t7%\t0.97 (0.67–4.00)\t\n Intravenous prednisolone\t7%\t6.94 (0.66–22.73)\t\n Intravenous methylprednisolone\t37%\t10.81 (1.63–30.00)\t\n Unknown oral CS\t1%\t–\t\nCS, corticosteroids; IV, intravenous.\n\nNinety-six per cent (131/137) of steroid-treated patients received oral corticosteroids. Median duration of oral corticosteroid treatment was 90 days (4–1365). Forty-four per cent (60/137) of steroid-treated patients were treated with intravenous corticosteroids with a median treatment duration (range) of 3 days (1–6).\n\nEighteen per cent (31/171) of all patients included in the study were treated with non-corticosteroid immunosuppressive drugs. Of these, all but one patient (patient with TIN as a complication of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) type 1) were additionally treated with corticosteroids (oral and/or intravenous). MMF was the most frequently used non-corticosteroid immunosuppressant in 12% (21/171) of all cases. Details of immunosuppressive treatment are given in table 4.\n\nTable 4 Immunosuppressants in 31 patients with acute tubulointerstitial nephritis (TIN)\n\nImmunosuppressant\tIndication (number of treated patients)\tTotal number of treated patients\t\nMycophenolate mofetil\tDrug-induced TIN (3), TINU (11), idiopathic TIN (5), systemic disease (2)\t21\t\nAzathioprine\tDrug-induced TIN (1), TINU (1), idiopathic TIN (3)\t5\t\nCyclosporine\tTINU (1), idiopathic TIN (2)\t3\t\nMethotrexate\tTINU (2), systemic disease (1)\t3\t\nCyclophosphamide\tIdiopathic TIN (1), systemic disease (1)\t2\t\nRituximab\tSystemic disesase\t1\t\nEculizumab\tSystemic disesase\t1\t\nHydroxychloroquine\tSystemic disesase\t1\t\nMore than one medication was administered in several cases.\n\nTINU, tubulointerstitial nephritis with uveitis.\n\nRenal function and residual damage\n\nSerum creatinine levels were collected at time of renal biopsy, 2 weeks and 3–6 months later. Renal function parameters at biopsy were available for all 171 patients, serum creatinine levels 2 weeks and 3–6 months after renal biopsy were given for 168 and 164 patients, respectively.\n\nFor all patients, median eGFR rose significantly from 31 (3–182) mL/min/1.73 m2 at renal biopsy to 86 (7–169) mL/min/1.73 m2 3–6 months after renal biopsy (p<0.001). After 2 weeks, renal function had already significantly improved with a median eGFR of 67 mL/min/1.73 m2 (5–167) (p<0.001) (see figure 3A). Significant improvement in renal function was detectable in every aetiological subgroup 2 weeks and 3–6 months after renal biopsy (see figure 3B and C). The median rise in eGFR was 22–96 mL/min/1.73 m2 in drug-induced TIN, 36–85 mL/min/1.73 m2 in TINU syndrome, 36–81 mL/min/1.73 m2 in idiopathic TIN, 35–72 mL/min/1.73 m2 in TIN associated with systemic diseases and 28–98 mL/min/1.73 m2 in TIN associated with infections.\n\nFigure 3 (A) Significant improvement of estimated glomerular filtration rate (eGFR) 2 weeks and 3–6 months after renal biopsy in patients with acute tubulointerstitial nephritis (TIN). (B and C) Significant improvement of GFR in all etiological subgroups with acute TIN. TINU, tubulointerstitial nephritis with uveitis.\n\neGFR was normalised (>90 mL/min/1.73 m2) in 41% (67/164; no data=7) after 3–6 months, 59% (97/164) had an impaired eGFR (<90 mL/min/1.73 m2). Most patients (47%=77/164) showed a mild reduction in glomerular filtration rate (60–89 mL/min/1.73 m2), while a mild to moderate impairment (30–59 mL/min/1.73 m2) was present in 9% (14/164). Only 3% (6/164) had eGFR <30 mL/min/1.73 m2 (see table 5).\n\nTable 5 Development of estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2)] 2 weeks and 3–6 months after diagnosis of acute tubulointerstitial nephritis (TIN)\n\n\tNumber of patients\teGFR (mL/min/1.73 m2)\t\n≥90\t60–89\t30–59\t15–29\t<15\t\nBiopsy\t171\t3%\t11%\t40%\t27%\t19%\t\n2 weeks\t168\t20%\t42%\t34%\t2%\t2%\t\n3–6 months\t164\t41%\t47%\t9%\t1%\t2%\t\n\nMedian eGFR after 3–6 months was 85 (8–168) mL/min/1.73 m2 in the steroid group and 91 (7–135) mL/min/1.73 m2 in the non-steroid group (p=0.10). Before initiation of treatment, steroid-treated patients had a significantly lower eGFR than patients who were not treated with steroids (30 mL/min/1.73 m2 compared with 38 mL/min/1.73 m2) (p=0.03) (see table 6).\n\nTable 6 Development of estimated glomerular filtration rate (eGFR) in patients without corticosteroid treatment versus patients with corticosteroid treatment\n\n\tCorticosteroid treatment (n=137)\tNo corticosteroid treatment (n=34)\tP value\t\nBiopsy\t30 (3–182)\t38 (9–112)\t0.03\t\n2 weeks\t67 (5–167)\t67 (25–132)\t0.86\t\n3–6 months\t85 (8–169)\t91 (7–135)\t0.10\t\nValues for eGFR (mL/min/1.73 m2) are given as median with range.\n\nSeven per cent (12/171) needed renal replacement therapy either as haemodialysis (7/171) or peritoneal dialysis (5/171). Median duration (range) of renal replacement therapy was 6.5 (2–180) days. Seven (12/164; no data=7) of patients had glomerular proteinuria 3–6 months after renal biopsy and in 19% (32/164) urinalysis showed persistent tubular proteinuria. Mixed proteinuria (glomerular and tubular) was detected in 9% (14/164). The majority of patients (65%=106/164) had no residual proteinuria. The prevalence of proteinuria (glomerular and/or tubular) did not differ between steroid-treated and untreated patients (p=0.50).\n\nArterial hypertension treated with medication was present in 19% (32/171), 17% (28/171) needed one or two antihypertensive drugs, 2% (4/171) were treated with three or more antihypertensives. Most patients (81%=139/171) did not need antihypertensive treatment. Significantly more steroid-treated patients than patients without steroid treatment needed antihypertensive treatment 3–6 months later (22% vs 6%, p=0.03).\n\nDiscussion\n\nThe results of this survey shed some light on cause, clinical management and outcome of TIN in paediatric patients. To the best of our knowledge, our findings are from the largest paediatric TIN cohort to date.\n\nThe clinical presentation of TIN was unspecific with fatigue, vomiting or nausea and fever being the most frequent features. Only one patient of 171 (0.6%) showed the ‘classic’ triad of fever, arthralgia and skin rash or exanthema that dominated the clinical picture in early reports of mainly drug-induced cases. Actually, this symptom triad occurred in 5%–10% of patients in earlier reports.9 18\n\nDrug-induced TIN is the underlying cause in 60%–70% of cases in adults.6 18 In our cohort, drugs were responsible for only 30% of TIN cases. The fact that only biopsy-proven cases were included in our analysis might be responsible for a lower percentage of drug-induced cases since in clinical practice patients with typical clinical hallmarks of drug-induced TIN and mild to moderate renal failure do not always undergo renal biopsy. NSAIDs and antimicrobials are the most common culprits in drug-induced TIN.6 19 Whether NSAIDs or antimicrobials are the leading class of drugs in the aetiology of TIN, however, is a matter of debate.1 11 20 21 In our paediatric cohort, NSAIDs were identified as the leading cause in 48% of patients with drug-induced TIN, and another 10% had a history of NSAIDs plus antimicrobial intake. Coadministration of two or more drugs can make it difficult to identify the culpable agent, but NSAIDs clearly represent the main cause for drug-induced TIN in our study, followed by antibiotics (21% of drug-induced cases). Although proton-pump inhibitors (PPIs) are a widely prescribed class of drugs and have been considered a relevant cause of acute TIN since the first published report of PPI-induced TIN in 1992,22–25 no case of PPI-induced TIN was found in our cohort.\n\nRemarkably, three patients had a history of herbal medicine intake. Aristolochic acid and other plant alkaloids have been identified as nephrotoxic ingredients in Chinese herbal medicine, and interstitial nephritis is one possible manifestation of its nephrotoxic capacity.26 27 Furthermore, interstitial nephritis was triggered by bee stings in two patients. Acute kidney injury due to immune-mediated acute interstitial nephritis has been reported as a rare complication of Hymenoptera stings (bees and wasps) in a number of case reports or case series.28–30 Another patient developed acute TIN after smoking a potentially nephrotoxic substance. A number of legal and illegal drugs should be taken into consideration as possible triggers of TIN, particularly in adolescents. For example, synthetic cannabinoids have become popular recreational drugs with Δ9-tetrahydrocannabinol-like effects that are solubilised, sprayed onto herbal mixtures and usually smoked. Renal manifestations of synthetic cannabinoid use are acute tubular necrosis and acute interstitial nephritis.31 Our results show that a variety of drugs, medications and toxic agents are involved in the pathogenesis of acute interstitial nephritis and should be considered as a potential aspect of the patient’s medical history.\n\nTIN was associated with systemic diseases in 7% of patients. In adults, systemic diseases underlie 10%–15% of cases.19 Sjögren’s syndrome and sarcoidosis are well described autoimmune disorders with TIN as typical renal manifestation. Interstitial nephritis is the prevalent renal finding in Sjögren’s syndrome; 98% of patients with renal involvement show TIN in renal biopsy.32 TIN associated with APECED type 1,33 34 microscopic polyangiitis,35 familial Mediterranean fever,36 37 rheumatoid arthritis38 and malignant infiltration39 has been described in the literature. The case of a 17-year-old girl with atypical haemolytic uraemic syndrome and acute TIN included in our analysis has also been described by Basak et al.40\n\nInfectious causes were found in 4% (in adults 5%–10%19). Only viral and no bacterial, fungal or parasitic pathogens were identified. Adenovirus, BK polyoma virus (both predominantly in renal transplant patients) and hepatitis C have been described as infectious causes of TIN.41–43 Three patients had symptoms of upper respiratory tract infection without pathogen identification, and rhinovirus was identified in another patient. It remains unclear if a bacterial or viral pathogen was the unequivocal cause of TIN in these cases or if other underlying factors played a role in the pathogenesis (eg, intake of NSAIDs or antibiotics to treat respiratory symptoms). It has to be noted that all diagnoses were established by the participating physicians based on biopsy results and clinical findings.\n\nTINU is thought to be a rare condition with an incidence of uveitis among TIN patients of less than 10%.18 Jahnukainen et al 44 reported that uveitis was diagnosed in 46% in a case series of 26 children with ‘idiopathic TIN’, supporting the assumption that the prevalence of uveitis among TIN patients is higher than previously assumed. In our study, 58% of TINU patients had no ocular symptoms at onset of renal disease. This is in line with previous reports that uveitis may evolve up to 14 months after the onset of TIN45 46 and that a high percentage of TINU patients are ophthalmologically asymptomatic at the onset of renal symptoms.44 Thorough ophthalmological examinations over months after the onset of TIN are necessary even in patients without ocular symptoms.44 46 Our results support the rationale for this recommendation.\n\nIn our study, the overall renal outcome 3–6 months after diagnosis of TIN was favourable with a rise in median eGFR from 31 to 86 mL/min/1.73 m2. Only 2% (two patients with idiopathic TIN, one patient with drug-induced TIN and another patient with systemic disease) had eGFR <15 mL/min/1.73 m2 (CKD 5).\n\nThe role of corticosteroids in the treatment of TIN has remained controversial. Available studies in adults are retrospective and not controlled and deliver partially contradictory results.1 11–15 A prospective paediatric study with 17 patients showed that prednisone speeds up renal recovery, but there was no significant difference in renal function between prednisone and control patients after 6 months’ follow-up.16\n\nIn our study, renal function improved significantly after 2 weeks and showed further significant improvement 3–6 months after kidney biopsy. This development of eGFR was found in all aetiological subgroups. Corticosteroid treatment of TIN seems well established among paediatric nephrologists, since 80% of included patients received steroids. Whereas patients who were not treated with steroids had a significantly better median eGFR than patients who underwent steroid therapy at time of renal biopsy, there was no significant difference in eGFR 2 weeks and 3–6 months later and the rate of glomerular and/or tubular proteinuria 3–6 months later. However, we were not able to evaluate the efficacy of corticosteroid treatment of acute TIN since the number of patients was not equally distributed between the steroid-treated and untreated group (80% receiving steroid treatment) and long-term effects of corticosteroid treatment were not monitored. MMF is an additional treatment option in paediatric TIN patients with different etiological backgrounds but was exclusively used in combination with corticosteroids (the exception being one patient with APECED type 1 syndrome, treated with MMF and rituximab). MMF has been described as a successful therapeutic option for steroid-resistant or intolerant patients.47\n\nStrengths and limitations of our study\n\nOur results are based on retrospective data collected in an online survey. This method of data collection requires concise and comprehensive questions but at the same time needs to be feasible and low threshold. We were not able to check the data for correctness but relied on the clinical data given by the participants.\n\nOur follow-up period of 3–6 months is relatively short. In a larger and, at best, prospective study on paediatric TIN, we propose a follow-up period of at least 1 year. Biopsy results were not available as original copies apart from a few cases. Thus, we were not able to grade the degree of histological changes (eg, interstitial fibrosis). Ideally, all original biopsy samples should be re-evaluated by one pathologist. As many TIN patients with mild or moderate renal failure do not undergo kidney biopsy in all centres, severe cases were presumably over-represented in our study population.\n\nThe main strength of our study is the high number of patients and participating centres. It is the largest collection of children with TIN until now.\n\nConclusion\n\nData from this large cohort suggest an overall positive outcome of biopsy-proven acute TIN in paediatric patients. Eighty-eight per cent of patients showed no or mild impairment of renal function 3–6 months after TIN was diagnosed. Prospective randomised controlled trials are required to determine the efficacy of corticosteroids in the management of acute TIN in paediatric patients.\n\nSupplementary Material\n\nReviewer comments\n\nAuthor's manuscript\n\nWe would like to thank the German Society of Pediatric Nephrology (GPN), the European Society of Pediatric Nephrology (ESPN), the European Network of Rare Kidney Diseases (ERKnet) and the Pediatric Nephrology Research Consortium (PNRC) for the support of this project.\n\nData availability statement\n\nData are available on reasonable request. The data underlying this article will be shared on reasonable request to the corresponding author.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nThe study received approval from the ethics committee of Hannover Medical School Nr. 3210–2016.\n\nTwitter: @FrancescaBeche2, @sehasaygili\n\nCollaborators: The international TIN study group consists of the authors listed, as well as of: Olivia Boyer (Hôpital Necker-Enfants malades, MARHEA, Institut Imagine, Université de Paris, Paris, France); Kathrin Buder (Pediatric Department, University Hospital Carl Gustav Carus, Technical University Dresden, Germany); İpek Kaplan Bulut (Ege University Faculty of Medicine, Izmir, Turkey); Elisabeth AM Cornelissen (Radboud University Medical Center, Nijmegen, Netherlands); Maria del Mar Espino Hernández (Hospital Universitario 12 de Octubre, Madrid, Spain); Nakysa Hooman (Ali-Asghar Clinical Research Development Center, Iran University of Medical Sciences, Tehran, Iran); Markus Kemper (Asklepios Medical School, Hamburg, Germany); Julie Maquet (CHC Liège, Belgium); Fernando Santos (Pediatric Nephrology, Hospital Universitario Central de Asturias & University of Oviedo, Spain); Ulrike Walden (Universitätsklinikum Kinderklinik Augsburg, Germany).\n\nContributors: SW-S collected data, did the statistical analyses and wrote the first draft of the manuscript. SW-S, LP, MA, AA, FB, CGA, FE, MF, TF, IG, BG, MH, TJ, MK, KK, SM, AM, FM, BN-F, MR, RR, SS, ES, ST, RT, EV, RW, SY and JZ provided patient data. LP designed the project and revised the manuscript. All authors accepted the final version of the manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 Clarkson MR , Giblin L , O’Connell FP , et al . Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dial Transplant 2004;19 :2778–83. 10.1093/ndt/gfh485 15340098\n2 Goicoechea M , Rivera F , López-Gómez JM . Spanish registry of glomerulonephritis. increased prevalence of acute tubulointerstitial nephritis. Nephrol Dial Transplant 2013;28 :112–5.22759386\n3 Raghavan R , Eknoyan G . Acute interstitial nephritis - a reappraisal and update. Clin Nephrol 2014;82 :149–62. 10.5414/CN10838 25079860\n4 Verghese PS , Luckritz KE , Eddy AA . 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Renal dysfunction in patients with direct infiltration by B-cell lymphoma. Kidney Int Rep 2019;4 :688–97. 10.1016/j.ekir.2019.02.008 31080924\n40 Basak R , Wang X , Keane C , et al . Atypical presentation of atypical haemolytic uraemic syndrome. BMJ Case Rep 2018;31 :bcr2017222560. 10.1136/bcr-2017-222560\n41 Veer M , Abdulmassih R , Como J , et al . Adenoviral nephritis in a renal transplant recipient: case report and literature review. Transpl Infect Dis 2017;19 :e12716. 10.1111/tid.12716\n42 Menter T , Mayr M , Schaub S , et al . Pathology of resolving polyomavirus-associated nephropathy. Am J Transplant 2013;13 :1474–83. 10.1111/ajt.12218 23721552\n43 Sumida K , Ubara Y , Hoshino J , et al . Hepatitis C virus-related kidney disease: various histological patterns. Clin Nephrol 2010;74 :446–56. 21084048\n44 Jahnukainen T , Ala-Houhala M , Karikoski R , et al . Clinical outcome and occurrence of uveitis in children with idiopathic tubulointerstitial nephritis. Pediatr Nephrol 2011;26 :291–9. 10.1007/s00467-010-1698-4 21120539\n45 Mandeville JT , Levinson RD , Holland GN . The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol 2001;46 :195–208. 10.1016/S0039-6257(01)00261-2 11738428\n46 Mackensen F , Billing H . Tubulointerstitial nephritis and uveitis syndrome. Curr Opin Ophthalmol 2009;20 :525–31. 10.1097/ICU.0b013e3283318f9a 19752730\n47 Preddie DC , Markowitz GS , Radhakrishnan J , et al . Mycophenolate mofetil for the treatment of interstitial nephritis. Clin J Am Soc Nephrol 2006;1 :718–22. 10.2215/CJN.01711105 17699278\n\n",
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"issue": "11(5)",
"journal": "BMJ open",
"keywords": "acute renal failure; paediatric nephrology; paediatrics",
"medline_ta": "BMJ Open",
"mesh_terms": "D000328:Adult; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D020407:Internet; D008297:Male; D009395:Nephritis, Interstitial; D011446:Prospective Studies; D012189:Retrospective Studies",
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"pubdate": "2021-05-28",
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"title": "Aetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients: a cross-sectional web-based survey.",
"title_normalized": "aetiology course and treatment of acute tubulointerstitial nephritis in paediatric patients a cross sectional web based survey"
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"abstract": "Methadone is one of the most popular synthetic opioids in the world with some favorable properties making it useful both in the treatment of moderate to severe pain and for opioid addiction. Increased use of methadone has resulted in an increased prevalence of its toxicity, one aspect of which is cardiotoxicity. In this paper, we review the effects of methadone on the heart as well as cardiac concerns in some special situations such as pregnancy and childhood.\n\n\nMETHODS\nWe searched for the terms methadone, toxicity, poisoning, cardiotoxicity, heart, dysrhythmia, arrhythmia, QT interval prolongation, torsade de pointes, and Electrocardiogram (ECG) in bibliographical databases including TUMS digital library, PubMed, Scopus, and Google Scholar. This review includes relevant articles published between 2000 and 2013. The main cardiac effects of methadone include prolongation of QT interval and torsade de pointes. Other effects include changes in QT dispersion, pathological U waves, Taku-Tsubo syndrome (stress cardiomyopathy), Brugada-like syndrome, and coronary artery diseases. The aim of this paper is to inform physicians and health care staff about these adverse effects. Effectiveness of methadone in the treatment of pain and addiction should be weighed against these adverse effects and physicians should consider the ways to lessen such undesirable effects. This article presents some recommendations to prevent heart toxicity in methadone users.",
"affiliations": "Atherosclerosis and Coronary Artery Research Center, Birjand University of Medical Sciences,Birjand, Iran.;Atherosclerosis and Coronary Artery Research Center, Birjand University of Medical Sciences,Birjand, Iran.;Department of Clinical Toxicology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Division of Medical Toxicology, Ronald O. Pereleman Department of Emergency Medicine, New York University School of Medicine, New York, NY, USA.;Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences (BUMS), Pasdaran Avenue, Birjand, 9713643138 Iran.",
"authors": "Alinejad|Samira|S|;Kazemi|Toba|T|;Zamani|Nasim|N|;Hoffman|Robert S|RS|;Mehrpour|Omid|O|",
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"doi": "10.17179/excli2015-553",
"fulltext": "\n==== Front\nEXCLI JEXCLI JEXCLI JEXCLI Journal1611-2156Leibniz Research Centre for Working Environment and Human Factors 2014-55310.17179/excli2015-553Doc577Review ArticleA systematic review of the cardiotoxicity of methadone Alinejad Samira 1Kazemi Toba 1Zamani Nasim 2Hoffman Robert S. 3Mehrpour Omid *41 Atherosclerosis and Coronary Artery Research Center, Birjand University of Medical Sciences,Birjand, Iran2 Department of Clinical Toxicology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran3 Division of Medical Toxicology, Ronald O. Pereleman Department of Emergency Medicine, New York University School of Medicine, New York, NY, USA4 Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences (BUMS), Pasdaran Avenue, Birjand, 9713643138 Iran*To whom correspondence should be addressed: Omid Mehrpour, Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences (BUMS), Pasdaran Avenue, Birjand, 9713643138 Iran, E-mail: omid.mehrpour@yahoo.com.au05 5 2015 2015 14 577 600 25 8 2014 14 1 2015 Copyright © 2015 Alinejad et al.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/) You are free to copy, distribute and transmit the work, provided the original author and source are credited.This article is available from http://www.excli.de/vol14/Mehrpour_05052015_proof.pdfMethadone is one of the most popular synthetic opioids in the world with some favorable properties making it useful both in the treatment of moderate to severe pain and for opioid addiction. Increased use of methadone has resulted in an increased prevalence of its toxicity, one aspect of which is cardiotoxicity. In this paper, we review the effects of methadone on the heart as well as cardiac concerns in some special situations such as pregnancy and childhood. Methods: We searched for the terms methadone, toxicity, poisoning, cardiotoxicity, heart, dysrhythmia, arrhythmia, QT interval prolongation, torsade de pointes, and Electrocardiogram (ECG) in bibliographical databases including TUMS digital library, PubMed, Scopus, and Google Scholar. This review includes relevant articles published between 2000 and 2013. The main cardiac effects of methadone include prolongation of QT interval and torsade de pointes. Other effects include changes in QT dispersion, pathological U waves, Taku-Tsubo syndrome (stress cardiomyopathy), Brugada-like syndrome, and coronary artery diseases. The aim of this paper is to inform physicians and health care staff about these adverse effects. Effectiveness of methadone in the treatment of pain and addiction should be weighed against these adverse effects and physicians should consider the ways to lessen such undesirable effects. This article presents some recommendations to prevent heart toxicity in methadone users.\n\nmethadonetoxicityheartECGtorsade de pointesQT interval\n==== Body\nIntroduction\nAcute overdose is one of the main complications of abuse and causes of mortality in opioid addicted patients (Afshari et al., 2007[2]; Ayatollahi et al., 2011[12]). Approximately, eight million people are substance abusers worldwide, most of whom, are from southeast and southwest Asia (Justo et al., 2006[67]). Iran has the highest rate of opioid addiction in the world (Karrari et al., 2012[70]; Mehrpour, 2012[101]; Mehrpour and Sezavar, 2012[103]). This country appears to be involved in both traditional and modern drug use and abuse problems and has an important role in the transportation of opium from Afghanistan to western countries (Day et al., 2006[31]; Karrari et al., 2013[69]). While in western countries, alcohol, cannabis, methamphetamine, and heroin are the most common abused drugs, in Iran opium remains the most commonly abused drug with opium poisoning and overdose being the major cause of drug-related hospital admissions (Movaghar et al., 2005[105]; Ayatollahi et al., 2011[12]; Jafari et al., 2010[63]; Koushesh and Afshari, 2009[78]; Taghaddosinejad et al., 2011[152]).\n\nMethadone, a synthetic opioid, was first produced in 1937 in Germany during world war II. The US Food and Drug Administration (FDA) approved it as an analgesic in 1947 (Ehret et al., 2007[36]; Noorzurani et al., 2009[109]; Shields et al., 2007[141]; Stimmel, 2011[150]). Methadone is an agonist of mu receptors (Izadi-Mood et al., 2008[62]) that has been used as an alternative treatment in the control of opioid dependency since the 1960s (Justo et al., 2006[67]). Methadone Maintenance Treatment (MMT) is the common for methadone treatment in opioid addiction (Izadi-Mood et al., 2008[62]) and is the best choice for treatment of opioid dependence (Pani et al., 2011[111]; Peles et al., 2007[118]). The use of MMT began in the US in 1964 when Dole and Nyswander first used this synthetic opioid for narcotic addiction (Palmiere et al., 2011[110]) and is an appropriate option for patients with a history of long-term opioid addiction when abstinence and other therapies have failed (Kobek et al., 2009[76]).\n\nAt least 750000 patients are on MMT worldwide (Ehret et al., 2007[36]). In America and Australia, about 250000 and 23300 patients are on MMT, respectively (Thanavaro and Thanavaro, 2011[154]; Zador and Sunjic, 2000[167]). Also, methadone is the most common prescribed drug for opioid dependence in Ireland (Roy et al., 2012[130]; Teichtahl et al., 2004[153]). In Europe, use of MMT ranges from 6-22 % in the United Kingdom (UK) to 41-86 % in Spain (Justo et al., 2006[67]). The higher incidence of methadone poisoning in Iran may be due to MMT, which has only been started in recent years and has increased access to methadone (Ayatollahi et al., 2011[12]).\n\nMethadone has different applications in the clinics. It is highly lipid-soluble and can therefore be administered once daily; it has long elimination half-life and is metabolized by liver (renal function does not interfere with half-life), and is an antagonist of the N-methyl-D-aspartate (NMDA) receptor causing reducing neuropathic pain (Ehret et al., 2007[36]). Methadone is different from other drugs in that it causes less stupor and does not interfere with mental and physical activities causing the patients to have better social relationships (Kobek et al., 2009[76]). MMT has five main benefits: reduction in the use of illegal substances, decreasing viral transmission through reduced injection of drugs, declining deaths due to excessive use of drugs, improvement in physical and mental health, and diminishing criminal activities (Fahey et al., 2003[40]). Other important uses of methadone are obviating moderate to severe pain (Palmiere et al., 2011[110]) and resistant cough in patients with lung cancer (Izadi-Mood et al., 2008[62]).\n\nAlthough methadone is a safe drug, overdoses have been reported (Cruciani 2008[28]; Paulozzi et al., 2009[116]). It also causes some side effects on central nervous system, skin, gastrointestinal tract, and urogenital and cardiovascular systems (Izadi-Mood et al., 2008[62]). One of the adverse events of methadone is its cardiotoxicity (Kumar, 2010[84]). Indeed, increased QT dispersion, QT interval prolongation, and torsade de pointes (TDP) -a life-threatening arrhythmia- are all reported in patients treated with methadone (Cruciani 2008[28]; Price et al., 2013[122]). These cardiovascular side effects were so prominent when a derrivative Levacetyl methadol (LAAM) or Orlaam (Deamer et al., 2001[33]) which caused LAAM was introduced, that it had to be eliminated from European markets (Deamer et al., 2001[33]; Guay, 2009[52]; Kumar, 2010[84]).\n\nThe goal of this paper is to review, in detail, the cardiotoxic potential of methadone, its mechanisms and possible treatments, and provide recommendations for physicians and healthcare staff to prevent it.\n\nMaterials and Methods\nWe searched for the terms methadone, toxicity, poisoning, cardiotoxicity, heart, dysrhythmia, arrhythmia, QT interval prolongation, torsade de pointes, and electrocardiogram (ECG) in bibliographical databases including TUMS digital library, PubMed, Scopus, and Google Scholar. This review includes relevant articles published between 2000 and 2013. We chose only the articles in this time frame because we wanted to work as much as possible on newer articles and also we did not find any different related papers before this time. We included not only human studies but also animal works in our study. \n\nPharmacology of methadone\nMethadone is the drug of choice for the treatment of opioid addiction due to its special pharmacokinetics (Strain, 2002[151]). It is also a good alternative to morphine and other opiate analgesics in the treatment of severe chronic pain (Kumar, 2010[84]). The average bio-availability of methadone (about 80 %) is higher than other opioids and its elimination half-life is long ranging from 7 to 65 hours (Fredheim et al., 2008[45]). Because of high solubility, 98 % of methadone that has reached the central compartment is quickly transported to tissues, especially to the liver, kidneys, lungs, and in small proportion, to the brain. Almost 1-2 % remains in the blood with 60-90 % bound to plasma proteins (mostly alpha1-acid glycoprotein) (Corkery et al., 2004[26]; Ferrari et al., 2004[43]; Gallagher 2009[48]; Shir et al., 2001[142]). Methadone passes the placenta and is also secreted in the breast milk.\n\nMethadone hydrocholoride is a racemic combination of two enantiomers (R and S), which differ in diffusion, elimination, and effects. The R-enantiomer has 10-times the potency at the opioid receptor in vitro, a longer elimination half-life, and a higher total volume of distribution. It is responsible for almost all analgesic effects of the drug (Ehret et al., 2007[36]).\n\nCertain cytochrome P450 enzymes in liver or other organs metabolize methadone. Methadone is mainly metabolized by Cytochrome P450 3A4 (CYP3A4) and (CYP2D6) with the latter having a secondary role (Pimentel and Mayo, 2008[121]; Sticherling et al., 2005[149]). Expression of CYP3A4 is the main factor causing diversity of methadone bioavailability in different people. It also participates in the metabolism of other drugs including benzodiazepines, calcium antagonists, macrolides, rifampin, and anticonvulsants. On the other hand, some drugs including ketoconazole, fluoxetine, and grapefruit juice in the large amount inhibit CYP3A4 activity and may cause the risk of drug-drug interaction. In Iran, the frequency of CYP2D6 metabolizers is up to 12 % of the population; thus, we expect people in this region to be more susceptible to opioid effects such as dependency and sedation (Mehrpour, 2013[100]).\n\nThe kidneys are the main organs in the excretion of methadone and its metabolites (15-40 % during the first 24 hours). Fecal excretion is responsible for 20-40 % of the drug elimination (Ferrari et al., 2004[43]). In a retrospective review conducted on 185 patients with cancer pain to measure the clearance of methadone, it was shown that a mean methadone clearance was 186 mL/min and a mean elimination half-life was 61.8 hours (Karir, 2002[68]).\n\nMethadone is preferably orally administered (Palmiere et al., 2011[110]) and is available as an oral solution (1-2 mg/mL), tablets (5-10 mg), dispersible tablets (40 mg), and injectable solutions (10 mg/mL). Methadone, has also a local use in the form of mouth wash for the treatment of painful oral ulcers and in powder as an analgesic on open wounds (Palmiere et al., 2011[110]).\n\nIn order to reduce the debate of suitable methadone dosing, low-dose, intermediate-dose, and high dose of methadone have been defined as doses < 50 mg/day, 50-100 mg/ day, and > 100 mg/day, respectively (Strain, 2002[151]). The recommended dose for the relief of severe pain is 2.5-10 mg every 3-4 hours. This dose is 60-80 mg/day for methadone maintenance varying from 30 to 120 mg/ day (Couper et al., 2005[27]). The treatment, toxic, and fatal serum concentrations of methadone range between 0.075 and 1.1 microgram/mL, 0.2 and 2 microgram/mL, and 0.4 and 2.8 microgram/mL, respectively (Kobek et al., 2009[76]) and vary dramatically with dependence.\n\nCardiotoxicity\nExperimental studies have found that methadone can affect many cardiac function parameters through various mechanisms (Sánchez Hernández et al., 2005[133]). Despite being considered to be safe, there have been some cases of cardiotoxicity leading to sudden death (Chugh et al., 2008[23]; Cruciani, 2008[28]).\n\nQT prolongation\nThe QT interval represents the required time for ventricular depolarization and repolarization (Spevak et al., 2012[146]) measured from the beginning of QRS complex to the end of the T wave. This interval changes with heart rate and is often corrected for this yielding a corrected QT (QTc) (Atkinson et al., 2007[11]; Wilcock and Beattie, 2009[164]). A QTc less than 450 and 430 msec is normal in females and males, respectively (Goldenberg et al., 2006[51]; Kornick et al., 2003[77]). Drugs such as methadone and cocaine can cause QT prolongation through the direct effects on the resting membrane potential (Wallner et al., 2008[161]). Methadone and QT prolongation is a subject of international debate (Krook et al., 2004[83]; Mayet et al., 2011[99]). This relation was elucidated almost four decades ago (Mayet et al., 2011[99]). It has been shown that daily use of methadone can increase QT interval by 12 msec (Abramson et al., 2008[1]; Krantz et al., 2005[81]).\n\nAs mentioned previously, early studies reported a relationship between methadone use and QT prolongation. Several cross-sectional studies have since confirmed this association (Anchersen et al., 2009[4]); Ehret et al. (2006[37]), compared drug-using patients receiving methadone with those who did not receive it among all patients hospitalized over a 5-year period in a tertiary care hospital. Of 167 methadone patients, QT prolongation was detected in 16.2 %. They concluded that QT prolongation was common among methadone maintenance patients. Wedam et al., 2007[162], compared QT interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Baseline QTc was similar in the three groups. The levomethadyl and methadone groups were significantly more likely to show QTc greater than 470 to 490 msec or an increase from baseline in QTc of greater than 60 msec.\n\nQT interval dispersion\nMethadone can increase QT dispersion in addition to QT interval (Hassanian-Moghaddam et al., 2014[55]). QT dispersion reflects the variety of QT intervals in the 12-lead ECG and is indicative of abnormal cardiac repolarization (Krantz et al., 2005[81]; Somberg and Molnar, 2002[145]). The normal range for QT dispersion is 30-60 msec (Krantz et al., 2005[81]).\n\nKrantz et al., investigated the effects of methadone on QT interval dispersion in 118 patients who had joined the MMT facility. Twelve-lead ECGs were performed at both baseline and 6 months after the start of methadone therapy. Mean baseline QT dispersion was 32.9 msec, which increased to 42.4 msec after 6 months of therapy. The QTc increased by a similar magnitude. No QT dispersion value exceeded 100 msec. They concluded that methadone could increase QT dispersion as well as QT interval (Krantz et al., 2005[81]).\n\nTorsade de pointes (Tdp)\nQT prolongation is common in patients on MMT; however, in patients with profoundly prolonged QT (≥ 500 msec), undesirable complications may occur that expose the patients to development of Tdp (Almehmi et al., 2003[3]; Drew et al., 2010[34]; Fredheim et al., 2006[46]; Gallagher et al., 2008[48]; Priori et al., 2003[123]; Thanavaro and Thanavaro, 2011[154]; Walley et al., 2013[160]). Tdp is an abnormal heart rhythm that causes regular and wide polymorphic QRS complex tachycardia twisting around the iso-electric baseline (Tdp is a French word meaning \"twisting of the points”). This rhythm is potentially fatal because it may progress to ventricular fibrillation and therefore should not be left untreated (Anchersen et al., 2010[5]; Tünsmeyer et al., 2012[155]). The most common cause of Tdp is drug use (Roden, 2008[128]). Dessertenne first described Tdp in 1966 (Chiang, 2006[22]; Ehret et al., 2007[36]) and Krantz et al. (2002[80]), reported the association between methadone and Tdp for the first time in 2002. The increase in the dosages of the drug in recent years has resulted in more cases of this abnormal rhythm. Another possibility is that patients taking methadone use newer drugs and therefore are at risk of dangerous drug interactions including prolongation of the QT interval when they use them in combination with their methadone.\n\nMethadone inhibits the Human Ether-a-go-go Related Gene (hERG) and causes QTc prolongation and development of Tdp (Eap et al., 2007[35]; Esfahani et al., 2012[38]; Sekine et al., 2007[140]; Zünkler and Wos-Maganga, 2010[169]). hERG, first identified in 1994, is located on chromosome 7 and codes for the potassium ion channel which intercedes repolarization of the cardiac action potential (Parikh et al., 2011[112]). This gene is expressed in multiple tissues and cells including neural, smooth muscle, and tumor cells. However, it is most highly expressed in the heart (Sanguinetti and Tristani-Firouzi, 2006[135]; Smith et al., 2002[144]).\n\nThe action potential of human ventricular myocytes can be divided into five distinct phases. Inward sodium current triggers a rapid membrane depolarization (phase 0). Repolarization occurs in three phases; phase 1 which proceeds rapidly and lasts a few milliseconds; phase 2 called the plateau which is a prolonged because the K+ currents activated during this phase are slow to activate and have a reduced conductance at positive trans-membrane potentials; phase 3 in which the action potential terminates, and phase 4 in which the membrane returns to its resting level. The most important component of phase 3 is the rapid delayed rectifier K+ current (IKr) conducted by hERG channels (Sanguinetti and Tristani-Firouzi, 2006[135]).\n\nhERG is highly susceptible to pharmacological blockade (Sanguinetti and Mitcheson 2005[134]). Methadone blocks the hERG channels at concentrations close to those clinically achieved (Chugh et al., 2008[23]). This blockage in turn prolongs the end part of cardiac action potential and finally reprieves repolarization represented as QTc interval prolongation (Esfahani et al., 2012[38]; Fonseca et al., 2009[44]; Hassnain-Moghaddam et al., 2013[55]). Methadone's R-isomer inhibits the hERG channel less than the S-isomer (Lin et al., 2008[92]). Methadone can cause QT prolongation and Tdp with other mechanisms, as well, including producing negative chronotropic effects via Ca++ channel antagonism and anti-cholinesterase effect. The bradycardia induced by these mechanisms makes the patient more susceptible to Tdp (Esfahani et al., 2012[38]). Accepted risk factors for QT prolongation and Tdp are low K+, Mg++, or Ca++ concentrations, diabetes mellitus, thyroid or pituitary insufficiency, cardiomyopathy, recent myocardial infarction (MI), sinus bradycardia, certain drugs, toxins (organophosphates, insecticides, and heavy metals), female gender, older age, subarachnoid hemorrhage, starvation, genetic susceptibility, obesity, alcoholism, and cirrhosis (Bednar et al., 2001[14]; Gupta et al., 2007[53]; John et al., 2010[65]; Kobek et al., 2009[76]; Laqueille et al., 2012[88]; Pasquier et al., 2012[113]; Raschi et al., 2009[126]; Schmidt, 2005[137]; Vieweg et al., 2013[156]; Viskin et al., 2003[158]).\n\nPatients on MMT often receive concomitant medications for psychiatric disorders and infections such as Human Immunodeficiency Virus (HIV) which can raise the risk of drug-drug interactions (Lüthi et al., 2007[93]). In methadone users, drug-drug interaction results in TdP via a pharmacodynamic combined effect and causing an alteration of metabolism. Some medications can cause QTc prolongation per se (including amiodarone, chloroquine, clarithromycin, erythromycin, haloperidol, lithium, sotalol, terfenadine, and venlafaxine as well as grapefruit juice). They, when given with methadone, may increase the risk of development of TdP. Among them are some commonly used medications such as amiodarone, chlorpromazine, cisapride, clarithromycin, droperidol, erythromycin, haloperidol, pentamidine, pimozide, procainamide, quinidine, sotalol, thioridazine, quinolones, and antifungals. With regard to the pharmacokinetics, methadone is mainly metabolized by CYP3A4 enzyme and to a lesser extent by CYP2B6 and CYP 2D6. Induction or inhibition of these enzymes by any means including certain drugs can increase or decrease the serum concentrations of methadone. HIV antivirals (e.g., indinavir, nelfinavir, and ritonavir), antibiotics and antifungals such as clarithromycin, itraconazole, and ketoconazole strongly inhibit CYP3A4 while efavirenz induces it (Prosser et al., 2008[124]).\n\nNair et al. (2008[106]) introduced a 56-year-old man receiving methadone brought to their emergency department because Tdp developed after using ciprofloxacin in whom CYP1A and CYP3A enzymes likely caused a pharmacokinetic reaction. Sánchez Hernández et al. (2005[133]) reported four cases of Tdp during methadone treatment all of whom were on MMT. Three of them were HIV-infected and one received antiretroviral therapy. Two patients had low serum potassium concentrations. In fact, these patients had some associated risk factors that caused QT interval prolongation. Justo and colleagues (2006[67]) reviewed all the publications on methadone-associated Tdp in addicted patients to identify the situations leading to this complication. All patients had at least one risk factor for Tdp including high-dose methadone, concomitant use of agents that increased serum methadone concentrations, HIV infection, hypokalemia, female gender, liver cirrhosis, or renal failure. Kuryshev and associates (2010[85]) evaluated the cardiac risk in co-administration of methadone and diazepam. They found that diazepam alone did not prolong the QT interval; but, its concomitant use with methadone interacted with Na+ channels and caused hERG K+ channel block. Winton and Twilla (2013[165]) reported a 47-year-old addicted man who was on methadone and azithromycin for an upper respiratory tract infection and experienced a fatal arrhythmia. Schmittner et al. (2009[138]) evaluated the ECG effects of co-administration of lofexidine and methadone in 14 participants dependant to opioids. There were significant changes in four ECG parameters; decreased heart rate and increased PR, QRS complex, and QT intervals. In three participants, QTc prolongation was clinically significant (it increased by > 40 msec from baseline).\n\nReinhold et al. (2009[127]) reported a 57-year-old man with comorbid conditions who developed Tdp after use of methadone and voriconazole. The probable cause was voriconazole-inhibited methadone metabolism via cytochrome P450 isoenzymes (CYP2B6). Krantz and colleagues (2005[82]) introduced a patient on MMT who developed syncope due to Tdp hours after cocaine use. They found that cocaine and methadone prolonged QT interval via the same mechanism.\n\nMethadone dose dependency in QT prolongation and Tdp\nIdeal methadone dosage in treatment of opioid dependence is a matter of debate (Liao et al., 2013[91]). Several large studies have been performed to evaluate the relationship between the dose of methadone and QTc prolongation. Some have reported a direct relationship (Table 1(Tab. 1); References in Table 1: Krantz et al. (2003[79]); Routhier et al. (2007[129]); Walker et al. (2003[159]); Ehret et al. (2006[37]); Cruciani et al. (2005[29]); Martel et al. (2005[98]); Thanavaro and Thanavaro (2011[154])), while others could not find such an association (Table 2(Tab. 2)Krantz et al., 2005[81]; References in Table 2: Maremmani et al. (2004[96]); Peles et al. (2007[118]); Huh and Park, 2010[57]; Pearson and Woosley, 2005[117]; Roy et al., 2012[130]). There are several case reports and data on methadone-induced QT prolongation in a dose-dependent manner that have caused considerable concern for practitioners in addiction medicine (Butler et al., 2011[17]). Oral recommended doses range from 60 to 100 mg per day. It has been shown that use of a mean dose of 100 mg or more of methadone leads to significant dose-dependent QTc prolongation in these patients (Chang et al., 2012[21]). Krantz et al. (2003[79]), investigated the relationship between the daily dose of methadone and QTc interval in methadone-treated patients who developed Tdp. They concluded that daily methadone dose correlated positively with the QTc interval. Routhier and associates (2007[129]) presented a 52-year-old woman without any underlying cardiac disease who developed QTc prolongation and Tdp secondary to high-dose methadone therapy. This case report suggested that methadone induced QTc prolongation and Tdp in a dose-dependent manner. Walker and associates (2003[159]) published a report of three cases of Tdp in patients on daily doses of methadone exceeding 600 mg, two of whom, presented with syncope and one with respiratory distress. Each of the three was on other medications that inhibited the metabolism of methadone. Extra caution should be given for arrhythmias when high dosages of methadone (> 600 mg/day) are used, especially in patients on other drugs that can interact with the CYP3A4 isoenzyme system. Ehret et al. (2006[37]) investigated the frequency of QT prolongation in MMT patients hospitalized in a tertiary center and identified associated risk factors. Methadone dose, CYP 3A4 inhibitors, potassium concentration, and liver function contributed to QT prolongation and QTc length was weakly but significantly associated with methadone daily dose. In the study by Cruciani and colleagues (2005[29]), the median methadone dose was 110 mg/day. Significant dose-response was observed in males on methadone for less than 12 months. Martell and assistants (2005[98]) carried out a study on 160 patients, all of whom were initiated on 30-mg oral methadone with subsequent 10-mg incremental increases. They observed that there was a positive correlation between serum methadone concentration and the prolongation of QTc interval. Thanavaro and Thanavaro (2011[154]), reported a case of methadone-induced Tdp who was on high dose of the drug (110 mg/day) without using any concomitant medications. They concluded that methadone dose should be adjusted or the drug should be switched to an alternative one and ECG should be repeated in case of QTc prolongation. Although several studies indicated an association between methadone dose and QTc interval, other investigations did not detect such effect (Krantz et al., 2005[81]). QT interval prolongation has been detected with daily doses below 65 mg, as well (Huh and Park, 2010[57]).\n\nMaremmani et al. (2004[96]) evaluated abnormal QTc interval in 83 heroin addicts who were on long-term MMT and received methadone dosages between 10-600 mg/day. Almost 83 % of them had QT prolongation more than the reference values. No correlation existed between QT prolongation and methadone dosages. Peles and associates (2007[118]) studied 138 patients on MMT with methadone dose of 40-290 mg/day. An ECG was done and a serum methadone concentration was determined about 24 hours after the last oral methadone dose. It was shown that methadone dose and serum concentrations did not correlate with QTc. \n\nHuh and Park (2010[57]) conducted a study on 130 patients with 90 patients in the methadone and 40 patients in the control group. Heart rate, QT interval, and QTc were recorded. The patients’ demographics, methadone dose and serum concentration, duration of methadone use, and past medical history were collected. QTc interval was significantly longer in the methadone group. QTc interval was not associated with methadone dose (P = 0.9) and serum concentration or duration of treatment. Pearson and Woosley (2005[117]) reviewed and analyzed adverse events (QT prolongation and Tdp reported to FDA from 1969 to 2002) to determine the patients’ characteristics, dosages of methadone, and outcomes of methadone-treated patients. Analysis of the cases showed that QT prolongation and Tdp could occur over a wide range of dosages even those recommended for treatment of addiction. Roy and colleagues (2012[130]) evaluated the correlation between QT interval and methadone dose. Mean methadone dose was 80.4 ± 27.5 mg in their study. They concluded that prolongation of QT interval was seen even in patients receiving low doses of methadone without any dose-response relationship.\n\nNo cut-off level for safe dose has been identified. Although some studies have detected positive association between methadone dose and QTc prolongation, the relationship is usually stronger with additional factors such as gender, duration of treatment, and concomitant drug use (Huh and Park, 2010[57]).\n\nU-waves\nMethadone can cause pathological U waves (larger than the T wave) and impending Tdp (John et al., 2010[65]). Drug-induced or prolonged QT syndromes can create U waves. In a study on the effects of methadone and buprenorphine on ECG, methadone subjects were significantly more likely to have U waves (Athanasos et al., 2008[10]).\n\nVentricular bigeminy\nVentricular bigeminy may be due to different mechanisms involving a disturbance of impulse form/conduction or both (Langendorf et al., 1955[87]). Scholler et al. (2011[139]) demonstrated ventricular bigeminy in a Caucasian woman with concomitant administration of methadone, voriconazole, and esomeprazole. She had high plasma concentrations of voriconazole and methadone. It was concluded that a pharmacokinetic interaction between methadone and voriconazole was reinforced by the addition of esomeprazole.\n\nTako-Tsubo Syndrome\nStress cardiomyopathy (Tako-Tsubo syndrome) is defined as left ventricular functional and ECG changes that mimic acute myocardial infarction without any evidence of involvement of coronary arteries. It is more common in postmenopausal women and an acute medical illness or emotional/physical stress may typically trigger this syndrome (Lemesle et al., 2010[90]; Saiful et al., 2010[132]). It has been demonstrated that huge release of catecholamines (maybe due to opioid withdrawal) may be responsible for development of this cardiomyopathy. Only two cases of Taku-Tsubo syndrome have been reported in relation with acute opioid withdrawal. Lemesle et al. (2010[90]), reported the first case as a result of methadone withdrawal secondary to drug-drug interaction.\n\nBrugada-like syndrome\nBrugada-like syndrome is another condition in methadone users predisposing the patients to life-threatening ventricular tachycardia and sudden cardiac death. The disease is due to a mutation in the cardiac sodium channel SCNSA gene in one-fourth of the cases. Although the patients may have normal ECGs, coved-type ST elevation in precordial leads V1–V3 is characteristic of the disease. Agents causing Brugada-like ECG include fever, cocaine and methadone, sodium channel blockers (e.g. propafenone, procainamide, flecainide, bupivacaine, lidocaine, and tricyclic antidepressants), propofol, and electrolyte imbalances (Deamer et al., 2001[33]). Srivatsa and colleagues (2005[147]) reported a case of consecutive appearance of Brugada and long QT patterns on ECG in a patient receiving methadone. Junttila et al conducted a multi-center observational trial on 47 patients presenting with typical Brugada-like ECGs during an acute medical event, 16, 26, and 5 cases were due to febrile episodes, drugs, and electrolyte imbalances, respectively. Fifty-one percent had severe arrhythmias with 38 % leading to sudden cardiac death and 6 % developing ventricular tachycardia and syncope. One of the victims of sudden cardiac death was receiving methadone (Junttila et al., 2008[66]).\n\nMethadone and coronary artery disease\nCardiovascular diseases are the most common causes of death in both genders (Kazemi, 2012[73]; Kazemi et al., 2011[74]) and have been noticed to lead to morbidity and mortality in MMT clinics. Although long-term methadone exposure may relieve the fatal outcomes of coronary diseases (Marmor et al., 2004[97]; Patane et al., 2007[114]; Safaei, 2008[131]), opiate-related ischemia has been described in some cases. Backmund and associates presented a 22-year-old addicted man who suffered myocardial infarction after concomitant use of methadone and dihydrocodeine (Backmund et al., 2001[13]). Patane and assistants (2007[114]) presented a case of acute myocardial infarction in a chronic methadone user after aspirin use (due to the paradoxical activation of major platelet receptors after administration of aspirin).\n\nMethadone and hemodynamic effects\nThe cardiovascular toxicity of opioids causes significant morbidity and mortality in overdose; but, the hemodynamic effects of opioids reported in animal and human studies are contradictory (Afshari et al., 2007[2]). Afshari et al. (2007[2]) performed a prospective observational study of patients admitted to hospital following an overdose of methadone, dihydrocodeine, or low-dose paracetamol (10 each). They observed that dihydrocodeine and methadone significantly reduced peripheral and aortic systolic, mean and end systolic pressures. Both significantly decreased peripheral pulse pressure, but only methadone decreased aortic blood pressure. Dihydrocodeine reduced systemic and aortic diastolic blood pressure, an effect not induced by methadone. Methadone reduced peripheral pulse pressure. Augmentation index and heart rate, however, did not change. Both opioids decreased arterial oxygen saturation. It was suggested that dihydrocodeine and methadone had a significant effect on central and peripheral hemodynamic when overdosed. Anderson and Alvarado (2003[6]) assessed acute hemodynamic effects of intravenous methadone in 21 patients all of whom were scheduled for cardiac surgery. They found that there were no significant changes in any hemodynamic parameter at any time point. This study indicates that no adverse hemodynamic effects accompany a 20-mg intravenous bolus of methadone.\n\nUse of methadone in pregnancy\nOpioid dependence is a major public health problem during pregnancy. A recent study showed that 2.6 % of pregnant women in the United States had positive opioid tests at time of admission for delivery. It is estimated that in Europe 30000 opioid-addicted women become pregnant annually (Schmid et al., 2010[136]).\n\nMethadone is the routine substitution therapy for heroin-addicted pregnant women (Navaneethakrishnan et al., 2006[107]; Burns et al., 2010[16]). It easily crosses the placenta and the final concentration of methadone in the umbilical cord is one-fourth of that in maternal serum (Schmid et al., 2010[136]). Pregnant women on MMT have better prenatal care in comparison with the untreated women (Ramirez-Cacho et al., 2006[125]), which confers higher birth weights and less obstetric complications, preterm births, and neonatal morbidity. Despite these benefits, common harmful perinatal complications have also been reported in methadone-exposed pregnant women (Cleary et al., 2012[25]). Methadone use by mother changes fetal heart rate (FHR) patterns; for example, reduces the baseline heart rate and variability and increases the possibility of a non-reactive non-stress test (Jansson et al., 2005[64]; Leeman et al., 2011[89]). Ramirez-Cacho (2006[125]) and colleagues compared intrapartum FHR tracings from 56 mothers in their 36th gestational age and on MMT with a healthy control group matched for maternal age, parity, gestational age, and ethnicity. It was concluded that chronic maternal methadone treatment affected intrapartum FHR patterns by reducing the variability, baseline, and proportion of accelerations during the first stage. Schmid and colleagues (2010[136]) evaluated the FHR by Doppler ultrasound between 11+0 and 13+6 gestational weeks in methadone-using mothers and a healthy control group. They concluded that in opioid-dependent mothers' fetuses a decreased FHR could be observed in that time period.\n\nUse of methadone in infancy\nDrug dependence is dangerous in infancy. Babies of opioid-dependent mothers have a higher risk of mortality in their first year of life (Burns et al., 2010[16]). Occurrence of sudden infant death syndrome has also been reported in newborns of mothers on MMT. Although there is transient benign increase in QT interval up to 500 msec in healthy newborns, maternal methadone use prolongs QTc in infants in the first two days of their life, which is similar to the effects of methadone in adults (Nekhayeva et al., 2005[108]; Parikh et al., 2011[112]; Philipp et al., 2003[120]; Villain et al., 1992[157]). Hussain and Ewer (2007[58]) presented a case of significant QT interval prolongation in a neonate secondary to use of methadone by its mother. They showed that methadone, even in low maternal doses, could cause conduction disturbances in neonates. Parikh et al. (2011[112]), compared QTc interval in infants born to mothers on MMT with healthy controls. In the first group, QTc interval was significantly prolonged on days 1 and 2 of life. On days 4 and 7, this increase was no longer present. It was concluded that maternal methadone therapy could prolong QTc in newborns and infants and put them at risk of cardiac rhythm disturbances. Wheeler and Tobias (2006[163]) reported a case of methadone use in an infant whose heart rate decreased from 130-140 beats/min to 80-90 beats/min after the first dose of methadone concluding that methadone had the same structure as calcium channel antagonists and led to bradycardia.\n\nAs previously shown, elimination of methadone from the body is slower in neonates compared with older children or adults. Methadone is greatly lipid-soluble and highly protein-bound which is responsible for its larger volume of distribution and slower clearance. In fact, neonates have more lipid tissue and higher plasma protein concentrations, which may change drug distribution and metabolism significantly (Chana and Anand, 2001[20]).\n\nUse of methadone in children\nMethadone is currently more available in American houses which predisposes the toddlers to its toxicity (Boyer et al., 2010[15]). Opioids are often used as sedatives in pediatric intensive care unit (PICU). Administration of methadone in PICU was first reported in 1990 to prevent opioid withdrawal (Siddappa et al., 2003[143]); however, it is now increasingly being administered as a treatment of chronic pain syndromes in children (Boyer et al., 2010[15]; Wood et al., 2002[166]). There have also been case reports of methadone use to prevent abstinence syndrome in the PICU and for the treatment of burns in children (Davies et al., 2008[30]). The factors that have made methadone attractive in pediatrics include its comfortable oral use, longer half-life, and ease in calculation of the dose because of its equivalent potency with morphine (Siddappa et al., 2003[143]). \n\nAlthough methadone use is beneficial in pediatrics, it has known toxic effects on cardiac conduction that may worsen medical problems appearing in puberty (Boyer et al., 2010[15]; Katchman et al., 2002[72]). Children are particularly susceptible to effects from QT prolongation (Boyer et al., 2010[15]). Yet, in some cases, there is a transient and benign QT prolongation in apparently healthy children (Hussain and Ewer, 2007[58]). Pediatric methadone toxicity in children has been shown to cause peripheral vasodilation (predisposing to orthostatic hypotension), sinus bradycardia, and cerebrovascular vasodilatation (due to decreased sensitivity of the respiratory center to CO2 leading to an increased PCO2), which can increase intracranial pressure. No arrhythmias such as Tdp are described (Guay, 2009[52]).\n\nAnimal studies\nIn animals, opioids are used as part of balanced anesthetic methods and for treating pain (Maiante et al., 2009[94]; Ingvast‐Larsson et al., 2010[59]). However, there is little information about the safety and analgesic efficacy of methadone in veterinary medicine (Maiante et al., 2009[94]).\n\nThere are several studies about pharmacology of methadone in dogs (Ingvast‐Larsson et al., 2010[59], 2007[60]; Maiante et al., 2009[94]; Pimentel and Mayo, 2008[121]). Elimination of methadone in canines is different from humans. Methadone is rapidly eliminated from the animal body because of a high clearance rate. The oral bioavailability is low in dogs with half-lives of 1.75-6 hours and 2-12 hours following intravenous (IV) and subcutaneous (SC) administration, respectively (Ingvast‐Larsson et al., 2010[59]). Methadone causes cardiovascular depression in dogs. Maiante et al. (2009[94]), compared the effect of methadone and morphine in dogs. Methadone was concluded to induce depressant dose-related cardiovascular changes in conscious dogs. In fact, methadone causes a dose-dependent decrease in heart rate and cardiac index as well as increase in the systemic vascular resistance index. Garofalo and colleagues (2009[49]) compared the cardio-respiratory and neuro-hormonal effects of methadone in conscious and in isoflurane-anaesthetized dogs. Methadone induced dysphoria in all conscious dogs and significantly increased mean arterial pressure, catecholamines, and vasopressin concentrations. During anesthesia, in addition to greater decreases in heart rate and cardiac index, methadone induced apnea and mechanical ventilation was necessary in all dogs. In anaesthetized animals, methadone administration significantly increased vasopressin concentrations and systemic vascular resistance index, while mean arterial pressure did not differ from baseline. In contrast, isoflurane enhanced the intensity of the cardio-respiratory changes induced by methadone. Vasoconstrictive responses associated with methadone did not appear to be induced by vasopressin. Increases in circulating catecholamines, possibly caused by dysphoric reactions to methadone administration, may attenuate the negative chronotropism and the decrease in cardiac index observed when methadone is administered to conscious dogs.\n\nMethadone use increases plasma vasopressin up to 40 times in dogs and goats (Garofalo et al., 2012[49]; Ingvast‐Larsson et al., 2010[59]; Pimentel and Mayo, 2008[121]). Vasopressin released by the pituitary stimulates V1a receptors leading to peripheral vasoconstriction. This has been suggested as the possible responsible cause of systemic vasoconstriction detected after methadone administration (Garofalo et al., 2012[49]).\n\nIt was shown that high methadone doses affected cardiac function in guinea pig heart cell preparations. Methadone strengthens the inotropic heart response to sympathetic stimulation in a dose-dependent manner that can be antagonized by increased extracellular calcium concentration (Anguera et al., 2008[8]; Gil et al., 2003[50]; Lamont and Hunt, 2006[86]).\n\nAt concentrations of ≥ 10 μM in isolated sheep Purkinje fibers, methadone decreases the maximum rate of depolarization and increases the duration of action potential. High concentrations of methadone can affect several parameters of cardiac function through a mechanism different from opioid receptor stimulation causing QT prolongation (Gil et al., 2003[50]).\n\nTreatment\nThe treatment of methadone cardiotoxicity depends on patients' signs and symptoms. The asymptomatic or symptomatic prolongation of QTc interval are differently managed (Deamer et al., 2001[33]). In the case of prolonged QT syndrome and Tdp, predisposing factors should be corrected and use of special medications should be evaluated (Nair et al., 2008[106]). If an increased serum methadone concentration is the reason of cardiotoxicity, it is advised to lower the methadone dose (Krook et al., 2004[83]). Methadone-induced Tdp associated with hypokalemia should be treated with IV potassium. Magnesium administration is suggested for those with QTc prolongation even if the serum concentration of Mg is normal (Deamer et al., 2001[33]; Zipes et al., 2006[168]). Since R-isomer less inhibits the hERG channel, substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value (Ansermot et al., 2010[9]). If the patient has a QTc ≥ 500 msec, it is reasonable to change methadone with another drug and refer the patient to a cardiologist (Somberg and Molnar, 2002[145]). The proper alternatives include buprenorphine, naltrexone, or slow-release oral morphine (Deamer et al., 2001[33]; Kastelic et al., 2008[71]).\n\nBuprenorphine is a partial μ-agonist and a κ-antagonist effective at lowering the use of opioids among opiate-addicted people. No report of QT prolongation has been given with buprenorphine. Thus, it is a good alternative for methadone in opiate dependency and chronic pain (Esses et al., 2008[39]). During the first years of methadone and buprenorphine administration, death rate of these two drugs was compared concluding that buprenorphine was associated with a much lower mortality rate than methadone (Perrin‐Terrin et al., 2011[119]). A 56-year-old man with syncope and Tdp secondary to methadone has been presented in the literature in whom, after transition to buprenorphine, QT interval normalized and ventricular arrhythmias resolved (Esses et al., 2008[39]). De Jong and De Ruiter (2013[32]) introduced a 52-year-old man who was admitted to the hospital due to Tdp. He had used methadone two days earlier. Buprenorphine was substituted and QTc normalized after two weeks. In a cross-sectional study by Fanoe and colleagues (2007[41]), methadone was associated with long QT interval, but there was not any association between buprenorphine and QTc interval. Stallvik et al. (2013[148]), found that buprenorphine was a suitable alternative for methadone regarding the risk of QTc prolongation.\n\nIn cases of recurrent methadone-associated Tdp whose medication cannot be changed, permanent pacing with the use of defibrillator Implantable Cardioverter Defibrillator (ICD) can be done (Miller et al., 2011[104]). Patel and coworkers (2008[115]) reported that from their eight patients undergoing this treatment, three who continued taking methadone after ICD placement received shocks for Tdp within the 2-year follow-up. The procedure was therefore heralded as potentially lifesaving for people with a history of Tdp who continued to take methadone. However, one of the eight patients died because of unknown causes, and two suffered serious peri-operative complications (pericardial tamponade and device infection).\n\nAnother choice of treatment in these patients with limitations in switching the drug or those at risk of device infection is left cardiac sympathetic denervation (LCSD). This method is a preganglionic denervation with antifibrillatory effects and emerging as an important adjunctive therapy in the management of ventricular arrhythmias. Miller et al. (2011[104]), introduced the first case of drug-induced QT prolongation successfully managed with LCSD. \n\nThe efficacy of oral activated charcoal for adsorption of drugs and poisons has been widely described in the literature. Activated charcoal is helpful if administrated within 1-2 hours after ingestion. Since routine use of AC is discouraged, it is important to consider the risks and benefits of AC on a drug-by-drug basis (Chyka et al., 2005[24]; Khosrojerdi et al., 2013[75]).\n\nRecommendations\nMMT personnel, patients, and their families need to be better informed about the manifestations of methadone poisoning and their suitable management to reduce the morbidity and mortality rates associated with methadone (Caplehorn and Drummer, 2002[19]). It is recommended that methadone patients and their families be evaluated regarding any history of syncope, sudden death, structural heart disease, or any other cardiac-related signs and symptoms. In addition, physicians should seek for the use of agents inhibiting CYP3A4 or CYP2B6 enzymes especially cimetidine, ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, and pink grapefruit or Seville orange juice (Anderson and Kearney, 2000[7]; Boyer et al., 2010[15]). Clinicians prescribing methadone should also notice the wide inter-individual variability in the rate of methadone metabolism and the small difference between its therapeutic and toxic doses (Backmund et al., 2001[13]; Mehrpour et al., 2013[102]).\n\nBefore administration of methadone, conducting cardiovascular screening is reasonable and cheap. Screening includes echocardiography (to exclude heart disease) and check of possible electrolyte imbalances (Justo et al., 2006[67]). ECG assessment might be considered in new patients with history of known heart disease or recent symptoms like unexplained seizures, exertional chest pain or discomfort, exertional dyspnea, unexplained syncope or heart palpitations (Maremmani et al., 2004[96]). QT interval calculation should be conducted before prescription of methadone. The ECG should be checked at regular intervals. This is especially important within days of starting methadone therapy (Krook et al., 2004[83]); the ECG should be obtained before initiation of methadone and 4-7 days after its initiation. Additional ECGs are recommended 4-7 days after increase of dosage, when patients have unexplained syncope or seizures, and/or when there are changes in condition or therapy, which increase the risk of arrhythmia (Deamer et al., 2001[33]). ECG screening may not be possible in all patients on MMT. Although the screening procedure itself is not expensive, interpretation of ECGs by cardiologists may be expensive (Fareed et al., 2010[42]). Automated measurement of the QT interval may be used but is not accurate or trustworthy enough to be applied (Calver et al., 2012[18]; Isbister et al., 2009[61]; Malik and Camm, 2001[95]).\n\nIn order to better show the effect of methadone on the QT interval over a 24-hour period, high-resolution digital holter recorders are the most accurate tools to measure the QT with modern algorithms. Calver et al. (2012[18]), found that this method could make a risk assessment; however, this still required manual interpretation of the QT using on-screen magnification and calipers (Hnatkova et al., 2006[56]).\n\nConclusion\nMethadone has become popular in the treatment of opioid addiction and pain because of its special pharmacokinetic and pharmacodynamic characteristics. But, patients are at risk of methadone cardiotoxicity. Effectiveness of methadone in the treatment of pain and addiction should be weighed against these adverse effects and physicians should consider the ways to minimize these undesirable effects.\n\nConflict of interest\nAuthors declare no conflict of interest.\n\nAcknowledgement\nThis article is supported by Atherosclerosis and Coronary Artery Research Center in Birjand University of Medical Sciences. It is M.D thesis of the first author.\n\nTable 1 Positive dose-response relationship between methadone and cardiotoxicity\nTable 2 Negative dose-response relationship between methadone and cardiotoxicity\n==== Refs\n1 Abramson DW Quinn DK Stern TA Methadone-associated QTc prolongation: a case report and review of the literature Prim Care Companion J Clin Psychiatry 2008 10 470 476 19287558 \n2 Afshari R Maxwell S Bateman D Hemodynamic effects of methadone and dihydrocodeine in overdose Clin Toxicol 2007 45 763 772 \n3 Almehmi A Malas AM Yousufuddin M Rosencrance JG Methadone-induced torsade de pointes in a patient with normal baseline QT interval W V Med J 2003 100 147 148 15471174 \n4 Anchersen K Clausen T Gossop M Hansteen V Waal H Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study Addiction 2009 104 993 999 19392907 \n5 Anchersen K Hansteen V Gossop M Clausen T Waal H Opioid maintenance patients with QTc prolongation: Congenital long QT syndrome mutation may be a contributing risk factor Drug Alcohol Depend 2010 112 216 219 20702049 \n6 Anderson DM Alvarado SJ Hemodynamic effects of intravenous methadone Anesthesiology 2003 99 A190 \n7 Anderson IB Kearney TE Use of methadone Western J Med 2000 172 43 46 \n8 Anguera I Gil M Sla M Chapinal O Cervantes M Guè JR Syncope due to torsade de pointes in an HIV‐infected patient receiving methadone treatment Syncope Cases 2008 165 167 \n9 Ansermot N Albayrak O Schläpfer J Crettol S Croquette-Krokar M Bourquin M Substitution of (R, S)-methadone by (R)-methadone: impact on QTc interval Arch Intern Med 2010 170 529 536 20308640 \n10 Athanasos P Farquharson AL Compton P Psaltis P Hay J Electrocardiogram characteristics of methadone and buprenorphine maintained subjects J Addict Dis 2008 27 31 35 18956527 \n11 Atkinson D Dunne A Parker M Torsades de pointes and self‐terminating ventricular fibrillation in a prescription methadone user Anaesthesia 2007 62 952 955 17697226 \n12 Ayatollahi V Behdad S Oliwiaie H Hajiesmaili MR Dehghan M Mehrpour O Characteristic features of patients hospitalized with Narcotic poisoning in Yazd, Iran Iran J Toxicol 2011 4 362 366 \n13 Backmund M Meyer K Zwehl W Nagengast O Eichenlaub D Myocardial infarction associated with methadone and/or dihydrocodeine Eur Addict Res 2001 7 37 39 11316924 \n14 Bednar MM Harrigan EP Anziano RJ Camm AJ Ruskin JN The QT interval Prog Cardiovasc Dis 2001 43 1 45 11269621 \n15 Boyer EW McCance‐Katz EF Marcus S Methadone and buprenorphine toxicity in children Am J Addict 2010 19 89 95 20132125 \n16 Burns L Conroy E Mattick RP Infant mortality among women on a methadone program during pregnancy Drug Alcohol Rev 2010 29 551 556 20887580 \n17 Butler B Rubin G Lawrance A Batey R Bell J Estimating the risk of fatal arrhythmia in patients in methadone maintenance treatment for heroin addiction Drug Alcohol Rev 2011 30 173 180 21355903 \n18 Calver L Dunlop AJ Isbister GK Individual patient assessment of methadone-induced QT prolongation with digital holter recording J Addict Med 2012 6 92 93 22146148 \n19 Caplehorn JR Drummer OH Fatal methadone toxicity: signs and circumstances, and the role of benzodiazepines Aust N Z J Public Health 2002 26 358 362 12233958 \n20 Chana S Anand K Can we use methadone for analgesia in neonates? 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"fulltext_license": "CC BY",
"issn_linking": "1611-2156",
"issue": "14()",
"journal": "EXCLI journal",
"keywords": "ECG; QT interval; heart; methadone; torsade de pointes; toxicity",
"medline_ta": "EXCLI J",
"mesh_terms": null,
"nlm_unique_id": "101299402",
"other_id": null,
"pages": "577-600",
"pmc": null,
"pmid": "26869865",
"pubdate": "2015",
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"abstract": "The aim of this study was to investigate the safety and feasibility of neoadjuvant nab-paclitaxel plus gemcitabine therapy for patients with borderline resectable pancreatic carcinoma (BRPC).\n\n\n\nThe study was a prospective single-center phase I trial for patients with BRPC. The primary endpoint was the toxicity, and secondary endpoints were the resection rate, the R0 resection rate and quality of life (QOL) regarding the peripheral sensory neuropathy (PSN). This trial was registered on the UMIN Clinical Trials Registry (UMIN000018382) and on ClinicalTrials.gov (NCT02506803).\n\n\n\nThe overall rate of any grade and grade 3-4 events (CTCAE ver. 4.0 criteria) were 100% and 90%. The majority of these adverse events represented expected neutropenia. The resection and R0 resection rates were 80% and 70%, respectively.\n\n\n\nWe found that neoadjuvant nab-paclitaxel plus gemcitabine therapy was safe and feasible without stringent selection of patients with BRPC.",
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"authors": "Okada|Ken-Ichi|KI|;Hirono|Seiko|S|;Kawai|Manabu|M|;Miyazawa|Motoki|M|;Shimizu|Atsushi|A|;Kitahata|Yuji|Y|;Ueno|Masaki|M|;Hayami|Shinya|S|;Yamaue|Hiroki|H|",
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"mesh_terms": "D000368:Aged; D000418:Albumins; D000505:Alopecia; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009503:Neutropenia; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D011446:Prospective Studies; D016896:Treatment Outcome",
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"abstract": "The frequency and types of adverse events after initial antithyroid drug (ATD) therapy during pregnancy have never been reported, nor has whether the frequency of adverse events is the same as among nonpregnant subjects ever been investigated. We investigated retrospectively the frequency of adverse events after initial ATD administration to previously untreated Graves' disease (GD) patients during pregnancy. We reviewed the charts of cases of 91 untreated pregnant women who came to our hospital for the first time and were newly diagnosed with GD during the period between January 1, 1999, and December 31, 2011. Thiamazole (MMI) was used to treat 40 patients and 51 patients were treated with propylthiouracil (PTU). Adverse events occurred in 5 patients (5/40; 12.5%) treated with MMI, and they consisted of cutaneous reactions in 5 patients. Adverse events occurred in five patients (5/51; 9.8%) treated with PTU, and they consisted of hepatotoxicity in two patients and cutaneous reactions in three patients. No patients experienced agranulocytosis or ANCA-related vasculitis. Comparison with the expected rate of adverse events in nonpregnant individuals showed that the frequency of adverse events in pregnant individuals was low.",
"affiliations": "Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.;Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.",
"authors": "Yoshihara|Ai|A|;Noh|Jaeduk Yoshimura|JY|;Watanabe|Natsuko|N|;Iwaku|Kenji|K|;Kobayashi|Sakiko|S|;Suzuki|Miho|M|;Ohye|Hidemi|H|;Matsumoto|Masako|M|;Kunii|Yo|Y|;Mukasa|Koji|K|;Sugino|Kiminori|K|;Ito|Koichi|K|",
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"fulltext": "\n==== Front\nJ Thyroid ResJ Thyroid ResJTRJournal of Thyroid Research2090-80672042-0072Hindawi Publishing Corporation 10.1155/2014/952352Clinical StudyFrequency of Adverse Events of Antithyroid Drugs Administered during Pregnancy Yoshihara Ai *Noh Jaeduk Yoshimura Watanabe Natsuko Iwaku Kenji Kobayashi Sakiko Suzuki Miho Ohye Hidemi Matsumoto Masako Kunii Yo Mukasa Koji Sugino Kiminori Ito Koichi Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan*Ai Yoshihara: a-yoshihara@ito-hospital.jpAcademic Editor: Julie A. Sosa\n\n2014 9 1 2014 2014 9523522 10 2013 26 11 2013 15 12 2013 Copyright © 2014 Ai Yoshihara et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The frequency and types of adverse events after initial antithyroid drug (ATD) therapy during pregnancy have never been reported, nor has whether the frequency of adverse events is the same as among nonpregnant subjects ever been investigated. We investigated retrospectively the frequency of adverse events after initial ATD administration to previously untreated Graves' disease (GD) patients during pregnancy. We reviewed the charts of cases of 91 untreated pregnant women who came to our hospital for the first time and were newly diagnosed with GD during the period between January 1, 1999, and December 31, 2011. Thiamazole (MMI) was used to treat 40 patients and 51 patients were treated with propylthiouracil (PTU). Adverse events occurred in 5 patients (5/40; 12.5%) treated with MMI, and they consisted of cutaneous reactions in 5 patients. Adverse events occurred in five patients (5/51; 9.8%) treated with PTU, and they consisted of hepatotoxicity in two patients and cutaneous reactions in three patients. No patients experienced agranulocytosis or ANCA-related vasculitis. Comparison with the expected rate of adverse events in nonpregnant individuals showed that the frequency of adverse events in pregnant individuals was low.\n==== Body\n1. Introduction\nThyrotoxicosis occurs in approximately 0.2% of pregnancies, and the most common cause of thyrotoxicosis is Graves' disease (GD) [1, 2]. GD is common in young women of childbearing age, and poorly controlled GD during pregnancy can cause serious complications in both the mother and the fetus. The differential diagnosis of GD from gestational thyrotoxicosis is supported by a typical goiter, the presence of TSH receptor antibody (TRAb), and signs of Graves' ophthalmopathy. Thiamazole (MMI) and propylthiouracil (PTU) are antithyroid drugs (ATDs) that are used to treat GD. ATDs are associated with a rather high frequency of adverse events; hepatotoxicity, cutaneous reactions, and agranulocytosis are the main adverse events [3]. Frequencies of adverse events in Japanese GD patients after initial ATD treatment have recently been reported [3, 4], and according to the reports the percentage of patients with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels more than twice the upper limit of the reference range was 25.8–26.9% among patients treated with PTU as opposed to 6.6–9.0% among patients treated with MMI, and the percentage of patients with a cutaneous reaction (skin eruption or urticarial eruption) was 18.3–22.1% among the patients treated with PTU and 6.6–31.9% among the patients treated with MMI. There have been no reports on the frequencies and types of adverse events of initial ATD treatment during pregnancy. In this study we investigated the frequency of adverse events in untreated pregnant GD patients after initial ATD treatment during pregnancy.\n\n2. Subjects and Methods\nWe reviewed the cases of 91 untreated pregnant women who came to our hospital for the first time and were newly diagnosed with GD during the period between January 1, 1999, and December 31, 2011. The diagnosis of GD was made on the basis of elevation of the serum free triiodothyronine (fT3) level and free thyroxine (fT4) level, suppression of the serum TSH level, a typical goiter, ophthalmopathy, and the presence of TSH receptor antibody (TRAb). Gestational transient thyrotoxicosis was differentiated and excluded by the presence of TRAb. Patients were assessed for adverse events by a careful health interview and physical examination. Patients visited our hospital every two weeks for two months after initiation of their treatment. Then, they were followed up every 1 to 2 months according to their thyroid function and symptoms. Serum thyroid hormone levels, TSH, AST, and ALT and hematological values were measured and a blood examination was performed at each outpatient visit. AST and ALT levels more than twice the upper limit of their reference ranges were considered evidence of hepatotoxicity as an adverse effect of the ATD.\n\n3. Statistical Analysis\nData were statistically analyzed by using the chi-squared test or Fisher's exact test. Calculations were performed using the JMP software program, version 10.0.0 (SAS Institute Inc., Cary, NC). The results of the statistical analyses were considered significant at P values < 0.05.\n\n4. Results\nMMI was used to treat 40 patients, and 51 patients were treated with PTU. There were no significant differences between the two groups in serum fT3, fT4, serum TRAb, AST, or ALT values (data not shown). The characteristics of the 91 patients are shown in Table 1. Among 40 patients treated with MMI, 21 patients started treatment during the first trimester, 18 patients started during the second trimester, and one patient started during the third trimester. Adverse events occurred in 5 patients (5/40; 12.5%) treated with MMI, and they consisted of cutaneous reactions. Three of them started MMI during the first trimester of pregnancy and the other 2 patients started during the second trimester of pregnancy.\n\nTwo of the 5 patients in the MMI group who had cutaneous reactions continued taking MMI, and their pruritus and drug rashes resolved. Treatment in the other 3 patients was switched from MMI to PTU or potassium iodide and their symptom resolved. The cutaneous reactions in these 5 patients had occurred two to six weeks after the start of MMI. All 5 patients successfully delivered full-term healthy infants. As shown in Table 1 and Figure 1, there were no significant differences between maternal age and the starting dose of MMI in the group that developed adverse events and the group that did not develop adverse events. Figure 1 shows the starting dose of MMI in the group that developed adverse events and the group that did not develop adverse events. The rate of preterm delivery was 7.5% (3/40), and one newborn had a congenital abnormality, an omphalocele. The mother of the infant with the omphalocele had started taking a 30 mg dose of MMI daily at 4 weeks of pregnancy and had continued until delivery.\n\nAmong 51 patients treated with PTU, 26 patients started treatment during the first trimester, 22 patients started during the second trimester, and 3 patients started during the third trimester. Adverse events occurred in five patients (5/51; 9.8%); four of them started PTU during the first trimester of pregnancy and the other one patient started during the second trimester of pregnancy. Adverse events consisted of hepatotoxicity in two patients and cutaneous reactions in three patients. No patients experienced hematologic side-effects including agranulocytosis [5] or ANCA-related vasculitis [6]. The two patients who developed hepatotoxicity discontinued PTU. In one of the patients, PTU was started from the fourth week of pregnancy and the AST and ALT levels had increased to more than twice the upper limit of the normal range at 9 weeks after the start of treatment. In the other patient, PTU was started from the fourth week of pregnancy and the AST level had increased to 3 times the upper limit of the normal range and the ALT level to more than 5 times the upper limit of the normal range at two weeks, and PTU was discontinued. Both patients' liver function improved immediately after PTU was discontinued. Treatment in these two patients was switched from PTU to potassium iodide, and their thyroid status was well controlled. Both of them successfully delivered full-term healthy infants. Cutaneous reactions occurred in three patients treated with PTU. Two of them continued taking PTU, and their pruritus and drug rashes resolved. It was necessary to discontinue PTU in the third patient. Her treatment was switched from PTU to potassium iodide, and she successfully delivered a full-term healthy infant. The cutaneous reactions in these three patients developed two to ten weeks after the start of PTU treatment. As shown in Table 1 and Figure 1, there were no significant differences between maternal age and the starting dose of PTU in the group that developed adverse events and the group that did not develop adverse events. The rate of preterm delivery was 7.8% (4/51), and none of the infants of the mothers treated with PTU were born with a congenital abnormality. There was no significant difference in frequency of adverse events between MMI and PTU.\n\n5. Discussion\nHyperthyroidism in pregnancy is a serious condition that entails an increased risk of adverse obstetric outcomes, including miscarriage, stillbirth, preterm birth, and intrauterine growth restriction. ATDs should be used to treat hyperthyroidism due to GD during pregnancy. In the last decades, MMI and PTU have been used equally to treat GD during pregnancy, regardless of trimester. In recent years, PTU has been the preferred drug because of concerns about teratogenicity associated with MMI during the first trimester of pregnancy. The ATA recommendation suggests using PTU during the first trimester and MMI during the second trimester. The majority of cases in our study were treated before the recommendation was published, and in 21 patients treatment with MMI was started in the first trimester. The only infant born with an omphalocele was delivered by a mother treated with MMI starting in the first trimester, and this congenital abnormality may be related to administration of MMI starting in the first trimester of pregnancy [7]. The rate of preterm delivery by patients treated with an ATD was high in comparison with the rate of 5% in the general population [8]. Before treating patients with an ATD they should be informed of the possible development of adverse events such as pruritic rashes, liver dysfunction, and agranulocytosis. In Japan, a physical examination and blood testing are mandated every two weeks especially within 2 months after the start of ATD treatment to enable early detection of agranulocytosis and liver dysfunction. This practice may be useful for early detection of mild cutaneous reactions and liver dysfunction associated with ATD treatment.\n\nA previous study of the frequency of adverse events of MMI and PTU in nonpregnant GD patients at our hospital reported the development of cutaneous reactions in 31.9% of the patients treated with MMI and in 18.3% of the patients treated with PTU. The frequency of hepatotoxicity was 9.0% in the MMI group and 25.8% in the PTU group. Our study in pregnant GD patients showed that the frequency of cutaneous reactions among the patients treated with MMI was 12.5% and 5.9% among the patients treated with PTU. No patients treated with MMI developed hepatotoxicity, and the frequency of hepatotoxicity among the patients treated with PTU was 3.9%. Since the study design was completely different, it is difficult to compare the frequencies of adverse events between the pregnant patients and the nonpregnant patients. Comparison with the expected rate of adverse events in nonpregnant individuals showed that the frequency of adverse events in pregnant individuals was low. At least, the frequencies of adverse events in the pregnant patients were not higher than in the nonpregnant patients. The reason for the lower frequencies of adverse drug reactions in the pregnant women is unclear. Reduced immune reaction during pregnancy may be the cause of low frequency of adverse reaction. However, whether the mechanisms of the rashes or hepatotoxicity induced by ATDs are related to immune reactions has never been investigated. It should be noted that the occurrence of severe liver injury in patients treated with PTU is rare. It has been estimated that 4 of the approximately 4000 pregnant women treated with PTU each year in the United States develop PTU-related severe liver injury [9]. Six cases of PTU-induced hepatitis during pregnancy have been reported in the medical literature [10–13]. Based on this small sample the outcome appears to be particularly poor in pregnancy, because there was 1 maternal death and 2 patients required a liver transplant. One case of neonatal hepatitis as an adverse effect of maternal treatment with PTU has also been reported [14].\n\nLimitation of this study was that the number of subjects was relatively small because we selected untreated hyperthyroid pregnant women diagnosed with GD for the first time during their pregnancy. Prospective study is preferable; however, it seems to be difficult because pregnant women newly diagnosed as GD during pregnancy are rare, and initial MMI administration to untreated GD patients during the first trimester of pregnancy is not recommended from guideline of Endocrine Society and guideline of the American Thyroid Association [15, 16].\n\nIn conclusion, this is the first study that studied the frequencies of adverse events after initial treatment with an ATD during pregnancy in newly diagnosed GD patients.\n\nConflict of Interests\nThe authors declare that they have no competing financial interests.\n\nFigure 1 Starting dose of ATD in the group that developed adverse events and the group that did not develop adverse events.\n\nTable 1 The ages and initial dose of the patients treated with antithyroid drug who developed and did not develop adverse events.\n\n \t \tAge, yr\tInitial dose (mg/day)\t\n \tNo. of patients\tMean ± SD\tMedian \tRange \t\n \tMMI\tPTU\tMMI\tPTU\tMMI\tPTU\tMMI\tPTU\t\nWithout adverse events \t35 \t46 \t29.7 ± 4.9 \t32.1 ± 4.7 \t30 \t300 \t10~45 \t50~450 \t\nWith adverse events \t5 \t5 \t29.2 ± 2.7 \t33.3 ± 4.2 \t30 \t200 \t15~30 \t150~300 \t\n\n\n\t\n\nP value \t \t \tn.s. \tn.s. \tn.s. \tn.s. \t \t \t\nThere were no significant differences between maternal age and the starting dose of ATD (MMI and PTU) in the group that developed adverse events and the group that did not develop adverse events.\n\nThere was no significant difference in frequency of adverse events between MMI and PTU.\n==== Refs\n1 Ecker JL Musci TJ Treatment of thyroid disease in pregnancy Obstetrics and Gynecology Clinics of North America 1997 24 3 575 589 2-s2.0-0030861668 9266579 \n2 Mestman JH Hyperthyroidism in pregnancy Best Practice & Research 2004 18 2 267 288 15157840 \n3 Otsuka F Noh JY Chino T Hepatotoxicity and cutaneous reactions after antithyroid drug administration Clinical Endocrinology 2012 77 2 310 315 22332800 \n4 Nakamura H Noh JY Itoh K Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease Journal of Clinical Endocrinology and Metabolism 2007 92 6 2157 2162 2-s2.0-34347220167 17389704 \n5 Watanabe N Narimatsu H Noh JY Antithyroid drug-induced hematopoietic damage: A retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves’ disease Journal of Clinical Endocrinology and Metabolism 2012 97 1 E49 E53 2-s2.0-84855499793 22049174 \n6 Noh JY Yasuda S Sato S Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis caused by antithyroid drugs Journal of Clinical Endocrinology and Metabolism 2009 94 8 2806 2811 2-s2.0-68549117057 19491223 \n7 Yoshihara A Noh J Yamaguchi T Treatment of Graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation Journal of Clinical Endocrinology & Metabolism 2012 97 7 2396 2403 22547422 \n8 Rosenfeld H Ornoy A Shechtman S Diav-Citrin O Pregnancy outcome, thyroid dysfunction and fetal goitre after in utero exposure to propylthiouracil: a controlled cohort study British Journal of Clinical Pharmacology 2009 68 4 609 617 2-s2.0-70449107192 19843064 \n9 Cooper DS Rivkees SA Putting propylthiouracil in perspective Journal of Clinical Endocrinology and Metabolism 2009 94 6 1881 1882 2-s2.0-66749168252 19401361 \n10 Taylor PN Vaidya B Side effects of anti-thyroid drugs and their impact on the choice of treatment for thyrotoxicosis in pregnancy European Thyroid Journal 2012 1 3 176 185 24783017 \n11 Kontoleon P Ilias I Koutras DA Kontogiannis D Papapetrou PD Successful treatment with carbimazole of a hyperthyroid pregnancy with hepatic impairment after propylthiouracil administration: a case report Clinical and Experimental Obstetrics and Gynecology 2002 29 4 304 305 2-s2.0-0036987780 12635752 \n12 Parker WA Propylthiouracil-induced hepatotoxicity Clinical Pharmacology 1982 1 5 471 474 \n13 Taylor P Bhatt S Gouni R Quinlan J Robinson T A case of propylthiouracil-induced hepatitis during pregnancy European Thyroid Journal 2012 1 1 41 44 24782996 \n14 Hayashida CY Duarte AJS Sato AE Yamashiro-Kanashiro EH Neonatal hepatitis and lymphocyte sensitization by placental transfer of propylthiouracil Journal of Endocrinological Investigation 1990 13 11 937 941 2-s2.0-0025651009 2090674 \n15 de Groot L Abalovich M Alexander EK Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline The Journal of Clinical Endocrinology & Metabolism 2012 97 8 2543 2565 22869843 \n16 Stagnaro-Green A Abalovich M Alexander E Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum Thyroid 2011 21 10 1081 1125 2-s2.0-80053181984 21787128\n\n",
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"abstract": "Ozurdex is a dexamethasone intravitreal implant used for the treatment of macular oedema. A rare but serious complication is the migration of the implant into the anterior chamber (AC) in eyes with absent or incomplete posterior capsules that may lead to corneal decompensation. We report the case of a 75-year-old woman who presented with a 1-day history of decreased vision in her left eye. She had a history of complicated cataract surgery and had received multiple Ozurdex implants for postoperative cystoid macular oedema in the same eye. She had significant left corneal decompensation and a mobile Ozurdex implant in the AC. We report a simple but novel surgical technique for removing an Ozurdex implant from the AC using an intravenous cannula (Venflon). This technique can also be applied to removing a fluocinolone acetonide (Iluvien) implant in similar situations.",
"affiliations": "Department of Eye and Vision Science, University of Liverpool, Liverpool, UK jku@liverpool.ac.uk.;Department of Glaucoma, Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester, UK.;Department of Glaucoma, Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester, UK.",
"authors": "Ku|Jae Yee|JY|http://orcid.org/0000-0002-5758-7346;Mercieca|Karl|K|;Yau|Kenneth|K|",
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"title": "Removal of a migrated dexamethasone implant (Ozurdex) from the anterior chamber using an intravenous cannula.",
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"companynumb": "GB-ALLERGAN-2126841US",
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"patient": {
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"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "Infectious complications constitute a leading cause of morbidity and mortality in chronic lymphocytic leukemia (CLL). Patients respond poorly to vaccines, particularly pneumococcal polysaccharide and influenza vaccines. In addition, patients with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated clinical activity in CLL, can potentially restore immune system dysfunction associated with CLL while improving disease outcomes.\n\n\n\nPhase II study randomized 49 patients with genetically high-risk CLL or small lymphocytic lymphoma [SLL; defined as unmutated Ig heavy chain variable region, deletion(17p) or (11q), and/or complex abnormal karyotype], to receive lenalidomide either concurrent (arm A) or sequential to (arm B) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13) administered 2 months apart, in patients not meeting International Workshop on Chronic Lymphocytic Leukemia treatment criteria.\n\n\n\nFour serotypes (3, 4, 5, 6B) achieved the additional seroprotection definition of a fourfold increase in arm A, and six serotypes (3, 4, 5, 6B, 19A, 19F) in arm B. All patients achieved the defined concentration of 0.35 μg/mL for at least one serotype tested. No significant difference was observed with the addition of lenalidomide. At median time on treatment of 3.6 years, median progression-free survival (PFS) was 5.8 years [95% confidence interval (CI), 3.1-not reached]. PFS at 1, 2, and 3 years was 85% (95% CI, 72-93), 79% (95% CI, 64-88), and 72% (95% CI, 57-83), respectively.\n\n\n\nLenalidomide is efficacious with manageable toxicities as an early intervention strategy in patients with high-risk CLL, but did not enhance humoral response to PCV13 vaccine.",
"affiliations": "Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. farrukh.awan@utsouthwestern.edu john.byrd@osumc.edu.;Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. farrukh.awan@utsouthwestern.edu john.byrd@osumc.edu.",
"authors": "Thangavadivel|Shanmugapriya|S|0000-0001-9542-9050;Zhao|Qiuhong|Q|;Epperla|Narendranath|N|;Rike|Lindsey|L|;Mo|Xiaokui|X|;Badawi|Mohamed|M|;Bystry|Darlene M|DM|;Phelps|Mitch A|MA|0000-0002-1615-5280;Andritsos|Leslie A|LA|;Rogers|Kerry A|KA|0000-0001-5748-7874;Jones|Jeffrey|J|;Woyach|Jennifer A|JA|;Byrd|John C|JC|;Awan|Farrukh T|FT|0000-0003-1813-9812",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-20-1280",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "26(23)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "6187-6195",
"pmc": null,
"pmid": "32958702",
"pubdate": "2020-12-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "22547582;26337493;28958469;29748028;20055657;20956622;30030269;21292668;18628480;15982350;1244564;26161926;18024648;9490560;18053620;28916311;24990888;27185642;23801633;11166890;11557327;30104242;19965642;27465919;29288818;11040852;29160119;10340906;29468645;32239979;2446736;32555297;25639448;28622959",
"title": "Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia.",
"title_normalized": "early intervention with lenalidomide in patients with high risk chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-CELGENEUS-USA-20201003940",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
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"drugadditional": "3",
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{
"abstract": "There is uncertainty about the safety of kidney transplantation during the SARS-CoV-2 pandemic due to the risk of donor transmission, nosocomial infection and immunosuppression use. We describe organ donation and transplant practice in the UK and assess whether kidney transplantation conferred a substantial risk of harm. Data from the UK transplant registry were used to describe kidney donation and transplant activity in the UK, and a detailed analysis of short-term, single-center, patient results in two periods: during the pre-pandemic era from 30th December 2019 to 8th March 2020 (\"Pre-COVID era\") and the 9th March 2020 to 19th May 2020 (\"COVID era\"). Donor and recipient numbers fell by more than half in the COVID compared to the pre-COVID era in the UK, but there were more kidney transplants performed in our center (42 vs. 29 COVID vs. pre-COVID respectively). Overall outcomes, including re-operation, delayed graft function, primary non-function, acute rejection, length of stay and graft survival were similar between COVID and pre-COVID era. 6/71 patients became infected with SARS-CoV-2 but all were discharged without critical care requirement. Transplant outcomes have remained similar within the COVID period and no serious sequelae of SARS-CoV-2 infection were observed in the peri-transplant period.",
"affiliations": "Department of Surgery, University of Cambridge, Cambridge, UK.;Department of Surgery, University of Cambridge, Cambridge, UK.;Department of Surgery, University of Cambridge, Cambridge, UK.;Department of Transplantation, Cambridge University Hospitals, Cambridge, UK.;Department of Medicine, University of Cambridge, Cambridge, UK.;Department of Transplantation, Cambridge University Hospitals, Cambridge, UK.",
"authors": "Georgiades|Fanourios|F|0000-0003-0440-2720;Summers|Dominic M|DM|0000-0003-3360-0726;Butler|Andrew J|AJ|0000-0003-3869-9120;Russell|Neil K I|NKI|0000-0002-3265-4514;Clatworthy|Menna R|MR|0000-0002-3340-9828;Torpey|Nicholas|N|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.14150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "35(1)",
"journal": "Clinical transplantation",
"keywords": "COVID-19; SARS-CoV-2; coronavirus pandemic; kidney transplantation; organ donation",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D006084:Graft Rejection; D061847:Hospitals, High-Volume; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D066027:Transplant Recipients; D006113:United Kingdom",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e14150",
"pmc": null,
"pmid": "33170982",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Renal transplantation during the SARS-CoV-2 pandemic in the UK: Experience from a large-volume center.",
"title_normalized": "renal transplantation during the sars cov 2 pandemic in the uk experience from a large volume center"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1893683",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "This retrospective study investigated the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory multiple myeloma (MM). A total of 30 patients who relapsed or progressed after ≥6 months since the last dose of their previous bortezomib therapy were included in this study. During the median 6 cycles (range: 2-12) of bortezomib retreatment, 10 (33.3%), 2 (6.7%), and 6 (20.0%) patients achieved complete response, very good partial response, and partial response, respectively. Grade 3 or 4 neutropenia (47.0%), thrombocytopenia (43.0%), anemia (10.0%), and peripheral sensory neuropathy (3.0%) were observed. The median time to progression, progression-free survival, and overall survival were 5.8 months (95% CI: 2.6-9.0), 5.5 months (95% CI: 4.2-6.8), and 13.4 months (95% CI: 6.1-20.7), respectively. Patients who received bortezomib retreatment ≥12 months from initial last therapy had a 1-year OS rate of 65.8% (95% CI: 43.5-88.1) while patients receiving retreatment after 6-12 months interval had a 1-year OS rate of 41.7% (95% CI: 13.9-69.5) (P = 0.038). In conclusion, this study demonstrates that retreatment with bortezomib is an effective strategy for patients with MM who relapsed at a long interval after initial bortezomib therapy.",
"affiliations": "Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea.",
"authors": "Ahn|Jae-Sook|JS|;Jung|Sung-Hoon|SH|;Lee|Seung-Shin|SS|;Ahn|Seo-Yeon|SY|;Yang|Deok-Hwan|DH|;Kim|Yeo-Kyeoung|YK|;Kim|Hyeoung-Joon|HJ|;Lee|Je-Jung|JJ|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": "10.1155/2014/145843",
"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi Publishing Corporation 10.1155/2014/145843Clinical StudyClinical Outcome of Bortezomib Retreatment in Patients with Relapsed or Refractory Multiple Myeloma Ahn Jae-Sook Jung Sung-Hoon Lee Seung-Shin Ahn Seo-Yeon Yang Deok-Hwan Kim Yeo-Kyeoung Kim Hyeoung-Joon Lee Je-Jung \n*\nDepartment of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 519-763, Republic of Korea*Je-Jung Lee: drjejung@chonnam.ac.krAcademic Editor: John B. Vincent\n\n2014 30 10 2014 2014 14584326 8 2014 8 10 2014 Copyright © 2014 Jae-Sook Ahn et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This retrospective study investigated the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory multiple myeloma (MM). A total of 30 patients who relapsed or progressed after ≥6 months since the last dose of their previous bortezomib therapy were included in this study. During the median 6 cycles (range: 2–12) of bortezomib retreatment, 10 (33.3%), 2 (6.7%), and 6 (20.0%) patients achieved complete response, very good partial response, and partial response, respectively. Grade 3 or 4 neutropenia (47.0%), thrombocytopenia (43.0%), anemia (10.0%), and peripheral sensory neuropathy (3.0%) were observed. The median time to progression, progression-free survival, and overall survival were 5.8 months (95% CI: 2.6–9.0), 5.5 months (95% CI: 4.2–6.8), and 13.4 months (95% CI: 6.1–20.7), respectively. Patients who received bortezomib retreatment ≥12 months from initial last therapy had a 1-year OS rate of 65.8% (95% CI: 43.5–88.1) while patients receiving retreatment after 6–12 months interval had a 1-year OS rate of 41.7% (95% CI: 13.9–69.5) (P = 0.038). In conclusion, this study demonstrates that retreatment with bortezomib is an effective strategy for patients with MM who relapsed at a long interval after initial bortezomib therapy.\n==== Body\n1. Introduction\nOver the past decade the introduction of novel agents, such as thalidomide, lenalidomide, and bortezomib, has advanced the treatment outcomes of patients with multiple myeloma (MM) [1, 2]. These agents are considered effective in controlling both newly diagnosed and relapsed MM. However, most patients with MM are observed to progress over various durations. The basic treatment strategy for relapsed or refractory MM is sequential drug treatment with untreated agents, because the disease is likely to have become resistant to the particular class of drug used for initial treatment [3].\n\nGenerally, relapse is thought to be due to the changing tumor biology and evolution of drug resistant phenotypes within the tumor [4, 5]. However, incorporation of novel agents into the first-line therapy raises new theories about the feasibility of retreatment with such agents. The factors influencing treatment choice in the relapsed setting include the duration of response to prior therapy and the associated toxicity profiles [6]. The National Comprehensive Cancer Network clinical guidelines recommend repeating the same primary induction therapy if the relapse occurs with an interval of ≥6 months after primary therapy [7]. Several studies reported the results of bortezomib retreatment in MM. In a prospective phase II study, retreatment with bortezomib resulted in an overall response rate (ORR) of 40%, time to progression (TTP) was 8.4 months, and grade 3-4 thrombocytopenia (35%) was the most common adverse event [6]. In retrospective reviews of relatively large numbers of patients, the ORR was 21–63.3% and TTP was 9.3 months [8–10]. One of the most important considerations for the choice of retreatment is the generation of cumulative toxicities. Bortezomib treatment produces different toxicities in Asians compared to Western populations, and bortezomib-based salvage therapy studies on Asians showed higher response rates compared to those performed on Western populations [11–13]. Bortezomib retreatment response rates and toxicities could also differ.\n\nThe purpose of this retrospective study was to evaluate the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory MM in Korea.\n\n2. Patients and Methods\n2.1. Patients\nThis study was a retrospective clinical trial conducted at the Chonnam National University Hwasun Hospital in Korea. Clinical records from November 2004 to April 2013 were reviewed. Eligibility criteria for the study included MM patients who underwent bortezomib retreatment after bortezomib-based salvage therapy, and patients had ≥1 measurable lesions at relapse. Measurable lesions were defined as (1) serum or urine M-protein, (2) measurable bone lesions or plasmacytomas, (3) measurable difference between involved and uninvolved FLC levels, and (4) bone marrow plasma cell percentage (absolute percentage must be ≥10%). We selected patients who relapsed or progressed ≥6 months after the last dose of the previous bortezomib therapy. Exclusion criteria included immunoglobulin M type MM, primary amyloidosis, and plasma cell leukemia.\n\n2.2. Treatment\nAll patients received combination therapy during bortezomib retreatment. Treatment of Vel-CTD consisted of 3-week cycles of bortezomib (1.3 mg/m2 intravenously on days 1, 4, 8, and 11); dexamethasone (20 mg/m2/day intravenously on days 1, 4, 8, and 11); cyclophosphamide (150 mg/m2 orally on days 1 to 4); and thalidomide (50 mg orally daily for the entire 21 days) [13]. Vel-CD was the same regimen with the exclusion of thalidomide [12]. The start of a new cycle could be delayed on a weekly basis (for a maximum of 3 weeks) until recovery of toxicity (to a grade 2 or less) was achieved, allowing therapy to continue. If the patient had peripheral neuropathy of grade 2, or grade 1 with pain, bortezomib was reduced to 1.0 mg/m2; for ≥grade 3 peripheral neuropathy, bortezomib was withheld until the peripheral neuropathy resolved to baseline and then restarted at 0.7 mg/m2. Simultaneously, thalidomide was omitted until the toxicity resolved to baseline or decreased to below grade 1. Most of the patients were also given gabapentin (300–1,800 mg/day), nonsteroidal anti-inflammatory drugs, or opioids as adjuvants for pain control depending on pain severity. Since 2010, bortezomib was administered by weekly subcutaneous injection in patients with peripheral neuropathy of grade 2 or grade 1 with pain. Routine antiviral prophylaxis (acyclovir 400 mg once daily) for herpes zoster infection was administered [14] and patients in the Vel-CTD group were administered 100 mg aspirin to prevent deep vein thrombosis during thalidomide administration. All patients prophylactically received a proton pump inhibitor and monthly bisphosphonate treatment with zoledronate or pamidronate if they had lytic bone lesions. Thalidomide was discontinued permanently in the event of thrombosis despite prophylaxis [12].\n\n2.3. Response and Toxicities Assessment\nThe myeloma response was evaluated during each cycle of bortezomib retreatment. After each cycle, the measurable disease was routinely checked including serum or urine M-protein, serum FLC and its ratio, and the size of plasmacytoma if physically possible. For evaluation of response the International Myeloma Working Group (IMWG) uniform response criteria were used [15], but there was no discrimination between complete response (CR) and stringent CR because the absence of clone cells in the bone marrow could not be confirmed in the retrospective data. Adverse events were graded for every cycle according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.0, 2009).\n\n2.4. Statistical Analysis\nDescriptive statistics are summarized as frequency counts and percentages for categorical variables and as medians and ranges for continuous variables. The chi-square test was used to establish differences in the distribution of categorical data and Student's t-test to compare continuous variables. TTP was defined as the time from start of bortezomib retreatment to disease progression, with death from causes other than progression censored. Progression-free survival (PFS) was defined as the duration from start of bortezomib retreatment to disease progression or death, regardless of cause of death. Overall survival (OS) was defined as the duration from the start of bortezomib retreatment until the last follow-up or death [15]. TTP, PFS, and OS were analyzed using Kaplan-Meier survival curve estimates, and the differences between groups were compared using stratified log-rank tests. P < 0.05 was considered to indicate statistical significance, and 95% confidence intervals were calculated accordingly. All statistical computations were performed using the Statistical Package for the Social Sciences version 18.0 (SPSS, Chicago, IL, USA).\n\n3. Results\n3.1. Patients' Characteristics\nBetween November 2004 and April 2012, 165 patients received bortezomib-based salvage therapy and 34 of the 165 patients received bortezomib retreatment. Four patients were excluded because they received bortezomib retreatment within 6 months of the last dose of bortezomib salvage therapy. Therefore, 30 patients were enrolled in this study.\n\nThe baseline characteristics and disease demographics are described in Table 1. The median age at commencement of bortezomib retreatment was 67 years (range: 51–81) and 60% were ≥65 years. At the start of bortezomib retreatment 20% of patients were diagnosed with light-chain disease. The median time from diagnosis to bortezomib retreatment therapy was 43.6 months (range: 16.9–249.6) and the duration from initial last dose of bortezomib to retreatment was 12.9 months (6.7–63.6). At study enrollment 44% of patients were classified as Stage II or Stage III by the International Staging System (ISS). Patients had previously received the median number of 2 line chemotherapies (range: 2–5) and 50% of patients had previously received autologous stem cell transplantation (ASCT). Most of the patients had received prior thalidomide combination therapy (93.3%). For the bortezomib retreatment combination therapy regimen, 21 (70%) patients received We already defined the Vel-CTD and Vel-CD in methods, as reported previously [12]. Additionally 2 (6.7%) patients were enrolled in a clinical trial of dexamethasone and panobinostat combination therapy.\n\n3.2. Treatment Response\nThe median number of treatment cycles was 6 (range: 2–12) and the number of cycles delivered was 196. For the best response after the initial bortezomib salvage chemotherapy, 73.3% of patients had CR, 10% had very good partial response (VGPR), 10% had partial response (PR), and 6.7% had SD. After the bortezomib retreatment therapies, 10 patients (33.3%) achieved CR, 2 patients (6.7%) had VGPR, and 6 patients (20%) had PR. The ORR (≥PR) was 60%. The relationship between best response to initial bortezomib therapy and bortezomib retreatment is shown in Table 1.\n\nThe median follow-up duration was 23.9 months (range: 10.5–55.8). The median TTP was 5.8 months [95% confidence interval (CI): 2.6–9.0], median PFS was 5.5 months (95% CI: 4.2–6.8), and median OS was 13.4 months (95% CI: 6.1–20.7; Figure 1). There was no significant difference in PFS or OS according to the combination therapy regimen with bortezomib retreatment (Vel-CD versus Vel-CTD) (P = 0.747). Survival was analyzed according to the time interval between the last dose of the initial therapy and retreatment with bortezomib. Eighteen patients commenced bortezomib retreatment with a ≥12-month interval and the remaining 12 patients commenced bortezomib retreatment with a <12-month interval. Of the patients who had a ≥12-month interval for bortezomib retreatment, the 1-year OS rate was 65.8% (95% CI: 43.5–88.1) compared to 41.7% (95% CI: 13.9–69.5) for patients with a <12-month interval (P = 0.038; Figure 2).\n\n3.3. Adverse Events\nDuring bortezomib retreatment, the most common adverse events were hematologic toxicities. Of the 30 patients, grade 3 or 4 hematologic toxicities including neutropenia (47%), thrombocytopenia (43%), leukopenia (37%), and anemia (10%) were observed (Table 3). Nonhematological toxicities were also observed (Table 2). The most frequently observed nonhematologic toxicity was asthenia (70%) and the second most common was sensory neuropathy (63%). The peripheral sensory neuropathy observed was grades 1, 2, and 3 in 33%, 27%, and 3% of patients, respectively. Gastrointestinal toxicity was mainly due to constipation; however, only 10% of patients experienced the maximal grade 2 constipation. Serious infection was observed in eight (27%) patients during bortezomib retreatment: pneumonia in five patients, fever in two, and bacteremia in one. No thromboembolic or bleeding episodes were observed during bortezomib retreatment.\n\nA total of 17 (57%) patients experienced dose reduction from the originally planned bortezomib dosage. The median number of cycles for the start of bortezomib dose modification was 3 (range: 1–9). The change to weekly subcutaneous administration of bortezomib was observed in 13 patients and dosage reduction (from 1.3 mg/m2 to 1.0 mg/m2) in 4 patients. The causes of dose reduction were grade 2 sensory neuropathy in six patients and grade 2 asthenia in six patients. Another five patients received bortezomib dose modification because of diarrhea (grade 2), pain (grade 2), nausea (grade 2), neutropenia (grade 4), and poor compliance. Two patients received the weekly bortezomib administration schedule at the start of the first cycle because of grade 2 sensory neuropathy and concomitantly received gabapentin and opioids for pain control. Only two (7%) patients had interrupted bortezomib retreatment due to grade 3 sensory neuropathy and grade 3 asthenia. The majority of patients (70%) had the bortezomib retreatment interrupted due to disease progression, while 23% of patients achieved CR and received maintenance therapy thereafter.\n\n4. Discussion\nThe purpose of this retrospective study was to evaluate the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory MM. The study included only patients who received bortezomib retreatment ≥6 months after the last dose of the initial treatment with bortezomib. All patients received three- or four-drug combination therapy and had also previously received bortezomib combined chemotherapy as a salvage treatment. The ORR was 60% and the median TTP, PFS, and OS were 5.8 months (CI: 2.6–9.0), 5.5 months (CI: 4.2–6.8), and 13.4 months (95% CI: 6.1–20.7), respectively. After initial bortezomib treatment, retreatment by later exposure to bortezomib was more effective in the control of progressed disease. Serious infection was observed in 27% of patients during bortezomib retreatment, and dose reduction was performed in 57% of patients. However, no patients died due to adverse events during bortezomib retreatment.\n\nPetrucci et al. [6] reported a phase II study of bortezomib retreatment in patients with relapsed MM. This prospective study included 130 patients and demonstrated an ORR of 40%. There were two main differences between this prospective study and the retrospective study reported here: patients in the prospective trial received bortezomib only or bortezomib-dexamethasone combination therapy and 30% of patients in the prospective study received stem cell transplantation, compared to 50% in our cohort. Based on these results, multiple drug combination in bortezomib retreatment is considered an effective and relatively safe method, even if patients were previously exposed to bortezomib. In the phase III VISTA trial, 77 (22%) patients received subsequent bortezomib and/or bortezomib combined retreatment after the first-line therapy (bortezomib, melphalan, and prednisone; VMP), and an investigator-assessed response rate of 50% was observed [16]. The VISTA trial used the VMP regimen for the initial first-line therapy and this might be the reason for the higher ORR compared to the phase II prospective trial [6, 16].\n\nTwo retrospective studies have included relatively large numbers of patients and showed marked differences in the best response to retreatment with bortezomib [8, 9]. Conner et al. [8] reported that only 21% of patients showed at least a PR to bortezomib retreatment. However, 41% of their cohort were nonresponders who did not achieve at least a PR to initial bortezomib treatment, and this study defined the gap between the final dose of the initial treatment and retreatment as only 60 days. Among patients for whom response assessment was available for both treatments, 32% of initial bortezomib responders had at least a PR to retreatment. Hrusovsky et al. [9] enrolled only patients who achieved at least a PR in previous bortezomib treatment and included all patients regardless of the duration from the end of initial treatment to the start of bortezomib retreatment. The ORR to bortezomib retreatment was 63.3%, and the patients with a ≥6-month interval from the last dose of initial bortezomib had an ORR of 76.9%. The major reason for the difference in ORR after bortezomib retreatment between the two retrospective studies is that Hrusovsky et al. [9] included only patients who showed an initial response to bortezomib therapy. Our patients were observed the higher CR rate (33.3%) than the other Caucasian data (0–13.3%) like that previous study of salvage bortezomib treatment results in Korean. However, there were no differences in the TTP or OS between our Korean data and Caucasian data [6, 8, 9, 12]. While our study enrolled only patients who received bortezomib retreatment after ≥6 months from the last dose of initial bortezomib treatment, the ORR was lower than that reported by Hrusovsky et al. [9]. Our cohort could be considered a heavily treated group because 50% of patients received the ASCT despite being of similar age, most patients were exposed to thalidomide (93%), and all patients received cyclophosphamide and dexamethasone combination therapy during initial bortezomib treatment.\n\nDose-limiting peripheral neuropathy is the major toxicity caused by bortezomib. Retreatment with bortezomib showed similar rates of sensory neuropathy when compared to initial bortezomib therapy [12]. While 70% of patients received the Vel-CTD regimen, grade 3 or more sensory neuropathy was rare in this study compared to our previous report [12]. Approximately 40% of patients received bortezomib dose adjustment due to treatment toxicity in the initial bortezomib therapy study, and 17 (57%) patients underwent dose reduction from the planned bortezomib dosage in this study [12]. Early modification of bortezomib administration to the weekly subcutaneous regimen may have contributed to the reduction of ≥grade 3 sensory neuropathy, even though the combination of thalidomide and bortezomib was used. Grade 4 hematologic toxicities were frequently observed, especially in neutropenia (17%) and thrombocytopenia (20%). However, there was no difference in the incidence of pneumonia or grade 4 hematologic toxicities in the initial bortezomib therapy, and only two (7%) patients had disrupted bortezomib retreatment due to sensory neuropathy and asthenia in this study [12]. The major cause of bortezomib retreatment cessation was disease progression (70%). The major concern for retreatment with bortezomib is drug resistance and toxicity, and this could be relatively controllable with vigorous monitoring of toxicities and modification of dosage. The recent meta-analysis reported the grade 3/4 toxicities in patients with bortezomib retreatment as 4.2% of peripheral neuropathy, 16.9% of neutropenia, and 37.6% of thrombocytopenia [17]. This meta-analysis mostly included the Caucasian and the hematologic toxicities were less frequently observed in comparison with our Korean data. However, there was no difference in grade 3/4 sensory neuropathy (4.2% versus 3%) between our Korean data and Caucasian data. The analysis of the OS according to the interval between initial therapy and retreatment revealed that bortezomib retreatment after ≥12 months from the last dose of initial therapy provided a significant survival benefit. This suggests that the sensitive relapse group could be selected using the time interval between initial bortezomib therapy and retreatment. The limitation of this study for generalization of the efficacy and safety of bortezomib retreatment is that this was a retrospective analysis of a small number of patients enrolled in a single institute. However, this study has clinical significance due to the scarcity of clinical data regarding the effectiveness of bortezomib retreatment with regard to response and toxicities, especially in the Asian population.\n\nIn conclusion, this study suggests that retreatment with bortezomib is an effective strategy for patients who relapsed with a long interval after initial bortezomib therapy. The data support the safety of bortezomib retreatment with active dosage modification.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 (a) Time to progression (TTP), (b) progression-free survival (PFS), and (c) overall survival (OS) of patients who received bortezomib retreatment. The median TTP was 5.8 months (95% CI: 2.6–9.0), median PFS was 5.8 months (95% CI: 4.2–6.8), and median OS was 13.4 months (95% CI: 6.1–20.7).\n\nFigure 2 Overall survival (OS) according to time interval (months) between initial bortezomib-based therapy and retreatment. Patients who received bortezomib retreatment ≥12 months from the final initial therapy had a 1-year OS rate of 65.8% (95% CI: 43.5–88.1) and patients receiving retreatment after <12-month interval had a 1-year OS rate of 41.7% (95% CI: 13.9–69.5) (P = 0.038).\n\nTable 1 Patients' characteristics for bortezomib retreatment.\n\nCharacteristic\tPatients, n (%)\t\nTotal number of patients\t30\t\nGender, male \t10 (33.3)\t\nMedian age at start of bortezomib retreatment, years (range)\t67 (51–81)\t\n Age ≥65 years, n (%)\t18 (60)\t\nMedian time in months from diagnosis to bortezomib retreatment (range)\t43.6 (16.9–249.6)\t\nMedian time in months from initial bortezomib treatment to retreatment (range)\t12.9 (6.7–63.5)\t\nParaprotein type at bortezomib retreatment\t \t\n IgG\t17 (56.7)\t\n IgA\t7 (23.3)\t\n Light-chain disease\t6 (20.0)\t\nDurie-Salmon stage at diagnosis, n (%)\t\nn = 28\t\n I\t4 (14.3)\t\n II\t6 (21.4)\t\n III\t18 (64.3)\t\nCreatinine ≥2 mg/dL at diagnosis\t4 (13.3)\t\nISS stage at diagnosis (%)\t\nn = 28\t\n I\t12 (42.9)\t\n II\t6 (21.4)\t\n III\t10 (35.7)\t\nISS stage at the study enrollment (%) \t\nn = 25\t\n I\t14 (56.0)\t\n II\t5 (20.0)\t\n III\t6 (24.0)\t\nPrior treatments, median (range)\t2 (2–5)\t\nPrior line of therapy, n\n\t \t\n 2\t17 (57)\t\n 3\t6 (20)\t\n 4\t4 (13)\t\n 5\t3 (10)\t\nPrior autologous stem cell transplantation, n (%)\t15 (50.0)\t\nPrior thalidomide exposure\t28 (93.3)\t\nPrior bortezomib combination therapy \t \t\n Vel-CD\t10 (33)\t\n Vel-CTD\t20 (67)\t\nCombination chemotherapy during bortezomib retreatment \t \t\n Vel-CD\t7 (33.3)\t\n Vel-CTD\t21 (70)\t\n Velcade, dexamethasone, panobinostat\t2 (6.7)\t\nISS: International Staging System; Vel-CD: bortezomib, cyclophosphamide, and dexamethasone; Vel-CTD: bortezomib, cyclophosphamide, thalidomide, and dexamethasone; FISH: fluorescence in situ hybridization; CR: complete response; VGPR: very good partial response; PR: partial response; SD: stable disease; PD: progressive disease.\n\nTable 2 Relationship between best response to initial bortezomib treatment and best response to bortezomib retreatment.\n\n \t \tBest response to bortezomib retreatment \t\n \t \tORR (%)\tCR\tVGPR\tPR\tSD\tPD\t\nBest response to initial bortezomib treatment\tORR (%)\t30\t10 (33)\t2 (7)\t6 (20)\t10 (33)\t2 (7)\t\nCR\t22 (73)\t9\t2\t5\t4\t2\t\nVGPR\t3 (10)\t0\t0\t1\t2\t0\t\nPR\t3 (10)\t1\t0\t0\t2\t0\t\nSD\t2 (7)\t0\t0\t0\t2\t0\t\nORR: overall response rate; CR: complete response; VGPRL very good partial response; PR: partial response; SD: stable disease; PD: progressive disease.\n\nTable 3 Hematologic and nonhematologic toxicities during bortezomib retreatment therapy according to the NCI-CTCAE 4.0.\n\nGrade\tNumber of patients in total 30, n (%)\t\n1\t2\t3\t4\t\nLeukopenia \t5 (17)\t9 (30)\t8 (27)\t3 (10)\t\nNeutropenia \t3 (10)\t8 (27)\t9 (30)\t5 (17)\t\nAnemia \t8 (27)\t15 (50)\t3 (10)\t0\t\nThrombocytopenia\t5 (17)\t10 (33)\t7 (23)\t6 (20)\t\nCreatinine\t2 (7)\t3 (10)\t1 (3)\t0\t\nAnorexia \t8 (27)\t0\t0\t0\t\nNausea \t6 (20)\t1 (3)\t0\t0\t\nVomiting \t1 (3)\t1 (3)\t0\t0\t\nDiarrhea \t2 (7)\t3 (10)\t0\t0\t\nConstipation \t5 (17)\t3 (10)\t0\t0\t\nDyspnea\t3 (10)\t1 (3)\t0\t0\t\nPneumonia \t0\t0\t5 (17)\t0\t\nFever/bacteremia\t0\t0\t3 (10)\t0\t\nSensory neuropathy \t10 (33)\t8 (27)\t1 (3)\t0\t\nMotor neuropathy\t4 (13)\t1 (3)\t1 (3)\t0\t\nPain\t10 (33)\t4 (13)\t0\t0\t\nDizziness \t11 (37)\t0\t0\t0\t\nDelirium \t1 (3)\t0\t0\t0\t\nInsomnia/somnolence\t6 (20)\t0\t0\t0\t\nAsthenia \t9 (30)\t11 (37)\t1 (3)\t0\t\nRash \t2 (7)\t0\t0\t0\t\nNCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.\n==== Refs\n1 Kumar S. K. Rajkumar S. V. Dispenzieri A. Lacy M. Q. Hayman S. R. Buadi F. K. Zeldenrust S. R. Dingli D. Russell S. J. Lust J. A. Greipp P. R. Kyle R. A. Gertz M. A. Improved survival in multiple myeloma and the impact of novel therapies Blood 2008 111 5 2516 2520 10.1182/blood-2007-10-116129 2-s2.0-41949130070 17975015 \n2 Park H. J. Park E. H. Jung K. W. Kong H. J. Won Y. J. Lee J. Y. Yoon J. H. Park B. K. Lee H. Eom H. S. Park S. Statistics of hematologic malignancies in korea: incidence, prevalence and survival rates from 1999 to 2008 Korean Journal of Hematology 2012 47 1 28 38 10.5045/kjh.2012.47.1.28 2-s2.0-84866894342 22479275 \n3 Mohty B. El-Cheikh J. Yakoub-Agha I. Avet-Loiseau H. Moreau P. Mohty M. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and retreatment approaches in the era of novel agents Leukemia 2012 26 1 73 85 2-s2.0-84856725064 10.1038/leu.2011.310 22024721 \n4 Kumar S. K. Therneau T. M. Gertz M. A. Lacy M. Q. Dispenzieri A. Rajkumar S. V. Fonseca R. Witzig T. E. Lust J. A. Larson D. R. Kyle R. A. Greipp P. R. Clinical course of patients with relapsed multiple myeloma Mayo Clinic Proceedings 2004 79 7 867 874 10.4065/79.7.867 2-s2.0-3042775299 15244382 \n5 Dimopoulos M. A. San-Miguel J. F. Anderson K. C. Emerging therapies for the treatment of relapsed or refractory multiple myeloma European Journal of Haematology 2011 86 1 1 15 10.1111/j.1600-0609.2010.01542.x 2-s2.0-78650087357 20942854 \n6 Petrucci M. T. Giraldo P. Corradini P. Teixeira A. Dimopoulos M. A. Blau I. W. Drach J. Angermund R. Allietta N. Broer E. Mitchell V. Bladé J. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma British Journal of Haematology 2013 160 5 649 659 10.1111/bjh.12198 2-s2.0-84873990173 23293914 \n7 NCCN NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Multiple Myeloma Version 1 2014 \n8 Conner T. M. Doan Q. C. D. Walters I. B. LeBlanc A. L. Beveridge R. A. An observational, retrospective analysis of retreatment with bortezomib for multiple myeloma Clinical Lymphoma and Myeloma 2008 8 3 140 145 10.3816/CLM.2008.n.016 2-s2.0-49649083607 18650176 \n9 Hrusovsky I. Emmerich B. Von Rohr A. Voegeli J. Taverna C. Olie R. A. Pliskat H. Frohn C. Hess G. Bortezomib retreatment in relapsed multiple myeloma-results from a retrospective multicentre survey in Germany and Switzerland Oncology 2011 79 3-4 247 254 2-s2.0-79952105543 10.1159/000322866 \n10 Mateos M. V. Richardson P. G. Schlag R. Khuageva N. K. Dimopoulos M. A. Shpilberg O. Kropff M. Spicka I. Petrucci M. T. Palumbo A. Samoilova O. S. Dmoszynska A. Abdulkadyrov K. M. Schots R. Jiang B. Esseltine D. L. Liu K. Cakana A. van de Velde H. San Miguel J. F. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial Journal of Clinical Oncology 2010 28 13 2259 2266 10.1200/JCO.2009.26.0638 2-s2.0-77952310929 20368561 \n11 Bang S. M. Lee J. H. Yoon S. S. et al A multicenter retrospective analysis of adverse events in Korean patients using bortezomib for multiple myeloma International Journal of Hematology 2006 83 4 309 313 10.1532/IJH97.A30512 2-s2.0-33744489589 16757429 \n12 Ahn J.-S. Yang D.-H. Jung S.-H. Park H. C. Moon J. H. Sohn S. K. Bae S.-Y. Kim Y.-K. Kim H.-J. Lee J.-J. A comparison of bortezomib, cyclophosphamide, and dexamethasone (Vel-CD) chemotherapy without and with thalidomide (Vel-CTD) for the treatment of relapsed or refractory multiple myeloma Annals of Hematology 2012 91 7 1023 1030 10.1007/s00277-012-1420-7 2-s2.0-84862769560 22314843 \n13 Kim Y. K. Sohn S. K. Lee J. H. Yang D. H. Moon J. H. Ahn J. S. Kim H. J. Lee J. J. Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study Annals of Hematology 2010 89 5 475 482 10.1007/s00277-009-0856-x 2-s2.0-77950563131 19921192 \n14 Kim S. J. Kim K. Do Y. R. Bae S. H. Yang D.-H. Lee J.-J. Low-dose acyclovir is effective for prevention of herpes zoster in myeloma patients treated with bortezomib: a report from the Korean Multiple Myeloma Working Party (KMMWP) retrospective study Japanese Journal of Clinical Oncology 2011 41 3 353 357 10.1093/jjco/hyq194 2-s2.0-79952410108 20947927 \n15 Rajkumar S. V. Harousseau J. L. Durie B. Anderson K. C. Dimopoulos M. Kyle R. Blade J. Richardson P. Orlowski R. Siegel D. Jagannath S. Facon T. Avet-Loiseau H. Lonial S. Palumbo A. Zonder J. Ludwig H. Vesole D. Sezer O. Munshi N. C. San Miguel J. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1 Blood 2011 117 18 4691 4695 10.1182/blood-2010-10-299487 2-s2.0-79955977910 21292775 \n16 Miguel J. F. S. Schlag R. Khuageva N. K. Dimopoulos M. A. Shpilberg O. Kropff M. Spicka I. Petrucci M. T. Palumbo A. Samoilova O. S. Dmoszynska A. Abdulkadyrov K. M. Delforge M. Jiang B. Mateos M.-V. Anderson K. C. Esseltine D.-L. Liu K. Deraedt W. Cakana A. Van De Velde H. Richardson P. G. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma Journal of Clinical Oncology 2013 31 4 448 455 10.1200/JCO.2012.41.6180 2-s2.0-84874768399 23233713 \n17 Knopf K. B. Duh M. S. Lafeuille M. H. Meta-analysis of the efficacy and safety of bortezomib re-treatment in patients with multiple myeloma Clinical Lymphoma Myeloma and Leukemia 2014 14 5 380 388 10.1016/j.clml.2014.03.005\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2014()",
"journal": "BioMed research international",
"keywords": null,
"medline_ta": "Biomed Res Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D011719:Pyrazines; D016896:Treatment Outcome",
"nlm_unique_id": "101600173",
"other_id": null,
"pages": "145843",
"pmc": null,
"pmid": "25530955",
"pubdate": "2014",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "22479275;21292775;20942854;16757429;15244382;21372599;23233713;22024721;19921192;20368561;25023616;20947927;18650176;23293914;22314843;17975015",
"title": "Clinical outcome of bortezomib retreatment in patients with relapsed or refractory multiple myeloma.",
"title_normalized": "clinical outcome of bortezomib retreatment in patients with relapsed or refractory multiple myeloma"
} | [
{
"companynumb": "KR-TAKEDA-2017MPI006286",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "[18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is useful for primary staging and evaluation of treatment outcome in diffuse large B cell lymphoma (DLBCL) patients. The reduction in the maximum standardized uptake value (ΔSUVmax) from the initial to the interim 18F-FDG PET scan has been reported to predict survival in DLBCL patients. We retrospectively evaluated ΔSUVmax obtained by PET or PET-computed tomography before and after initial therapy in 31 newly diagnosed DLBCL patients who were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy. Receiver observation characteristic curve analysis was used to evaluate the optimal cutoff value for the ΔSUVmax for disease progression. The 3-year progression-free survival rate of patients with ΔSUVmax≥83 and <83% was found to be 91 and 25%, respectively (P<0.001). The 4-year overall survival rate of patients with ΔSUVmax≥83 and <83% was found to be 100 and 83%, respectively (P=0.046). The ΔSUVmax observed before and after R-CHOP therapy could be useful in the prediction of disease progression and survival in newly diagnosed DLBCL patients.",
"affiliations": "Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama, 236-0004, Japan.",
"authors": "Ishii|Yoshimi|Y|;Tomita|Naoto|N|;Tateishi|Ukihide|U|;Ishiyama|Yasufumi|Y|;Yamamoto|Eri|E|;Hattori|Yukako|Y|;Hagihara|Maki|M|;Yamazaki|Etsuko|E|;Ishigatsubo|Yoshiaki|Y|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-014-0880-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "31(3)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018450:Disease Progression; D004317:Doxorubicin; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011239:Prednisolone; D011379:Prognosis; D019275:Radiopharmaceuticals; D012189:Retrospective Studies; D000069283:Rituximab; D015996:Survival Rate; D014750:Vincristine",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "880",
"pmc": null,
"pmid": "24504845",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article",
"references": "23344136;19289424;23079891;20212248;17873129;23238895;22234681;21518924;23649463;15980161;19074215;5121694;2418167;1710919;17242397;12196360;19544140;17242396;15860666",
"title": "The rate of reduction in the maximum standardized uptake value from the initial to the post-R-CHOP therapy in positron emission tomography scan predicts disease progression in diffuse large B cell lymphoma patients.",
"title_normalized": "the rate of reduction in the maximum standardized uptake value from the initial to the post r chop therapy in positron emission tomography scan predicts disease progression in diffuse large b cell lymphoma patients"
} | [
{
"companynumb": "JP-BAXTER-2014BAX048980",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "A 4 year-old girl with bilateral, non-familial retinoblastoma (RB) was referred to our care after primary enucleation OS and active tumor OD refractory to multiple therapies (intravenous chemotherapy, laser/cryotherapy, and I-125 plaque radiotherapy). Vitreous seeding OD, initially controlled by several sessions of Ophthalmic Artery Infusion Chemotherapy (OAIC) and periocular chemotherapy, recurred shortly thereafter. The patient underwent intravitreal (IVit) Melphalan injections achieving tumor control despite the concurrent development of keratopathy, pupillary synechiae, cataract, and necrosis of the inferior fornix and the adjacent orbital fat, all secondary to the treatments administered. Repeated amniotic membrane implants and tarsorrhaphy were performed to alleviate the symptoms. Despite being tumor free for 6 months, a poor fundus view and treatment-related complications prompted us to consider enucleation, but parents declined. Following recent negative magnetic resonance imaging (MRI), her cataract was removed. She was then found to have tumor recurrence. Her eye was enucleated 12 months ago and she recovered well from the surgery. As ocular oncology embarks in eye-preserving treatments for retinoblastoma, it is important to address the cumulative effects and associated impact of such treatments and the possibility of failure.",
"affiliations": "University of Cincinnati Medical School, University of Cincinnati Medical Center, Cincinnati, OH, USA.;University of Cincinnati Medical School, University of Cincinnati Medical Center, Cincinnati, OH, USA.;University of Cincinnati Medical School, University of Cincinnati Medical Center, Cincinnati, OH, USA.;University of Cincinnati Medical School, University of Cincinnati Medical Center, Cincinnati, OH, USA.;University of Cincinnati Medical School, University of Cincinnati Medical Center, Cincinnati, OH, USA.",
"authors": "Brink|Aubrey|A|;Correa|Zélia Maria|ZM|;Geller|James|J|;Abruzzo|Todd|T|;Augsburger|James J|JJ|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-2749",
"issue": "77(4)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": "D002675:Child, Preschool; D003131:Combined Modality Therapy; D015353:Eye Enucleation; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D019572:Retinal Neoplasms; D012175:Retinoblastoma",
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "256-8",
"pmc": null,
"pmid": "25410179",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Managing the consequences of aggressive conservative treatment for refractory retinoblastoma with vitreous seeding.",
"title_normalized": "managing the consequences of aggressive conservative treatment for refractory retinoblastoma with vitreous seeding"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2014GSK030347",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPOTECAN\\TOPOTECAN HYDROCHLORIDE"
},
... |
{
"abstract": "The epidemic of prescription and non-prescription opioid misuse is of particular importance in pregnancy. The Society of Obstetricians and Gynaecologists of Canada currently recommends opioid replacement therapy with methadone or buprenorphine for opioid-dependent women during pregnancy. This vulnerable segment of the population has been shown to be at increased risk of blood-borne infectious diseases, nutritional insecurity and stress. The objective of this study was to describe an urban cohort of pregnant women on opioid replacement therapy and to evaluate potential effects on the fetus. A retrospective chart review of all women on opioid replacement therapy and their infants who delivered at The Ottawa Hospital General and Civic campuses between January 1, 2013 and March 24, 2017 was conducted. Data were collected on maternal characteristics, pregnancy outcomes, neonatal outcomes and corresponding placental pathology. Maternal comorbidities identified included high rates of infection, tobacco use and illicit substance use, as well as increased rates of placental abruption compared with national averages. Compared with national baseline averages, the mean neonatal birth weight was low, and the incidence of small for gestational age infants and congenital anomalies was high. The incidence of NAS was comparable with estimates from other studies of similar cohorts. Findings support existing literature that calls for a comprehensive interdisciplinary risk reduction approach including dietary, social, domestic, psychological and other supports to care for opioid-dependent women in pregnancy.",
"affiliations": "1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;2Department of Pathology and Laboratory Medicine,Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.;3Department of Obstetrics and Gynecology,School of Epidemiology, Public Health and Preventive Medicine,Ottawa Hospital,University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.;4Department of Pediatrics,University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.;7Department of Pediatrics,Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.;8Department of Obstetrics and Gynecology,Ottawa Hospital, Ottawa, Ontario, Canada.;1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;8Department of Obstetrics and Gynecology,Ottawa Hospital, Ottawa, Ontario, Canada.;8Department of Obstetrics and Gynecology,Ottawa Hospital, Ottawa, Ontario, Canada.;8Department of Obstetrics and Gynecology,Ottawa Hospital, Ottawa, Ontario, Canada.",
"authors": "Miller|C|C|0000-0002-5404-9841;Grynspan|D|D|;Gaudet|L|L|;Ferretti|E|E|;Lawrence|S|S|;Moretti|F|F|;Lafreniere|A|A|;McGee|A|A|;Lattuca|S|S|;Black|A|A|",
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"abstract": "Brucellosis is a multisystem zoonotic disease. We report an unusual case of neurobrucellosis with seizures in an immunocompromised patient in Saudi Arabia who underwent renal transplantation. Magnetic resonance imaging of the brain showed diffuse white matter lesions. Serum and cerebrospinal fluid were positive for Brucella sp. Granuloma was detected in a brain biopsy specimen.",
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"authors": "Alqwaifly|Mohammed|M|;Al-Ajlan|Fahad S|FS|;Al-Hindi|Hindi|H|;Al Semari|Abdulaziz|A|",
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"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n28518039\n16-1173\n10.3201/eid2306.161173\nDispatch\nDispatch\nCentral Nervous System Brucellosis Granuloma and White Matter Disease in Immunocompromised Patient\nCentral Nervous System Brucellosis Granuloma and White Matter Disease in Immunocompromised Patient\nCNS Brucellosis Granuloma and White Matter Disease\nAlqwaifly Mohammed\nAl-Ajlan Fahad S.\nAl-Hindi Hindi\nAl Semari Abdulaziz\nQassim University College of Medicine, Qassim, Saudi Arabia (M. Alqwaifly);\nKing Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (F.S. Al-Ajlan, H. Al-Hindi, A. Al Semari)\nAddress for correspondence: Mohammed Alqwaifly, Qassim University College of Medicine, Qassim 51391, Saudi Arabia: email: dr.qwaifly@hotmail.com\n6 2017\n23 6 978981\nBrucellosis is a multisystem zoonotic disease. We report an unusual case of neurobrucellosis with seizures in an immunocompromised patient in Saudi Arabia who underwent renal transplantation. Magnetic resonance imaging of the brain showed diffuse white matter lesions. Serum and cerebrospinal fluid were positive for Brucella sp. Granuloma was detected in a brain biopsy specimen.\n\nKeywords:\n\ncentral nervous system\nbrucellosis\nneurobrucellosis\nepilepsy\nrefractory epilepsy\nBrucella\nbacteria\nwhite matter disease\nintracranial granuloma\nimmunocompromised patient\nmeningitis/encephalitis\nzoonoses\nSaudi Arabia\n==== Body\nHuman brucellosis is a major zoonotic disease in Saudi Arabia (1). This disease is caused by Brucella spp., gram-negative bacteria usually transmitted through consumption of raw meat or unpasteurized dairy products (2). Brucellosis is endemic to the Arabian Peninsula and countries bordering the Mediterranean Sea (3).\n\nNeurobrucellosis occurs in 5%–10% of patients with brucellosis (4). The most frequent clinical manifestation is meningoencephalitis (5). Mass lesions in the brain are uncommon (4). Intracerebral granuloma associated with brucellosis had been reported in a community-acquired infection (6). We report an unusual case of neurobrucellosis and seizures in an immunocompromised patient.\n\nThe Study\n\nThe patient was a 46-year-old Saudi woman who had chronic hepatitis C, end-stage renal disease of undetermined etiology, and a renal transplant in 1993. She reported a 5-month history of headaches and seizures. Seizures were usually preceded by epigastric pain and a sensation of nausea for few seconds, followed by left arm posturing and loss of consciousness. She did not have fever, weight loss, or joint pain. She lived in a rural area, was involved in animal husbandry, and consumed unpasteurized milk products. Her husband had been treated for brucellosis. Her medications included mycophenolate mofetil (500 mg 2×/d since 1993), prednisone (5 mg 1×/d since 1993), levetiracetam (500 mg 2×/d for 5 mo), and phenytoin (200 mg every night for 1 mo).\n\nNeurologic examination showed left homonymous hemianopia, increased deep tendon reflexes in the left hemibody, and the Babinski sign on the left hallux. Initial laboratory test results, including those for complete blood count, erythrocyte sedimentation rate, C-reactive protein, and liver and renal profiles, were within references ranges. Results of serologic analysis for HIV and hepatitis B virus were negative.\n\nA standard agglutination tube (SAT) test result for Brucella spp. was positive (titer 1:320), and a 2-mercaptoethanol test result for Brucella spp. agglutination was positive (titer 1:160). An ELISA showed antibodies against Brucella spp. in serum (titer 1:5,120). Cerebrospinal fluid (CSF) had a leukocyte count of 21 (90% lymphocytes). Levels of protein, glucose, and lactate dehydrogenase in CSF were within references ranges.\n\nGram staining of a CSF sample and cultures for bacteria, virus, fungi, and acid-fast bacilli (AFB) showed negative results. Results of PCRs for AFB, cytomegalovirus, and JC polyomavirus were negative.\n\nSerologic analysis of CSF showed Brucella IgG (titer <1:20) and antibodies against Brucella (titer 1:320). Test results were negative for antibodies against Aspergillus, Aspergillus galactomannan, Blastomyces, Borrelia, Coccidia, Cryptococcus, Histoplasma, and Toxoplasma.\n\nAn electroencephalogram showed sharp waves over the right temporal region and continuous slow activity over the right temporooccipital region. Magnetic resonance imaging (MRI) of the brain showed diffuse T2/fluid-attenuated inversion recovery hyperintense white matter lesions involving the right frontal, parietal and temporal lobes (Figure 1). No appreciable mass effect or enhancement after administration of gadolinium was observed. Positive emission tomography of the brain showed hypometabolic cerebral activity involving a large area of right cerebral hemisphere. Magnetic resonance spectroscopy shows a low peak of n-acetyl aspartate (2.2 ppm).\n\nFigure 1 Magnetic resonance imaging of the brain of a 46-year-old immunocompromised woman with central nervous system brucellosis granuloma and white matter disease, Saudi Arabia. A) Axial T2 images showing hyperintensity in the right frontoparietal lobe and right temporal lobe. B) Axial fluid-attenuated inversion recovery (FLAIR) and C) coronal FLAIR images showing that hypersensitivity extends to U-fibers without involvement of the cortex. D) Gadolinium-enhanced image showing that no appreciable mass effect and no central or peripheral enhancement after administration of gadolinium were observed. Each image within each panel shows involvement in different levels of frontal, parietal, and temporal lobes.\n\nA brain biopsy specimen of cerebral cortex and superficial white matter showed a moderate lymphoplasmacytic and focally histiocytic infiltrate that involved deep cortex, white matter, and leptomeninges. The histiocytic component formed small epithelioid granulomas that were nonnecrotizing. The inflammatory reaction, including granulomas, was mainly perivascular with some angiocentric patterns and focal parenchymal involvement. The white matter portion was heavily infiltrated by macrophages. Reactive astrogliosis was prominent. There were no morphologic signs of a specific etiology: no viral inclusions, and staining results microorganisms (AFB, fungi, Epstein-Barr virus, and JC polyomavirus) were negative (Figure 2).\n\nFigure 2 Histologic analysis of a brain biopsy specimen from a 46-year-old immunocompromised woman with central nervous system brucellosis granuloma and white matter disease, Saudi Arabia. A) Low magnification view of cerebral cortex showing infiltration by perivascular lymphocytes and histiocytes. Histiocytes form small nonnecrotizing granuloma (center) (original magnification ×100). B) High magnification view showing an angiocentric epithelioid granuloma cuffed by mature lymphocytes (original magnification ×200). Hemotoxylin and eosin stain.\n\nA gram stain was initially negative for bacteria. At day 5, Brucella spp. were isolated from brain biopsy specimens. An antibiogram showed that the Brucella sp. was sensitive to gentamicin, streptomycin, tetracycline, trimethoprim/sulfamethoxazole, and rifampin.\n\nThe patient received intravenous ceftriaxone (2 g every 12 h), oral doxycycline (100 mg every 12 h), oral rifampin (600 mg 1×/d), and trimethoprim/sulfamethoxazole (1 tablet [160 mg/800 mg] every 12 h) for 2 wk. After discharge, she was receiving oral doxycycline (100 mg every 12 h), rifampin (600 mg, 1×/d), trimethoprim/sulfamethoxazole (1 tablet every 12 h), and ciprofloxacin (500 mg every 12 h) for 6 mo: she was also receiving levitiracetam (750 mg 2×/d), carbamazepine (200 mg 2×/d), mycophenolate mofetil (500 mg 2×/d), and prednisone (5 mg 1×/d).\n\nThree months later, repeat MRI of the brain showed decreased T2 hyperintensity associated with volume loss and ex vacuo dilatation of the subjacent right lateral ventricle. We did not observe any appreciable new lesions.\n\nAfter 6 months of follow-up, her headaches had resolved. However, she continued to have auras without major seizures.\n\nConclusions\n\nNeurobrucellosis can affect the central or peripheral nervous systems and lead to diverse clinical syndromes (4). Diagnosis of neurobrucellosis depends on clinical manifestations, CSF findings suggestive of pinocytosis, high protein levels, low or standard glucose levels, and a positive antibody titer for Brucella spp. Although the patient had mild pleocytosis with a predominance of lymphocytes and high antibody titers against Brucella spp. in CSF, the CSF protein level was within the reference range. Antibodies against Brucella spp. in CSF are usually an indication of neurobrucellosis. However, low levels of antibodies might not be detected by SAT. In suspicious cases in which the SAT result is negative, SAT and a Coombs test, ELISA, and PCR are helpful in making a diagnosis.\n\n77The clinical−radiologic correlation for neurobrucellosis ranges from uneventful results for imaging studies, despite positive clinical findings, to imaging abnormalities (3). Neurobrucellosis with a focal brain mass has been rarely observed in imaging studies (7,8).\n\nRadiologic results in this case suggested an infectious disease, autoimmune disease, or malignancy in an immunocompromised patient. Because we deemed it necessary to exclude other conditions, such as progressive multifocal leukoencephalopathy or lymphoma, we performed a brain biopsy. The diagnosis was established by detecting antibodies against a Brucella sp. in serum and CSF and confirmed by isolation of a Brucella sp. from brain tissue.\n\nWe found that the patient had epilepsy and extensive white matter changes secondary to brucellosis. She continued to have auras without major seizures. MRI of the brain showed abnormal results (prominent white matter disease and focal encephalomalacia). Inflammation can cause permanent cellular biochemical dysfunction, which can lead to electrically irritable tissue and parenchymal damage despite successful treatment. This finding might explain the persistency of brain lesion. Appropriate antimicrobial therapy can eliminate the infection.\n\nLongitudinal studies of white matter hyperintensities caused by vascular, noninfectious, infectious, and inflammatory conditions showed white matter hyperintensities over time despite effective treatment. Fincham et al. reported that white matter changes in neurobrucellosis were sequelae of demyelination, as confirmed by the pathologic analysis (9). We believe that unresolved white matter hyperintensities in this patient were a sequela of the inflammatory process. A case report documented similar clinical features in a patient with seizures caused by chronic neurobrucellosis for 2.5 years (10).\n\nGranuloma is a pathogenesis of epilepsy (11). Solitary cysticercus granuloma and calcified lesion are 2 common neuroimaging abnormalities in patients with epilepsy. Treatment for underlying cysticercosis does not cure epilepsy (12). Seizures associated with central nervous system tuberculomas are often resolved after successful treatment (13). The underlying pathogenesis for relapsing epilepsy in neurocysticercosis is probably related to abnormal neurons and their arrangement within calcified nodules (13). The epilepsy prognosis for neurobrucellosis is probably similar to that for central nervous system neurocysticercosis (13).\n\nA perivascular nonnecrotizing granuloma is a histopathologic feature of neurobrucellosis. Neurocellosis granuloma is a pathogenesis of refractory epilepsy. Our findings indicate the need for suspecting neurobrucellosis as a cause of epilepsy and white matter disease in immunocompromised patients in disease-endemic areas.\n\nDr. Alqwaifly is an assistant professor of neurology at Qassim University College of Medicine, Qassim, Saudi Arabia. His research interests are central nervous system infections, neuropathy, and movement disorders.\n\nSuggested citation for this article: Alqwaifly M, Al-Ajlan FS, Al-Hindi H, Al Semari A. Central nervous system brucellosis granuloma and white matter disease in immunocompromised patient. Emerg Infect Dis. 2017 Jun [date cited]. http://dx.doi.org/10.3201/eid2306.161173\n==== Refs\nReferences\n\n1. Kiel FW, Khan MY. Brucellosis in Saudi Arabia. Soc Sci Med. 1989;29 :999–1001. 10.1016/0277-9536(89)90056-7 2814586\n2. Adams LG. The pathology of brucellosis reflects the outcome of the battle between the host genome and the Brucella genome. Vet Microbiol. 2002;90 :553–61. 10.1016/S0378-1135(02)00235-3 12414171\n3. Al-Sous MW, Bohlega S, Al-Kawi MZ, Alwatban J, McLean DR. Neurobrucellosis: clinical and neuroimaging correlation. AJNR Am J Neuroradiol. 2004;25 :395–401.15037461\n4. Shakir RA. Neurobrucellosis. Postgrad Med J. 1986;62 :1077–9. 10.1136/pgmj.62.734.1077 3309909\n5. Türel O, Sanli K, Hatipoğlu N, Aydoğmuş C, Hatipoğlu H, Siraneci R. Acute meningoencephalitis due to Brucella: case report and review of neurobrucellosis in children. Turk J Pediatr. 2010;52 :426–9.21043393\n6. Sohn AH, Probert WS, Glaser CA, Gupta N, Bollen AW, Wong JD, et al. Human neurobrucellosis with intracerebral granuloma caused by a marine mammal Brucella spp. Emerg Infect Dis. 2003;9 :485–8. 10.3201/eid0904.020576 12702232\n7. Martínez-Chamorro E, Muñoz A, Esparza J, Muñoz MJ, Giangaspro E. Focal cerebral involvement by neurobrucellosis: pathological and MRI findings. Eur J Radiol. 2002;43 :28–30. 10.1016/S0720-048X(01)00390-4 12065117\n8. Erdem M, Namiduru M, Karaoglan I, Kecik VB, Aydin A, Tanriverdi M. Unusual presentation of neurobrucellosis: a solitary intracranial mass lesion mimicking a cerebral tumor : a case of encephalitis caused by Brucella melitensis. J Infect Chemother. 2012;18 :767–70. 10.1007/s10156-011-0365-4 22231602\n9. Fincham RW, Sahs AL, Joynt RJ. Protean manifestation of nervous system brucellosis. JAMA. 1963;184 :269–76. 10.1001/jama.1963.03700170061009 13945207\n10. Yilmaz M, Ozaras R, Ozturk R, Mert A, Tabak F, Aktuglu Y. Epileptic seizure: an atypical presentation in an adolescent boy with neurobrucellosis. Scand J Infect Dis. 2002;34 :623–5. 10.1080/00365540210147561 12238582\n11. Sotelo-Morales J, García-Cuevas E, Rubio-Donnadieu F. [Granuloma in cerebral parenchyma. A human model for the study of epilepsy] [in Spanish]. Gac Med Mex. 1989;125 :31–5, discussion 36.2517420\n12. Sharma LN, Garg RK, Verma R, Singh MK, Malhotra HS. Seizure recurrence in patients with solitary cystic granuloma or single parenchymal cerebral calcification: a comparative evaluation. Seizure. 2013;22 :840–5. 10.1016/j.seizure.2013.07.001 23880307\n13. AlSemari A, Baz S, Alrabiah F, Al-Khairallah T, Qadi N, Kareem A, et al. Natural course of epilepsy concomitant with CNS tuberculomas. Epilepsy Res. 2012;99 :107–11. 10.1016/j.eplepsyres.2011.10.032 22119105\n\n",
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"keywords": "Brucella; Saudi Arabia; bacteria; brucellosis; central nervous system; epilepsy; immunocompromised patient; intracranial granuloma; meningitis/encephalitis; neurobrucellosis; refractory epilepsy; white matter disease; zoonoses",
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"mesh_terms": "D000900:Anti-Bacterial Agents; D001921:Brain; D002002:Brucella; D002006:Brucellosis; D005260:Female; D006099:Granuloma; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D056784:Leukoencephalopathies; D008875:Middle Aged; D012640:Seizures; D016896:Treatment Outcome",
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"title": "Central Nervous System Brucellosis Granuloma and White Matter Disease in Immunocompromised Patient.",
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"abstract": "Candida auris is a species of fungus that has gained importance in recent years owing to its ability to cause hospital infections and epidemics, resistant to antifungal agents and disinfection processes and frequently misidentified by commercial systems. Hospital outbreaks caused by C.auris have been reported from some countries. It has been determined that C.auris has lower virulence than Candida albicans; however, it is associated with high mortality rates in immunocompromised individuals. An increase in the incidence of invasive fungal infections which can lead to serious complications and death, has been identified in severe coronavirus-2019 (COVID-19) patients or immunocompromised individuals with underlying disease. Studies demonstrated an increase in the frequency of C.auris isolation in COVID-19 patients with candidemia. In this report, the first case of COVID-19 positive C.auris fungemia detected in Turkey was presented. A 71-year-old male patient with a history of myocardial infarction, diabetes mellitus, donation of a single kidney and lobectomy surgery due to lung cancer was hospitalized in the pandemic thoracic surgery service due to the findings consistent with viral pneumonia on thoracic computed tomography. Favipiravir 2 x 600 mg and intravenous dexamethasone 1 x 6 mg therapy was administered. The patient tested positive for SARS-CoV-2 polymerase chain reaction, and severe involvement of the left lung was detected in the following days. Antibiotics were administered, followed by insertion of a right jugular vein catheter and initation of tocilizumab. The patient was transferred to the intensive care unit due to increased respiratory distress. Yeast growth was detected in the patient's hemoculture. The yeast strain could not be identified using API ID 32C (bioMerieux, France) (Sacchromyces kluyveri, Candida sake, unacceptable profile), but was identified as C.auris using the VITEK MALDI TOF MS (bioMerieux, France) (99.9%) system and confirmed by sequencing. The minimum inhibitor concentration values were detected as 3 µg/ml for amphotericin B; > 256 µg/ml for fluconazole; 0.19 µg/ml for voriconazole; 0.19 µg/ml for itraconazole; 0.016 µg/ml for posaconazole; 1 µg/ml for caspofungin and 0.094 µg/ml for anidulafungin by using the antibiotic gradient method. The patient's initial treatment comprised meropenem 3 x 1 g, vancomycin 2 x 1 g, caspofungin 1 x 70 mg, and continued as caspofungine 1 x 50 mg after the loading dose, and vancomycin 1 x 1 g/48 hours from the third day of treatment. The patient died on the ninth day after developing candidemia. The present case is the first case of fungemia caused by C.auris in a COVID-19 positive patient in Turkey, and it emphasizes the need of caution for fungemia due to C.auris in intensive care units in our country which has a high COVID-19 incidence.",
"affiliations": "Istanbul University Istanbul Faculty of Medicine, Department of Medical Microbiology, Istanbul, Turkey.;Istanbul University Istanbul Faculty of Medicine, Department of Medical Microbiology, Istanbul, Turkey.;İstanbul University Istanbul Faculty of Medicine, Department of Anesthesiology and Reanimation, Istanbul, Turkey.;Istanbul University-Cerrahpasa Cerrahpasa Faculty of Medicine, Department of Medical Microbiology, İstanbul, Turkey.;İstanbul University Istanbul Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, İstanbul, Turkey.;Istanbul University Istanbul Faculty of Medicine, Department of Medical Microbiology, Istanbul, Turkey.;Istanbul University Istanbul Faculty of Medicine, Department of Medical Microbiology, Istanbul, Turkey.;Istanbul University Istanbul Faculty of Medicine, Department of Medical Microbiology, Istanbul, Turkey.;İstanbul University Istanbul Faculty of Medicine, Department of Anesthesiology and Reanimation, Istanbul, Turkey.;Istanbul University Istanbul Faculty of Medicine, Department of Medical Microbiology, Istanbul, Turkey.",
"authors": "Bölükbaşı|Yasemin|Y|;Erköse Genç|Gonca|G|;Orhun|Günseli|G|;Kuşkucu|Mert Ahmet|MA|;Çağatay|Atahan|A|;Önel|Mustafa|M|;Öngen|Betigül|B|;Ağaçfidan|Ali|A|;Esen|Figen|F|;Erturan|Zayre|Z|",
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"title": "First Case of COVID-19 Positive Candida auris Fungemia in Turkey.",
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"abstract": "Talaromyces marneffei (T. marneffei) is an important opportunistic pathogen found in human immunodeficiency virus-positive individuals in Southeast Asia, Southern China, and Northeastern India. Patients with disseminated talaromycosis commonly develop multi-organ involvement including the skin. In this report, we describe the clinical presentation, investigation, management, and clinical outcome of an acquired immune deficiency syndrome (AIDS) patient with newly diagnosed disseminated talaromycosis without skin involvement.\nA 27-year-old male with AIDS presented with acute onset of abdominal pain for 4 days and fever for 2 days. He had been diagnosed with AIDS, pneumocystis pneumonia, and presumptive smear-negative pulmonary tuberculosis 2 months previously. His initial CD4 count was 91 cells/mm3. After a 3-week course of trimethoprim/sulfamethoxazole and anti-tuberculosis treatment, anti-retroviral therapy was initiated. Physical examination revealed left upper quadrant tenderness but no abnormal skin lesions. On this visit, his CD4 count rose to 272 cells/mm3 (19%). Computed tomography of the abdomen showed evidence of a small hypodense lesion with a thin enhancing rim at the spleen and extensive intra-abdominal lymphadenopathy. Empirical amphotericin B deoxycholate was administered in response to positive serum galactomannan, although this was switched to intravenous liposomal amphotericin B 1 week later because of acute kidney injury. Blood and bone marrow cultures for fungus grew T. marneffei on days 9 and 12, respectively. After 21 days of treatment, oral itraconazole replaced intravenous therapy. The patient was discharged home after 29 days in the hospital and continued to improve clinically at a follow-up visit as an outpatient.\nTalaromycosis is a fairly common opportunistic infection among AIDS patients in Thailand, despite a rise in CD4 count which may reflect a change in immune status. To a lesser extent, a systemic disease without skin involvement can be expected in real clinical practice.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Pongpech|Nisha|N|;Rotjanapan|Porpon|P|",
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"fulltext": "\n==== Front\nInfect Drug ResistInfect Drug ResistIDRidrInfection and Drug Resistance1178-6973Dove 20781910.2147/IDR.S207819Case ReportAbsence of cutaneous involvement in disseminated Talaromyces marneffei infection in an AIDS patient: a case report and literature review Pongpech and RotjanapanPongpech and RotjanapanPongpech Nisha 1Rotjanapan Porpon 11 Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, ThailandCorrespondence: Porpon RotjanapanDivision of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Bangkok10400, ThailandTel +662 201 1581Email porpon.rot@mahidol.ac.th04 6 2019 2019 12 1493 1499 06 3 2019 17 5 2019 © 2019 Pongpech and Rotjanapan.2019Pongpech and Rotjanapan.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Background\nTalaromyces marneffei (T. marneffei) is an important opportunistic pathogen found in human immunodeficiency virus-positive individuals in Southeast Asia, Southern China, and Northeastern India. Patients with disseminated talaromycosis commonly develop multi-organ involvement including the skin. In this report, we describe the clinical presentation, investigation, management, and clinical outcome of an acquired immune deficiency syndrome (AIDS) patient with newly diagnosed disseminated talaromycosis without skin involvement.\n\nCase presentation\nA 27-year-old male with AIDS presented with acute onset of abdominal pain for 4 days and fever for 2 days. He had been diagnosed with AIDS, pneumocystis pneumonia, and presumptive smear-negative pulmonary tuberculosis 2 months previously. His initial CD4 count was 91 cells/mm3. After a 3-week course of trimethoprim/sulfamethoxazole and anti-tuberculosis treatment, anti-retroviral therapy was initiated. Physical examination revealed left upper quadrant tenderness but no abnormal skin lesions. On this visit, his CD4 count rose to 272 cells/mm3 (19%). Computed tomography of the abdomen showed evidence of a small hypodense lesion with a thin enhancing rim at the spleen and extensive intra-abdominal lymphadenopathy. Empirical amphotericin B deoxycholate was administered in response to positive serum galactomannan, although this was switched to intravenous liposomal amphotericin B 1 week later because of acute kidney injury. Blood and bone marrow cultures for fungus grew T. marneffei on days 9 and 12, respectively. After 21 days of treatment, oral itraconazole replaced intravenous therapy. The patient was discharged home after 29 days in the hospital and continued to improve clinically at a follow-up visit as an outpatient.\n\nConclusion\nTalaromycosis is a fairly common opportunistic infection among AIDS patients in Thailand, despite a rise in CD4 count which may reflect a change in immune status. To a lesser extent, a systemic disease without skin involvement can be expected in real clinical practice.\n\nKeywords\ntalaromycosisAIDSdisseminated fungal infectioncutaneous involvement\n==== Body\nBackground\nTalaromyces marneffei (formerly Penicillium marneffei) is a thermally dimorphic fungus that was first isolated from a bamboo rat in 1956. The first disseminated talaromycosis in a human immunodeficiency virus (HIV)-infected patient was reported in 1988 in Chicago, USA.1 Talaromycosis has become an important cause of morbidity and mortality in HIV-infected patients who live in or travel to Southeast Asia, Southern China, and Northeastern India.2,3 However, this fungal infection increasingly occurs outside these epidemic areas as a result of increased migration and international travel.3 During the potent antiretroviral era, the incidence of talaromycosis in Thailand has declined significantly, but it remains the third most common cause of HIV-associated death, after tuberculosis and cryptococcosis.4,5 A seasonal pattern of talaromycosis with a mostly predominant peak is seen during the rainy season from May to November.6 Common presentations in HIV-infected patients are fever, lymphadenopathy, splenomegaly, and cutaneous lesions.7 We report a 27-year-old man with well-controlled acquired immune deficiency syndrome (AIDS) with disseminated talaromycosis without cutaneous involvement.\n\nCase presentation\nA 27-year-old Thai male with AIDS from Saraburi Province presented with acute abdominal pain that had lasted for 4 days. He originated from Mukdahan Province, in Northeastern Thailand, but had moved to Saraburi Province which is situated in the southern part of Northeastern Thailand, 200 km from Bangkok. He denied other travel histories outside these areas during the past year. He was diagnosed with AIDS 2 months before at another hospital, which recorded an initial CD4 count of 91 cells/mm3 (unknown percentage and HIV viral load) and no complete immune status evaluation was performed. At the time, he presented with respiratory distress which was later identified as pneumocystis pneumonia and presumptive smear-negative pulmonary tuberculosis. He was given a 3-week course of trimethoprim/sulfamethoxazole, and anti-tuberculosis treatment consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol during hospitalization. Anti-retroviral therapy (ART) comprising tenofovir disoproxil fumarate, emtricitabine, and efavirenz was introduced 2 weeks later when he was an outpatient. The anti-tuberculosis regimen was adjusted to isoniazid, rifampicin, ethambutol, and levofloxacin after 4 days, and a chest radiograph demonstrated complete resolution of prior pulmonary opacities after 50 days of treatment. He reported 100% adherence to both anti-tuberculosis treatment and ART and no other new medications had been added to the regimen. The CD4 count 8 weeks before this admission was 91 cells/mm3 (unknown percentage).\n\nAt this admission, he presented with abdominal pain mainly in the left upper quadrant that he described as a dull ache, without radiation. The pain was not related to eating food, physical activity, or position. He reported no other associated gastrointestinal complaints such as diarrhea or nausea. Two days later, he developed a high-grade fever without chills, with the highest temperature of 38.9 °C. Abdominal pain persisted and partially responded to acetaminophen. In response to this, he attended the emergency department where a physical examination revealed a blood pressure of 120/75 mmHg, a heart rate of 110 beats/min, a temperature of 38.7 °C, and a respiration rate of 20 breaths/min. His abdomen was soft, normal bowel sounds were heard, but tenderness on palpation in the left upper quadrant was evident. The spleen could not be palpated. The remaining physical examination was unremarkable including a negative complete skin examination, with no cutaneous lesions on his face, trunk, or extremities, and a neurological examination within normal limits.\n\nInitial laboratory investigations revealed hemoglobin levels of 9.8 g/dL, a white blood cell count of 14,000 cells/mm3, and a platelet count of 225,000 cells/mm3 on a complete blood count. Serum galactomannan (GM) levels by Platelia enzyme-linked immunosorbent assay (ELISA) (BioRad)® were 6.84. The CD4 count on admission was 272 cells/mm3 (19%). A fungal blood culture obtained on hospital day 1 grew white to tan-colored, velvety and flat colonies with red soluble pigment (Figure 1) on day 9. Direct microscopic examination of the colonies with lactophenol cotton blue staining demonstrated septate hyphae and smooth conidia aloft phialides directly borne on metulae (Figure 2). A bone marrow culture grew similar colonies to the blood specimen (Figure 3) on day 12 after the procedure. Contrast-enhanced computed tomography of the abdomen revealed a small hypodense lesion with a thin enhancing rim at the spleen and extensive intra-abdominal lymphadenopathy (Figure 4). At the time, the patient was not able to provide sputum sample for culture and due to the high-risk procedure, intra-abdominal lymph node biopsy for culture and histologic analysis was not performed.Figure 1 Fungal blood culture demonstrating white to tan-colored, velvety and flat colonies with red soluble pigment.\n\nFigure 2 Lactophenol cotton blue staining from fungal blood culture demonstrating septate hyphae and smooth conidia aloft phialides which are borne to metulae.\n\nFigure 3 Bone marrow fungal culture demonstrating white to tan-colored, velvety and flat colonies with red soluble pigment.\n\nFigure 4 Contrast-enhanced computed tomography of the whole abdomen demonstrating small hypodense lesion with a thin enhancing rim at the spleen and extensive intra-abdominal lymphadenopathy.\n\n\n\nBecause of a concern of disseminated fungal infection on admission, empirical intravenous amphotericin B deoxycholate was given at a dose of 1.5 mg/kg/day for 7 days. This was switched to liposomal amphotericin B at 3.2 mg/kg/day in response to acute kidney injury for a total of 21 days. Before discharge, a loading dose of itraconazole was initiated at 600 mg/day for 3 days, then 400 mg/day for the maintenance phase. Of note, plasma itraconazole levels drawn on day 4 were 0.13 mcg/mL, with the highest value throughout the treatment course of 0.21 mcg/mL. The patient continued to improve clinically and was discharged from the hospital after 29 days. Repeat imaging was initially planned at 6 months but was deferred at the patient’s request. Serum GM levels 9 months after therapy had declined to 0.11, and he remained asymptomatic at the 12-month follow-up.\n\nDiscussion and conclusions\nT. marneffei is a dimorphic fungus that can infect both immunocompromised and immunocompetent hosts. The yeast form with a centrally transverse septum is found at 37 °C whereas the hyphae form with a red diffusible pigment is found at room temperature (25 °C).8 Endemic areas of T. marneffei include Southeast Asia, Southern China, and Northeastern India.9\n\nPrevious studies suggested that inhalation of conidia was the primary route of infection that can later disseminate to the reticuloendothelial system, skin, and gastrointestinal organs. The bamboo rat is the only non-human host, and there is no evidence of direct transmission to humans.10 However, occupational exposure to plants and animals has been associated with human infection.3\n\nDisseminated talaromycosis is the third most common opportunistic infection in the northern area of Thailand after tuberculosis and cryptococcosis. Talaromycosis has the highest incidence rate in the rainy season whereas other opportunistic infections show no seasonal predilection.6 The incubation period of the acute disease is approximately 1–3 weeks, while reactivation of the disease in immunocompromised hosts can occur many years after the initial exposure.3\nT. marneffei mainly affects individuals with impaired cellular immunity, particularly those with low CD4 counts (ie, HIV-infected patients), and clinical manifestations may vary depending on organ system involvement. Moreover, the severity of the disease reflects the immune status of the individual. HIV-infected patients with talaromycosis commonly have a CD4 count below 100 cells/mm3 at diagnosis, but talaromycosis has also been reported in non-HIV infected patients, including those afflicted with lupus, diabetes mellitus, lymphoma, or in receipt of immunosuppressive drugs.7\n\nFrequent presentations of talaromycosis in HIV-infected patients include fever (87.1%), followed by cutaneous lesions (40.5%), hepatomegaly (36.2%), lymphadenopathy (31.9%), and cough (27.6%).7 However, several studies have reported skin involvement in >80% of all patients.11–14 For example, a report from Manipur state, India in 2002 documented cutaneous lesions in 29 of 36 (81%) HIV-infected patients with disseminated talaromycosis.11 Similarly, a study from North Vietnam reported cutaneous lesions in 83% of patients.12 In HIV-uninfected individuals with talaromycosis, skin involvement remains the most common presentation (up to 78.6%), followed by fever according to Kawila et al7. Therefore, cutaneous involvement in disseminated talaromycosis is often used to aid diagnosis.\n\nUmbilicated lesions are the most common form of cutaneous lesion found in this patient group, and these are usually distributed over the face and neck areas.7 A study from King Chulalongkorn Memorial Hospital, Bangkok during 2001–2010 reported umbilicated skin lesions in 78.5% of talaromycosis cases,13 whereas a study from Ramathibodi Hospital, Bangkok during 2005–2010 reported such lesions in 46% of all cases.14 Despite the anticipated skin manifestation among individuals with talaromycosis, regardless of the HIV serostatus, there is no definite pathophysiologic mechanism to explain why this is such a common finding, and no distinguished associated factors among infected individuals with and without skin involvement have been identified.\n\nIn the present case, dull abdominal pain and fever indicated an inflammatory process of the solid organ system rather than the hollow viscus. And based on the location of the pain in the left upper quadrant, the inflammation of the spleen was suspected. The etiology of the inflammation with relatively rapid progression made indolent infection such as tuberculosis less likely. Therefore, a concern of splenic abscess secondary to either bacterial or endemic fungal infections was raised. In this patient, fever was not an initial presentation which suggested a lower likelihood of hematogenous bacterial infection as the culprit but rather fungal infection. His clinical presentation did not suggest talaromycosis at first diagnosis despite the fact that the clinical course began in the rainy season. Instead, histoplasmosis, cryptococcosis, and other non-infectious etiologies including lymphoma were suspected. A diagnosis of talaromycosis can be recognized by clinicians when the patient presents with classic cutaneous lesions but is often missed when no skin lesions are documented in individuals suspected to have systemic infections. In 1997, Kuntipong et al reported six patients from Chiangrai Province, in Northern Thailand, who experienced hepatic talaromycosis without skin lesions and presented with high-grade fever, acute abdominal pain, and elevated alkaline phosphatase levels. T. marneffii was isolated from the blood of all six patients. Abundant septate hyphae were identified from the hepatic histopathology of two patients. Only two patients completed conventional amphotericin B treatment followed by itraconazole; they recovered fully but the remaining patients died before the treatment was started because of delayed diagnosis in three patients and leaving the hospital against medical advice by one.15\n\nIn 2006, a 26-year-old male with HIV infection who resided in Guangxi Province, China presented with a 2-month history of high-grade fever and cough without skin lesion. His chest radiograph was normal, and pulmonary tuberculosis was provisionally diagnosed. He was treated with anti-tuberculosis drugs for 1 month without clinical improvement. He was then referred to West China Hospital where bronchoscopy revealed granulomatous nodules at the bronchial orifices to the left lower basilar segment. His blood, bone marrow, and bronchoscopic biopsy cultures were positive for T. marneffei. A combination of amphotericin B deoxycholate and itraconazole treatment was instituted with an excellent clinical response.16\n\nTalaromycosis can present either as a part of a new infection or as part of immune reconstitution inflammatory syndrome (IRIS). IRIS can occur during immune recovery after the initiation of ART that leads to an increased CD4 count and a decline of the HIV viral load. The emergence of a pre-existing undiagnosed infection is known as “unmasking IRIS”, and is less common than newly acquired infection.17 To date, only four cases have been reported worldwide, of which three presented as paradoxical IRIS.18 In 2007, Gupta et al reported a 35-year-old treatment naïve HIV-infected male from Manipur, India who presented with fever, weight loss, and heaviness in the abdomen for 2 months. His CD4 count was 4 cells/mm3 (unknown percentage), and chest computed tomography revealed a small round opacity in the basal segment of the left lung. He was given ART (stavudine, lamivudine, and nevirapine) and empirical anti-tuberculosis drugs despite a negative sputum acid-fast bacilli smear. One month later, he returned to the hospital with marked lymphadenopathy and hepatosplenomegaly. No abnormal cutaneous lesions were appreciated. T. marneffei was isolated from axillary lymph node aspirates and blood cultures. The final diagnosis was IRIS from T. marneffei. After a 2-week course of the amphotericin B deoxycholate, he continued with itraconazole 400 mg/day for 10 weeks and thereafter maintenance therapy of 200 mg/day. His condition dramatically improved.19\n\nThe clinical syndrome of our patient developed 2 months after the initiation of ART, making unmasking IRIS the most plausible diagnosis although this could not be verified. Other reasons to support unmasking IRIS include the lack of recent travel history to endemic areas and no notable exposure to soil, plants, or reservoir animals.\n\nCytological and histological examinations of talaromycosis clinical samples may reveal either intracellular or extracellular yeasts following periodic acid–Schiff or silver methenamine staining. The detection of non-budding yeast cells with a central transverse septum would give a presumptive diagnosis while confirmation by microbiological culture is considered the gold standard.11 The specimen that gives the highest yield in fungal culture is bone marrow (100%) followed by skin biopsy (90%) and blood culture (76%). The time to positivity of the blood culture varies from 1.5–7 days with a median time of 4 days. The morphology of the colony is granular with a greenish-yellowish or grayish color and the production of diffusible red pigment.2 Septate hyphae were also identified on Gram staining of the colonies in our patient.\n\nSerology and direct antigen detection were not performed in this case because of their lack of availability at the national level. GM is a carbohydrate molecule composed of a backbone of mannose residues with side chains of β 1–5 linked galactofuranosyl residues. It is found in the cell wall of mold-like fungi, especially Aspergillus spp. and Talaromyces spp., but it is also found in other species such as Fusarium spp., Alternaria spp., and Histoplasma spp..20,21 In 1992, Stynen discovered a monoclonal antibody (EB-A2) which specifically targeted galactofuranosyl residues, and later resulted in the development of a diagnostic ELISA.22,23 The GM assay is generally used to detect Aspergillus spp., but serum GM is used as a surrogate marker of talaromycosis in some institutes.24\n\nThailand National Guidelines on HIV/AIDS Treatment and Prevention 2017 recommends the administration of amphotericin B deoxycholate 0.7–1 mg/kg/day for 7–14 days, followed by itraconazole 200 mg three times daily for 3 days and then 200 mg twice daily for 10–12 weeks. No routine plasma itraconazole level monitoring is recommended in clinical practice. The once-daily 200 mg itraconazole regimen is recommended as secondary prophylaxis among patients who sustain low CD4 counts until the value has reached >100 cells/mm3 for at least 6 months.25\n\nVoriconazole is a broad-spectrum antifungal agent that has activity against yeast and mold forms of T. marneffei. Voriconazole was reported to have superior activity compared with amphotericin B and itraconazole according to an in vitro study, but in vivo data are limited.26 In 2017, Ouyang and colleagues studied 17 disseminated talaromycosis cases with and without a diagnosis of HIV infection who had been treated with voriconazole. Voriconazole had been administered at a loading dosage of 6 mg/kg every 12 h on the first day followed by 4 mg/kg every 12 h for at least 3 days, then 200 mg twice daily thereafter. The total duration of treatment was solely determined by the investigators dependent on clinical responses. Patients were monitored from treatment initiation until 16 weeks of treatment. Three of 17 patients prematurely discontinued treatment because of financial concerns and other unidentified reasons, 10 had a complete recovery, three had partial recovery, and one was a clinical failure at week 16. No adverse effects were recorded during the study period. This study concluded that voriconazole is an effective alternative and more convenient than the standard itraconazole regimen.27 However, voriconazole is considered a high-cost drug in lower-middle income countries and according to the national guidelines and reimbursement program, voriconazole has not yet been approved for the treatment of invasive fungal infection other than aspergillosis. And to comply with the national policy on a reimbursement program, when conventional amphotericin B is contraindicated, liposomal amphotericin B can be used. Therefore, voriconazole was not the option in this patient.\n\nIn conclusion, despite the rarity of disseminated talaromycosis among well-controlled AIDS patients without skin involvement, a history of residing in or visiting endemic areas should lead to a consideration of talaromycosis in the differential diagnosis. Indeed, high awareness of this condition remains key to early diagnosis and treatment success. Notably, unmasking IRIS is not the major presentation of talaromycosis compared with newly acquired infection.\n\nAcknowledgments\nThe authors would like to thank the Faculty of Medicine at Ramathibodi Hospital, Mahidol University for their permission to conduct this study and Subencha Pinsai, MD for assistance in clinical management.\n\nAbbreviation list\nAIDS, Acquired Immune Deficiency Syndrome; ART, Anti-retroviral therapy; BP, Blood pressure; ELISA, enzyme-linked immunosorbent assay; GM, Galactomannan: HIV, Human Immunodeficiency Virus; IRIS, Immune Reconstitution Inflammatory Syndrome.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Series Editor of this journal.\n\nEthics approval and consent to participate\nEthical approval was granted by the Research Ethics Committee of the Faculty of Medicine Ramathibodi Hospital, Mahidol University (approval no. MURA2018/345).\n\nAuthor contributions\n All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors declare that they have no competing interests in this work.\n==== Refs\nReferences\n1. Piehl \nMR , Kaplan \nRL , Haber \nMH . Disseminated penicilliosis in a patient with acquired immunodeficiency syndrome . Arch Pathol Lab Med . 1988 ;112 :1262 –1264 .3190413 \n2. Supparatpinyo \nK , Khamwan \nC , Baosoung \nV , Nelson \nKE , Sirisanthana \nT . Disseminated Penicillium marneffei infection in Southeast Asia . Lancet . 1994 ;344 :110 –113 .7912350 \n3. Limper \nAH , Adenis \nA , Le \nT , Harrison \nTS . Fungal infections in HIV/AIDS . Lancet Infect Dis . 2017 ;17 :e334 –e343 . doi:10.1016/S1473-3099(17)30303-1 28774701 \n4. Wong \nKH , Lee \nSS , Chan \nKC , et al. Redefining AIDS: case exemplified by Penicillium marneffei infection in HIV-infected people in Hong Kong . Int J STD AIDS . 1998 ;9 :555 –556 .\n5. Supparatpinyo \nK , Chiewchanvit \nS , Hirunsri \nP , Uthammachai \nC , Nelson \nKE , Sirisanthana \nT . Penicillium marneffei infection in patients infected with human immunodeficiency virus . Clin Infect Dis . 1992 ;14 :871 –874 . doi:10.1093/clinids/14.4.871 1315586 \n6. Le \nT , Wolbers \nM , Chi \nNH , et al. Epidemiology, seasonality, and predictors of outcome of AIDS-associated Penicillium marneffei infection in Ho Chi Minh City, Vietnam . Clin Infect Dis . 2011 ;52 :945 –952 . doi:10.1093/cid/cir028 21427403 \n7. Kawila \nR , Chaiwarith \nR , Supparatpinyo \nK . Clinical and laboratory characteristics of penicilliosis marneffei among patients with and without HIV infection in Northern Thailand: a retrospective study . BMC Infect Dis . 2013 ;13 :464 . doi:10.1186/1471-2334-13-464 24094273 \n8. Antinori \nS , Gianelli \nE , Bonaccorso \nC , et al. Disseminated Penicillium marneffei infection in an HIV-positive Italian patient and a review of cases reported outside endemic regions . J Travel Med . 2006 ;13 :181 –188 . doi:10.1111/j.1708-8305.2006.00039.x 16706952 \n9. Wong \nSY , Wong \nKF . Penicillium marneffei infection in AIDS . Patholog Res Int . 2011 ;2011 :10 .\n10. Cao \nC , Liang \nL , Wang \nW , et al. Common reservoirs for Penicillium marneffei infection in humans and rodents, China . Emerg Infect Dis . 2011 ;17 :209 –214 . doi:10.3201/eid1702.100718 21291590 \n11. Ranjana \nKH , Priyokumar \nK , Singh \nTJ , et al. Disseminated Penicillium marneffei infection among HIV-infected patients in Manipur state, India . J Infect . 2002 ;45 :268 –271 .12423616 \n12. Larsson \nM , Nguyen \nLH , Wertheim \nHF , et al. Clinical characteristics and outcome of Penicillium marneffei infection among HIV-infected patients in northern Vietnam . AIDS Res Ther . 2012 ;9 :24 . doi:10.1186/1742-6405-9-24 22897817 \n13. Uppathamnarakorn \nP , Jindamporn \nA , Suankratay \nC \nPenicilliosis, cryptococcosis, and histoplasmosis: a comparative study between epidemiology, clinical features, microbiology, treatment, and outcome . Poster session presented at ECCMID 2012 , London, UK .\n14. Chantharit \nP , Watcharananan \nS , Sunkanuparph \nS \nComparison of clinical characteristics and survival among patients with cryptococcosis, histoplasmosis, and penicillosis in Ramathibodi Hospital, 2005–2010 . Poster session presented at 28th International Congress of Chemotherapy and Infection , Yokohama, Japan .\n15. Kantipong , Panich V , Pongsurachet \nV , Watt \nG. \nHepatic penicilliosis in patients without skin lesions . Clin Infect Dis . 1998 ;26 :1215 –1217 . doi:10.1086/520282 9597255 \n16. Zhiyong \nZ , Mei \nK , Yanbin \nL . Disseminated Penicillium marneffei infection with fungemia and endobronchial disease in an AIDS patient in China . Med Princ Pract . 2006 ;15 :235 –237 . doi:10.1159/000092189 16651843 \n17. Elston \nJWT , Thaker \nH . Immune reconstitution inflammatory syndrome . Int J STD AIDS . 2009 ;20 :221 –224 . doi:10.1258/ijsa.2008.008449 19304962 \n18. Sudjaritruk \nT , Sirisanthana \nT , Sirisanthana \nV . Immune reconstitution inflammatory syndrome from Penicillium marneffei in an HIV-infected child: a case report and review of literature . BMC Infect Dis . 2012 ;12 :28 . doi:10.1186/1471-2334-12-166 22289885 \n19. Gupta \nS , Mathur \nP , Maskey \nD , et al. Immune restoration syndrome with disseminated Penicillium marneffei and cytomegalovirus co-infections in an AIDS patient . AIDS Res Ther . 2007 ;4 :21 . doi:10.1186/1742-6405-4-21 17922912 \n20. Swanink \nCM , Meis \nJF , Rijs \nAJ , Donnelly \nJP , Verweij \nPE . Specificity of a sandwich enzyme-linked immunosorbent assay for detecting Aspergillus galactomannan . J Clin Microbiol . 1997 ;35 :257 –260 .8968919 \n21. Wong \nKF . Marrow penicilliosis: a readily missed diagnosis . Am J Clin Pathol . 2010 ;134 :214 –218 . doi:10.1309/AJCPWVBQCW13DJLO 20660323 \n22. Huang \nYT , Hung \nCC , Hsueh \nPR . Aspergillus galactomannan antigenemia in penicilliosis marneffei . Aids . 2007 ;21 :1990 –1991 . doi:10.1097/QAD.0b013e3282eeb413 17721116 \n23. Stynen \nD , Sarfati \nJ , Goris \nA , et al. Rat monoclonal antibodies against Aspergillus galactomannan . Infection and Immunity . 1992 ;60 :2237 –2245 .1375195 \n24. Mennink-Kersten \nMA , Donnelly \nJP , Verweij \nPE . Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis . Lancet Infect Dis . 2004 ;4 :349 –357 . doi:10.1016/S1473-3099(04)01045-X 15172343 \n25. Department of Disease Control . National guidelines on HIV/AIDS treatment and prevention ; 2017 \nAvailable from: \nhttp://www.thaiaidssociety.org/images/PDF/hiv_thai_guideline_2560.pdf. Accessed 1 14 , 2019.\n26. Liu \nD , Liang \nL , Chen \nJ . In vitro antifungal drug susceptibilities of Penicillium marneffei from China . J Infect Chemother . 2013 ;19 :776 –778 . doi:10.1007/s10156-012-0511-7 23104584 \n27. Ouyang \nY , Cai \nS , Liang \nH , et al. Administration of voriconazole in disseminated Talaromyces (Penicillium) marneffei infection: a retrospective study . Mycopathologia . 2017 ;182 :569 –575 . doi:10.1007/s11046-016-0107-3 28108867\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6973",
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"keywords": "AIDS; cutaneous involvement; disseminated fungal infection; talaromycosis",
"medline_ta": "Infect Drug Resist",
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"nlm_unique_id": "101550216",
"other_id": null,
"pages": "1493-1499",
"pmc": null,
"pmid": "31239726",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12423616;1315586;1375195;15172343;16651843;16706952;17721116;17922912;19304962;20660323;21291590;21331327;21427403;22289885;22897817;23104584;24094273;28108867;28774701;3190413;7912350;8968919;9597255;9764944",
"title": "Absence of cutaneous involvement in disseminated Talaromyces marneffei infection in an AIDS patient: a case report and literature review.",
"title_normalized": "absence of cutaneous involvement in disseminated talaromyces marneffei infection in an aids patient a case report and literature review"
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"abstract": "Immunothrombocytopenic purpura is a possible complication after liver transplant. The therapy for immunothrombocytopenic purpura after liver transplant is similar to that of primary immunothrombocytopenic purpura. This therapy consists of corticosteroids, intravenous immunoglobulin, and immunosuppressive agents such as cyclosporine and rituximab. There are a few cases of immunothrombocytopenic purpura in patients who recovered after cessation of tacrolimus administration. Here, we show an intractable case of immunothrombocytopenic purpura in a living related liver transplant recipient treated with some of these. We observed complete remission after switch ofthe immunosuppressive agent from tacrolimus to cyclosporine. The patient was an infant girl aged 18 months who underwent livingr elated liver transplant for biliary atresia when she was 6 months old. Liver graft was a left lateral segment from her father. Purpura and severe thrombocytopenia developed after 11 months.There was no effect of the first-line therapies, as described in the Japan guidelines for immunothrombocytopenic purpura.Thrombocytopenia was extreme, as shown by a blood count of 0 platelets/μL. Administration of rituximab was started. However, her platelet count had not increased 8 weeks after rituximab initiation. As a trial therapy, we switched tacrolimus to cyclosporine. She showed complete remission 1 month after this drug conversion. Thus, a switch from tacrolimus to other immunosuppressive agents as a therapy for immunothrombocytopenic purpura after living related liver transplant should be considered.",
"affiliations": "From the Department of Pediatrics, Kumamoto University of Medicine, Kumamoto, Japan.",
"authors": "Hamaguchi|Masayoshi|M|;Sakamoto|Rieko|R|;Kohrogi|Kensaku|K|;Yamashita|Takahiro|T|;Furuie|Keishiro|K|;Anan|Tadashi|T|;Nakamura|Kimitoshi|K|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2021.0272",
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"issn_linking": "1304-0855",
"issue": "19(11)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": null,
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "1228-1231",
"pmc": null,
"pmid": "34812712",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Complete Remission of Refractory Immunothrombocytopenic Purpura After Tacrolimus Replacement With Cyclosporine in a Case of Living Related Liver Transplant.",
"title_normalized": "complete remission of refractory immunothrombocytopenic purpura after tacrolimus replacement with cyclosporine in a case of living related liver transplant"
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{
"companynumb": "JP-MYLANLABS-2022M1004124",
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{
"abstract": "Two infants treated for syphilis born to at risk mothers who screened negative at their first prenatal visit but were not rescreened at delivery are described. The first presented with classic, but unrecognized, features of congenital syphilis. In the second case, possible early maternal syphilis was diagnosed soon after delivery using the treponemal first reverse-screening algorithm. Although the child's physical exam was normal and the maternal rapid plasma reagin (RPR) negative, the child was treated for syphilis because maternal confirmatory treponemal tests suggested recent seroconversion. Given the re-emergence of congenital syphilis, our report aims to demonstrate the importance of rescreening women at increased risk and improve awareness of common manifestations of the syphilis disease in the newborn. For women at increased risk, repeat syphilis testing early in the third trimester and again at delivery in communities and populations with a high prevalence of syphilis is recommended.",
"affiliations": "Center for Pediatric Infectious Diseases, Cleveland Clinic Children's, Cleveland Clinic, Cleveland, OH, United States.;Center for Pediatric Infectious Diseases, Cleveland Clinic Children's, Cleveland Clinic, Cleveland, OH, United States.;Center for Pediatric Infectious Diseases, Cleveland Clinic Children's, Cleveland Clinic, Cleveland, OH, United States.;Section of Pediatric Dermatology, Cleveland Clinic, Cleveland, OH, United States.;Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, United States.;Center for Pediatric Infectious Diseases, Cleveland Clinic Children's, Cleveland Clinic, Cleveland, OH, United States.",
"authors": "O'Connor|Nicola P|NP|;Gonzalez|Blanca E|BE|;Esper|Frank P|FP|;Tamburro|Joan|J|;Kadkhoda|Kamran|K|;Foster|Charles B|CB|",
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"doi": "10.1016/j.idcr.2020.e00964",
"fulltext": "\n==== Front\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30272-9\n10.1016/j.idcr.2020.e00964\ne00964\nCase Report\nCongenital syphilis: Missed opportunities and the case for rescreening during pregnancy and at delivery\nO’Connor Nicola P. a Gonzalez Blanca E. a Esper Frank P. a Tamburro Joan b Kadkhoda Kamran c Foster Charles B. fosterc3@ccf.orga⁎ a Center for Pediatric Infectious Diseases, Cleveland Clinic Children’s, Cleveland Clinic, Cleveland, OH, United States\nb Section of Pediatric Dermatology, Cleveland Clinic, Cleveland, OH, United States\nc Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, United States\n⁎ Corresponding author at: Center for Pediatric Infectious Diseases, Cleveland Clinic Children’s Cleveland Clinic, Cleveland, OH 44195, United States. fosterc3@ccf.org\n23 9 2020 \n2020 \n23 9 2020 \n22 e009641 9 2020 18 9 2020 18 9 2020 © 2020 The Authors. Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Two infants treated for syphilis born to at risk mothers who were not rescreened at delivery are described.\n\n• Screening for syphilis at the first prenatal visit is the standard of care but may fail to detect late term acquisition of maternal infection.\n\n• In high risk populations, rescreening for syphilis should be performed during pregnancy both early in the third trimester and again at delivery.\n\n• Early maternal syphilis may be recognized using the treponemal first reverse-screening algorithm.\n\n\n\nTwo infants treated for syphilis born to at risk mothers who screened negative at their first prenatal visit but were not rescreened at delivery are described. The first presented with classic, but unrecognized, features of congenital syphilis. In the second case, possible early maternal syphilis was diagnosed soon after delivery using the treponemal first reverse-screening algorithm. Although the child’s physical exam was normal and the maternal rapid plasma reagin (RPR) negative, the child was treated for syphilis because maternal confirmatory treponemal tests suggested recent seroconversion. Given the re-emergence of congenital syphilis, our report aims to demonstrate the importance of rescreening women at increased risk and improve awareness of common manifestations of the syphilis disease in the newborn. For women at increased risk, repeat syphilis testing early in the third trimester and again at delivery in communities and populations with a high prevalence of syphilis is recommended.\n\nAbbreviations\nCDC, Centers for Disease Control and PreventionCSF, cerebrospinal fluidHSV, Herpes Simplex VirusHIV, Human Immunodeficiency VirusPCR, Polymerase Chain ReactionRPR, Rapid Plasma ReaginSTIs, sexually transmitted infectionsVDRL, Venereal Disease Research LaboratoryKeywords\nCongenital syphilisCondyloma lataPregnancyReverse-sequence screeningRescreeningDelivery\n==== Body\nIntroduction\nBetween 2014 and 2018 the United States has recognized a 165 % increase in primary and secondary syphilis among women of reproductive age [1]. Concurrently, congenital syphilis has increased and now occurs at a rate of 33.1 cases per 100,000 live births [1,2]. If untreated during pregnancy, maternal syphilis may result in fetal demise, or congenital infection, which may lead to severe physical and neurological disability or newborn death [[3], [4], [5], [6]]. Key to prevention is screening pregnant women for syphilis at the initial prenatal visit, and if at increased risk, again in the third-trimester and at delivery [1,7,8]. The State of Ohio where our cases originated, requires syphilis screening of all pregnant women at the first antenatal visit but does not require repeat testing later in pregnancy nor at delivery [9]. Highlighting the importance of rescreening, we report two infants born to mothers whose initial first trimester screens were negative and who were not rescreened at delivery despite having risk factors. One case demonstrates a classic presentation of congenital syphilis infection while the other was only recognized because of maternal serologic testing using the treponemal first reverse-screening algorithm. Together these cases illustrate the spectrum of presentation of syphilis in young infants, the lack of recognition among clinicians of the disease, the extremely imperfect strategy of using risk-based rescreening guidelines especially in communities and populations where the prevalence of syphilis is high, and highlights missed opportunities for identifying exposed infants.\n\nCase 1\nA 3 ½ month old male infant presented on four occasions for persistent erythematous perianal papules, rhinorrhea and peeling of the lower and upper extremities. He was born at term via caesarean section to a 19-year-old primigravida mother with negative first-trimester screening results, including for human immunodeficiency virus (HIV) and syphilis, the latter by syphilis antibody screen (BioPlex™ 2200 Syphilis IgG, Biorad Assay). At 38 weeks gestation, the mother developed genital lesions presumed by the obstetrical team to be primary herpes simplex virus (HSV). The HSV-1 IgG serology was positive but polymerase chain reaction (PCR) assays from the lesions were negative for both HSV-1 and HSV-2. She was not rescreened for syphilis. The mother was treated for presumed primary HSV infection with oral valacyclovir and with metronidazole for bacterial vaginosis. She also received cefazolin once as surgical prophylaxis for caesarean section at delivery. The child had a normal newborn examination. HSV skin surface cultures, blood PCR and cerebrospinal fluid (CSF) PCR from the infant were all negative. Given the presumed first-episode non-primary maternal HSV infection, the child received preemptive therapy with intravenous acyclovir per American Academy of Pediatrics guidance [10]. At one month of life, he developed a rash on the arms and feet that subsequently desquamated. He also had persistent rhinorrhea. At two months of life, two erythematous perianal papules developed and progressed to large plaques. At 3 ½ months of life, he was seen in the Emergency Department for rhinorrhea and the perianal rash. A dermatology referral was made, where condyloma lata (Fig. 1) was suspected and testing for syphilis was performed in both the infant and the mother.Fig. 1 Perianal condyloma lata at time of syphilis diagnosis.\n\nFig. 1\n\nThe infant’s syphilis antibody screen (BioPlex™ 2200 Syphilis IgG, Biorad Assay), was positive with an antibody index >8.0 and the Rapid Plasma Reagin (BD Macro-Vue™ RPR, Becton Dickinson) was reactive at >1:512 dilution. A CSF Venereal Disease Research Laboratory (VDRL) test was also reactive (1:1), with 18 nucleated cells/μL in the CSF. CSF protein was 45 mg/dL (normal range 15−48 mg /dL) and CSF glucose was 47 mg /dL (normal range 60–80 mg /dL). Long bone radiographs revealed features of congenital syphilis, including periostitis (Fig. 2). The mother’s antibody screen (BioPlex™ 2200 Syphilis IgG, Biorad Assay) was positive with an antibody index >8.0 and her RPR (BD Macro-Vue™ RPR, Becton Dickinson) was reactive at 1:64. He received intravenous crystalline penicillin G for 10 days. The condyloma lata resolved within 72 h of treatment. By 6 months the infant’s RPR had decreased fourfold and the CSF VDRL was non-reactive. Reflecting the lack of awareness of the clinical features of syphilis, 3 outpatient caregivers were exposed to potentially infectious lesions or secretions while examining the child. All 3 tested negative for syphilis three months after exposure.Fig. 2 Radiograph of the left tibia and fibula showing sandwich-shaped metaphysitis (lower arrow), seen as an alternation of hyperdense and hypodense layers. The upper arrow shows the formation of a medial tibial beak with osteochondondritis.\n\nFig. 2\n\nCase 2\nAn eight day old male infant was hospitalized for neonatal HSV, limited to the scalp. He was born at 38 2/7 weeks gestation via spontaneous vaginal delivery to an 18-year-old primigravida mother. At 7 weeks gestation, the mother tested positive for trichomoniasis, but negative for other sexually transmitted infections (STIs) including HIV and for syphilis by antibody screen (BioPlex™ 2200 Syphilis IgG, Biorad Assay). At the mother’s request, she was again screened for syphilis at 16 and 30 weeks, testing negative by treponemal IgG antibody assay. Testing for syphilis was not repeated at delivery. During labor, the mother developed fever and received single doses of cefazolin and clindamycin. On day 8 of life the child was admitted with cutaneous HSV lesions without dissemination. Due to concern that the mother had had recent primary HSV, she was re-tested for STIs including syphilis. Using a reverse-sequence testing algorithm, her syphilis total antibodies treponemal screen was positive (BioPlex™ 2200 Syphilis Total (IgM/IgG), Biorad Assay) but the reflex non-treponemal RPR (Becton Dickinson technology) assay was non-reactive. A confirmatory treponemal antibody enzyme immunoassay was subsequently positive with an antibody index value of 2.5 (Trep-Sure™ Syphilis Total Antibody EIA, Trinity Biotech). A prozone phenomenon was excluded. The infant’s evaluation demonstrated a normal exam, negative syphilis total antibodies screen and RPR, non-reactive CSF VDRL, and normal radiographs of the long bones. As the mother had not received treatment for syphilis during pregnancy, the child was in hospital already, and follow-up could not be assured for the infant, he was treated as a high risk exposure/possible congenital syphilis and received empiric intravenous crystalline penicillin G for 10 days, in addition to intravenous acyclovir.\n\nDiscussion\nScreening for syphilis during pregnancy is an important public health practice aimed at preventing congenital infections. The Centers for Disease Control (CDC) recommends that all pregnant women be screened for syphilis at the first prenatal visit [11]. Women at increased risk of infection are recommended to be rescreened at 28–32 weeks gestation to allow time for treatment and resolution of infection to occur prior to delivery. A third screening may be performed at delivery to detect any late term acquisition of infection. In the United States, the laws regulating syphilis screening during pregnancy vary by state. Forty-six states require testing of all pregnant women at the first prenatal visit [12,13]. Twenty-one states require some form of repeat screening for syphilis during the third-trimester and or at delivery, in some cases only if the mother is at increased risk.\n\nThese two cases illustrate a need for heightened clinical awareness of syphilis by providers and emphasize the importance of rescreening pregnant woman at risk for syphilis infection early during the third-trimester and again at delivery. In the first case, there were multiple failures to recognize clinical findings of syphilis, both in the mother and the infant. The second case emphasizes the importance of rescreening at delivery women from populations at high risk for syphilis, even in asymptomatic mothers, and the potential benefit of using a reverse-screening approach to detect early disease. The syphilis total antibodies assay used as the treponemal screening test typically becomes positive 2–3 weeks after exposure whereas non-treponemal assays such as the RPR do not become reactive until several weeks after the treponemal assays [14,15]. Reverse-sequence testing algorithms offer a potential advantage over traditional screening in detecting very recent infections because of the shorter window period and may be particularly useful when testing women who are at increased risk, whether due to personal or epidemiological factors.\n\nAs a result of the recent increase in syphilis among women and the concomitant rise in congenital syphilis among infants, several states have legislated that all pregnant women be screened at three time points: the first prenatal visit, early third-trimester and at delivery [12]. Louisiana and Florida have mandated universal third-trimester rescreening and have effectively prevented most cases of congenital syphilis [16]. Minnesota mandated universal rescreening at 3 time points in 2016 [13]. During the following two years, 69 cases of syphilis were identified among pregnant women including 18 acute infections. Five infants (28 %) would not have been identified with screening at the first prenatal visit only. Their report found no documented case in which a negative screening test during the early third-trimester was followed by a positive test at delivery.\n\nInterestingly, in the second case the diagnosis of maternal syphilis was made only through the use of the reverse-screening algorithm (Fig. 3); screening by the traditional approach (initial screening with a non-treponemal test) would not have detected the infection as the maternal RPR was non-reactive. An explanation for the non-reactive RPR in the setting of recent treponemal seroconversions would be early syphilis infection. The risks and benefits for treatment were considered given that congenital syphilis may cause significant morbidity to infants. As follow up for this infant was uncertain, the decision was made to treat the infant with a 10 day course of crystalline penicillin G rather than a single dose of benzathine penicillin G.Fig. 3 Algorithms for traditional and reverse-sequence screening for syphilis.\n\nFig. 3\n\nThe optimal approach to screening pregnant women for syphilis has not been established. Advantages and disadvantages to both the traditional and reverse-screening approach exist with regard to cost, laboratory throughput, false-positive rates, ability to discern previous or latent infection, and improved sensitivity for diagnosis of acute infection [7,15,17]. In addition, where syphilis PCR is available, lesions should be swabbed and tested for confirmatory diagnosis.\n\nWhether and how to rescreen women at increased risk for syphilis both early in the third-trimester and again at delivery are important questions. Although cost effectiveness analyses have not favored universal third-trimester rescreening of all pregnant women, this calculation may require adjustment especially for communities with a high-prevalence of syphilis [18,19]. While the mothers of the infants described in these case reports both screened negative for syphilis initially, neither was rescreened at delivery despite residing in communities with a high-prevalence of syphilis and having histories of STIs.\n\nConclusion\nScreening for syphilis at the first prenatal visit is the standard of care and currently required in most states but may fail to detect late term acquisition of maternal infection. The case reports presented highlight the importance of rescreening women at increased risk for syphilis both early in the third-trimester and again at delivery. Given the reemergence of syphilis and the inconsistency with which risk-based rescreening guidelines are followed, a strong argument can be made for adopting universal rescreening protocols to stem the rise of congenital syphilis.\n\nConsent\nWritten informed consent was obtained from the guardian of the patient in Case 1 for publication of this case report and the accompanying clinical images.\n\nContributors’ Statement Page: Dr. O’Connor drafted the initial manuscript. Drs. Foster, Gonzalez, Tamburro, Esper and Khadkoda revised and edited the manuscript. The clinical images were provided by Dr. Tamburro. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nFunding source\nNo funding was secured for this study.\n\nFinancial disclosure\nThe authors have no financial relationships relevant to this article to disclose.\n\nDeclaration of Competing Interest\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Sexually transmitted disease surveillance Syphilis. Centers for disease control and prevention Atlanta, GA. (Accessed December 12, 2019, at 2018 https://www.cdc.gov/std/stats18/syphilis.htm.) \n2 Cooper J.M. Sanchez P.J. Congenital syphilis Semin Perinatol 42 3 2018 176 184 29627075 \n3 Gomez G.B. Kamb M.L. Newman L.M. Mark J. Broutet N. Hawkes S.J. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis Bull World Health Organ 91 3 2013 217 226 23476094 \n4 Hawkes S.J. Gomez G.B. Broutet N. Early antenatal care: does it make a difference to outcomes of pregnancy associated with syphilis? A systematic review and meta-analysis PLoS One 8 2 2013 e56713 \n5 Qin J. Yang T. Xiao S. Tan H. Feng T. Fu H. Reported estimates of adverse pregnancy outcomes among women with and without syphilis: a systematic review and meta-analysis PLoS One 9 7 2014 e102203 \n6 Qin J.B. Feng T.J. Yang T.B. Hong F.C. Lan L.N. Zhang C.L. Risk factors for congenital syphilis and adverse pregnancy outcomes in offspring of women with syphilis in Shenzhen, China: a prospective nested case-control study Sex Transm Dis 41 1 2014 13 23 24326577 \n7 Preventive Services Task Force U.S. Curry S.J. Krist A.H. Owens D.K. Barry M.J. Caughey A.B. Screening for syphilis infection in pregnant women: US Preventive Services Task Force reaffirmation recommendation statement Jama 320 9 2018 911 917 30193283 \n8 Stafford I.A. Sanchez P.J. Stoll B.J. Ending congenital syphilis Jama 322 21 2019 2073 2074 \n9 Cooper J.M. Porter M. Bazan J.A. Nicholson L.M. Sanchez P.J. Re-emergence of congenital syphilis in Ohio Pediatr Infect Dis J 37 12 2018 1286 1289 29570589 \n10 Kimberlin D.W. Baley J. Committee on infectious diseases, Committee on fetus and newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions Pediatrics 131 2 2013 e635 46 23359576 \n11 Sexually transmitted diseases treatment guidelines, Syphilis during pregnancy 2019 Centers for Disease Control and Prevention Atlanta, GA (Accessed December 12at https://www.cdc.gov/std/tg2015/syphilis-pregnancy.htm.) \n12 State statutory and regulatory language regarding prenatal syphilis screenings in the United States 2018 Centers for Disease Control and Prevention Atlanta, GA (Accessed December 12, 2019, at https://www.cdc.gov/std/treatment/syphilis-screenings-2018.htm.) \n13 Revised syphilis screening recommendations for pregnant women. 2/15/19: MDH letter to prenatal, perinatal, and pediatric health care providers. Minnesota Department of Health 2019 (Accessed December 12, 2019, at https://www.health.state.mn.us/diseases/syphilis/hcp/syphpreg2019.pdf.) \n14 Henao-Martinez A.F. Johnson S.C. Diagnostic tests for syphilis: new tests and new algorithms Neurol Clin Pract 4 2 2014 114 122 27606153 \n15 Peeling R.W. Ye H. Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview Bull World Health Organ 82 6 2004 439 446 15356937 \n16 Matthias J.M. Rahman M.M. Newman D.R. Peterman T.A. Effectiveness of prenatal screening and treatment to prevent congenital syphilis, Louisiana and Florida, 2013-2014 Sex Transm Dis 44 8 2017 498 502 28703731 \n17 Park I.U. Fakile Y.F. Chow J.M. Gustafson K.L. Jost H. Schapiro J.M. Performance of treponemal tests for the diagnosis of syphilis Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 68 6 2019 913 918 29986091 \n18 Albright C.M. Emerson J.B. Werner E.F. Hughes B.L. Third-trimester prenatal syphilis screening: a cost-effectiveness analysis Obstet Gynecol 126 3 2015 479 485 26244531 \n19 Hersh A.R. Megli C.J. Caughey A.B. Repeat screening for syphilis in the third trimester of pregnancy: a cost-effectiveness analysis Obstet Gynecol 132 3 2018 699 707 30095767\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "22()",
"journal": "IDCases",
"keywords": "CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; Condyloma lata; Congenital syphilis; Delivery; HIV, Human Immunodeficiency Virus; HSV, Herpes Simplex Virus; PCR, Polymerase Chain Reaction; Pregnancy; RPR, Rapid Plasma Reagin; Rescreening; Reverse-sequence screening; STIs, sexually transmitted infections; VDRL, Venereal Disease Research Laboratory",
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"pmid": "33024697",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "Congenital syphilis: Missed opportunities and the case for rescreening during pregnancy and at delivery.",
"title_normalized": "congenital syphilis missed opportunities and the case for rescreening during pregnancy and at delivery"
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"abstract": "Early in the course of immunotherapy there is frequently a transient enlargement of tumor masses (pseudo-progression) due to tumor infiltration by TILs. Current clinical imaging modalities are not able to distinguished pseudo-progression from true tumor progression. Thus, patients often remain on treatment 4-8 weeks longer to confirm disease progression. Nuclear medicine offers the possibility to image immune cells and potentially discriminate pseudo-progression and progression. We conducted a pilot study in patients with metastatic melanoma receiving ipilimumab (IPI) or pembrolizumab (PEMBRO) to assess safety and feasibility of SPECT/CT imaging with 99mTc- interleukin-2 (99mTc-HYNIC-IL2) to detect TILs and distinguish between true progression from pseudo- progression. Scans were performed prior to and after 12w treatment. After labelling,99mTc-HYNIC-IL2 was purified and diluted in 10 mL of 5% glucose with 0.1% human serum albumin. Of the 5 patients (2 treated with IPI and 3 with PEMBRO) enrolled, two failed to complete the second scan as they discontinued IPI due grade 3 colitis (1 patient) or patient refusal after developing multiple toxicities attributed to IPI (1 patient). Following the first scan, one patient reported to have a grade 1 pruritus with grade 1 pain. No other toxicities attributed to the radiopharmaceutical infusion were reported. Metastatic lesions could be visualized by 99mTc-IL2 imaging and there was positive correlation between size and 99mTc-HYNIC-IL2 uptake, both before and after 12 weeks of therapy. The results of this pilot study demonstrate the safety and feasibility of 99mTc-IL2 imaging and has led to a number of hypotheses to be tested in future studies.",
"affiliations": "Department of Oncology, Mayo Clinic, Rochester, MN, USA.;Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, \"Sapienza\" University of Rome, Rome, Italy.;Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.;Department of Immunology, Mayo Clinic, Rochester, MN, USA.;Department of Radiology, Division of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Radiology, Division of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Radiology, Division of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.;Oncology Unit, Department of Clinical and Molecular Medicine, \"Sapienza\" University of Rome, and IDI-IRCCS, Rome, Italy.;Department of Radiology, Division of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA.;Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, \"Sapienza\" University of Rome, Rome, Italy.",
"authors": "Markovic|Svetomir N|SN|;Galli|Filippo|F|;Suman|Vera J|VJ|;Nevala|Wendy K|WK|;Paulsen|Andrew M|AM|;Hung|Joseph C|JC|;Gansen|Denise N|DN|;Erickson|Lori A|LA|;Marchetti|Paolo|P|;Wiseman|Gregory A|GA|;Signore|Alberto|A|",
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"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 301009882566610.18632/oncotarget.25666Research PaperNon-invasive visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: a pilot study Markovic Svetomir N. 14Galli Filippo 2Suman Vera J. 3Nevala Wendy K. 4Paulsen Andrew M. 5Hung Joseph C. 5Gansen Denise N. 5Erickson Lori A. 6Marchetti Paolo 7Wiseman Gregory A. 5Signore Alberto 21 Department of Oncology, Mayo Clinic, Rochester, MN, USA2 Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, Rome, Italy3 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA4 Department of Immunology, Mayo Clinic, Rochester, MN, USA5 Department of Radiology, Division of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA6 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA7 Oncology Unit, Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, and IDI-IRCCS, Rome, ItalyCorrespondence to:Alberto Signore,alberto.signore@uniroma1.it13 7 2018 13 7 2018 9 54 30268 30278 28 12 2017 4 6 2018 Copyright: © 2018 Markovic et al.2018This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Early in the course of immunotherapy there is frequently a transient enlargement of tumor masses (pseudo-progression) due to tumor infiltration by TILs. Current clinical imaging modalities are not able to distinguished pseudo-progression from true tumor progression. Thus, patients often remain on treatment 4-8 weeks longer to confirm disease progression. Nuclear medicine offers the possibility to image immune cells and potentially discriminate pseudo-progression and progression.\n\nWe conducted a pilot study in patients with metastatic melanoma receiving ipilimumab (IPI) or pembrolizumab (PEMBRO) to assess safety and feasibility of SPECT/CT imaging with 99mTc- interleukin-2 (99mTc-HYNIC-IL2) to detect TILs and distinguish between true progression from pseudo- progression. Scans were performed prior to and after 12w treatment. After labelling,99mTc-HYNIC-IL2 was purified and diluted in 10 mL of 5% glucose with 0.1% human serum albumin.\n\nOf the 5 patients (2 treated with IPI and 3 with PEMBRO) enrolled, two failed to complete the second scan as they discontinued IPI due grade 3 colitis (1 patient) or patient refusal after developing multiple toxicities attributed to IPI (1 patient). Following the first scan, one patient reported to have a grade 1 pruritus with grade 1 pain. No other toxicities attributed to the radiopharmaceutical infusion were reported. Metastatic lesions could be visualized by 99mTc-IL2 imaging and there was positive correlation between size and 99mTc-HYNIC-IL2 uptake, both before and after 12 weeks of therapy.\n\nThe results of this pilot study demonstrate the safety and feasibility of 99mTc-IL2 imaging and has led to a number of hypotheses to be tested in future studies.\n\ncheck point inhibitorsipilimumabpembrolizumabmelanoma99mTc-IL2\n==== Body\nINTRODUCTION\nIncreased understanding of the immunobiology of cancers has led to development of immune checkpoint inhibitors (anti-CTLA4 and/or anti-PD1) such as ipilimumab, pembrolizumab, and nivolumab in advanced melanoma. These agents block ligand engagement by normal T cell down regulatory receptors (CTLA4 or PD1) thereby promoting T cell survival, most notably in the PDL1 rich tumor microenvironment. Tumor infiltration by cytotoxic T-cells, the common mechanism of action of all immune checkpoint inhibitors, may lead to transient tumor enlargement. There have been reports of a number of patients treated with these agents that experience tumor burden increases early in their treatment course that met RECIST criteria for disease progression but with continued treatment have reductions in disease burden. In clinical practice, this problem (referred to as pseudo-progression) is often handled by continuing treatment for 4–8 weeks to verify persistence of tumor enlargement, in the hopes of avoiding discontinuation of immunotherapy in patients that may be experiencing pseudo- progression and could ultimately benefit from treatment. Unfortunately, this approach can also prolong therapy with an ineffective agent. Alternative imaging approaches are being explored to provide a means to distinguish between pseudo-progression and true disease progression.\n\nWe have developed methodology for clinical visualization of T lymphocyte organ infiltration using radioactively labeled clinical grade recombinant interleukin-2 (Aldesleukin®, IL-2) [2]. We first began with iodine-123 (123I) labeled IL2 and demonstrated its ability to visualize lymphocyte infiltration in bowel (Celiac disease) [3–6]. Due to concerns about potential adverse effects on the thyroid from a radioactive iodine based radiopharmaceutical, the investigators next employed a 99mTechnicium labeled interleukin-2 (99mTc-IL2). We have demonstrated that this approach was able to visualize lymphocyte infiltration in the bowel (Crohn's disease) as well as in the thyroid (autoimmune thyroiditis) [7–9]. Next, we examined 21 early stage melanoma primary skin lesions prior to surgical resection with 99mTc-IL2 imaging for the presence of TIL and corresponding 99mTc-IL2 uptake by histologic evaluation of the surgical specimen. All 21 melanoma lesions had lymphocytic infiltration at histology and 15 were judged to have positive 99mTc-IL2 scan findings. Of the 17 lesions assessed for CD25 expression (IL-2 receptor), 2 lesions had no CD25+ TIL and no 99mTc-IL2 uptake on imaging; 7 of the 8 lesions with CD25+ TIL constituting > 15% of all TIL had 99mTc-IL2 uptake on imaging, and 4 of the 7 lesions with CD25+ TIL present at ≤ 15% of all TIL had 99mTc-IL2 uptake on imaging. 99mTc-IL2 estimates of TIL correlated significantly with histologic estimates of CD25+ TIL (r = 0.745, p = 0.001). Although these results were promising, the cumbersome multi-step labeling process requiring post- labeling purification and the associated cost of imaging greatly limited further clinical testing of this technology.\n\nIn recent years, we simplified the 99mTc-IL2 labeling method using HYNIC-NHS and tricine as co-ligands (99mTc-HYNIC-IL-2) [10]. The approach was shown to be an improvement over prior IL2 labeling efforts in terms of reduced cost, simplified production methodology, enhanced labeling reproducibility, high specific activity and high stability and capable of binding in vitro to CD25+ cells [10]. Moreover, bio-distribution studies in a healthy volunteer demonstrated similar results to those of prior radiopharmaceuticals with no significant toxicity [10]. Liver and the kidneys are the organs that normally metabolize IL2. 99mTc-HYNIC-NHS demonstrated rapid plasma clearance with kidneys as the major organ of accumulation (peak at 1 hour post injection). Liver and spleen were also detectable, with no evidence of other organ accumulation up to 3 hours post injection.\n\nHerein we present the results of a pilot clinical trial designed to examine the safety and feasibility of 99mTc-HYNIC-IL2 SPECT/CT imaging and to examine the changes in TIL content of sites of metastatic melanoma in patients undergoing therapy with immune checkpoint inhibitors. These data will inform the development of studies to assess the ability of 99mTc-HYNIC-IL2 SPECT/CT imaging to distinguish true progression from pseudo-progression,\n\nRESULTS\nStudy cohort\nEnrolment to this pilot study began March 2014 and closed May 2015 after 5 individuals were accrued due to funding limitations. None of these 5 individuals were found to be ineligible or withdrew consent prior to first 99mTc-HYNIC-IL2 scan. Patient and disease characteristics are presented in\n\nTable 1. Two patients chose to receive ipilimumab and the remaining 3 patients chose to receive pembrolizumab.\n\nTable 1 Patient characteristics\n\tPatients (%)\t\nMedian Age 66 (range 51–82)\t\t\nMales\t4 (80.0%)\t\nECOG performance status\t\t\n 0\t4 (80.0%)\t\n 1\t1 (20.0%)\t\nM stage\t\t\n M1a-b\t3 (60.0%)\t\n M1c\t2 (40.0%)\t\nImmunotherapy regimen\t\t\n Ipilimumab\t2 (40.0%)\t\n Pembrolizumab\t3 (60.0%)\t\nAll 5 patients had a pre-treatment 99mTc-HYNIC-IL2 scan of sites of disease involvement, namely soft tissue (2 patients.), lung (2 patients), and both soft tissue and lung (1 patient). Two patients refused to complete a 99mTc-HYNIC-IL2 scan after 12 weeks of treatment. The first of these two patients was receiving pembrolizumab and was feeling quite poorly as a result of grade 3 skin rash with grade 2 fatigue, pruritus, renal insufficiency and lung infection (all attributed to pembrolizumab). The second patient discontinued ipilimumab treatment as a result of developing grade 3 colitis (attributed to ipilimumab). Following the first scan, one patient reported to have a grade 1 pruritus with grade 1 pain. No other adverse events were reported following the first or second 99mTc- HYNIC-IL2 scan. Thus, none of these 5 patients developed 99mTc-HYNIC-IL2 scintigraphy limiting toxicities (0%: 90% CI: 0–45.1%)\n\nImaging results\nThe number of metastatic lesions identified on pre-treatment 99mTc-HYNIC-IL2 scans of these 5 patients ranged for 3 to 16 (median = 5; total number = 36). 99mTc-HYNIC-IL2 scans showed a normal bio-distribution of the radiopharmaceutical at 1h images with clear disappearance from blood and concentration in liver and kidneys being the organs that normally metabolize IL2. Planar and SPECT images of neoplastic lesions showed the uptake of radiopharmaceutical to varying extents (Figures 1–5). The correlation between a lesion's maximum tumor dimension and its SUVmax prior to treatment was 0.592 (n = 36; p = 0.0001, Figure 6A). Among the 3 patients with a 12 week on treatment 99mTc-HYNIC- IL2 scan, 22 of the 24 lesions seen on CT scan prior to treatment were still present at 12 weeks. The SUVmax in the area where the other two lesions were on their pre-treatment CT scan was 0.1 and 0.2 The correlation between maximum tumor dimension and SUVmax after 12 weeks on treatment was 0.618 (n = 24; p = 0.0013, Figure 6B), Moreover, the correlation between the percent change in SUVmax and the percent change in maximum tumor dimension was 0.654 (n = 24; p = 0.005) and the correlation between the change in SUVmax and the change in tumor dimension was 0.524 (n = 24; p = 0.0086). Results were similar when analyses were carried out using SUVmean.\n\nFigure 1 Pre-therapy (left) and post-therapy (right) images of 99mTc-HYNIC-IL2 uptake in metastatic lesions of patient #1\nWe identified 16 lesions in the affected leg for quantitative analysis. It can be seen that some lesion increased uptake over time, other decreased.\n\nFigure 2 Pre-therapy images of 99mTc-HYNIC-IL2 uptake in metastatic lesions of patient #2\nWe identified 7 lesions in the lungs.\n\nFigure 3 Pre-therapy (upper images) and post-therapy (lower images) images of 99mTc-HYNIC-IL2 uptake in metastatic lesions of patient #3\nWe identified 5 lesions in the lungs and sub-cutaneous tissue for quantitative analysis. It can be seen that most lesions disappear after therapy.\n\nFigure 4 Pre-therapy (upper image) and post-therapy (lower image) images of 99mTc-HYNIC-IL2 uptake in metastatic lesions of patient #4\nWe identified 3 lesions in the affected leg for quantitative analysis. It can be seen that one lesion increased uptake over time, the other two decreased.\n\nFigure 5 Pre-therapy images of 99mTc-HYNIC-IL2 uptake in metastatic lesions of patient #5\nWe identified 3 lesions in the lungs. Patient refused to perform the post-therapy scan and therefore these lesions were not included for quantitative analysis.\n\nFigure 6 Correlations between tumor size (maximal diameter) and SUVmax of individual sites of tumor metastases pre-immunotherapy (A) and post-immunotherapy (B).\n\nOf the 3 patients with a 12 week 99mTc-HYNIC-IL2 scan, one patient had a 91.1% reduction in tumor burden with a corresponding 71.8% reduction in total SUVmax from 7.1 to 2; a second patient had a 16.8% increase in tumor burden with a corresponding 6.3% reduction in total SUVmax from 29.3 to 27.45; and the third patient had a 9.1% increase in tumor burden with a corresponding 22.2% increase in total SUVmax 4.5 to 5.5.\n\nHistopathologic results\nDue to the small number of patients, the histologic analysis of the biopsied lesions is only descriptive (Table 2). The tissue samples were analysed for presence of TIL by H&E, and immunostained for CD3 (detection of T cells). The biopsied tumor metastases that exhibited SUV signals between 1.7 and 2.6 revealed low to moderate TIL invasion with predominantly CD3+ T cells. Of note, patient #5 underwent a pre-IO therapy biopsy of a tumor lesion with an SUV value of 0.1 (no tracer uptake), with a tissue biopsy demonstrating diffuse TIL involvement throughout the sampled tumor tissue (predominantly CD3+ cells). This unexpected result may represent a lack of IL2 receptor expression of the TIL suggesting a state of inactivation, possibly explaining the growing tumor mass in the context of TIL. Unfortunately, patient #5 refused week 12 reimaging due to IO treatment related side effects.\n\nTable 2 Summary of tissue analyses for TIL (CD3)\n\tPre-IO therapy\tPost-IO therapy\t\nPatient\n#\tSUVmax\tTIL within TME (H&E)\tTIL\nphenotype (IHC)\tSUVmax\tTIL within TME (H&E)\tTIL\nphenotype (IHC)\t\n1\t2.5\tNecrotic tissue,\ndiffuse TIL, +1\tCD3\t2.6\tDiffuse, +1\tCD3\t\n2\t1.7\tDiffuse (+1) and some patches of\n+2\tCD3\tna\tna\tna\t\n4\t2.1\tDiffuse, +2\tCD3\t2.1\tPatchy and diffuse +2 with\nareas of +3\tCD3\t\n5\t0.1\tDiffuse, +4\tCD3\tna\tna\tna\t\nNote: Patient #3's biopsied tumor lesion was not imaged; na = not available; TME = tumor microenvironment.\n\nDISCUSSION\nAt times, early tumor infiltration by CTL may manifest as pseudo-progression presenting as transient tumor enlargement followed by tumor regression [1]. Unfortunately, present clinical imaging methods are unable to discriminate pseudo-progression from a true progression. Over the past decades, our work has focused on the search of a reliable imaging probe for non-invasive in vivo\n\nimaging of TIL [11–13]. To date our best results have been obtained using 99mTc-IL2 labelling with HYNIC-NHS and tricine as co-ligands. In the current study, we demonstrated that 99mTc-HYNIC-IL2 scintigraphy is a safe non-invasive clinical examination to assess the presence and changes in TIL in metastatic melanoma lesions in patients undergoing IO therapy with ipilimumab or pembrolizumab. The correlation between maximum tumor dimension seen on CT scan and 99mTc-HYNIC-IL2 uptake was 0.592 (p = 0.0001) prior to treatment and was 0.618 (p = 0.0013) after treatment. These data suggest that the heavier the infiltration of TIL the larger the lesion.\n\nBased on prior study, 99mTc-HYNIC-IL2 uptake in vivo has been shown to reflect the presence of CD25+ activated T-lymphocytes and the findings of this study, we believe that our hypothesize that lesions that appear larger on CT scan after treatment with increased max SUV values are pseudo progression due to increased TIL infiltration should be further explored in a larger patient population. Moreover, the observation from patient #5 that the high CD3+ TIL content in the tumor biopsy did not reflect a “SUV” content may be that the level of 99mTc-HYNIC-IL2 tumor uptake is reflective of a TIL population that lacks the high-affinity IL2 receptor (activated T cells) and is therefore inactive, potentially as a result of PD1-PDL1 interactions in the TME. Recent improvements in multiomic immunohistochemical analyses of TME will allow testing of this hypothesis in future studies.\n\nTo date, several other approaches have been described for imaging T-cells in vivo. Anti-CD3 monoclonal antibodies have been radiolabelled, but they showed either long plasma half-life or high grade toxicity [11, 14–15]. To bypass the long half-life of monoclonal antibodies, radiolabelled diabodies have been proposed as an alternative, but human studies have not been published yet [16]. Tavarè et al. have reported on the possibility to selectively image CD8+ cells in humans [17] whereas others have preferred to directly label T-cells in vitro with long half-life isotopes such as 111In for SPECT or 89Zr for PET [18] but this may result in a high radiation dose to labelled cells with possible damage and altered circulation and migration capacity in vivo. Recently a guanosine analogue ([18F]F- AraG) has been investigated as potential probe to image T cells in vivo by PET/CT [19] but preliminary human results were not encouraging. Other attempts have been reported using engineered human T- cells [20].\n\nA different strategy to predict the efficacy of check point immunotherapy could be an evaluation of the in vivo lesion uptake of radiolabelled ipilimumab or pembrolizumab [21]. However, these antibodies have a long half-life and images should be taken 24–72 h after injection thus requiring the use of long half-life radioisotopes such as 89Zr with high radiation exposure to the patient. More promising seems the use of 64Cu to radiolabel antibodies [22]. Thus, until the availability of a better radiopharmaceutical, radiolabelled IL2 remains the most specific and suitable probe to in vivo image CD25+ T-cells.\n\nOverall, the results of our pilot study have provided preliminary evidence of the safety and feasibility of 99mTc- HYNIC-IL2 scintigraphy and have led to a number of hypotheses to be tested in future studies.\n\nMATERIALS AND METHODS\nPatients and methods\nThis study enrolled individuals ≥18 years of age with histologically confirmed stage IV malignant melanoma who were to begin treated with standard-of-care ipilimumab or pembrolizumab. Patients were required to have either: (1) two lesions in the same organ such that at least one of these two lesions was measurable by RECIST criteria using either IV contrast enhanced CT or CT component of PET/CT or (2) three lesions in different organs and at least one of these 3 lesions was measurable by RECIST criteria using either IV contrast enhanced CT or CT component of PET/CT. Additional eligibility criteria included: Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2; adequate blood chemistries (absolute neutrophil count ≥1500/mm3; platelet count ≥50,000/mm3; hemoglobin >10g/dL; AST ≤3 × the institutional upper limit of normal (ULN); and Alkaline phosphatase ≤3 × ULN [up to 5× allowed for patients with liver metastases]); and a tumor accessible for biopsy. Individuals were excluded from participation if they had had discontinued radiation, surgery, or systemic therapy ≤21 days prior to registration, more than 2 prior systematic regimens in the metastatic setting; uncontrolled or current infection, failure to recover from the side effects of prior chemotherapy or surgery, or known allergy to 99mTc-HYNIC-IL2 or its components.\n\nWomen of child-bearing potential also underwent a serum pregnancy test within 7 days of registration. Pregnant and nursing mothers were not allowed to enroll. The Mayo Clinic Institutional Review Board approved this study and informed consents were obtained from each patient prior to study entry.\n\nPatients underwent physical examination, blood tests and disease evaluation within two weeks prior to study entry. Following registration but prior to the start of treatment, and at completion of induction therapy (approximately week 12, concurrent with first standard of care assessment of treatment response in asymptomatic patients), patients underwent blood draws, toxicity evaluations, and CT imaging followed by 99mTc-HYNIC-IL2 SPECT/CT imaging and subsequent core needle biopsy of a clinically accessible lesion.\n\nImmunotherapeutic treatment\nPatients who chose to receive ipilimumab for their metastatic melanoma were to follow standard-of-care clinical guidelines (FDA approved) for therapy and supportive care. That is, Ipilimumab (3 mg/kg) was administered by IV infusion over 90 minutes every 3 weeks for a total of 4 doses. If the full treatment course could not be completed within 16 weeks, the drug was to be permanently discontinued. IPI therapy toxicities and dose modifications were to be managed in accordance to practice standards. Similarly, patients who chosed to receive pembrolizumab for their metastatic melanoma were treated according to standard-of-care clinical guidelines. Pembrolizumab was administered at a dose of 2 mg/kg intravenously every 3 weeks until tumor progression or a maximum of 2 years. Pembrolizumab therapy toxicities were to be managed in accordance to practice standards.\n\n99mTc-HYNIC-IL2 preparation and imaging\nSuccinimidyl-6-hydrazinopyridine-3-carboxylate (HYNIC-NHS) was conjugated to the commercially obtained IL2 as previously described [9–10]. Briefly, HYNIC-IL2 (100 μg) was incubated with tricine, 99mTcO - (370–740 MBq) and SnCl2 for 10 min at room temperature. After labelling, 99mTc-IL2 was purified by reverse-phase chromatography using Sep-Pak cartridges and diluted in 10 mL of 5% glucose with 0.1% human serum albumin (HAS) before injection. Ultrafiltration through a 0.22 μm filter was performed to assure sterility. Labelling efficiency was analyzed using reverse phase HPLC and ITLC-SG chromatographic strips (Pall Corporation) with 0.9% NaCl as the mobile phase. Bacterial endotoxin test (BET) with the gel clot method, as well as the sterility test was carried out as part of the quality control evaluation. Negative result of BET had to be secured before the radiolabeled drug product was released for administration to a patient. Scintigraphy was performed, before starting immunotherapy and approximately 12 weeks later. Images were acquired 1h after IV injection of the radiopharmaceutical using clinically available tomographic SPECT/CT (Philips Precedence). Both planar antero-posterior images and SPECT/CT images of the regions of interest (known for the presence of metastases) were acquired. Planar images were acquired with a 512 × 512 matrix up to 500.000 counts and SPECT images were acquired with a 3° step modality for 20 seconds per frame. After iterative reconstruction and attenuation corrections by CT scan, SPECT\n\nimages were qualitatively analyzed and the degree of 99mTc-HYNIC-IL2 uptake was calculated in each lesion by SUVmax and SUVmean measurement using commercially available software kindly provided by Hermes Medical Solutions ltd (Stockholm, Sweden; SUV = activity concentration in tumor/injected dose/body weight). Each detectable lesion was also scored for its size (CT trans-axial slides) by measuring the largest diameter, as per RECIST. If a patient developed a ≥ grade 2 hypersensitivity/allergic reaction no further 99mTc-HYNIC-IL2 imaging was to be done.\n\nStudy design\nA pilot study was conducted to assess the feasibility and safety of 99mTc-HYNIC-IL2 scintigraphy in patients with metastatic melanoma undergoing cancer immunotherapy therapy. 99mTc- HYNIC-IL2 scintigraphy limiting toxicities (SLT) were defined as: ≥ grade 2 allergic reaction; ≥ grade 3 anaphylaxis, ≥ grade 2 injection site reaction, or ≥ grade 3 non-hematologic toxicity (not attributed to immunotherapy treatment/progression or a co-morbid condition). A sample size of 10 patients was chosen. If none of these 10 patients develop a SLT, then we can say with 90% confidence that the true percentage of patients who will develop a SLT is less than 33%. A secondary aim was to examine changes in TIL invasion of the metastatic melanoma in patients undergoing therapy with immune checkpoint inhibitors. An exploratory aim was to gain preliminary data on whether changes in 99mTc- HYNIC-IL2 scintigraphy uptake correspond to changes in tumor size on CT imaging.\n\nTumor burden was defined as sum of the longest dimension of all the lesions present on CT scan Total SUVmax was defined as the sum of the SUVmax of these lesions Spearman rank correlation coefficients were used to assess the association between: a lesion's maximum tumor dimension and its SUVmax prior to treatment, maximum tumor dimension and SUVmax after 12 weeks on treatment, percent change in SUVmax and the percent change in maximum tumor dimension and the change in SUVmax and the change in tumor dimension. A t-test was used to assess whether the correlation coefficient is significantly different than zero. All analyses were carried out using SAS 9.4 software.\n\nHistopathologic analysis of tumor core biopsies\nCore needle biopsies of clinically accessible tumor masses were performed after 99mTc-HYNIC- IL2 imaging was completed. The biopsy material was then immediately fixed in formalin and processed to paraffin embedding (FFPE), per standard clinical guidelines. At the end of the study, all available tissues were stained by H&E (tissue identification and lymphocyte infiltration) and immunostained for CD3 using clinically validated IHC methodology. In brief, FFPE tissue blocks were sectioned at 5 μm. Deparaffinization and immunohistochemistry (IHC) staining were carried out per standard clinical practice guidelines on the Ventana Benchmark XT auto-staining (Ventana Medical Systems, Tucson, AZ) Slides were pretreated with Cell Conditioner 1 for 32 minutes followed by incubation with, 1:250 diluted anti-CD3, mouse anti-human monoclonal antibody (Clone LN10, Leica,\n\n#NCL-L-CD3-565) at 37° C for 15 minutes. CD3 detection was done with OptiView DAB (Ventana Medical Systems). Normal tonsil was used as a positive control and normal tonsil without primary antibody used as a negative control. Level of lymphocyte tumor infiltration (TIL estimate) was performed using a semi-quantitative scoring scale: 0 = absent TIL, +1 = sparse/scattered TIL infiltrate (TIL comprising <1% visualized cells); +2 = mild TIL infiltrate, (TIL comprising 1–5% of visualized cells); +3 = moderate TIL infiltrate (TIL comprising 5–15% of all visualized cells); and +4 = marked TIL infiltrate (TIL comprising >15% of visualized cells).\n\nThis work was supported by a grant from the National Cancer Institute (CA170062). The associated clinical study is registered as NCT01789827 on clinicaltrials.gov.\n\nCONFLICTS OF INTEREST\n\nNone.\n==== Refs\nREFERENCES\n1 Hodi FS Hwu WJ Kefford R Weber JS Daud A Hamid O Patnaik A Ribas A Robert C Gangadhar TC Joshua AM Hersey P Dronca R Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab J Clin Oncol 2016 34 1510 17 26951310 \n2 Signore A Procaccini E Annovazzi A Chianelli M van der Laken C Mire-Sluis A The developing role of cytokines for imaging inflammation and infection Cytokine 2000 12 1445 54 11023659 \n3 Signore A Beverley PC Parman A Negri M Pozzilli P Labelling of interleukin-2 (IL-2) with 123-iodine with retention of its capacity to bind to activated lymphocytes Exp Clin Endocrinol 1987 89 301 6 3499331 \n4 Signore A Picarelli A Annovazzi A Britton KE Grossman AB Bonanno E Maras B Barra D Pozzilli P 123I-Interleukin-2: biochemical characterization and in vivo use for imaging autoimmune diseases Nucl Med Commun 2003 24 305 16 12612472 \n5 Signore A Picarelli A Chianelli M Biancone L Annovazzi A Tiberti C Anastasi E Multari G Negri M Pallone F Pozzilli P I-interleukin-2 scintigraphy: a new approach to assess disease activity in autoimmunity J Pediatr Endocrinol Metab 1996 9 139 44 8887165 \n6 Signore A Chianelli M Annovazzi A Bonanno E Spagnoli LG Pozzilli P Pallone F Biancone L 123I-interleukin-2 scintigraphy for in vivo assessment of intestinal mononuclear cell infiltration in Crohn's disease J Nucl Med 2000 41 242 9 10688106 \n7 Annovazzi A Biancone L Caviglia R Chianelli M Capriotti G Mather SJ Caprilli R Pallone F Scopinaro F Signore A 99mTc-interleukin-2 and (99m)Tc-HMPAO granulocyte scintigraphy in patients with inactive Crohn's disease Eur J Nucl Med Mol Imaging 2003 30 374 82 12634965 \n8 Signore A Annovazzi A Barone R Bonanno E D'Alessandria C Chianelli M Mather SJ Bottoni U Panetta C Innocenzi D Scopinaro F Calvieri S 99mTc-interleukin-2 scintigraphy as a potential tool for evaluating tumor-infiltrating lymphocytes in melanoma lesions: a validation study J Nucl Med 2004 45 1647 52 15471828 \n9 Chianelli M Mather SJ Grossman A Sobnak R Fritzberg A Britton KE Signore A 99mTc-interleukin-2 scintigraphy in normal subjects and in patients with autoimmune thyroid diseases: a feasibility study Eur J Nucl Med Mol Imaging 2008 35 2286 93 18542959 \n10 D'Alessandria C di Gialleonardo V Chianelli M Mather SJ de Vries EF Scopinaro F Dierck RA Signore A Synthesis and optimization of the labeling procedure of 99mTc-HYNIC-interleukin-2 for in vivo imaging of activated T lymphocytes Mol Imaging Biol 2010 12 539 46 19949980 \n11 Malviya G D'Alessandria C Bonanno E Vexler V Massari R Trotta C Scopinaro F Dierckx R Signore A Radiolabeled humanized anti-CD3 monoclonal antibody visilizumab for imaging human T-lymphocytes J Nucl Med 2009 50 1683 91 19759100 \n12 Signore A Mather SJ Piaggio G Malviya G Dierckx RA Molecular imaging of inflammation/infection: nuclear medicine and optical imaging agents and methods Chem Rev 2010 110 3112 45 20415479 \n13 Galli F Histed S Aras O NK cell imaging by in vitro and in vivo labelling approaches Q J Nucl Med Mol Imaging 2014 58 276 83 25265248 \n14 Marcus C Thakur ML Huynh TV Louie JS Leibling M Minami C Diggles L Imaging rheumatic joint diseases with anti-T lymphocyte antibody OKT-3 Nucl Med Commun 1994 15 824 30 7838446 \n15 Griessinger CM Maurer A Kesenheimer C Kehlbach R Reischl G Ehrlichmann W Bukala D Harant M Cay F Brück J Nordin R Kohlhofer U Rammensee HG 64Cu antibody-targeting of the T-cell receptor and subsequent internalization enables in vivo tracking of lymphocytes by PET Proc Natl Acad Sci U S A 2015 112 1161 6 25587131 \n16 Freise AC Zettlitz KA Salazar FB Lu X Tavaré R Wu AM ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging Mol Imaging Biol 2017 19 599 609 27966069 \n17 Tavaré R Escuin-Ordinas H Mok S McCracken MN Zettlitz KA Salazar FB Witte ON Ribas A Wu AM An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy Cancer Res 2016 76 73 82 10.1158/0008-5472.CAN-15-1707 26573799 \n18 Sato N Wu H Asiedu KO Szajek LP Griffiths GL Choyke PL (89)Zr-Oxine Complex PET Cell Imaging in Monitoring Cell-based Therapies Radiology 2015 275 490 500 25706654 \n19 Namavari M Chang YF Kusler B Yaghoubi S Mitchell BS Gambhir SS Synthesis of 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine: a novel agent for imaging T-cell activation with PET Mol Imaging Biol 2011 13 812 8 20838911 \n20 Mall S Yusufi N Wagner R Klar R Bianchi H Steiger K Straub M Audehm S Laitinen I Aichler M Peschel C Ziegler S Mustafa M Immuno-PET Imaging of Engineered Human T Cells in Tumors Cancer Res 2016 76 4113 23 27354381 \n21 England CG Ehlerding EB Hernandez R Rekoske BT Graves SA Sun H Liu G McNeel DG Barnhart TE Cai W Preclinical Pharmacokinetics and Biodistribution Studies of 89Zr-Labeled Pembrolizumab J Nucl Med 2017 58 162 168 27493273 \n22 Natarajan A Mayer AT Xu L Reeves RE Gano J Gambhir SS Novel Radiotracer for ImmunoPET Imaging of PD-1 Checkpoint Expression on Tumor Infiltrating Lymphocytes Bioconjug Chem 2015 26 2062 9 26307602\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "9(54)",
"journal": "Oncotarget",
"keywords": "99mTc-IL2; check point inhibitors; ipilimumab; melanoma; pembrolizumab",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "30268-30278",
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"pmid": "30100988",
"pubdate": "2018-07-13",
"publication_types": "D016428:Journal Article",
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"title": "Non-invasive visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: a pilot study.",
"title_normalized": "non invasive visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy a pilot study"
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"abstract": "Generalized pustular psoriasis of pregnancy (GPPP) is a rare and severe variant of pustular psoriasis. It has been called the most dangerous and life-threatening dermatosis in pregnant woman. To explore the treatment of GPPP, we conducted a retrospective study of two cases of GPPP in our clinic and other related reported cases and manuscripts. In 1992, a GPPP patient came to our clinic. We prescribed her antibiotics and dexamethasone. The pregnancy was artificially terminated. After delivery, she took a retinoid and a topical steroid and recovered progressively. In 2012, we treated another GPPP patient. Methylprednisolone and cyclosporine were administered. Maternal and fetal statuses were monitored closely. The treatment was effective and a healthy baby was delivered. We compared our two GPPP cases and found that cyclosporine and a sufficient dosage of steroid were an effective treatment. Antibiotics could be tried in mild cases or the initial stages before excluding sepsis. Based on other reported GPPP cases, TNF-α antagonists are used as rescue therapy in GPPP refractory to steroid and cyclosporine therapy, but careful consideration of the advantages and disadvantages is warranted before using them. Supportive measures are necessary to maintain pregnancy and prevent complications in cases of GPPP.",
"affiliations": "Dermatology Department, 1st Affiliated Hospital of Dalian Medical University, Dalian, China.",
"authors": "Luan|Li|L|;Han|Shixin|S|;Zhang|Zhenying|Z|;Liu|Xiaoming|X|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D013256:Steroids",
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"issue": "27(3)",
"journal": "Dermatologic therapy",
"keywords": "generalized pustular psoriasis of pregnancy; treatment",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000028:Abortion, Induced; D000900:Anti-Bacterial Agents; D001706:Biopsy; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D050498:Live Birth; D011247:Pregnancy; D011248:Pregnancy Complications; D011565:Psoriasis; D012867:Skin; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "174-7",
"pmc": null,
"pmid": "24517287",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Personal treatment experience for severe generalized pustular psoriasis of pregnancy: two case reports.",
"title_normalized": "personal treatment experience for severe generalized pustular psoriasis of pregnancy two case reports"
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"companynumb": "PHHY2014CN082624",
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"abstract": "This report describes a fatal case of the propofol infusion syndrome in an adult patient being sedated for a closed head injury using high doses of propofol. The features of circulatory collapse, metabolic acidosis, mild rhabdomyolysis and renal impairment are consistent with the syndrome and not readily attributable to alternative aetiologies. Potential mechanisms for the syndrome may relate to antagonism of beta-receptors, impaired myocardial oxygen utilization and a specific disruption to fatty-acid oxidation. This is the first published Australian case of the propofol infusion syndrome in an adult and should serve as an additional case report to the existing literature highlighting this potentially fatal syndrome in adults.",
"affiliations": "Intensive Care Units, Box Hill Hospital and Western Hospital, Melbourne, Victoria.",
"authors": "Ernest|D|D|;French|C|C|",
"chemical_list": "D006993:Hypnotics and Sedatives; D015742:Propofol",
"country": "United States",
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"issn_linking": "0310-057X",
"issue": "31(3)",
"journal": "Anaesthesia and intensive care",
"keywords": null,
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000328:Adult; D004562:Electrocardiography; D017809:Fatal Outcome; D016489:Head Injuries, Closed; D006801:Humans; D006993:Hypnotics and Sedatives; D007262:Infusions, Intravenous; D008297:Male; D015742:Propofol; D013577:Syndrome",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "316-9",
"pmc": null,
"pmid": "12879680",
"pubdate": "2003-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Propofol infusion syndrome--report of an adult fatality.",
"title_normalized": "propofol infusion syndrome report of an adult fatality"
} | [
{
"companynumb": "AU-PFIZER INC-06H-008-0307241-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": "4",
... |
{
"abstract": "Anti-CD19 Chimeric Antigen Receptor T cells (CAR-T) have shown dramatic efficacy in treating refractory aggressive B cell Lymphomas leading to FDA approval of axicabtagene ciloleucel and tisagenlecleucel. While long-term remission rate for both is higher than 33%, this treatment is associated with life-threatening complications including cytokine-release syndrome, encephalopathy, and lethal cerebral edema. Here we describe a case series of bone marrow failure syndromes with or without co-existing clonal myelodysplastic syndrome. Bone marrow failure was defined as absolute neutrophil count (ANC) <500 neutrophils/μL day 42 after infusion of CAR-T cells or filgrastim support to reach that number. We use \"persistent cytopenias after T-cell therapy (PCTT)\" to describe this syndrome which has an incidence of 38% with axicabtagene ciloleucel. Platelets <75,000/μL at the time of initiation of lymphodepleting chemotherapy and occurrence of maximum severity of cytokine-release syndrome (CRS) on day 0 or 1 after infusion of CAR-T cells are independent predictors of PCTT.",
"affiliations": "Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.;Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.;Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.;Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.;Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.;Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.;Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.;Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA.",
"authors": "Nahas|George R|GR|;Komanduri|Krishna V|KV|;Pereira|Denise|D|;Goodman|Mark|M|;Jimenez|Antonio M|AM|;Beitinjaneh|Amer|A|;Wang|Trent P|TP|;Lekakis|Lazaros J|LJ|",
"chemical_list": "D018941:Antigens, CD19; D001688:Biological Products; D000076962:Receptors, Chimeric Antigen; C000629083:axicabtagene ciloleucel",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2019.1697814",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "61(4)",
"journal": "Leukemia & lymphoma",
"keywords": "CAR-T cells; bone marrow failure; cytokine release syndrome; lymphoma",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D018941:Antigens, CD19; D001688:Biological Products; D016026:Bone Marrow Transplantation; D064987:Cell- and Tissue-Based Therapy; D006801:Humans; D016219:Immunotherapy, Adoptive; D015994:Incidence; D009190:Myelodysplastic Syndromes; D000076962:Receptors, Chimeric Antigen; D012307:Risk Factors; D013601:T-Lymphocytes; D016896:Treatment Outcome",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "940-943",
"pmc": null,
"pmid": "31793821",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence and risk factors associated with a syndrome of persistent cytopenias after CAR-T cell therapy (PCTT).",
"title_normalized": "incidence and risk factors associated with a syndrome of persistent cytopenias after car t cell therapy pctt"
} | [
{
"companynumb": "US-AMGEN-USASP2019206773",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ELTROMBOPAG"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGuidelines recommend treatment with direct-acting antivirals for a minimum duration of 8 weeks in all patients with hepatitis C virus. Minimizing treatment duration is desirable because of decreased cost and increased adherence. Studies with treatment durations of less than 8 weeks have conflicting data.\n\n\nOBJECTIVE\nThe purpose of this study was to evaluate the clinical efficacy of hepatitis C treatment in patients who did not complete the guideline-recommended duration of therapy.\n\n\nMETHODS\nThis was a retrospective, observational case series of patients with hepatitis C virus treated with 7 weeks or less of direct-acting antivirals between November 1, 2017 and July 31, 2019 at a large, academic medical center. The primary end point was cure, defined as sustained virologic response at 12 weeks after the end of treatment. Secondary end points included average duration of therapy, direct-acting antiviral used, and reason for early discontinuation.\n\n\nRESULTS\nOf the 472 patients treated, 13 met criteria for inclusion. Sustained virologic response was achieved in 61.5% of the patients. Two patients (15.3%) were not cured, and 3 patients (23.1%) were lost to follow-up. Median duration of therapy was 4 weeks. All patients who received at least 4 weeks of therapy and remained in care were cured.\n\n\nCONCLUSIONS\nIn situations in which patients inadvertently stop hepatitis C treatment early, there is still the possibility of cure. Further studies are needed to determine which patient population may benefit from a shorter duration of therapy.",
"affiliations": null,
"authors": "Thieneman|Claire|C|;Frederick|Emily|E|;Palmer|Emma|E|;Spencer|Catherine|C|;Vories|Sabrina|S|;Maier|Chelsea|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.japh.2021.08.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1086-5802",
"issue": null,
"journal": "Journal of the American Pharmacists Association : JAPhA",
"keywords": null,
"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": null,
"nlm_unique_id": "101176252",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34454865",
"pubdate": "2021-08-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of cure rate in patients with hepatitis C virus completing shortened courses of treatment.",
"title_normalized": "evaluation of cure rate in patients with hepatitis c virus completing shortened courses of treatment"
} | [
{
"companynumb": "US-009507513-2202USA000295",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "4",
... |
{
"abstract": "This report describes an 8-year-old child with acute anthracycline-induced cardiomyopathy triggered by human herpesvirus 6 and the subsequent implantation of an intracorporeal continuous-flow left ventricular assist device (LVAD) and the process to discharge the child from the hospital. After barely 3 months on mechanical support, the device was explanted after thorough examination. Experiences regarding LVAD removal are limited, and no guidelines for echocardiographic and hemodynamic criteria for LVAD removal in children have been published thus far. We present our institutional algorithm for device selection, surveillance in an ambulatory setting, and testing for myocardial recovery, as well as our criteria for LVAD explantation in children.",
"affiliations": "Divisions of Pediatric Cardiology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland; and.;Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland; and Congenital Cardiovascular Surgery, and martin.schweiger@kispi.uzh.ch.;Divisions of Pediatric Cardiology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland; and.;Divisions of Pediatric Cardiology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland; and.;Department of Molecular Pathology, University of Tübingen, Tübingen, Germany.;Divisions of Pediatric Cardiology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland; and.;Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland; and Congenital Cardiovascular Surgery, and.",
"authors": "Cavigelli-Brunner|Anna|A|;Schweiger|Martin|M|;Knirsch|Walter|W|;Stiasny|Brian|B|;Klingel|Karin|K|;Kretschmar|Oliver|O|;Hübler|Michael|M|",
"chemical_list": "D018943:Anthracyclines",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2013-2272",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "134(3)",
"journal": "Pediatrics",
"keywords": "assist device; cardiomyopathy; congestive heart failure",
"medline_ta": "Pediatrics",
"mesh_terms": "D018943:Anthracyclines; D002648:Child; D005260:Female; D006353:Heart-Assist Devices; D015654:Herpesvirus 6, Human; D006801:Humans; D009205:Myocarditis; D020127:Recovery of Function; D019349:Roseolovirus Infections",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e894-9",
"pmc": null,
"pmid": "25092940",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "VAD as bridge to recovery in anthracycline-induced cardiomyopathy and HHV6 myocarditis.",
"title_normalized": "vad as bridge to recovery in anthracycline induced cardiomyopathy and hhv6 myocarditis"
} | [
{
"companynumb": "CH-JNJFOC-20141006163",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Despite the extensive use of botulinum toxin A (BoNTA) in medical and cosmetic treatments, the potential spreading of BoNTA to surrounding tissues remains unknown. A patient with hemifacial paralysis upon blepharospasm treatment with low dose of BoNTA, prompted us to investigate the spreading effect. A randomised, double-blind study was conducted in which 5 healthy women (33-52 years) were treated with different doses of onabotulinum toxin unilaterally in the corrugator muscle. Parameters of efficacy and diffusion (CMAP; EMG and jitter analysis) in both glabellar and frontalis muscles were assessed at baseline, 2 and 4 weeks following BoNTA injection. CMAP of the treated glabellar muscles was reduced to approximately 40% in all dose groups. Additionally, contralateral CMAP reduction was observed in 3 of 5 subjects. These data confirm regional diffusion of BoNTA in facial muscle application, which raises question on the reliability of split-face models in BoNTA studies.",
"affiliations": "Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden.",
"authors": "Punga|Anna Rostedt|AR|;Eriksson|Annika|A|;Alimohammadi|Mohammad|M|",
"chemical_list": "D065087:Acetylcholine Release Inhibitors; D019274:Botulinum Toxins, Type A",
"country": "Sweden",
"delete": false,
"doi": "10.2340/00015555-2093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5555",
"issue": "95(8)",
"journal": "Acta dermato-venereologica",
"keywords": null,
"medline_ta": "Acta Derm Venereol",
"mesh_terms": "D065087:Acetylcholine Release Inhibitors; D000200:Action Potentials; D000328:Adult; D000369:Aged, 80 and over; D001764:Blepharospasm; D019274:Botulinum Toxins, Type A; D018849:Controlled Clinical Trials as Topic; D004058:Diffusion; D004311:Double-Blind Method; D004576:Electromyography; D005152:Facial Muscles; D005158:Facial Paralysis; D005260:Female; D005546:Forehead; D006801:Humans; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D012107:Research Design",
"nlm_unique_id": "0370310",
"other_id": null,
"pages": "948-51",
"pmc": null,
"pmid": "25766591",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Regional diffusion of botulinum toxin in facial muscles: a randomised double-blind study and a consideration for clinical studies with split-face design.",
"title_normalized": "regional diffusion of botulinum toxin in facial muscles a randomised double blind study and a consideration for clinical studies with split face design"
} | [
{
"companynumb": "SE-IPSEN BIOPHARMACEUTICALS, INC.-2016-02438",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ABOBOTULINUMTOXINA"
},
"d... |
{
"abstract": "A hiccup is a myoclonic jerk of the diaphragm, and cases of hiccups may last for more than 48 hours (persistent hiccups) or even more than 2 months (intractable hiccups). Current pharmacologic treatment of persistent or intractable hiccups mainly includes antidopaminergic drugs. We describe the case of a 60-year-old man with a recent diagnosis of right insular ischemic stroke who presented with frequent, intense, and disabling hiccups for more than 1 month. As diagnosis of poststroke hiccups was assumed, the patient was treated over the next 6 months with adequate doses of various antipsychotic drugs commonly used for the treatment of hiccups; however, all were discontinued because of adverse effects. Indeed, dyskinesia after chlorpromazine (up to 75 mg/day for 4 wks), as well as somnolence and dyskinesia after haloperidol (up to 6 mg/day for 6 wks), somnolence after gabapentin (up to 1800 mg/day for 8 wks), and severe somnolence and hypotension after baclofen (up to 50 mg/day for 6 wks) were reported. The patient was then prescribed tetrabenazine at a starting dose of 12.5 mg twice/day (25 mg/day), with a nearly complete remission of the hiccup symptomatology after ~6 weeks, when a daily dose of 150 mg was reached. We therefore hypothesize that a supratentorial lesion may disrupt the modulation of dopaminergic pathways involved in the regulation of medullar centers responsible for the hiccup reflex. To our knowledge, this is the first case report of poststroke hiccups responding to tetrabenazine. The dramatic response of our patient to tetrabenazine monotherapy suggests that this drug may be a valuable pharmacologic alternative for patients with hiccups after stroke who are intolerant or unresponsive to classic antipsychotic agents.",
"affiliations": "IRCCS Centro Neurolesi \"Bonino-Pulejo\", Messina, Italy.",
"authors": "Naro|Antonino|A|;Bramanti|Placido|P|;Calabrò|Rocco Salvatore|RS|",
"chemical_list": "D018759:Adrenergic Uptake Inhibitors; D013747:Tetrabenazine",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1523",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "34(12)",
"journal": "Pharmacotherapy",
"keywords": "hiccup treatment; persistent hiccup; stroke; tetrabenazine",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D018759:Adrenergic Uptake Inhibitors; D003937:Diagnosis, Differential; D006606:Hiccup; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke; D013747:Tetrabenazine",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e345-8",
"pmc": null,
"pmid": "25471210",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful use of tetrabenazine in a patient with intractable hiccups after stroke.",
"title_normalized": "successful use of tetrabenazine in a patient with intractable hiccups after stroke"
} | [
{
"companynumb": "IT-JNJFOC-20141211788",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nExtranodal natural killer (NK)/T cell lymphomas, nasal type, are aggressive, non-Hodgkin lymphomas. Extranodal NK/T cell lymphomas, nasal type, involving the central nervous system (CNS) are rare; therefore, delayed diagnosis easily occurs and is associated with a poor prognosis. Early diagnosis and patented systemic chemotherapy are necessary.\n\n\nMETHODS\nWe present a case of 34-year-old male with facial numbness and diplopia. He was diagnosed with extranodal NK/T cell lymphoma, nasal type, involving the CNS. The tumor, located in the right middle fossa, was subtotally removed, and 3 cycles of systemic chemotherapy were given. He later died of severe neutropenia and infection.\n\n\nCONCLUSIONS\nNK/T cell lymphomas should be considered to be a potential cause of facial numbness and diplopia. A L-asparaginase-based regimen resulted in reasonable tumor suppression, but adverse effects, including fatal neutropenia, should be carefully considered.",
"affiliations": "Department of Geriatrics, Tongde Hospital of Zhejiang Province, Hangzhou Department of Neurosurgery, Lanxi People's Hospital, Lanxi Department of Neurological Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.",
"authors": "Wang|Han|H|;Xia|Xiaolong|X|;Qian|Cong|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000012028",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30142852MD-D-18-0294510.1097/MD.0000000000012028120287100Research ArticleClinical Case ReportExtranodal natural killer/T cell lymphoma, nasal type in the middle cranial fossa A case reportWang Han MDaXia Xiaolong MDbQian Cong MDc∗NA. a Department of Geriatrics, Tongde Hospital of Zhejiang Province, Hangzhoub Department of Neurosurgery, Lanxi People's Hospital, Lanxic Department of Neurological Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.∗ Correspondence: Cong Qian, Department of Neurosurgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88th, Hangzhou, Zhejiang Province 310009, China (e-mail: congqian@zju.edu.cn).8 2018 24 8 2018 97 34 e1202826 4 2018 31 7 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nIntroduction:\nExtranodal natural killer (NK)/T cell lymphomas, nasal type, are aggressive, non-Hodgkin lymphomas. Extranodal NK/T cell lymphomas, nasal type, involving the central nervous system (CNS) are rare; therefore, delayed diagnosis easily occurs and is associated with a poor prognosis. Early diagnosis and patented systemic chemotherapy are necessary.\n\nCase presentation:\nWe present a case of 34-year-old male with facial numbness and diplopia. He was diagnosed with extranodal NK/T cell lymphoma, nasal type, involving the CNS. The tumor, located in the right middle fossa, was subtotally removed, and 3 cycles of systemic chemotherapy were given. He later died of severe neutropenia and infection.\n\nConclusion:\nNK/T cell lymphomas should be considered to be a potential cause of facial numbness and diplopia. A L-asparaginase-based regimen resulted in reasonable tumor suppression, but adverse effects, including fatal neutropenia, should be carefully considered.\n\nKeywords\ncentral nervous systemchemotherapynatural killer/T cell lymphomapathologyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nExtranodal natural killer (NK)/T cell lymphomas, nasal type, are highly aggressive non-Hodgkin lymphomas; pathologically, they present as significant vascular damage and destruction, with apparent tissue necrosis and cytotoxicity.[1,2] Extranodal NK/T cell lymphomas are commonly located in the upper respiratory and digestive tracts, such as the nasal cavity, and sometimes occur in the skin or gastrointestinal (GI) tract, but rarely invade the central nervous system (CNS).[3] Only a few cases of a NK/T cell lymphoma invading the CNS have been reported;[4–6] here, we reported a case of an extranodal NK/T cell lymphoma in the right middle cranial fossa, with diplopia and facial numbness as the initial presenting symptoms.\n\nThis study was approved by the Ethics Committee of Zhejiang University School of Medicine Second Affiliated Hospital, and the informed consent form was signed by patient.\n\n2 Case report\nA 34-year-old man was admitted to our hospital on June 12, 2017, due to right facial numbness with diplopia, which had been present for 1 month. He progressively felt right facial numbness develop for no reason, and several days later, diplopia was present; no hearing loss, blurry vision, epistaxis, or fever occurred. He had a history of hepatitis B (HBV) infection, but no history of any other diseases. Upon neurological examination, right trigeminal, and abducens nerve paralysis was found; all other cranial nerves were intact. The general examination was normal. Other than the presence of a HBV infection, the results of the initial laboratory examination were normal, including the blood cell counts (CBC), routine urinalysis, activated partial thromboplastin time (APTT), prothrombin time (PT), and tumor markers. Enhanced magnetic resonance imaging (MRI) demonstrated a right middle fossa mass with obvious and uniform enhancement; no cysts or calcifications were found, and no obvious brain edema was present (Fig. 1). The patient was diagnosed with a right middle fossa neoplasm; schwannomas and meningiomas were considered.\n\nFigure 1 Preoperative cranial magnetic resonance imaging (MRI) demonstrated a right middle fossa mass with a low signal in T1WI, isodensity in TW2I and obvious enhancement after contrast agent injection in T1WI (white arrow). The tumor had invaded into the subarachnoid space at the right cerebellopontine angle (CPA) (white asterisk); no obvious brain edema was found. CPA = cerebellopontine angle, MRI = magnetic resonance imaging.\n\nHe received a right craniotomy with neoplasm resection via an infratemporal approach. The bulk of the tumor was ashen, with ill-defined borders; the tumor was subtotally removed. He developed fever after surgery, and his symptoms did not improve until methylprednisolone was given. Malignant NK/T cell lymphoma was diagnosed via a pathological examination, but his situation deteriorated with fever, bilateral hearing loss and impaired kidney function. Upon hematoxylin and eosin (H&E) staining, diffuse pleomorphic tumor cells were observed infiltrating the vessels and ganglia, along with a large number of necrotic cells. Immunohistochemical staining demonstrated that NK/T cell markers, including CD3ε, CD56, granzyme B, and T cell-restricted intracellular antigen 1 (TIA-1), were positive, but B cell markers, such as CD20, were negative (Fig. 2).\n\nFigure 2 Histological examination of extranodal natural killer (NK)/T cell lymphoma, nasal type. A, B & C diffuse tumor cell infiltrated ganglions with obvious angiocentric growth patterns and a large number of necrotic cells on hematoxylin and eosin (H&E) staining. D - I Immunohistochemical staining. CD3ε (D), CD56 (F), granzyme B (G), T cell-restricted intracellular antigen 1 (TIA-1) (H) and EB virus encoded early small RNA (EBER) (I) were positive, CD20 (E) was negative, which indicated extranodal NK/T cell lymphoma. H&E = hematoxylin and eosin.\n\nThe patient was transferred to the hematology department for further assessment and treatment, his Epstein–Barr (EB) virus test was positive, and single photon emission computed tomography (SPECT) demonstrated a malignant lymphoma involving multiple extranodal organs, including the head, lung, pericardium, kidney, and bone (Fig. 3). According to the Ann Arbor system, he was stage III/IV; he received 3 cycles of chemotherapy with dexamethasone, methotrexate (MTX), L-asparaginase, gemcitabine, and oxaliplatin. Although tumor invasion was temporarily blocked, severe neutropenia and infection made a 4th chemotherapy treatment impossible and resulted in his death after 6 months of illness.\n\nFigure 3 Single photon emission computed tomography (SPECT) image of extranodal natural killer (NK)/T cell lymphoma. A, Lesions of the NK/T cell lymphoma at the right cranial base. B, Extranodal NK/T cell lymphomas of the right lung. C, bilateral kidneys were invaded by NK/T cell lymphomas. D, Multiple lesions were found in the bones. NK = natural killer, SPECT = Single photon emission computed tomography.\n\n3 Discussion\nExtranodal NK/T cell lymphomas are rare but aggressive non-Hodgkin lymphomas and are closely related with EB virus infection, etiologically.[7] Generally, extranodal NK/T cell lymphomas, nasal type, easily invade the skin, digestive tract, respiratory tract, and testis; only 3% cases involve the CNS.[3]\n\nThe nasal type is the main subtype and is observed in roughly 80% of cases, and its prognosis is related to the clinical stage.[8] Limited disease, as observed in stage I/II cancers without invasiveness, is markedly better than extensive disease, such as stage I/II with local invasiveness, stage III/IV, and extranasal extranodal NK/T cell lymphomas. Extranodal NK/T cell lymphomas, nasal type, that affect the CNS or primary extranodal NK/T cell lymphomas are considered to be extensive disease and have a worse outcome.\n\nCurrently, diagnosis of NK/T cell lymphoma is dependent on a pathological examination; a large amount of pleomorphic tumor cell infiltration with vascular damage is a typical characteristic observed on H&E staining. The tumor usually presents as a typical NK cell phenotype, in addition to being CD2 positive; its cytoplasmic CD3ε is commonly positive, surface CD3 is negative, and CD56 is positive in most cases. Cytotoxic molecules, including granzyme B, perforin, and TIA-1 are usually positive. In addition, EB virus encoded early small RNA (EBER) is also positive due to widespread EB virus infection.[1,2] In our case, the features on H&E staining, such as diffuse pleomorphic tumor cell infiltrated vessels, along with a large number of necrotic cells, were typical and the characteristics of immunohistochemical staining presenting with positive CD3ε, CD56, granzyme B, and TIA-1 were consistent with the diagnostic standards. Although a delayed diagnosis is difficult to avoid due to its rarity, NK/T cell lymphoma must be included in the differential diagnosis.\n\nGenerally, a L-asparaginase-based regimen, such as SMILE, including dexamethasone, MTX, ifosfamide, L-asparaginase, and etoposide, is recommended to treat extranodal NK/T cell lymphomas,[2,9,10] but no extranodal NK/T cell lymphoma involving the CNS has previously been treated by a L-asparaginase-based regimen. Several articles on extranodal NK/T cell lymphomas involving the CNS or primary CNS NK/T cell lymphomas reported treatment strategies, including MTX-based chemotherapy and radiotherapy.[3,6] However, this treatment strategy is the standard treatment regimen for B cell lymphomas; the curative effect on extranodal NK/T cell lymphoma remains unknown.\n\nBased on the published literature, the overall survival (OS) of extranodal NK/T cell lymphoma involving the CNS, treated with MTX-based chemotherapy, was 2 to 29 months (median: 8.5 months), which is significantly shorter than the OS of cases not involving the CNS. In our case, the patient was treated with an L-asparaginase-based regimen (dexamethasone, methotrexate, L-asparaginase, gemcitabine, and oxaliplatin), the invasiveness of tumor was blocked by chemotherapy, but the patient developed severe neutropenia and infection and died before the 4th chemotherapy treatment. Severe side effects, such as neutropenia and infection, may prove to be a significant problems when using an L-asparaginase-based regimen.[2]\n\nThere are several limitations in our case report: individual differences made this case report lack universality; confounding factors, such as age and gender, were not corrected.\n\n4 Conclusion\nNK/T cell lymphoma should be considered to be a potential cause of facial numbness and diplopia. An L-asparaginase-based regimen induced reasonable tumor suppression, but adverse effects, such as fatal neutropenia, should be taken into consideration. Alternative potent and safe systemic chemotherapy regimens are needed immediately.\n\nAuthor contributions\nData curation: Han Wang, Cong Qian.\n\nFormal analysis: Cong Qian.\n\nMethodology: Cong Qian.\n\nResources: Cong Qian.\n\nSupervision: Cong Qian.\n\nWriting – original draft: Han Wang, Xiaolong Xia.\n\nWriting – review & editing: Han Wang, Cong Qian.\n\nAbbreviations: APTT = activated partial thromboplastin time, CBC = count of blood cell, CNS = central nervous system, CPA = cerebellopontine angle, CR = complete response, CSF = cerebrospinal fluid, EB = Epstein–Barr, EBER = EB virus encoded early small RNA, FPS = free progression survival, GI = gastrointestinal, H&E = hematoxylin and eosin, HBV = hepatitis B virus, MRI = magnetic resonance imaging, MTX = Methotrexate, NK = natural killer, OS = overall survival, PT = prothrombin time, SPECT = single photon emission computed tomography, TIA-1 = T cell-restricted intracellular antigen 1.\n\nThe data were curated by HW and CQ. Formal analysis was done by CQ. The methodology and resources were provided by CQ. This study was supervised by CQ and originally drafted by HW and XX. This paper was reviewed and edited by HW and CQ.\n\nDW and XX contributed equally to this work.\n\nThis work was supported by National Natural Science Foundation of China, No. 81701152.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Liang R \nAdvances in the management and monitoring of extranodal NK/T-cell lymphoma, nasal type . Br J Haematol \n2009 ;147 :13–21 .19604234 \n[2] Chaudhary RK Bhatt VR Vose JM \nManagement of extranodal natural killer/t-cell lymphoma, nasal type . Clin Lymphoma Myeloma Leuk \n2015 ;15 :245–52 .25659751 \n[3] Luther N Greenfield JP Chadburn A \nIntracranial nasal natural killer/T-cell lymphoma: immunopathologically-confirmed case and review of literature . J Neurooncol \n2005 ;75 :185–8 .16283442 \n[4] Jiang X Yin W Song J \nPrimary central nervous system extranodal NK/T cell lymphoma, nasal type, with antecedent hemophagocytic syndrome in a child . Pediatr Dev Pathol \n2014 ;17 :482–6 .25207703 \n[5] Mai HC Chen DX Lu D \nExtranodal natural killer/T-cell lymphoma presenting as cavernous sinus syndrome . Mol Clin Oncol \n2017 ;6 :543–6 .28413664 \n[6] Miyata-Takata T Takata K Kato S \nClinicopathological analysis of primary central nervous system NK/T cell lymphoma: rare and localized aggressive tumour among extranasal NK/T cell tumours . Histopathology \n2017 ;71 :287–95 .28342197 \n[7] Jaffe ES \nNasal and nasal-type T/NK cell lymphoma: a unique form of lymphoma associated with the Epstein-Barr virus . Histopathology \n1995 ;27 :581–3 .8838342 \n[8] Kim TM Heo DS \nExtranodal NK /T-cell lymphoma, nasal type: new staging system and treatment strategies . Cancer Sci \n2009 ;100 :2242–8 .19758393 \n[9] Lee J Suh C Park YH \nExtranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study . J Clin Oncol \n2006 ;24 :612–8 .16380410 \n[10] Tse E Kwong YL \nHow I treat NK/T-cell lymphomas . Blood \n2013 ;121 :4997–5005 .23652805\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "97(34)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D035301:Cranial Fossa, Middle; D017809:Fatal Outcome; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D019292:Skull Base Neoplasms",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e12028",
"pmc": null,
"pmid": "30142852",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extranodal natural killer/T cell lymphoma, nasal type in the middle cranial fossa: A case report.",
"title_normalized": "extranodal natural killer t cell lymphoma nasal type in the middle cranial fossa a case report"
} | [
{
"companynumb": "CN-ACCORD-129675",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
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"activesubstancename": "METHOTREXATE"
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{
"abstract": "BACKGROUND\nThe aim of this report is to present our long-term experiences with a series of 5 face-transplanted patients in terms of surgical aspects and postoperative outcomes, and to describe possible salvage strategies in case of difficulties.\n\n\nMETHODS\nFive patients, 4 receiving full-face transplantation and 1 undergoing partial transplantation at our institution were included. The patients were aged between 19 and 54 years. Two had extensive burn scars to the face, and 3 had suffered gunshot injuries. The post-transplant induction immunosuppressive regimen included ATG combined with tacrolimus, mycophenolate mofetil, and prednisone, while maintenance was provided by the last 3. We focused on patient summaries including their etiologies, preoperative preparations, surgical techniques, immunosuppressive regimen, postoperative courses, revisional surgeries, together with challenges including acute rejection episodes, and immunosuppressive drug complications.\n\n\nRESULTS\nNo re-surgery due to vascular compromise was required in any case. One of the 5 patients was eventually lost due to complicated infectious and metabolic events at the end of post-transplantation month 11. The other 4 patients were still alive, with a mean follow-up time of 53 months and had satisfactory functional transplants and cosmetic appearance.\n\n\nCONCLUSIONS\nFace transplantation still involves challenges and many issues including compliance and psychological maturity of patients, the risk of opportunistic infections and malignancies still need to be resolved for it to be accepted as a safe procedure. Surgical rescue procedures considering ideal timing should be kept in mind strictly as one of the most important issues in case of unexpected events.",
"affiliations": "Department of Plastic and Reconstructive Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey.;Department of Plastic and Reconstructive Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey.;Department of Plastic and Reconstructive Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey.;Department of Anaesthesiology and Reanimation, Akdeniz University Faculty of Medicine, Antalya, Turkey.;Department of Anaesthesiology and Reanimation, Akdeniz University Faculty of Medicine, Antalya, Turkey.;Dentist, Anaplastologist, Private practice, Antalya, Turkey.",
"authors": "Özkan|Ömer|Ö|https://orcid.org/0000-0002-9031-5596;Özkan|Özlenen|Ö|;Ubur|Mehmetcan|M|;Hadimioğlu|Necmiye|N|;Cengiz|Melike|M|;Afşar|İsmail|İ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/micr.30272",
"fulltext": null,
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"issn_linking": "0738-1085",
"issue": "38(8)",
"journal": "Microsurgery",
"keywords": null,
"medline_ta": "Microsurgery",
"mesh_terms": "D000328:Adult; D015331:Cohort Studies; D005151:Facial Injuries; D054445:Facial Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014421:Turkey; D055815:Young Adult",
"nlm_unique_id": "8309230",
"other_id": null,
"pages": "834-843",
"pmc": null,
"pmid": "29178479",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Face allotransplantation for various types of facial disfigurements: A series of five cases.",
"title_normalized": "face allotransplantation for various types of facial disfigurements a series of five cases"
} | [
{
"companynumb": "TR-ASTELLAS-2017US019216",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": nu... |
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"abstract": "Gabapentin is an anticonvulsant medication with an indication from the US Food and Drug Administration for use in partial onset seizures and postherpetic neuralgia in the United States. Currently, gabapentin is only classified as a controlled substance subject to stricter prescribing and distributing regulations in certain states, as opposed to pregabalin, an anticonvulsant with a similar mechanism of action which is a considered a Schedule V medication under federal law. Gabapentin shares a structural similarity to pregabalin, and several case reports have suggested that gabapentin has a similar propensity for abuse. The mechanisms of the gabapentin reward pathway, addiction, and withdrawal, however, are not well known. This case report describes a patient with long-term polysubstance abuse and new onset gabapentin dependence and demonstrates the need for increased surveillance of gabapentin prescribing.",
"affiliations": "KAHN: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY.",
"authors": "Kahn|David A|DA|",
"chemical_list": "D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000404",
"fulltext": null,
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"issn_linking": "1527-4160",
"issue": "25(4)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D006801:Humans; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "308-312",
"pmc": null,
"pmid": "31291213",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D016420:Comment",
"references": null,
"title": "Commentary on \"A Call for Caution in Prescribing Gabapentin to Individuals with Concurrent Polysubstance Abuse: A Case Report\".",
"title_normalized": "commentary on a call for caution in prescribing gabapentin to individuals with concurrent polysubstance abuse a case report"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP011008",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
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{
"abstract": "BACKGROUND\nTo determine the cardiotoxicity of paclitaxel (T) plus doxorubicin (A) combination therapy in women with advanced breast cancer. To define a dose range of A for use in AT.\n\n\nMETHODS\nThe effect of cumulative A dose on risk of congestive heart failure (CHF) and alterations of myocardial contractility (left ventricular ejection fraction [LVEF] decrease > or = 20% or to <50%) was estimated from pooled data from 10 trials of AT.\n\n\nRESULTS\nThirty-one of 657 patients (4.7%) developed CHF at a median of 6.6 months (range 0.3-24.6) after initiation of AT. CHF was stabilized in 29 patients at a median of 17.3 months after diagnosis (range 4.1-31.2 months). The risk of developing CHF was < or = 5% at a total A dose < or = 380 mg/m2. In patients who received a total A dose > 440 mg/m2, the incidence of CHF was >25% but similar to that of A monotherapy. The risk of CHF was similar in women receiving AT or A monotherapy at a dose < or = 380 mg/m2 (2%-3%). LVEF progressively decreased in patients who received AT, especially at a cumulative A dose > 380 mg/m2. LVEF decreases were more frequent in patients who later developed CHF, but the majority of CHF patients did not experience LVEF alterations prior to symptoms. LVEF recovered after discontinuation of A in 25 of 67 women who developed LVEF < 50%.\n\n\nCONCLUSIONS\nThe reported cardiac effects are consistent with anthracycline-related cardiotoxicity. AT is associated with a cardiac risk similar to that of A monotherapy up to a cumulative A dose of 340-380 mg/m2.",
"affiliations": "Unit of Medical Oncology A, Istituto Nazionale Tumori, Milan, Italy. gianni@istitutotumori.mi.it",
"authors": "Gianni|L|L|;Dombernowsky|P|P|;Sledge|G|G|;Martin|M|M|;Amadori|D|D|;Arbuck|S G|SG|;Ravdin|P|P|;Brown|M|M|;Messina|M|M|;Tuck|D|D|;Weil|C|C|;Winograd|B|B|",
"chemical_list": "D004317:Doxorubicin; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1023/a:1011655503511",
"fulltext": null,
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"issn_linking": "0923-7534",
"issue": "12(8)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D004317:Doxorubicin; D005260:Female; D006333:Heart Failure; D006801:Humans; D017239:Paclitaxel; D012189:Retrospective Studies; D013318:Stroke Volume; D016277:Ventricular Function, Left",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1067-73",
"pmc": null,
"pmid": "11583187",
"pubdate": "2001-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cardiac function following combination therapy with paclitaxel and doxorubicin: an analysis of 657 women with advanced breast cancer.",
"title_normalized": "cardiac function following combination therapy with paclitaxel and doxorubicin an analysis of 657 women with advanced breast cancer"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1056441",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"actiondrug": "6",
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"activesubstancename": "PACLITAXEL"
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... |
{
"abstract": "This multicenter, prospective trial was conducted to develop an effective and safe reinduction regimen for marrow-relapsed pediatric acute lymphoblastic leukemia (ALL) by modifying the dose of idarubicin. Between 2006 and 2009, the trial accrued 44 patients, 1 to 21 years old with first marrow-relapsed ALL. The reinduction regimen comprised prednisolone, vincristine, L-asparaginase, and idarubicin (10 mg/m²/week). The idarubicin dose was adjusted according to the degree of myelosuppression. The second complete remission (CR2) rate was 72.7%, obtained by 54.2% of patients with early relapse < 24 months after initial diagnosis and 95.0% of those with late relapse (P = 0.002). Five patients entered remission with extended treatment, resulting in a final CR2 rate of 84.1%. The CR2 rate was not significantly different according to the idarubicin dose. The induction death rate was 2.3% (1/44). The 5-year event-free and overall survival rates were 22.2% ± 6.4% and 27.3% ± 6.7% for all patients, 4.2% ± 4.1% and 8.3% ± 5.6% for early relapsers, and 43.8% ± 11.4% and 50.0% ± 11.2% for late relapsers, respectively. Early relapse and slow response to reinduction chemotherapy were predictors of poor outcomes. In conclusion, a modified dose of idarubicin was effectively incorporated into the reinduction regimen for late marrow-relapsed ALL with a low toxic death rate. However, the CR2 rate for early relapsers was suboptimal, and the second remission was not durable in most patients.",
"affiliations": "Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Pusan National University College of Medicine, Busan, Korea.;Department of Pediatrics, Ajou University College of Medicine, Suwon, Korea.;Center for Pediatric Cancer, National Cancer Center, Goyang, Korea.;Center for Pediatric Cancer, National Cancer Center, Goyang, Korea.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea. jjseo@amc.seoul.kr.",
"authors": "Koh|Kyung Nam|KN|http://orcid.org/0000-0002-6376-672X;Im|Ho Joon|HJ|http://orcid.org/0000-0001-8799-4068;Kim|Hyery|H|http://orcid.org/0000-0003-2852-6832;Kang|Hyoung Jin|HJ|http://orcid.org/0000-0003-1009-6002;Park|Kyung Duk|KD|http://orcid.org/0000-0002-6943-4398;Shin|Hee Young|HY|http://orcid.org/0000-0003-2091-1947;Ahn|Hyo Seop|HS|http://orcid.org/0000-0002-5618-7033;Lee|Ji Won|JW|http://orcid.org/0000-0003-0084-1304;Yoo|Keon Hee|KH|http://orcid.org/0000-0002-5980-7912;Sung|Ki Woong|KW|http://orcid.org/0000-0001-5989-4772;Koo|Hong Hoe|HH|http://orcid.org/0000-0001-8082-1412;Lim|Young Tak|YT|http://orcid.org/0000-0002-3300-7239;Park|Jun Eun|JE|http://orcid.org/0000-0003-4292-3500;Park|Byung Kiu|BK|http://orcid.org/0000-0001-9743-0610;Park|Hyeon Jin|HJ|http://orcid.org/0000-0002-9557-3412;Seo|Jong Jin|JJ|http://orcid.org/0000-0002-0191-7836",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D014750:Vincristine; D001215:Asparaginase; D011241:Prednisone; D015255:Idarubicin",
"country": "Korea (South)",
"delete": false,
"doi": "10.3346/jkms.2017.32.4.642",
"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 2824429110.3346/jkms.2017.32.4.642Original ArticlePediatricsOutcome of Reinduction Chemotherapy with a Modified Dose of Idarubicin for Children with Marrow-Relapsed Acute Lymphoblastic Leukemia: Results of the Childhood Acute Lymphoblastic Leukemia (CALL)-0603 Study http://orcid.org/0000-0002-6376-672XKoh Kyung-Nam 1http://orcid.org/0000-0001-8799-4068Im Ho Joon 1http://orcid.org/0000-0003-2852-6832Kim Hyery 1http://orcid.org/0000-0003-1009-6002Kang Hyoung Jin 2http://orcid.org/0000-0002-6943-4398Park Kyung Duk 2http://orcid.org/0000-0003-2091-1947Shin Hee Young 2http://orcid.org/0000-0002-5618-7033Ahn Hyo Seop 3http://orcid.org/0000-0003-0084-1304Lee Ji Won 4http://orcid.org/0000-0002-5980-7912Yoo Keon Hee 4http://orcid.org/0000-0001-5989-4772Sung Ki Woong 4http://orcid.org/0000-0001-8082-1412Koo Hong Hoe 4http://orcid.org/0000-0002-3300-7239Lim Young Tak 5http://orcid.org/0000-0003-4292-3500Park Jun Eun 6http://orcid.org/0000-0001-9743-0610Park Byung-Kiu 7http://orcid.org/0000-0002-9557-3412Park Hyeon Jin 7http://orcid.org/0000-0002-0191-7836Seo Jong Jin 11 Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea.2 Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.3 Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.4 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.5 Department of Pediatrics, Pusan National University College of Medicine, Busan, Korea.6 Department of Pediatrics, Ajou University College of Medicine, Suwon, Korea.7 Center for Pediatric Cancer, National Cancer Center, Goyang, Korea.Address for Correspondence: Jong Jin Seo, MD, PhD. Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. jjseo@amc.seoul.kr4 2017 13 2 2017 32 4 642 649 12 7 2016 07 1 2017 © 2017 The Korean Academy of Medical Sciences.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.This multicenter, prospective trial was conducted to develop an effective and safe reinduction regimen for marrow-relapsed pediatric acute lymphoblastic leukemia (ALL) by modifying the dose of idarubicin. Between 2006 and 2009, the trial accrued 44 patients, 1 to 21 years old with first marrow-relapsed ALL. The reinduction regimen comprised prednisolone, vincristine, L-asparaginase, and idarubicin (10 mg/m2/week). The idarubicin dose was adjusted according to the degree of myelosuppression. The second complete remission (CR2) rate was 72.7%, obtained by 54.2% of patients with early relapse < 24 months after initial diagnosis and 95.0% of those with late relapse (P = 0.002). Five patients entered remission with extended treatment, resulting in a final CR2 rate of 84.1%. The CR2 rate was not significantly different according to the idarubicin dose. The induction death rate was 2.3% (1/44). The 5-year event-free and overall survival rates were 22.2% ± 6.4% and 27.3% ± 6.7% for all patients, 4.2% ± 4.1% and 8.3% ± 5.6% for early relapsers, and 43.8% ± 11.4% and 50.0% ± 11.2% for late relapsers, respectively. Early relapse and slow response to reinduction chemotherapy were predictors of poor outcomes. In conclusion, a modified dose of idarubicin was effectively incorporated into the reinduction regimen for late marrow-relapsed ALL with a low toxic death rate. However, the CR2 rate for early relapsers was suboptimal, and the second remission was not durable in most patients.\n\nGraphical Abstract\n\n\nChildhoodAcute Lymphoblastic LeukemiaRelapseInductionIdarubicinMinistry of Health, Welfare and Family Affairshttp://dx.doi.org/10.13039/5011000036250520290 1420250\n==== Body\nINTRODUCTION\nThe outcome of childhood acute lymphoblastic leukemia (ALL) has considerably improved during recent decades (1234). Nonetheless, approximately 20% of childhood ALL patients relapse during or after frontline treatment (5). In particular, the outcome of bone marrow (BM) relapse of pediatric ALL is very poor, and relapsed ALL is one of the major causes of childhood cancer death (56). Challenges in the treatment of marrow-relapsed ALL include failure to achieve second complete remission (CR2), risk of induction death, and short-sustained second remission during post-remission treatment (578). Thus, an initial step to improve the outcome of marrow-relapsed ALL is the development of a more effective and safe reinduction platform.\n\nReinduction therapy usually consists of a 4-week regimen of prednisone, vincristine, L-asparaginase, and an anthracycline. Idarubicin is a second-generation anthracycline that has been effectively used to treat acute myeloid leukemia and relapsed ALL (91011). The maximum tolerated dose of idarubicin is reported to be 12.5 mg/m2/dose (9). The Children's Cancer Group (CCG)-1884 study reported that a weekly dose of idarubicin at 12.5 mg/m2 for 3 weeks could be effectively incorporated into reinduction regimens, with a requirement for intensive supportive care for serious hematopoietic toxicity (10). However, a previous Korean pilot study showed that 12.5 mg/m2/week of idarubicin was unacceptably toxic and had an inferior CR2 rate to a modified dose of 10 mg/m2/week due to a higher toxic death rate (12).\n\nBased on the previous pilot study, the Childhood Acute Lymphoblastic Leukemia (CALL)-0603 study sought to improve the CR2 rate by reducing toxic death during a reinduction attempt with a modified dose of idarubicin and to evaluate the long-term outcomes of Korean children with relapsed ALL, thereby providing baseline data for future trials.\n\nMATERIALS AND METHODS\nPatients\nBetween 2006 and 2009, the multicenter, prospective CALL-0603 study enrolled children and adolescents aged from 1 to 21 years with a first isolated or combined marrow-relapsed ALL. Patients with B-precursor and T-cell ALL were included, whereas those with mature B-cell ALL and Down syndrome were excluded. Patients who had undergone prior allogeneic hematopoietic stem cell transplantation (HSCT) were eligible.\n\nDefinitions\nBM relapse was defined as BM showing greater than 25% blasts (M3) by microscopic morphological examination. Central nervous system (CNS) relapse was defined as a cerebrospinal fluid white blood cell (WBC) count greater than 5/μL with lymphoblasts present on cytology or clinical signs of CNS disease. Testicular relapse was confirmed by open-wedge biopsy. Involvement of any other extramedullary site was confirmed histologically. Early and late marrow relapses were defined as relapse less than 24 months and ≥ 24 months after initial diagnosis, respectively. The risk groups at initial diagnosis were stratified based on age and WBC count at diagnosis and cytogenetic aberrations: standard risk as age ≥ 1 year and < 10 years with an initial WBC count < 50,000/μL, high risk as age < 1 year or ≥ 10 years and/or an initial WBC count ≥ 50,000/μL, and the presence of t(9;22)(q34;q11), mixed lineage leukemia (MLL) rearrangements, or hypodiploidy (< 45 chromosomes) irrespective of age and WBC count. Cytogenetic findings were divided into 4 groups: favorable (high hyperdiploidy [> 50 chromosomes] and t(12;21)(q23;p13)), unfavorable (t(9;22)(q34;q11), MLL rearrangements, and hypodiploidy), others, and normal karyotype.\n\nTreatment plan\nThe reinduction protocol consisted of oral prednisolone 60 mg/m2/day for 28 days, weekly intravenous vincristine 1.5 mg/m2, intramuscular L-asparaginase 6,000 IU/m2 3 times weekly with a total of nine doses, and weekly intravenous idarubicin 10 mg/m2 on days 0, 7, 14, and 21. If the absolute neutrophil count (ANC) was < 500/μL or the platelet count was < 50,000/μL on day 14 or 21, idarubicin administration was withdrawn. However, if BM examination on day 14 showed M3 marrow, idarubicin was administered regardless of the blood cell count. CNS-negative patients received intrathecal cytarabine and hydrocortisone on days 0, 7, and 28, whereas CNS-positive patients received intrathecal triple therapy containing cytarabine, hydrocortisone, and methotrexate on days 0, 7, 14, 21, and 28.\n\nIf the day 29 BM was 5% to 25% blasts (M2) or M3, patients proceeded immediately to consolidation chemotherapy at the physician's discretion. The aim of this trial was to evaluate the efficacy and safety of reinduction treatment. Thus, post-induction consolidation regimens were based on institutional preferences, and the investigators decided between maintenance with chemotherapy or allogeneic HSCT to their discretion.\n\nAssessment of treatment response and toxicities\nBM examinations were done on days 7, 14 (if not less than 5% blasts [M1] at day 7), and 28 of reinduction treatment. Rapid early response (RER) was defined as an M1 marrow on day 7 (< 5% lymphoblasts) and CR on day 28 or an M2 marrow (5%–25% lymphoblasts) on day 7 and an M1 marrow on day 14 and CR on day 28. Slow early response (SER) was defined as an M2 or M3 (> 25% lymphoblasts) marrow on day 14 and CR on day 28 or an M3 marrow on day 7 and CR on day 28. CR2 was defined as an M1 marrow with no evidence of circulating blasts or extramedullary disease and with peripheral blood cell count recovery (ANC ≥ 750/μL and platelet count ≥ 75,000/μL).\n\nToxicities were graded based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE v4.0; National Cancer Institute, Bethesda, MD, USA).\n\nStatistical methods\nThe primary objective of this study was to assess the efficacy and toxicity of a reinduction regimen, which were represented by CR2 rate and induction death rate. A CR2 rate of 75% (95% confidence interval, 60–90) was considered sufficient to warrant further study of this reinduction regimen. According to this design, it was necessary to recruit 36 patients. The secondary objective of this study is to assess the 5-year event-free survival (EFS) and overall survival (OS) of the enrolled patients.\n\nA χ2 test was used to identify factors associated with CR. EFS was defined as the time between relapse and the first event (either relapse or death in CR). OS was defined as the time between relapse and death from any cause. The Kaplan-Meier method was used to estimate survival probabilities, and a log-rank test was used to test the prognostic significance of various risk factors. A P value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 21.0 (Statistical Package for the Social Sciences; IBM Corp., Armonk, NY, USA).\n\nEthics statement\nThis study was approved by the Institutional Review Board of Asan Medical Center, Seoul, Korea (IRB No. 2009-0463). All the patients and/or their legal guardians provided their written informed consent.\n\nRESULTS\nPatient characteristics\nA total of 44 patients (31 males and 13 females) from 6 institutions (19 from Asan Medical Center Children's Hospital, 13 from Seoul National University Children's Hospital, 9 from Samsung Medical Center, 1 from National Cancer Center, 1 from Ajou University Hospital, 1 from Pusan National University Hospital) were enrolled in the trial. Demographic and clinical characteristics are summarized in Table 1. The median ages at initial diagnosis and relapse were 8.0 years (range, 1.1–15.8) and 11.5 years (range, 1.5–18.7), respectively. The median duration from initial diagnosis to relapse was 22.0 months (range, 2.0–107.0). Twenty-four patients relapsed less than 24 months after initial diagnosis (early relapsers) and 17 relapsed after more than 24 months (late relapsers). Thirty-four patients had isolated BM relapses, whereas 10 had combined BM and extramedullary relapses. At initial diagnosis, 17 patients had been allocated to the standard risk group, and 27 to the high-risk group. In addition, 35 patients had precursor B-cell leukemia and 9 had T-cell leukemia; 9 had favorable cytogenetic aberrations, 6 unfavorable, and 29 had normal karyotype or other aberrations. Six patients had received allogeneic HSCT in the first CR before relapse.\n\nTable 1 Patient characteristics and treatments\nCharacteristics\tNo. of patients\tCR, %\tP\tEFS, %\tP\tOS, %\tP\t\nSex\t\t\t0.740\t\t0.598\t\t0.341\t\n Male\t31\t74.2\t22.1 ± 7.6\t29.0 ± 8.2\t\n Female\t13\t69.2\t23.1 ± 11.7\t23.1 ± 11.7\t\nAge at relapse, yr\t\t\t0.820\t\t0.011\t\t0.562\t\n < 5\t6\t83.0\t0\t16.7 ± 15.2\t\n ≥ 5 and < 10\t14\t71.0\t35.7 ± 12.8\t35.7 ± 12.8\t\n ≥ 10\t24\t71.0\t20.0 ± 8.4\t25.0 ± 8.8\t\nTime point of relapse\t\t\t0.002\t\t0.001\t\t0.001\t\n Early (< 24 months)\t27\t54.2\t4.2 ± 4.1\t8.3 ± 5.6\t\n Late (≥ 24 months)\t17\t95.0\t43.8 ± 11.4\t50.0 ± 11.2\t\nSite of relapse\t\t\t0.560\t\t0.343\t\t0.371\t\n Isolated BM\t34\t70.6\t20.6 ± 6.9\t23.5 ± 7.3\t\n Combined\t10\t80.0\t30.0 ± 14.5\t40.0 ± 15.5\t\n BM + CNS\t7\t-\t-\t-\t\n BM + CNS + testis\t1\t-\t-\t-\t\n BM + testis\t1\t-\t-\t-\t\n BM + LNs/mass\t1\t-\t-\t-\t\nImmunophenotype\t\t\t0.700\t\t0.728\t\t0.447\t\n Precursor B-cell\t35\t71.4\t22.5 ± 7.1\t28.6 ± 7.6\t\n T-cell\t9\t77.8\t22.2 ± 13.9\t22.2 ± 13.9\t\nRisk group at initial diagnosis\t\t\t0.255\t\t0.226\t\t0.158\t\n Standard\t17\t82.4\t28.2 ± 11.2\t41.2 ± 11.9\t\n High-risk\t27\t66.7\t18.5 ± 7.5\t18.5 ± 7.5\t\nCytogenetics\t\t\t0.320\t\t0.151\t\t0.082\t\n Favorable\t9\t88.9\t44.4 ± 16.6\t55.6 ± 16.6\t\n Unfavorable\t6\t83.3\t0\t0\t\n Others/normal\t29\t65.5\t20.7 ± 7.5\t24.1 ± 7.9\t\nTreatment in CR1\t\t\t0.720\t\t0.943\t\t0.916\t\n Chemotherapy\t38\t73.7\t23.0 ± 7.0\t28.9 ± 7.4\t\n Allogeneic HSCT\t6\t66.7\t16.7 ± 15.2\t16.7 ± 15.2\t\nDose of idarubicin, mg/m2\t\t\t0.710\t\t0.096\t\t0.033\t\n ≤ 20\t20\t70.0\t35.0 ± 10.7\t45.0 ± 11.1\t\n ≥ 30\t24\t75.0\t12.5 ± 6.8\t12.5 ± 6.8\t\nEarly response\t\t-\t-\t\t< 0.001\t\t0.001\t\n RER\t11\t\t63.6 ± 14.5\t63.6 ± 14.5\t\n SER\t15\t\t20.0 ± 10.3\t26.7 ± 11.4\t\n Induction failure\t12\t\t0\t8.3 ± 8.3\t\n Induction death\t1\t\t-\t-\t\n NA*\t5\t\t-\t-\t\nPost-induction treatment\t\t-\t-\t\t\t\t\t\n CR not achieved\t6\t\t-\t-\t-\t-\t\n Induction death\t1\t\t-\t-\t-\t-\t\n Treatment\t\t\t\t0.354\t\t0.854\t\n Chemotherapy\t13\t\t20.5 ± 12.0\t30.8 ± 12.8\t\n Allogeneic HSCT\t24\t\t29.2 ± 9.3\t33.3 ± 9.6\t\nCR = complete remission, EFS = event-free survival, OS = overall survival, BM = bone marrow, CNS = central nervous system, LNs = lymph nodes, CR1 = first complete remission, HSCT = hematopoietic stem cell transplantation, RER = rapid early response, SER = slow early response, NA = not available.\n\n*NA indicates the patients whose BM data on day 7 and/or day 14 were not available.\n\nOutcome of reinduction treatment\nOverview of treatment and outcome regarding 44 patients with relapsed ALL is depicted in Fig. 1. Among 44 patients, 43 completed 4 weeks of reinduction treatment, and 1 died during reinduction therapy. The CR2 rate after 4 weeks of reinduction therapy was 72.7% (32 of 44 patients). Five patients achieved remission with extended treatment, resulting in a final CR2 rate of 84.1% (37/44). Among 43 patients who completed 4 weeks of reinduction treatment, 38 patients had available BM data on day 7 and/or day 14, thus could be designated according to their early morphological marrow responses to treatment as follows: 28.9% RER (11/38), 39.5% SER (15/38), and 31.6% induction failure (12/38).\n\nFig. 1 Overview of treatment and outcome regarding 44 patients with relapsed ALL.\n\nALL = acute lymphoblastic leukemia, CR = complete remission, CR2 = second complete remission, DOD = died of disease, TRM = treatment-related mortality, HSCT = hematopoietic stem cell transplantation.\n\nRegarding dosage, 19 patients received 20 mg/m2 of idarubicin, 22 patients 30 mg/m2, and 3 patients 40 mg/m2. The median dose of idarubicin was 30 mg/m2. Patients who received 30 mg/m2 or more of idarubicin included significantly more patients with M3 marrow on day 14 than those who received 20 mg/m2 of idarubicin (27.8% vs. 0.0%, P = 0.038). Factors associated with successful CR2 induction are listed in Table 1. There was no significant difference in the CR2 rate between idarubicin doses of 20 mg/m2 and 30 mg/m2 or more (70.0% vs. 75.0%, P = 0.736). Time from initial diagnosis to relapse less than 24 months was a significant predictor of failure to achieve CR2 (P = 0.002). Site of relapse, age at relapse, risk group allocation at initial diagnosis, and cytogenetic aberrations were not significantly associated with the probability of achieving CR2.\n\nHematological toxicities were as follows: grade 3–4 neutropenia in 100.0%, anemia in 68.1% (30/44), and thrombocytopenia in 90.9% (40/44). Non-hematological toxicities were as follows: grade 3–4 transaminase elevation in 11.3% (5/44), hyperbilirubinemia in 4.5% (2/44), hyperglycemia in 13.6% (6/44), mucositis in 10.0% (4/44), and pancreatitis in 4.5% (2/44). Of the 44 patients, 33 (75.0%) developed neutropenic fever during reinduction treatment: 9 developed documented bacteremia, 8 had documented or presumed fungal infection, 4 had viral infection, and 12 had no identifiable source of infection. One patient died due to septic shock during reinduction treatment, resulting in an induction death rate of 2.3%.\n\nOutcome of post-induction treatment\nAmong the 37 patients who achieved CR2, 13 (5 early relapsers and 8 late relapsers) continued consolidation and maintenance treatment with chemotherapy: 4 patients remained in remission, 8 subsequently relapsed and died of progressive disease, and 1 died in remission due to treatment-related complications. The remaining 24 patients (12 early relapsers and 12 late relapsers) proceeded to allogeneic HSCT in CR2: 8 remained in remission, 11 subsequently relapsed and died of disease, and 5 died of a transplant-related cause in remission. Of the 6 patients who did not achieve CR2, 5 patients continued chemotherapy and 1 patient received allogeneic HSCT in the refractory state; all died of progressive disease.\n\nAt a median follow-up duration of 99 months, the 5-year EFS and OS rates were 22.2% ± 6.4% and 27.3% ± 6.7% for all patients, 4.2% ± 4.1% and 8.3% ± 5.6% for early relapsers, and 43.8% ± 11.4% and 50.0% ± 11.2% for late relapsers, respectively (P = 0.001) (Fig. 2). Early time point of relapse and SER to reinduction chemotherapy were significantly related to poor EFS rates (Table 1). Notably, early response during reinduction treatment was a significant prognostic factor for late relapsers (RER vs. SER vs. induction failure = 100.0% vs. 33.3% ± 15.7% vs. 0.0%, P < 0.001), but it was not significant for early relapsers (RER vs. SER vs. induction failure = 20.0% ± 17.9% vs. 0.0% vs. 0.0%, P = 0.113) (Fig. 3).\n\nFig. 2 Survival of children with ALL. (A) OS and EFS in children with first BM relapse. Thick solid line = OS; dashed line = EFS. (B) EFS according to timing of relapse. Thick solid line = early relapse (< 24 months from initial diagnosis); thin solid line = late relapse (≥ 24 months from initial diagnosis).\n\nALL = acute lymphoblastic leukemia, OS = overall survival, EFS = event-free survival, BM = bone marrow.\n\nFig. 3 EFS based on timing of relapse and post-remission treatment. (A) EFS of all patients who achieved CR2 according to post-remission treatment. EFS of patients with (B) early relapse and (C) late relapse who achieved CR2 according to post-remission treatment. Thick solid line = chemotherapy; thin solid line = allogeneic HSCT.\n\nEFS = event-free survival, CR2 = second complete remission, HSCT = hematopoietic stem cell transplantation.\n\nEFS rates were not different between patients who received chemotherapy or allogeneic HSCT as a consolidative treatment (20.5% ± 12.0% vs. 29.2% ± 9.3%, P = 0.354). For early relapsers (n = 17) who achieved CR2, the EFS rates of patients who received chemotherapy or allogeneic HSCT were significantly different (0.0% vs. 8.3% ± 8.0%, P = 0.003), while those for late relapsers (n = 20) were not (50.0% ± 17.7% vs. 50.0% ± 14.4%, P = 0.649) (Fig. 4).\n\nFig. 4 EFS based on timing of relapse and early response to reinduction chemotherapy. (A) EFS of all patients with available data according to early response to reinduction chemotherapy. EFS of patients with (B) early relapse and (C) late relapse with available data according to early response to reinduction chemotherapy. Thick solid line = RER; thin solid line =SER; dashed line = induction failure.\n\nEFS = event-free survival, RER = rapid early response, SER = slow early response.\n\nDISCUSSION\nThe aim of our present study was to evaluate the efficacy and safety of reinduction chemotherapy with a modified dose of idarubicin. This regimen showed a 72.7% CR2 rate, which were within expected range to warrant further study. Especially, the CR2 rate was favorable for late relapsers, while suboptimal for early relapsers. From a toxicity standpoint, this regimen was tolerable to most patients with 2.3% of induction death rate. Toxicities were mostly hematological, and infections during neutropenia were treatable in most patients. The results suggest that a reinduction regimen with modified-dose idarubicin can be a safe and effective strategy to achieve CR2 in Korean children and adolescents with late marrow-relapsed ALL. However, the long-term survival outcomes were still poor, especially for early relapsers, emphasizing the need for a more effective reinduction regimen and post-remission treatment.\n\nThe CR2 rates of children with marrow-relapsed ALL reportedly range from 50% to > 90%, depending on the time point of relapse. Previous studies reported that the CR2 rate was < 50% in very early relapse, 70%–85% in early relapse, and > 90% in late relapse (810131415161718). One of the major obstacles to CR2 is toxic death during remission induction therapy; its reported incidence ranges from 4% to 10% (10141519).\n\nAnthracycline is a key component of the reinduction regimen for relapsed ALL. However, the optimal anthracycline and its dose remain controversial and have been evaluated in previous studies (91012). The CCG-1884 trial reported that the reinduction rate was similar for idarubicin and daunorubicin groups and that a higher dose of idarubicin (12.5 mg/m2/week for 3 weeks) resulted in better early EFS than daunorubicin and lower-dose idarubicin (10 mg/m2/week for 3 weeks) (10). However, a previous Korean study showed that high-dose idarubicin (12.5 mg/m2/week) led to a high toxic death rate of 44% and poor CR2 rate of 22%, suggesting that high-dose idarubicin might be unacceptably toxic for Korean children with relapsed ALL (12). Thus, the present trial chose the lower dose of idarubicin (10 mg/m2/week), which was adjusted based on myelosuppression during reinduction treatment and ranged from a total idarubicin dose of 20 mg/m2 to 40 mg/m2. Of the 44 patients, 20 (45.4%) received a total idarubicin dose of 20 mg/m2; these patients showed a comparable CR2 rate to higher-dose idarubicin with a low toxic death rate. The overall CR2 rate of the present study is comparable to those of previous studies (1014152021). Notably, most of the late relapsers achieved CR2. However, the CR2 rate of early relapsers was unsatisfactory. Moreover, the long-term outcomes of the patients who achieved CR2 were poor, especially early relapsers. Thus, the reinduction regimen can be stratified based on the time point of relapse, such as a less toxic regimen for late relapsers to decrease toxic death during reinduction treatment and a more effective regimen for early relapsers to improve the CR2 rate.\n\nA recent trial showed that mitoxantrone (10 mg/m2 on days 1, 2), an anthracenedione agent, had a significant benefit in reducing disease-related events, compared to idarubicin (10 mg/m2 on days 1, 2) in marrow-relapsed ALL (17) and CNS-relapsed ALL (22). Thus, the incorporation of mitoxantrone into reinduction regimens could be considered in a future trial. In addition, recent immunotherapeutic approaches such as a bispecific T-cell engager or a chimeric antigen receptor T-cell therapy has been reported to be promising for relapsed/refractory ALL (2324).\n\nBecause post-remission chemotherapy has been unsatisfactory in enabling sustainable second remission, allogeneic HSCT has been used as an intensive consolidation element for post-remission treatment (212526). However, the beneficial role and indications of allogeneic HSCT for relapsed ALL remain unclear. Previous studies suggested that patients with early BM relapse or those with BM relapse at any time of T-ALL can be considered to be indicated for allogeneic HSCT (25262728). However, its indication remains controversial for those with late BM relapse (252627). This study was to evaluate a reinduction regimen, and not intended to prospectively evaluate the role of post-remission therapy. The choice of post-remission therapy was to physician's discretion in this study. The differences in post-remission therapy in the present study do not always reflect the investigator's intention-to-treat. The patients who proceeded to allogeneic HSCT would have more durable remission, whereas those with short-lived second remission would not be eligible for allogeneic HSCT. Thus, the impact of allogeneic HSCT on the outcomes in this study was simply observational, with limited implications.\n\nAnother important prognostic factor in the present study was early response to reinduction chemotherapy. Notably, all late relapsers who showed a RER remained in remission with or without allogeneic HSCT, whereas the outcome was universally poor regardless of the early response in early relapsers. This suggests that the treatment response can be a guideline to consolidative treatment. Our study did not incorporate more sensitive method to detect minimal residual disease (MRD) into the protocol. MRD has been reported to be a significant prognostic factor for both newly diagnosed and relapsed ALL (293031). A recent study showed that a faster acquisition of MRD negativity was associated with a better outcome in relapsed ALL (32). Thus, future trials should evaluate the treatment response with measurements of MRD, which can predict the outcome more precisely.\n\nInterestingly, our present study showed that a higher dose of idarubicin trended to be associated with poor outcomes. This could be because idarubicin was designed to be administered to patients who showed M3 marrow on day 14, regardless of the blood cell count. Thus, poor responders were likely to receive a higher dose of idarubicin. Actually, all the patients with M3 marrow on day 14 received 30 mg/m2 or more of idarubicin. This suggests that dose intensification during reinduction treatment cannot improve the long-term outcome of poor responders.\n\nThe aim of our present study was to evaluate the reinduction chemotherapy. Thus, our study had a limited ability to evaluate the role of post-remission therapy, and the impact of post-remission treatment might have suffered from a selection bias. In addition, because patients were subdivided into late and early relapsers, the assessment of prognostic factors in each subgroup was limited by a small number of patients.\n\nIn conclusion, this study showed a favorable CR2 rate due to reduced toxicity during reinduction treatment of marrow-relapsed pediatric ALL. The CR2 rate of late relapsers was excellent, whereas that of early relapsers was unsatisfactory. Thus, a more effective induction treatment involving new agents should be considered for early relapsers. In addition, CR2 achievement was not translated into sustained remission in most patients. Thus, future trials are required to optimize the post-induction treatment and improve the long-term outcomes.\n\nFunding: This study was supported by grants of the National R & D Program for Cancer Control, Ministry of Health, Welfare and Family Affairs, Republic of Korea Government (grant No. 0520290 and 1420250).\n\nDISCLOSURE: The authors have no potential conflicts of interest to disclose.\n\nAUTHOR CONTRIBUTION: Conceptualization: Shin HY, Ahn HS, Koo HH, Seo JJ. Data curation: Koh KN, Im HJ, Kim H, Kang HJ, Park KD, Lee JW, Yoo KH, Lim YT, Park JE, Park BK, Park HJ. Investigation: Koh KN, Im HJ, Kim H, Kang HJ, Park KD, Lee JW, Yoo KH, Lim YT, Park JE, Park BK, Park HJ. Writing - original draft: Koh KN. Writing - review & editing: Koh KN, Im HJ, Seo JJ.\n==== Refs\n1 Pui CH Yang JJ Hunger SP Pieters R Schrappe M Biondi A Vora A Baruchel A Silverman LB Schmiegelow K Childhood acute lymphoblastic leukemia: progress through collaboration J Clin Oncol 2015 33 2938 2948 26304874 \n2 Hunger SP Mullighan CG Acute lymphoblastic leukemia in children N Engl J Med 2015 373 1541 1552 26465987 \n3 Kim H Recent advances in the treatment of pediatric acute leukemia J Korean Med Assoc 2016 59 690 697 \n4 Park KD How do we prepare ourselves for a new paradigm of medicine to advance the treatment of pediatric acute lymphoblastic leukemia? Blood Res 2014 49 3 4 24724058 \n5 Gaynon PS Childhood acute lymphoblastic leukaemia and relapse Br J Haematol 2005 131 579 587 16351633 \n6 Yang MH Eun SH Park CS Son JA Kim JY Ko JW Ahn DH A study of the survival rate of childhood cancer in Korea Cancer Res Treat 2001 33 191 198 26680785 \n7 Gaynon PS Harris RE Altman AJ Bostrom BC Breneman JC Hawks R Steele D Zipf T Stram DO Villaluna D Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children’s Oncology Group study CCG-1941 J Clin Oncol 2006 24 3150 3156 16717292 \n8 Raetz EA Bhatla T Where do we stand in the treatment of relapsed acute lymphoblastic leukemia Hematology Am Soc Hematol Educ Program 2012 2012 129 136 23233571 \n9 Feig SA Krailo MD Harris RE Baum E Holcenberg JS Kaizer H Steinherz L Pendergrass TW Saunders EF Warkentin PL Determination of the maximum tolerated dose of idarubicin when used in a combination chemotherapy program of reinduction of childhood ALL at first marrow relapse and a preliminary assessment of toxicity compared to that of daunorubicin: a report from the Childrens Cancer Study Group Med Pediatr Oncol 1992 20 124 129 1734217 \n10 Feig SA Ames MM Sather HN Steinherz L Reid JM Trigg M Pendergrass TW Warkentin P Gerber M Leonard M Comparison of idarubicin to daunomycin in a randomized multidrug treatment of childhood acute lymphoblastic leukemia at first bone marrow relapse: a report from the Children’s Cancer Group Med Pediatr Oncol 1996 27 505 514 8888809 \n11 Li X Xu S Tan Y Chen J The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia Cochrane Database Syst Rev 2015 CD010432 26037486 \n12 Yoon JH Park JA Kim EK Kang HJ Shin HY Ahn HS Improvement of induction remission rate by modifying the dose of idarubicin for relapsed childhood acute lymphoblastic leukemia J Korean Med Sci 2009 24 281 288 19399271 \n13 Tallen G Ratei R Mann G Kaspers G Niggli F Karachunsky A Ebell W Escherich G Schrappe M Klingebiel T Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90 J Clin Oncol 2010 28 2339 2347 20385996 \n14 Roy A Cargill A Love S Moorman AV Stoneham S Lim A Darbyshire PJ Lancaster D Hann I Eden T Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial Br J Haematol 2005 130 67 75 15982346 \n15 Raetz EA Borowitz MJ Devidas M Linda SB Hunger SP Winick NJ Camitta BM Gaynon PS Carroll WL Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: a Children’s Oncology Group Study [corrected] J Clin Oncol 2008 26 3971 3978 18711187 \n16 Einsiedel HG von Stackelberg A Hartmann R Fengler R Schrappe M Janka-Schaub G Mann G Hählen K Göbel U Klingebiel T Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87 J Clin Oncol 2005 23 7942 7950 16258094 \n17 Parker C Waters R Leighton C Hancock J Sutton R Moorman AV Ancliff P Morgan M Masurekar A Goulden N Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial Lancet 2010 376 2009 2017 21131038 \n18 Buchanan GR Rivera GK Boyett JM Chauvenet AR Crist WM Vietti TJ Reinduction therapy in 297 children with acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group Study Blood 1988 72 1286 1292 3167209 \n19 Morland BJ Shaw PJ Induction toxicity of a modified Memorial Sloan-Kettering-New York II Protocol in children with relapsed acute lymphoblastic leukemia: a single institution study Med Pediatr Oncol 1996 27 139 144 8699989 \n20 Kelly ME Lu X Devidas M Camitta B Abshire T Bernstein ML Billett A Homans A Sandler E Buchanan G Treatment of relapsed precursor-B acute lymphoblastic leukemia with intensive chemotherapy: POG (Pediatric Oncology Group) study 9411 (SIMAL 9) J Pediatr Hematol Oncol 2013 35 509 513 23887024 \n21 Kozlowski P Åström M Ahlberg L Bernell P Hulegårdh E Hägglund H Karlsson K Markuszewska-Kuczymska A Tomaszewska-Toporska B Smedmyr B High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-2007 Haematologica 2012 97 1414 1421 22511497 \n22 Masurekar AN Parker CA Shanyinde M Moorman AV Hancock JP Sutton R Ancliff PJ Morgan M Goulden NJ Fraser C Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial PLoS One 2014 9 e108107 25279465 \n23 Benjamin JE Stein AS The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia Ther Adv Hematol 2016 7 142 156 27247755 \n24 Davila ML Brentjens RJ CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia Clin Adv Hematol Oncol 2016 14 802 808 27930631 \n25 Borgmann A von Stackelberg A Hartmann R Ebell W Klingebiel T Peters C Henze G Berlin-Frankfurt-Münster Relapse Study Group Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis Blood 2003 101 3835 3839 12732501 \n26 Barrett AJ Horowitz MM Pollock BH Zhang MJ Bortin MM Buchanan GR Camitta BM Ochs J Graham-Pole J Rowlings PA Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission N Engl J Med 1994 331 1253 1258 7935682 \n27 Gaynon PS Qu RP Chappell RJ Willoughby ML Tubergen DG Steinherz PG Trigg ME Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children’s Cancer Group experience Cancer 1998 82 1387 1395 9529033 \n28 Locatelli F Moretta F Rutella S Management of relapsed acute lymphoblastic leukemia in childhood with conventional and innovative approaches Curr Opin Oncol 2013 25 707 715 24076579 \n29 Eckert C von Stackelberg A Seeger K Groeneveld TW Peters C Klingebiel T Borkhardt A Schrappe M Escherich G Henze G Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96 Eur J Cancer 2013 49 1346 1355 23265714 \n30 Campana D Coustan-Smith E Measurements of treatment response in childhood acute leukemia Korean J Hematol 2012 47 245 254 23320002 \n31 Koh KN Park M Kim BE Im HJ Park CJ Jang S Chi HS Seo JJ Prognostic significance of minimal residual disease detected by a simplified flow cytometric assay during remission induction chemotherapy in children with acute lymphoblastic leukemia Korean J Pediatr 2010 53 957 964 21218018 \n32 Jabbour E Short NJ Jorgensen JL Yilmaz M Ravandi F Wang SA Thomas DA Khoury J Champlin RE Khouri I Differential impact of minimal residual disease negativity according to the salvage status in patients with relapsed/refractory B-cell acute lymphoblastic leukemia Cancer 2017 123 294 302 27602508\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "32(4)",
"journal": "Journal of Korean medical science",
"keywords": "Acute Lymphoblastic Leukemia; Childhood; Idarubicin; Induction; Relapse",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000293:Adolescent; D000903:Antibiotics, Antineoplastic; D001215:Asparaginase; D001853:Bone Marrow; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015255:Idarubicin; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011241:Prednisone; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "8703518",
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"pubdate": "2017-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": "27930631;8888809;20385996;27247755;21218018;26680785;19399271;26304874;23320002;8699989;24724058;18711187;23887024;26037486;27602508;23265714;24076579;7935682;16258094;9529033;15982346;16717292;25279465;1734217;16351633;12732501;3167209;21131038;23233571;22511497;26465987",
"title": "Outcome of Reinduction Chemotherapy with a Modified Dose of Idarubicin for Children with Marrow-Relapsed Acute Lymphoblastic Leukemia: Results of the Childhood Acute Lymphoblastic Leukemia (CALL)-0603 Study.",
"title_normalized": "outcome of reinduction chemotherapy with a modified dose of idarubicin for children with marrow relapsed acute lymphoblastic leukemia results of the childhood acute lymphoblastic leukemia call 0603 study"
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"abstract": "We present the case of 20-year-old woman intoxicated with mixed drugs, composed of paracetamol (acetaminophen), ferrous sulphate, naproxen and benzodiazepines. Acute toxic liver damage with clinical symptoms of coma resolved at the patient. Lack of the past history doesn't let to specific therapy and systemic complications. In this data we confirm, that past history, clinical symptoms and laboratory results are needed in designing a treatment strategy.",
"affiliations": "Oddział Chorób Wewnetrznych i Ostrych Zatruć im. dr W. Błeńskiej, Szpital im. F. Raszei w Poznaniu. toksy@interia.pl",
"authors": "Adamek|Robert|R|;Wilczek|Lech|L|;Krupiński|Bogusław|B|",
"chemical_list": "D005296:Ferrous Compounds; D001569:Benzodiazepines; D000082:Acetaminophen; C020748:ferrous sulfate; D009288:Naproxen",
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"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D001569:Benzodiazepines; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005296:Ferrous Compounds; D006501:Hepatic Encephalopathy; D006801:Humans; D017114:Liver Failure, Acute; D009288:Naproxen; D016896:Treatment Outcome",
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"references": null,
"title": "Severe toxic liver failure after acute poisoning with paracetamol, ferrous sulphate and naproxen.",
"title_normalized": "severe toxic liver failure after acute poisoning with paracetamol ferrous sulphate and naproxen"
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"abstract": "As Rosai-Dorfman Disease presents generally nonspecific symptoms, differential diagnosis can be of great learning curve for physicians. Additionally, RDD does not usually threaten life and spontaneous remission is frequently observed. However, unusually in our case the patient passed away within 1 month of confirmed diagnosis.",
"affiliations": "Department of Thoracic Surgery Saint Marina Hospital Varna Bulgaria.;Meditsinski Universitet Varna Prof Dr Paraskev Stoyanov Varna Bulgaria.;Meditsinski Universitet Varna Prof Dr Paraskev Stoyanov Varna Bulgaria.;Department of Thoracic Surgery Saint Marina Hospital Varna Bulgaria.;Department of Thoracic Surgery Saint Marina Hospital Varna Bulgaria.",
"authors": "Bulyashki|Daniel|D|;Brady|Zarina|Z|;Arif|Shahswar|S|;Tsvetkov|Nikolay|N|;Radev|Radoslav Stoyanov|RS|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1036CCR31036Clinical ImageClinical ImagesA fatal case of Rosai–Dorfman disease D. Bulyashki et al.Bulyashki Daniel \n1\nBrady Zarina z.brady@my.westminster.ac.uk \n2\nArif Shahswar \n2\nTsvetkov Nikolay \n1\nRadev Radoslav Stoyanov \n1\n\n3\n\n1 \nDepartment of Thoracic Surgery\nSaint Marina Hospital\nVarna\nBulgaria\n\n2 \nMeditsinski Universitet Varna Prof Dr Paraskev Stoyanov\nVarna\nBulgaria\n\n3 \nFaculty of Medicine\nMedical University of Varna\nVarna\nBulgaria\n* Correspondence\n\nZarina Brady, ul. 83 General Kolev, Apartment 115, Floor 4, 9002 Varna, Bulgaria. Tel: +359 87 7417388; E‐mail: z.brady@my.westminster.ac.uk\n15 6 2017 8 2017 5 8 10.1002/ccr3.2017.5.issue-81407 1408 05 10 2016 03 5 2017 11 5 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nAs Rosai–Dorfman Disease presents generally nonspecific symptoms, differential diagnosis can be of great learning curve for physicians. Additionally, RDD does not usually threaten life and spontaneous remission is frequently observed. However, unusually in our case the patient passed away within 1 month of confirmed diagnosis.\n\nEmperipolesisfatalLymphodenopathynonspecific symptomsRosai–Dorfman disease source-schema-version-number2.0component-idccr31036cover-dateAugust 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:01.08.2017\n==== Body\nA 38‐year‐old male was admitted with a fever (39°C), abdominal and back discomfort, and extensive lymphadenopathy. Laboratory tests revealed progressive thrombocytopenia and leukocytosis, platelet count of 84 × 109/L and peak WBC of 46.52 × 109/L. CT scanning uncovered enlarged lymph nodes of the neck, axillary (28/23 mm), hilar (21/24 mm), subcarinal (19/18 mm), paraaortic (30/29 mm), mesenteric (41/35 mm) and curvatura minor gastritis (26/22 mm). Additionally, abdominal ultrasound revealed free fluid in the abdomen combined with an enlarged liver (157 mm) and spleen (157/56 mm). Sterile blood culture ruled out the possibility of a bacterial or fungal infection. An excisional biopsy of an axillary lymph node was performed with no complications. Microscopic examination of the specimen revealed a diffuse proliferation of histiocytes, fibrosis with inflammatory infiltration of the node's capsule and lymphocytes engulfed in the cytoplasm of the histocyte‐like cells (emperipolesis), typical pathology of Rosai–Dorfman 1.\n\nImmunohistochemical stain analysis revealed histiocytes staining strongly for S‐100 protein, CD68 protein, and expansion of sinusoids with an uncontrolled expression of plasma cells, lymphocytes and histiocytes with large oval nuclei. Despite the disease having relatively good prognosis, the patient was dead within a month of confirmed diagnosis, occurring in <3% of Rosai–Dorfman disease cases. The patient's condition progressively deteriorated prior to death. Enlargement of lymph nodes, acute circulatory deficiency, and acute respiratory failure was treated with Dexamethasone and Methylprednisolone. The cause of death was due to suspected respiratory infections resulting from therapy‐based immunosuppressants and initial chemotherapy treatment. No autopsy was carried out due to the patients family declining. As observed in our patient, common symptoms of Rosai–Dorfman disease are nonspecific and can be manifested in malignant and nonmalignant diseases, such as lymphomas, Langerhans cell histiocytosis 2, tuberculosis and sarcoidosis, creating a potential for misdiagnosis (Figs 1, 2, 3).\n\nFigure 1 Immunohistochemical analysis showing histiocytes staining strongly for CD68 protein, indicating the presence of lymphocytes within cytoplasmic vacuoles. (Magnification X40; CD68).\n\nFigure 2 Expansion of sinusoids with an uncontrolled expression of plasma cells, lymphocytes, and histiocytes with large oval nuclei. (Magnification X400; Haematoxylin stain).\n\nFigure 3 \nCT scan showing axillary lymph nodes.\n\nConflict of Interest\nNone declared.\n\nAuthorship\nDB: primary surgeon of the excisional biopsy; involved in critical analysis of report. ZB: wrote the report. SA: wrote the report. NT: surgeon of the excisional biopsy of lymph nodules. RR: involved in the final approval of report.\n==== Refs\nReferences\n1 \n\nWarpe , B. M. \n, and \nS. V. \nMore \n. 2014 \nRosai‐Dorfman disease: a rare clinico‐pathological presentation . Australas. Med. J. \n7 :68 –72 .24611075 \n2 \n\nDalia , S. \n, \nE. \nSagatys \n, \nL. \nSokol \n, and \nT. \nKubal \n. 2014 \nRosai‐Dorfman disease: tumor biology, clinical features, pathology, and treatment . Cancer Control \n21 :322 –327 .25310213\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "5(8)",
"journal": "Clinical case reports",
"keywords": "Emperipolesis; Lymphodenopathy; Rosai–Dorfman disease; fatal; nonspecific symptoms",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1407-1408",
"pmc": null,
"pmid": "28781868",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "24611075;25310213",
"title": "A fatal case of Rosai-Dorfman disease.",
"title_normalized": "a fatal case of rosai dorfman disease"
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"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "BACKGROUND\nPreclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer.\n\n\nMETHODS\nPatients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug.\n\n\nRESULTS\nIn cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib.\n\n\nCONCLUSIONS\nThe combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction.\n\n\nBACKGROUND\nClinicalTrials.gov NCT00764972.",
"affiliations": "Department of Medical Oncology, McGill University, Montreal, Canada.;Department of Cell Therapeutics, Sede Secondaria Della Cell Therapeutics, Bresso, Italy.;Department of Medical Oncology, McGill University, Montreal, Canada.;Department of Medical Oncology, McGill University, Montreal, Canada.;Department of Medical Oncology, McGill University, Montreal, Canada.;Department of statistics, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Rome, Italy.;Department of statistics, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Rome, Italy.;Department of Medical Oncology, McGill University, Montreal, Canada.;Department of Medical Oncology, McGill University, Montreal, Canada.",
"authors": "Ferrario|Cristiano|C|;Strepponi|Ivan|I|;Esfahani|Khashayar|K|http://orcid.org/0000-0003-2221-3755;Charamis|Helen|H|;Langleben|Adrian|A|;Scarpi|Emanuela|E|;Nanni|Oriana|O|;Miller|Wilson H|WH|;Panasci|Lawrence C|LC|",
"chemical_list": "D010671:Phenylurea Compounds; D009536:Niacinamide; D014747:Vinblastine; D000077157:Sorafenib; D000077235:Vinorelbine",
"country": "United States",
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"doi": "10.1371/journal.pone.0167906",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2799245110.1371/journal.pone.0167906PONE-D-16-27839Research ArticleBiology and Life SciencesToxicologyToxicityMedicine and Health SciencesPathology and Laboratory MedicineToxicologyToxicityMedicine and Health SciencesPharmacologyDrug InteractionsMedicine and Health SciencesOncologyCancer TreatmentMedicine and Health SciencesOncologyCancers and NeoplasmsBreast TumorsBreast CancerMedicine and Health SciencesPharmacologyPharmacokineticsDrug MetabolismMedicine and Health SciencesPharmacologyPharmacokineticsMedicine and Health SciencesPharmaceuticsDrug TherapyBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsNeutropeniaBiology and Life SciencesCell BiologyCellular TypesAnimal CellsImmune CellsWhite Blood CellsNeutropeniaBiology and Life SciencesImmunologyImmune CellsWhite Blood CellsNeutropeniaMedicine and Health SciencesImmunologyImmune CellsWhite Blood CellsNeutropeniaPhase I/II Trial of Sorafenib in Combination with Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer Sorafenib-Navelbine for Metastatic Breast CancerFerrario Cristiano 1*Strepponi Ivan 2http://orcid.org/0000-0003-2221-3755Esfahani Khashayar 1*Charamis Helen 1Langleben Adrian 1Scarpi Emanuela 3Nanni Oriana 3Miller Wilson H. Jr1Panasci Lawrence C. 11 \nDepartment of Medical Oncology, McGill University, Montreal, Canada2 \nDepartment of Cell Therapeutics, Sede Secondaria Della Cell Therapeutics, Bresso, Italy3 \nDepartment of statistics, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Rome, ItalyTagliabue Elda EditorFondazione IRCCS Istituto Nazionale dei Tumori, ITALYCompeting Interests: The study was funded by Bayer Pharmaceutical. IS, ES, and ON are affiliated with Sede Secondaria Della Cell Therapeutics and helped provide statistical analysis for the study, without further conflict of interest, financial or other. These do not alter our adherence to PLOS ONE policies on sharing data and materials.\n\nConceptualization: CF LP.\n\nData curation: CF IS KE HC AL ES ON WM LP.\n\nFormal analysis: CF KE IS ES ON LP.\n\nFunding acquisition: CF LP.\n\nInvestigation: CF KE HC AL WM LP.\n\nMethodology: CF IS KE HC AL ES ON WM LP.\n\nProject administration: HC.\n\nResources: IS ES ON.\n\nSoftware: IS ES ON.\n\nSupervision: CF LP.\n\nValidation: CF IS KE HC AL ES ON WM LP.\n\nVisualization: CF LP.\n\nWriting – original draft: CF IS KE ES ON LP.\n\nWriting – review & editing: CF IS KE HC AL ES ON WM LP.\n\n\n\n\n* E-mail: cristianoferrario@gmail.com (CF); Khashayar.esfahani@mail.mcgill.ca (KE)19 12 2016 2016 11 12 e016790624 7 2016 18 11 2016 © 2016 Ferrario et al2016Ferrario et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nPreclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer.\n\nMethods\nPatients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug.\n\nResults\nIn cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4–7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib.\n\nConclusion\nThe combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction.\n\nTrial Registration\nClinicalTrials.gov NCT00764972\n\nhttp://dx.doi.org/10.13039/100007659Bayer Corporation12661Panasci Lawrence C. The study is funded by Bayer Pharmaceutical (Grant number 12661; https://www.bayer.ca). The funder provided support in the form of research materials for author LP, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nMetastatic breast cancer is a virtually incurable disease, for which aggressive treatments are not justified in most cases. Rather, there is a need to develop new combinations that might maintain a good efficacy profile, without significantly compromising quality of life.\n\nVinorelbine is a semisynthetic vinca alkaloid that inhibits microtubule polymerization and has shown significant clinical activity as salvage therapy for metastatic breast cancer (MBC) [1]. Vinorelbine is often administered on days 1 and 8 of 21-day cycles, with no decrease in the administered dose intensity compared to more frequent schedules. The main dose limiting toxicity (DLT) is hematological, specifically neutropenia, and the most commonly reported toxicity is neurological, mainly occasional paresthesia, diminution of deep-tendon reflexes, and constipation.\n\nSorafenib was originally identified as a strong inhibitor of C- and B-RAF and reduces basal phosphorylation of the downstream MAPK pathway in a panel of breast cancer cell lines [2]. The Raf/MEK/ERK pathway is a strong inducer of proliferative and antiapoptotic genes involved in drug resistance and potentiation of tumor metastasis [3]. Further characterization of the compound also confirmed potent inhibition of a spectrum of receptor tyrosine kinases mainly involved in angiogenesis, including VEGFR2, Flt-3, PDGFR-beta, and c-kit [4]. Sorafenib is thus expected to exert a combined targeted antiproliferative effect on tumor cells together with antiangiogenesis properties.\n\nFavourable cytotoxic effects were reported after treatment of a broad spectrum of human cancer cell lines and xenografts, with sorafenib and several chemotherapeutic agents, including vinorelbine, suggesting a synergistic interaction [2,5]. Two preliminary reports of sorafenib as single agent in MBC showed clinical activity, with manageable toxicity profile consisting of mostly grade 1 cutaneous, constitutional, and gastrointestinal toxicity [6,7]. Sorafenib has also been safely combined with multiple chemotherapy agents.\n\nWe investigated the clinical safety and activity of vinorelbine and sorafenib (VS), defining the recommended doses for this combination and its efficacy as first-line in MBC patients.\n\nA parallel pharmacokinetic (PK) study was also run, to investigate a possible interaction, as the metabolism of both sorafenib and vinorelbine depends on hepatic CYP3A isoenzymes.\n\nMaterials and Methods\nStudy design\nThis is single center study, conducted with the approval of the Jewish General Hospital Research Ethics Committee in September 2016. Due to an administrative oversight, the first patient was recruited before the trial was officially registered. However, the authors confirm that all ongoing and related trials for this drug/intervention are registered. Written informed consent was obtained from all patients. The study planned first a phase 1b, to define the recommended doses of the VS combination. With a traditional 3+3 dose escalation in subsequent cohorts, we tested increasing doses of sorafenib (with a fixed starting dose of vinorelbine) up to the recommended dose for sorafenib monotherapy: 200 mg bid (cohort 1) and 400 mg bid (cohort 2). In case of dose-limiting toxicity (DLT) observed in cohort 1, the protocol allowed for testing of a cohort –1 (200 mg qd).\n\nThree patients were enrolled starting at the first dose level and observed until completion of cycle 1: if any patient experienced a DLT, up to three additional patients were to be enrolled at the same dose level.\n\nThe recommended dose for the second part of the study was the maximum tolerated dose (MTD), defined as the highest dose at which no more than one patient out of six would experience a DLT or, in the absence of a toxic dose, the dose of 400 mg bid.\n\nIn the second part of the trial (phase II) the cohort of patients treated at the MTD was expanded up to a total of 27 patients treated with this schedule of VS. Primary endpoint was overall response rate. Secondary endpoints included clinical benefit rate, progression-free survival and safety analysis.\n\nPatient selection\nWomen at least 18 years of age with histologically proven metastatic breast cancer and a life expectancy over 6 months were eligible for the study. Inclusion criteria included: HER-2 negative disease as defined by local testing, measurable disease by RECIST 1.0 criteria; ECOG performance status of 0–1, adequate bone marrow reserve, as well as normal heart, kidney and liver functions (creatinine ≤1.5 UNL, bilirubin ≤1.5 UNL, AST/ALT ≤2 UNL and a baseline left ventricular ejection fraction (LVEF) of at least 50%). Patients were excluded if they received previous chemotherapy for metastatic disease, any previous therapy with vinorelbine or any anti-angiogenic therapy, any breast cancer treatment in 4 weeks preceding enrolment, known central nervous system metastases, previous history of ischemic cardiovascular disease or thromboembolic events, and other uncontrolled relevant medical conditions.\n\nTreatment and procedures\nPatients received vinorelbine 30 mg/m2 on days 1,8 every 21 days and sorafenib daily (200 mg bid in cohort 1 and 400 mg in cohort 2). Radiological imaging was repeated every two cycles and cardiac monitoring (12-lead EKG plus echocardiogram or MUGA scan) was also scheduled every 12 weeks. In the absence of disease progression or unacceptable toxicity, patients received combination VS therapy for up to 8 cycles, or up to 4 cycles after achieving best response. Patients not progressing during the combination treatment continued to receive maintenance sorafenib monotherapy (400 mg bid). Dose adjustments and delays based on observed toxicities were detailed in the protocol.\n\nStatistical considerations\nFrom a pooled analysis of published data on monotherapy vinorelbine as first-line treatment for metastatic breast cancer, an overall response rate of 43% was selected as historical control. For the sample size calculation of the phase II portion of the study, we hypothesized that if the VS combination could lead to a response rate of 63% (20% over historical control), developing a randomized trial would have been reasonable. With a power of 80% to detect such an increase and a significance level (alpha) of 0.10, the minimum sample size needed was 27 evaluable patients. Kaplan-Meier estimates were used to analyze time-to-event data.\n\nFor PK analysis, nonparametric Wilcoxon signe-rank test was used to compare the profile of each drug (and the M2 active metabolite of sorafenib) in the absence or presence of the other drug.\n\nPharmacokinetics\nPlasma samples for PK were collected in six patients treated at the recommended dose and analyzed by Bayer using validated liquid chromatography–mass spectrometry (LC-MS/MS) assays. These patients started taking sorafenib on day 4 of the first cycle, allowing us to compare the plasma levels of vinorelbine, sorafenib and M2 (N-oxide active metabolite of sorafenib) when vinorelbine and sorafenib were administered concomitantly and when they were given apart from each other.\n\nPlasma samples for vinorelbine were collected on day 1 of the first cycle (before sorafenib treatment, starting on day 4) and on day 1 of cycle 2, in the presence of steady state levels of sorafenib. In both cases, collection time points for samples were: time 0 (pre-dose), at the end of the infusion, 0.5, 1, 2.5, 5, 7, 24, 48, 72 hours from the end of the infusion.\n\nSamples for sorafenib and M2 were collected with a similar schedule (0, 0.5, 1, 2.5, 5, 7, 24 hours after the first daily intake) on day 21 of cycle 1 (the day before vinorelbine administration) and on the following day (day 1 of cycle 2) after vinorelbine administration: time, plus 48 and 72 hours after the first sorafenib intake on cycle 2 day 1.\n\nResults\nBetween Dec 2007 and July 2011, 34 patients were screened and 33 were consented to participate in the study (Fig 1). Two patients discontinued treatment during the first cycle of treatment in the absence of DLT, one because of the discovery of brain metastases and the other one withdrew consent. These two patients were then deemed not evaluable for efficacy analysis, but were included in the safety analysis. There was no loss to follow-up.\n\n10.1371/journal.pone.0167906.g001Fig 1 Flow diagram of the patients enrolled in the study.\nPhase I\nIn the first cohort of patients (sorafenib 200 mg bid) one DLT after 1 cycle was observed in patient 2 (grade 3 pancreatitis), requiring expansion of this cohort to six patients total, with no further DLT reported at cycle 1. This dose level was confirmed to be safe also for repeated cycles: only one patient with a baseline borderline LVEF (< 55%) had to discontinue treatment after 8 cycles because of toxicity, developing a recurrent grade 2 LVEF decrease, that recovered to >50% after treatment was stopped.\n\nIn cohort 2 (sorafenib 400 mg bid) one patient out of six developed a DLT at cycle 1, consisting of a grade 4 increase in amylase and lipase. Even if this was compatible with the per-protocol definition of DLT, it was completely asymptomatic and felt to be clinically non-relevant. With repeated cycles no other patient had to discontinue treatment for DLT, but temporary drug suspensions or dose reductions were used for patients not tolerating sustained treatment. One patient decided to withdraw from the study for subjectively unacceptable grade 2 fatigue and was replaced by another evaluable patient.\n\nThe MTD was not formally reached and it was then established that the recommended dose for the phase II expansion was: vinorelbine 30 mg/m2 day 1,8 every 21 days and sorafenib 400 mg bid,\n\nPhase II: patient population\nIn the phase II part of the study 21 more patients started on treatment at the MTD, so as to have a total of 27 evaluable patients treated at this dose (including the 6 evaluable patients treated in the phase I cohort 2). Patients were all female, with a median age of 57 (range 35–71). They received a median of 8 cycles (1–28). Patient characteristics are summarized in Table 1.\n\n10.1371/journal.pone.0167906.t001Table 1 Baseline characteristics of the patients treated with the VS combination at the MTD.\nCharacteristics\tValue\t\nTotal patients\t27\t\nMedian age (range)\t57 (35–71)\t\nMedian number of cycles\t8 (1–28)\t\nCharacteristic\tPatients, no.\t\nHormone status\t\t\nER+/PR+\t17\t\nER+/PR-\t3\t\nER-/PR-\t7\t\nTumor subtype\t\t\nDuctal\t21\t\nLobular\t3\t\nInflammatory–NOS\t2\t\nMedullary\t1\t\nNumber of metastatic sites\t\t\n1\t6\t\n2\t10\t\n≥3\t11\t\nMetastatic sites\t\t\nLung\t6\t\nLiver\t13\t\nBone\t16\t\nNode\t7\t\nSkin\t5\t\nPhase II: toxicity\nOne patient experienced a toxic death at cycle 1, with febrile neutropenia complicated with shock before she was started on G-CSF. With repeated cycles 52% of patients required at least 1 dose reduction of either drug. One patient discontinued therapy for toxicity (sustained grade 3 fatigue). Other toxicities are listed in Table 2.\n\n10.1371/journal.pone.0167906.t002Table 2 Adverse events observed in the 27 patients treated at the recommended dose.\nGRADE\t1\t2\t3\t4\t5\t\nFebrile neutropenia\t\t2 (7%)\t1 (4%)\t\nUncomplicated neutropenia\t5 (18%)\t\t5 (19%)\t10 (37%)\t\t\nFatigue\t13(48%)\t\t5 (19%)\t\t\nHand-foot syndrome\t7 (26%)\t\t3 (11%)\t\t\nDiarrhea\t13 (48%)\t\t1 (4%)\t\t\nRash\t9 (34%)\t\t1 (4%)\t\t\nEnteritis\t\t1 (4%)\t\t\nHypertension\t\t1 (4%)\t\t\nDecrease LVEF\t\t1 (4%)\t\t\nLipase / amylase*\t5 (19%)\t\t2 (7%)\t\t\nBilirubin / GGT*\t3 (11%)\t\t3 (11%)\t\t\nAlopecia\t6 (22%)\t5 (19%)\t\t\nSensorial neuropathy\t5 (19%)\t2 (7%)\t\t\n*Asymptomatic increase\n\nOther adverse events max. grade 1–2, reported in 15–27% of patients:\nasymptomatic AST/ALT increase, asymptomatic ALK increase, mucositis, nausea, vomiting, diffuse pain, abdominal pain, dyspepsia, constipation.\n\nOther adverse events max. grade 1–2, reported in 4–11% of patients:\nthrombocytopenia, anemia, insomnia, depressed mood, weight loss, dyspnea, dysgeusia, increased creatinine, increased uric acid, headache, chills, myalgia, abscess, tinnitus, chest pain, hypothyroidism, dry mucosae, dry skin.\n\nPhase II: efficacy\nBest responses were as follows: 30% partial response, 55% stable disease ≥ 4 cycles, and 15% disease progression (including toxic death). Clinical benefit rate (defined as the absence of disease progression for at least 6 months) was 48%. Median progression-free survival was 5.7 months (95% CI 4.4–7.6) (Fig 2). Median time-to-progression was the same: 5.7 months (95% CI 4.5–8.7).\n\n10.1371/journal.pone.0167906.g002Fig 2 Progression-free survival of the VS combination\nExploratory analysis\nWe noticed a longer PFS in the patients treated in the cohort 1 of the phase I. We then ran an unplanned hypothesis-generating analysis comparing PFS between patients started on treatment at 400 mg bid of sorafenib and maintaining this dose during treatment versus those treated at 200 mg bid from the start or reducing their dose to 200 mg bid within the first 2 cycles.\n\nThere appears to be an advantage associated with the lower dose of sorafenib, with a PFS of 8.7 months in 18 patients treated at the lower dose versus 4.8 months in those treated at full doses of sorafenib (p = 0.002) (Fig 3). Results were similar when considering in the \"200 mg subgroup\" only the patients treated from the start at the lower dose or those requiring dose reduction because of toxicity.\n\n10.1371/journal.pone.0167906.g003Fig 3 Progression-free survival by the dose of the regorafenib\nPharmacokinetics\nOne of the six patients analyzed for PK analyses had to reduce the dose of sorafenib for toxicity after the first cycle, so in her case all PK analyses were re-run for treatment with 200 mg bid of sorafenib.\n\nAs sorafenib intake was every 12 hours, concentration curves for sorafenib and M2 metabolite were truncated at the 7-hour time point, in order to increase the sensitivity in the PK analysis in between doses.\n\nPlasma levels of vinorelbine showed little interpatient variability and were compatible with a triphasic elimination profile, as described in the literature.\n\nPlasma concentrations of sorafenib (Fig 4A) and M2 metabolite (Fig 4B) show noticeable variability across the 6 patients analyzed, here in the presence of vinorelbine. Similar variability was observed also in the absence of vinorelbine (data not shown).\n\n10.1371/journal.pone.0167906.g004Fig 4 A: Plasma concentration of Sorafenib over time. B: Plasma concentration of sorafenib metabolites (M2) over time\n\nTable 3 summarizes mean PK parameters (in all 6 patients) with SD.\n\n10.1371/journal.pone.0167906.t003Table 3 Mean pharmacokinetic parameters in all 6 patients with SD.\n\t\t\tt½ (hr)\tCmax (ng/mL)\t\tAUClast (hr*ng/mL)\t\t\nV\tV alone\tMean\t0.21\t1301\tp = 0.031\t856\tp = 0.219\t\n\tSD\t0.04\t553\t358\t\nV + S\tMean\t0.19\t2039\t1057\t\n\tSD\t0.04\t383\t189\t\nS\tS alone\tMean\t1.67\t9,135\tp = 0.156\t44800\tp = 0.093\t\n\tSD\t1.29\t1624\t3839\t\nS + V\tMean\t2.67\t10,502\t55413\t\n\tSD\t2.04\t3159\t11234\t\nM2\tS alone\tMean\t1.76\t2,224\tp = 0.312\t10662\tp = 0.312\t\n\tSD\t1.18\t988\t4054\t\nS + V\tMean\t3.42\t2,503\t12576\t\n\tSD\t2.69\t1352\t5461\t\nV = vinorelbine S = sorafenib M2 = M2 metabolite p = significance of Wilcoxon signed-rank test\n\nWe observe a significantly higher Cmax of vinorelbine when the drug is administered in the presence of steady-state concentrations of sorafenib (Fig 5). This was clear in 5 out of 6 patients analyzed and found to be statistically significant (both with Wilcoxon signed-rank test and with paired t-test).\n\n10.1371/journal.pone.0167906.g005Fig 5 Mean plasma concentrations of vinorelbine when administered as a single agent (cycle 1 day 1, blue curve) or in the presence of steady-state concentrations of sorafenib (cycle 2 day 1, red curve).\nThere was a marginal significance for an increase of the area under the curve until the last measurable concentration (AUClast) of sorafenib in the presence of vinorelbine.\n\nDiscussion\nAntiangiogenesis therapy for MBC has been the subject of many preclinical and large randomized clinical trials with potentially controversial results. The most widely studied agent is bevacizumab, a humanized monoclonal antibody against VEGF. In a phase III randomized trial, the addition of bevacizumab to paclitaxel significantly improved PFS (median 11.8 vs 5.9 months) and increased overall response rate (ORR 36.9% vs 21.2%), without improving OS (median 26.7 vs 25.2 months) [8]. Additional trials combining bevacizumab with multiple other chemotherapy agents reported very similar results [9,10,11]. A meta-analysis of these trials confirmed that bevacizumab combined with chemotherapy in the first-line treatment of MBC significantly improves ORR and PFS, but at the expense of increased rates of grade 3–4 toxicities, and without any statistically significant OS benefit [12].\n\nAs part of the Trials to Investigate the Efficacy of Sorafenib (TIES) in breast cancer program, sorafenib has been studied with various agents in MBC in four randomized, placebo-controlled, double-blinded trials: a phase IIB of sorafenib in combination with first- or second-line capecitabine in HER2- MBC (SOLTI-0701) that showed a significant improvement in PFS of 6.4 months vs 4.1 months [13], a combination with first line paclitaxel (NU07B1) that showed a PFS of 6.9 months vs 5.6 months [14], a first- or second-line trial in combination with capecitabine or gemcitabine (AC01B07) that showed a PFS of 3.4 months vs 2.7 months [15], and a first line combination with letrozole and/or docetaxel (FM-B07-01) trial that showed PFS of 9.2 months vs. 10.2 months [16]. The SOLTI-0701 trial of sorafenib in combination with capecitabine 1000 mg/m2 14 days of a 21-day cycle is the only trial that reported a statistically significant PFS improvement, without a significant impact on OS (22.2 vs 20.9 months) or overall response (38% vs 31%). To further investigate this combination, a phase III trial of sorafenib in combination with capecitabine (RESILIENCE- NCT01234337) is currently under way.\n\nOur results from this phase I/II trial also fail to report a response rate higher than historical control data matched for line of treatment (first line only), with our reported ORR of 30% in this study being lower than the historical control of 43%. Nevertheless, the PFS observed in this study is still interesting, with a clinical benefit >6 months in 16 of 33 patients (48%). Acting mainly as a cytostatic agent, sorafenib might contribute more to a longer disease control rather than increasing tumor shrinkage. This highlights the challenges involved in exploring combinations with biological agents in small-sized phase 2 trials, in particular for what concerns the selection of the ideal primary endpoint and the importance to also develop pharmacodynamics markers of biological activity.\n\nRecently, another phase I/II trial in MBC reported on the combination of vinorelbine and sorafenib [17]. With 44% patients free of progression at 4 months, authors concluded that the VS regimen did not appear clearly superior to historical data for single-agent vinorelbine, although we would point out that a reliable comparison is almost impossible given that patients were treated in this study in a combination of first-, second- and third-line therapies. Other characteristics of that trial distinguishing it from ours and making its interpretation somehow more complex include the fact that 41% of patients had triple negative disease, and 24% of patients had received bevacizumab as part of previous treatments for MBC.\n\nAnother significant finding in our study is that although the safety analysis after 1 cycle failed to determine a toxic dose level, with repeated cycles about half of the patients required at least one dose reduction of either drug. In most cases this was done to optimize treatment tolerability in the absence of life-threatening toxicities, although we also observed one case of fatal febrile neutropenia. Unexpected low-grade toxicity included a significant portion of patients with grade 1–2 hair loss, which is usually not observed when either drug is used as a single agent.\n\nWe believe that part of these findings derive from the significant pharmacokinetic interaction between sorafenib and vinorelbine that we observed, resulting in a marginally significant increase of AUClast of sorafenib and more importantly a statistically significant increase in Cmax of vinorelbine when the two drugs are combined. Considering all of the above, a reasonable option to pursue development of the VS combination in clinical practice with better tolerability would be to start therapy with sorafenib at 200 mg bid and full doses of vinorelbine, considering a gradual dose increase to full doses for those patients in which no grade 2–3 toxicity is observed. It is somehow reassuring that we observed no detrimental effect for patients receiving sorafenib at the reduced dose of 200 mg bid.\n\nConclusion\nCombining sorafenib and vinorelbine at full doses is feasible, but not devoid of toxicity for repeated cycles, most likely due to a significant PK interaction. Prolonged disease control is observed also with a reduced dose of sorafenib. This combination should be only pursued if valid pharmacodynamics biomarkers or predictive biomarkers become available.\n\nSupporting Information\nS1 File Nexavar Protocol.\n(PDF)\n\nClick here for additional data file.\n\n S2 File TREND Statement\n(PDF)\n\nClick here for additional data file.\n\n We would like to thank the McGill Department of Oncology for their help in publishing this article.\n==== Refs\nReferences\n1 Mano M . Vinorelbine in the management of breast cancer: New perspectives, revived role in the era of targeted therapy . Cancer treatment reviews . 2006 ;32 (2 ):106 –18 . Epub 2006/02/14. 10.1016/j.ctrv.2005.12.008 \n16473470 \n2 Wilhelm SM , Carter C , Tang L , Wilkie D , McNabola A , Rong H , et al\nBAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis . Cancer research . 2004 ;64 (19 ):7099 –109 . Epub 2004/10/07. 10.1158/0008-5472.CAN-04-1443 \n15466206 \n3 Hilger RA , Scheulen ME , Strumberg D . The Ras-Raf-MEK-ERK pathway in the treatment of cancer . Onkologie . 2002 ;25 (6 ):511 –8 . 12566895 \n4 Wilhelm SM , Adnane L , Newell P , Villanueva A , Llovet JM , Lynch M . Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling . Molecular cancer therapeutics . 2008 ;7 (10 ):3129 –40 . Epub 2008/10/15. 10.1158/1535-7163.MCT-08-0013 \n18852116 \n5 Carter CA , Chen C , Brink C , Vincent P , Maxuitenko YY , Gilbert KS , et al\nSorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma . Cancer chemotherapy and pharmacology . 2007 ;59 (2 ):183 –95 . 10.1007/s00280-006-0257-y \n16724239 \n6 Moreno-Aspitia A , Morton RF , Hillman DW , Lingle WL , Rowland KM Jr., Wiesenfeld M , et al\nPhase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336 . J Clin Oncol . 2009 ;27 (1 ):11 –5 . Epub 2008/12/03. PubMed Central PMCID: PMCPMC2645094. 10.1200/JCO.2007.15.5242 \n19047293 \n7 Bianchi G , Loibl S , Zamagni C , Salvagni S , Raab G , Siena S , et al\nPhase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer . Anti-cancer drugs . 2009 ;20 (7 ):616 –24 . Epub 2009/09/10. 19739318 \n8 Miller K , Wang M , Gralow J , Dickler M , Cobleigh M , Perez EA , et al\nPaclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer . N Engl J Med . 2007 ;357 (26 ):2666 –76 . 10.1056/NEJMoa072113 \n18160686 \n9 Robert NJ , Dieras V , Glaspy J , Brufsky AM , Bondarenko I , Lipatov ON , et al\nRIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer . J Clin Oncol . 2011 ;29 (10 ):1252 –60 . 10.1200/JCO.2010.28.0982 \n21383283 \n10 Brufsky AM , Hurvitz S , Perez E , Swamy R , Valero V , O'Neill V , et al\nRIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer . J Clin Oncol . 2011 ;29 (32 ):4286 –93 . Epub 2011/10/13. 10.1200/JCO.2010.34.1255 \n21990397 \n11 Miller KD , Chap LI , Holmes FA , Cobleigh MA , Marcom PK , Fehrenbacher L , et al\nRandomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer . J Clin Oncol . 2005 ;23 (4 ):792 –9 . Epub 2005/02/01. 10.1200/JCO.2005.05.098 \n15681523 \n12 Rossari JR , Metzger-Filho O , Paesmans M , Saini KS , Gennari A , de Azambuja E , et al\nBevacizumab and Breast Cancer: A Meta-Analysis of First-Line Phase III Studies and a Critical Reappraisal of Available Evidence . Journal of oncology . 2012 ;2012 :417673 PubMed Central PMCID: PMCPMC3447373. 10.1155/2012/417673 \n23008712 \n13 Baselga J , Segalla JG , Roche H , Del Giglio A , Pinczowski H , Ciruelos EM , et al\nSorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer . J Clin Oncol . 2012 ;30 (13 ):1484 –91 . Epub 2012/03/14. 10.1200/JCO.2011.36.7771 \n22412143 \n14 Gradishar WJ , Kaklamani V , Sahoo TP , Lokanatha D , Raina V , Bondarde S , et al\nA double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer . European journal of cancer (Oxford, England: 1990) . 2013 ;49 (2 ):312 –22 . Epub 2012/09/08.\n15 Schwartzberg LS , Tauer KW , Hermann RC , Makari-Judson G , Isaacs C , Beck JT , et al\nSorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab . Clinical cancer research: an official journal of the American Association for Cancer Research . 2013 ;19 (10 ):2745 –54 . Epub 2013/02/28.23444220 \n16 Mariani G BO , Roman L , et al\nA double-blind, randomized phase IIb study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with docetaxel and/or letrozole in patients with metastatic breast cancer (MBC): FM-B07e01 trial . Eur J Cancer . 2011 ; 47 (suppl 2 ):10 (abstract).\n17 Luu T , Frankel P , Chung C , Chow W , Mortimer J , Hurria A , et al\nPhase I/II trial of vinorelbine and sorafenib in metastatic breast cancer . Clinical breast cancer . 2014 ;14 (2 ):94 –100 . Epub 2013/12/29. 10.1016/j.clbc.2013.10.013 \n24370210\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(12)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "101285081",
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"pages": "e0167906",
"pmc": null,
"pmid": "27992451",
"pubdate": "2016",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "15466206;15681523;16724239;22412143;24370210;23008712;19047293;19739318;18852116;18160686;16473470;22954665;23444220;21990397;12566895;21383283",
"title": "Phase I/II Trial of Sorafenib in Combination with Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer.",
"title_normalized": "phase i ii trial of sorafenib in combination with vinorelbine as first line chemotherapy for metastatic breast cancer"
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"companynumb": "CA-BAYER-2017-000381",
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{
"abstract": "A 56-year-old man diagnosed with non-Hodgkin's lymphoma underwent autologous bone marrow transplantation. He was subsequently admitted to the hospital with fever, and his symptoms were initially controlled by multiple antibiotics, including tigecycline. He then developed a generalized body rash that improved after treatment with anti-allergy drugs and steroids. Furthermore, tigecycline treatment for a second time resulted in a severe skin reaction with systemic symptoms, suggesting toxic epidermal necrolysis syndrome (TEN). The patient was shown to have the slow-metabolizing cytochrome P450 2C19 allele, denoted CYP2C19*2. He was transferred to a laminar flow ward and given strict mucosal care, together with corticosteroids and intravenous immunoglobulin. He recovered after 3 weeks of treatment. Tigecycline-induced Stevens-Johnson syndrome (SJS)/TEN has rarely been reported in the Chinese population. However, our experience suggests that Asians are more likely to have adverse reactions to drugs metabolized by the cytochrome P450 enzyme. Early identification of drug reactions and immediate cessation of the suspected drug is essential. Additionally, a combined therapy scheme and a clean laminar flow environment may improve the cure rate of SJS/TEN.",
"affiliations": "Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.;Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.;Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.;Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.;Department of Neurosurgery, Shaanxi Provincial Rehabilitation Hospital, Xi'an, Shaanxi, P.R. China.;Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.;Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.",
"authors": "Yang|Jiahui|J|;Wu|Fangli|F|;Luo|Dan|D|;Li|Miaojing|M|;Gou|Xinming|X|;Xi|Jieying|J|;Zhu|Huachao|H|https://orcid.org/0000-0003-0941-2418",
"chemical_list": "D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D000078304:Tigecycline; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19",
"country": "England",
"delete": false,
"doi": "10.1177/0300060520922416",
"fulltext": "\n==== Front\nJ Int Med Res\nJ. Int. Med. Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520922416\n10.1177_0300060520922416\nCase Report\nToxic epidermal necrolysis syndrome induced by tigecycline: a case report\nYang Jiahui 1 Wu Fangli 1 Luo Dan 2 Li Miaojing 3 Gou Xinming 4 Xi Jieying 3 https://orcid.org/0000-0003-0941-2418Zhu Huachao 3 \n1 Department of Gastroenterology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China\n\n2 Department of Geriatrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China\n\n3 Department of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China\n\n4 Department of Neurosurgery, Shaanxi Provincial Rehabilitation Hospital, Xi’an, Shaanxi, P.R. China\nHuachao Zhu, Department of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an, Shaanxi 710061, P.R. China. Email: zhuhuachao@163.com\n13 5 2020 \n5 2020 \n48 5 030006052092241625 10 2019 7 4 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 56-year-old man diagnosed with non-Hodgkin’s lymphoma underwent autologous bone marrow transplantation. He was subsequently admitted to the hospital with fever, and his symptoms were initially controlled by multiple antibiotics, including tigecycline. He then developed a generalized body rash that improved after treatment with anti-allergy drugs and steroids. Furthermore, tigecycline treatment for a second time resulted in a severe skin reaction with systemic symptoms, suggesting toxic epidermal necrolysis syndrome (TEN). The patient was shown to have the slow-metabolizing cytochrome P450 2C19 allele, denoted CYP2C19*2. He was transferred to a laminar flow ward and given strict mucosal care, together with corticosteroids and intravenous immunoglobulin. He recovered after 3 weeks of treatment. Tigecycline-induced Stevens–Johnson syndrome (SJS)/TEN has rarely been reported in the Chinese population. However, our experience suggests that Asians are more likely to have adverse reactions to drugs metabolized by the cytochrome P450 enzyme. Early identification of drug reactions and immediate cessation of the suspected drug is essential. Additionally, a combined therapy scheme and a clean laminar flow environment may improve the cure rate of SJS/TEN.\n\nAdverse eventStevens–Johnson syndrometoxic epidermal necrolysistigecyclineCYP2C19skin rashedited-statecorrected-prooftypesetterts2\n==== Body\nIntroduction\nStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse reactions (SCARs) associated with high mortality. SJS and TEN represent different stages of the same disease characterized by blistering lesions and epithelial detachment. Many drugs have been reported to cause these conditions.1 Tigecycline is a broad-spectrum glycylcycline antibiotic that is widely used because of its satisfactory antibacterial activity against multidrug-resistant bacteria.2 However, tigecycline has been associated with several adverse events. Here, we present a case of tigecycline-induced TEN syndrome in a patient with diffuse large B-cell lymphoma (DLBCL) who underwent autologous stem cell transplantation (ASCT).\n\nCase report\nA 56-year-old male patient was admitted to the hospital with primary central nervous system malignant lymphoma. The pathology was DLBCL. He underwent excision of the primary lesion and six phases of chemotherapy. Autologous hematopoietic stem cells were collected between the 3rd and 4th chemotherapy phases and he underwent ASCT approximately 33 days after completion of the above treatment. He was then discharged with successful hematopoietic reconstitution. However, on the 18th day after transplantation, he developed a fever without shivering or chills and was admitted to hospital. Routine blood test results were almost normal, but his procalcitonin was increased to 4.55 ng/mL, and serum albumin was decreased to 24.5 g/L. Other laboratory tests were normal, including negative findings for mycoplasma IgM and herpes simplex virus IgM.\n\nThe patient’s cellular and particularly their humoral immune functions failed to recover within 2 months after ASCT. Additionally, empiric antibiotic therapy is the best choice for serious infections with no definite etiology or drug-sensitivity results. We therefore initiated a comprehensive anti-infective regimen consisting of sulperazone, teicoplanin, voriconazole, and ganciclovir. However, the patient’s fever persisted after 5 days of active treatment. Teicoplanin was replaced with tigecycline (50 mg every 12 hours by intravenous drip) because of suspected drug-resistant bacterial infection. The patient’s temperature rapidly normalized after starting the new therapy, but he developed widespread erythema within 72 hours after the change in the treatment scheme (Figure 1a). Based on the opinion of a dermatologist, the patient was diagnosed with a drug allergy, and all potentially responsible drugs were stopped immediately. Prednisone, loratadine, and calamine were given to control the rash. There was no new erythema and the skin lesions darkened. The patient was finally discharged after his temperature had remained normal for 1 week. He continued to take oral prednisone at a dose of 20 mg/day.\n\nThe patient experienced fever again with cough and phlegm on the 7th post-discharge day, with a peak temperature of 39.1°C. The results of etiological examinations were similar to the previous examinations, and similar therapy, including tigecycline at the same dose, was given to control his temperature. However, the erythematous rash unexpectedly covered up to 95% of his body surface area during the following 12 hours. Skin detachment occurred over most of the body, with minimal shearing forces causing the epidermis to peel back (with a positive Nikolsky sign) (Figure 1b). Skin biopsy from a lesion on the abdomen showed superficial and deep perivascular infiltrates of lymphocytes and histiocytes, in accordance with inflammatory changes (Figure 2). The patient was diagnosed with toxic epidermal necrolysis (TEN) syndrome. There was no evidence of any related drug–drug interactions, and notably, some drugs, including sulperazone, teicoplanin, voriconazole, and ganciclovir, had been used multiple times in previous treatment schemes with no adverse cutaneous reactions. After reviewing the patient’s treatment history and calculating the ALDEN scores (an algorithm for assessment of drug causality in SJS and TEN) for all the related drugs, tigecycline was suspected to be the responsible drug, with a high score suggesting that its involvement was “very probable” (Table 1).3 The patient subsequently experienced ocular inflammation and involvement of the mucous membranes of the mouth and genitalia (Figure 1c). He was transferred to the laminar flow ward to reduce the risk of infection and provided with comprehensive strict mucosal care. Calamine lotion, Vaseline, and ethacridine were applied to protect the skin surface and prevent skin infection. Injected corticosteroids (methylprednisolone, 40 mg/day) and intravenous immunoglobulin (20 g/day) were administered. The patient underwent whole-body excoriation and skin integrity was maintained, except for epidermal discoloration (Figure 3). He was finally discharged after 3 weeks, with a favorable prognosis. We analyzed the patient’s cytochrome P450 (CYP) 2C19 status and showed the presence of the slow-metabolizing allele, CYPC219*2.\n\nFigure 1. (a) Rashes before the second antibiotic treatment; (b) multiple central necrosis and flaccid bullae on the lower limbs with positive Nikolsky signs; (c) mucosal damage to the eyes.\n\nTable 1. Drugs potentially responsible for SJS/TEN according to ALDEN score.\n\nDrug\tTigecycline\tVoriconazole\tGanciclovir\tTeicoplanin\tSulperazone\tPrednisone\t\nTreatment period (days)\t4\t31\t29\t22\t30\t30\t\nFinal score*\t7\t2\t1\t2\t4\t1\t\n*Final score <0, very unlikely; 0–1, unlikely; 2–3, possible; 4–5, probable; ≥6, very probable.\n\nFigure 2. Histopathology of skin biopsy showing epidermal mild hyperplasia and superficial and deep perivascular infiltrates of lymphocytes and histiocytes (hematoxylin and eosin; a, ×10; b, ×40).\n\nFigure 3. Skin integrity following epidermal necrosis and exfoliation was maintained by combined therapy.\n\nCase reports do not need to be approved by a review board. The patient described in this report provided informed consent for the use of his data.\n\nDiscussion\nSJS and TEN are rare drug reactions, with an incidence of approximately one to two cases per million per year. However, affected patients might experience significant mortality, according to the TEN-specific severity of illness score (SCORTEN) system.4 This validated prognostic system was established to predict individual prognosis based on several important clinical factors, including age, malignancy, tachycardia, and epidermal-detachment area, together with the results of some relevant laboratory tests, such as serum urea, glucose, and bicarbonate levels.4 The characteristics of SJS/TEN are widespread epithelial necrosis caused by drug-induced cytotoxic T lymphocytes. SJS is typically diagnosed when <10% of the skin surface is involved, TEN is characterized by >30% involvement, and SJS/TEN overlap is defined as 10% to 30% skin detachment.5 The SCORTEN score in the current patient was 3, with an approximately 32% probability of death, and he was diagnosed with TEN because more than 30% of his body was covered by the skin lesions. However, direct immunofluorescence to exclude autoimmune bullous disorders was not performed in this case. Nevertheless, SJS/TEN is often induced by some kinds of drugs, such as allopurinol, carbamazepine, and non-steroidal anti-inflammatory drugs, and early identification of the culprit drug is critical to prevent progression of the disease.2\n\nA correlation between human leucocyte antigen (HLA) and SJS/TEN has recently been identified, and the incidence of this adverse event was found to be reduced in individuals of certain ethnicities. A previous study reported that patients of Southeast Asian descent carrying the HLA-B*1502 allele were at increased risk of SJS/TEN caused by some antiepileptic drugs, such as carbamazepine and phenytoin.6 Moreover, SJS/TEN might be associated with the HLA-B*5701 allele in patients receiving abacavir, and with the HLA-B*5801 allele in patients using allopurinol.7 Genetic polymorphisms of cytochrome P450 have also been proposed to be involved in the predisposition to drug-related SCARs. CYP2C9*3, encoded by the CYP2C9*3 mutant allele, might be an independent predictor of the risk of phenytoin-induced SJS/TEN based on several studies in Asia.8 Similarly, CYP2C9*2 was suggested to be related to phenobarbital-induced skin reaction syndrome.9 In the current case, we identified the CYP2C19*2/*3 polymorphism in the patient, indicating poor metabolism of relevant drugs.\n\nTigecycline is a broad-spectrum antibiotic that belongs to the glycylcycline family, with activity against a wide range of Gram-positive and Gram-negative bacterial families.10 Kadoyama et al. analyzed 248 tigecycline-associated spontaneous adverse event reports submitted to the U.S. Food and Drug Administration from 2004 to 2009, and noted that SJS/TEN was rare, but had been reported as a related adverse drug reaction.11 However, there have been few reports of SCARs in the Chinese population. Tigecycline was not metabolized by CYP enzymes according to the results of in vitro studies,12 suggesting a weak relationship between CYP polymorphisms and tigecycline-induced TEN. However, it is possible that there may be some complex and important correlations between tigecycline and drug metabolic pathways.13\n\nComprehensive management and treatment is recommended for SJS/TEN because of the severe and multisystemic injuries to the skin and membranes. Management involves careful and aseptic skin handling, similar to that for burn care, as well as strict fluid balance and nutritional support. Some mucosal protection of related systems, including ocular and gastrointestinal care, is also important, together with temperature management, pain control, and monitoring/treatment of super-infections. Furthermore, considering potential immune system involvement, immunomodulatory therapies, including corticosteroids, cyclosporine, tumor necrosis factor inhibitors, intravenous immunoglobulins, plasmapheresis, and hemoperfusion, have also been used in individual cases of SJS/TEN, but with insufficient evidence to support their use.2 In the current case, the patient recovered after transfer to a laminar flow ward and systemic treatment, suggesting that a clean laminar flow environment may help to prevent infections and improve the prognosis.\n\nImmediate cessation of the suspected drug is essential for all treatments. This was not performed in the current case, and it is possible that TEN could have been prevented if the culprit drug had been identified and discontinued sooner. In patients with a previous history of drug allergies, drugs with similar structures should be avoided. Furthermore, drugs associated with a high risk of inducing SJS/TEN should be monitored carefully during the medication period. For patients with a previous history of a rash or epidermal necrolysis, anti-infection schemes must be chosen cautiously according to the source of the infection and pathogens present in the patient. It is essential to check the drug instructions, and to consult reviews and pharmacovigilance databases, such as the Food and Drug Administration Adverse Event Reporting System (FAERS),14 to identify possible risks.\n\nWe report a rare case of SJS/TEN induced by tigecycline in a Chinese patient. Asians might be more likely to have adverse skin reactions because of genetic polymorphisms of cytochrome P450; however, further studies are needed to clarify this correlation. Use of a laminar flow environment and strict skin and mucosa care might improve the prognosis of patients with SJS/TEN. This case highlights the need to pay close attention to the use of drugs likely to cause this condition.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD\nHuachao Zhu https://orcid.org/0000-0003-0941-2418\n==== Refs\nReferences\n1 Schwartz RA Mcdonough PH Lee BW. \nToxic epidermal necrolysis: part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment.\n\nJ Am Acad Dermatol \n2013 ; \n69 : 187.e1 –e16\n.\n2 Nicolau DP. \nManagement of complicated infections in the era of antimicrobial resistance: the role of tigecycline.\n\nExpert Opin Pharmacother \n2009 ; \n10 : 1213 –1222\n.19405794 \n3 Sassolas B Haddad C Mockenhaupt M , et al\nALDEN, an algorithm for assessment of drug causality in Stevens–Johnson syndrome and toxic epidermal necrolysis: comparison with case–control analysis\n. Clin Pharmacol Ther \n88 : 60 –68\n.20375998 \n4 Bastuji-Garin S Fouchard N Bertocchi M , et al\nSCORTEN: a severity-of-illness score for toxic epidermal necrolysis.\n\nJ Invest Dermatol \n2000 ; \n115 : 149 –153\n.10951229 \n5 Bastuji-Garin S Rzany B Stern RS , et al\nClinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme\n. Arch Dermatol \n1993 ; \n129 : 92 –96\n.8420497 \n6 Nguyen DV Chu HC Nguyen DV , et al\nHLA-B * 1502 and carbamazepine-induced severe cutaneous adverse drug reactions in Vietnamese\n. Asia Pac Allergy \n2015 ; \n5 : 68 –77\n.25938071 \n7 Caudle KE Rettie AE Whirl-Carrillo M , et al\nClinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing.\n\nClin Pharmacol Ther \n2014 ; \n96 : 542 –548\n.25099164 \n8 Chung WH Chang WC Lee YS , et al\nGenetic variants associated with phenytoin-related severe cutaneous adverse reactions\n. JAMA \n2014 ; \n312 : 525 –534\n.25096692 \n9 Laska AJ Han MJ Lospinoso JA , et al\nCYP2C19*2 status in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.\n\nPharmgenomics Pers Med \n2017 ; \n10 : 183 –186\n.28553132 \n10 Slover CM Rodvold KA Danziger LH. \nTigecycline: a novel broad-spectrum antimicrobial.\n\nAnn Pharmacother \n2007 ; \n41 : 965 –972\n.17519296 \n11 Kadoyama K Sakaeda T Tamon A , et al\nAdverse event profile of tigecycline: data mining of the public version of the U.S. Food and Drug Administration adverse event reporting system.\n\nBiol Pharm Bull \n2012 ; \n35 : 967 –970\n.22687540 \n12 Livermore DM. \nTigecycline: what is it, and where should it be used?\n\nJ Antimicrob Chemother \n2005 ; \n56 : 611 –614\n.16120626 \n13 Wallace RJ JrBrown-Elliott BA Crist CJ , et al\nComparison of the in vitro activity of the glycylcycline tigecycline (formerly GAR-936) with those of tetracycline, minocycline, and doxycycline against isolates of nontuberculous mycobacteria\n. Antimicrob Agents Chemother \n2002 ; \n46 : 3164 –3167\n.12234839 \n14 Lin YF Yang CH Sindy H , et al\nSevere cutaneous adverse reactions related to systemic antibiotics.\n\nClin Infect Dis \n2014 ; \n58 : 1377 –1385\n.24599767\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "48(5)",
"journal": "The Journal of international medical research",
"keywords": "Adverse event; CYP2C19; Stevens–Johnson syndrome; skin rash; tigecycline; toxic epidermal necrolysis",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000483:Alleles; D001424:Bacterial Infections; D001706:Biopsy; D065731:Cytochrome P-450 CYP2C19; D005938:Glucocorticoids; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D012867:Skin; D013262:Stevens-Johnson Syndrome; D000078304:Tigecycline; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "300060520922416",
"pmc": null,
"pmid": "32400243",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20375998;25938071;24599767;28553132;25099164;8420497;23866879;22687540;10951229;19405794;16120626;25096692;12234839;17519296",
"title": "Toxic epidermal necrolysis syndrome induced by tigecycline: a case report.",
"title_normalized": "toxic epidermal necrolysis syndrome induced by tigecycline a case report"
} | [
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"companynumb": "CN-CHEPLA-C20201812",
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"activesubstancename": "TEICOPLANIN"
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{
"abstract": "OBJECTIVE\nTo present the first case of acute macular edema with serous retinal detachment after cataract surgery in a vitrectomized eye.\n\n\nMETHODS\nA 63-year-old female patient, with history of pars plana vitrectomy and epiretinal membrane removal, underwent uneventful phacoemulsification surgery with injection of standard intracameral dose of cefuroxime (1 mg/0.1 mL of solution) at the end of the procedure.\n\n\nRESULTS\nFirst day after cataract surgery, visual acuity did not correlate with anterior segment findings, and funduscopic eye examination revealed acute macular edema with serous retinal detachment, which was confirmed by spectral domain optical coherence tomography. Fluorescein angiography showed no retinal or choroidal hyperpermeability. At 2-week follow-up visit, visual acuity had significantly improved, and there was complete resolution of macular edema and subretinal fluid.\n\n\nCONCLUSIONS\nThe current case suggests that acute macular edema with serous retinal detachment after cataract surgery with standard cefuroxime prophylaxis can occur even in vitrectomized eyes. A high level of suspicious is needed when visual acuity does not correlate with anterior segment findings immediately after cataract surgery. Similar to reports from nonvitrectomized eyes, visual prognosis was favorable.",
"affiliations": "Barrett, The Honors College at Arizona State University, Tempe, Arizona.;Associated Retina Consultants, Phoenix, Arizona; and.;Arizona Eye Specialists, Phoenix, Arizona.;Barrett, The Honors College at Arizona State University, Tempe, Arizona.",
"authors": "Bryan|Eric A|EA|;Cruz-Iñigo|Yousef J|YJ|;Brems|Robert N|RN|;Bryan|J Shepard|JS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000884",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "15(6)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "745-748",
"pmc": null,
"pmid": "31274848",
"pubdate": "2021-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ACUTE MACULAR EDEMA WITH SEROUS RETINAL DETACHMENT AFTER CATARACT SURGERY IN A VITRECTOMIZED EYE: A CASE REPORT.",
"title_normalized": "acute macular edema with serous retinal detachment after cataract surgery in a vitrectomized eye a case report"
} | [
{
"companynumb": "US-MLMSERVICE-20190730-1875005-1",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "CEFUROXIME"
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... |
{
"abstract": "To determine the efficacy and safety of intravenous tocilizumab in refractory juvenile idiopathic arthritis associated uveitis.\nThis was a retrospective observational case series. Patients with refractory juvenile idiopathic arthritis associated uveitis, who had received tocilizumab were included in this study.\n8 patients (14 eyes) were included in this study. The average age of the patients at the first visit was 16.8 ± 11.2 years (7-40). The average duration of follow-up period after starting treatment was 28.6 ± 24.6 months (9-70). Intravenous tocilizumab infusions induced and maintained remission in 5 patients (8 eyes). Vasculitis was resolved within 8 months in all but one patient. The presence of papillitis before starting treatment was directly correlated with visual acuity improvement. No side effects were observed.\nIntravenous tocilizumab infusion can be an effective and safe method of treatment to induce and maintain remission in resistant juvenile idiopathic arthritis associated uveitis.",
"affiliations": "Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA.;Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA.;Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA.",
"authors": "Maleki|Arash|A|;Manhapra|Ambika|A|;Asgari|Soheila|S|;Chang|Peter Y|PY|;Foster|C Stephen|CS|;Anesi|Stephen D|SD|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1817501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "29(1)",
"journal": "Ocular immunology and inflammation",
"keywords": "Biologic response modifiers; immunomodulatory therapy; juvenile idiopathic arthritis; tocilizumab",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001171:Arthritis, Juvenile; D006801:Humans; D007262:Infusions, Intravenous; D014605:Uveitis; D014792:Visual Acuity",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "14-20",
"pmc": null,
"pmid": "33021415",
"pubdate": "2021-01-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Tocilizumab Employment in the Treatment of Resistant Juvenile Idiopathic Arthritis Associated Uveitis.",
"title_normalized": "tocilizumab employment in the treatment of resistant juvenile idiopathic arthritis associated uveitis"
} | [
{
"companynumb": "US-UCBSA-2021026814",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB PEGOL"
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... |
{
"abstract": "BACKGROUND\nRiluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events.\n\n\nMETHODS\nPatients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded.\n\n\nRESULTS\nA total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment.\n\n\nCONCLUSIONS\nRiluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.",
"affiliations": "Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. aokim@med.tohoku.ac.jp.",
"authors": "Inoue-Shibui|Aya|A|;Kato|Masaaki|M|;Suzuki|Naoki|N|;Kobayashi|Junpei|J|;Takai|Yoshiki|Y|;Izumi|Rumiko|R|;Kawauchi|Yuuko|Y|;Kuroda|Hiroshi|H|;Warita|Hitoshi|H|;Aoki|Masashi|M|",
"chemical_list": "D018696:Neuroprotective Agents; D019782:Riluzole",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-019-1299-1",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 129910.1186/s12883-019-1299-1Research ArticleInterstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study Inoue-Shibui Aya ayashibui@med.tohoku.ac.jp Kato Masaaki katom@mui.biglobe.ne.jp Suzuki Naoki naoki@med.tohoku.ac.jp Kobayashi Junpei jkobayashi@med.tohoku.ac.jp Takai Yoshiki y-takai@med.tohoku.ac.jp Izumi Rumiko zumiko@med.tohoku.ac.jp Kawauchi Yuuko yuuko.kawauchi.c5@tohoku.ac.jp Kuroda Hiroshi dakuro@med.tohoku.ac.jp Warita Hitoshi warita-ns@umin.net Aoki Masashi +81-22-717-7189aokim@med.tohoku.ac.jp 0000 0001 2248 6943grid.69566.3aDepartment of Neurology, Tohoku University Graduate School of Medicine Japan, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574 Japan 27 4 2019 27 4 2019 2019 19 7229 9 2018 11 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nRiluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events.\n\nMethods\nPatients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded.\n\nResults\nA total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment.\n\nConclusion\nRiluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.\n\nKeywords\nAmyotrophic lateral sclerosisInterstitial pneumoniaRiluzoleLiver dysfunctionAdverse eventsSide-effectissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, primarily affecting upper and lower motor neurons. Glutamate excitotoxicity, which leads to neural damage, is one of the causative mechanisms [18]. Riluzole, the only approved oral drug for ALS, is a presynaptic glutamate release inhibitor, which may prevent neural damage and delay muscle-strength deterioration. Moreover, it decreases peak sodium (Na+) current and mediates voltage-gated Na + channel inactivation, which inhibit persistent Na + current in motor neurons, decreasing neuronal excitability and leading to neural protection [1, 18]. Although riluzole was well tolerated by and increased survival of ALS patients [4, 15], whether the survival benefit is elicited at the early or late stage or throughout the course of the disease remains controversial [7, 8, 14]. In terms of adverse events due to riluzole, few reports have focused on summative assessment [3, 4, 7, 8, 10, 15]. Effects of riluzole on the overall quality of life (QOL) of patients remain unknown. To investigate potential adverse events during riluzole treatment and to establish strategies to prevent or manage such events, we performed a retrospective study of ALS patients treated with riluzole, focusing on cases of withdrawal.\n\nMethods\nThe study was submitted to and approved by the Ethics Committee of Tohoku University Graduate School of Medicine (2010–253, 2017–1-005). Consent to participate was directly provided by patients or their families.\n\nPatients diagnosed with ALS (clinically definite, clinically probable, clinically probable-laboratory supported, or clinically possible) according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at 6 six months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses before and after riluzole administration, and medical events and histories were recorded. When alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were > 3× the upper limit of the normal level [2, 12] and accompanied by additional subjective symptoms, such as anorexia, nausea, or dizziness, liver dysfunction was considered and riluzole was discontinued. In addition, in cases of withdrawal, causes of discontinuation and durations of disease and drug administration were recorded. Wald chi-square and t-test were used for data analysis. P < 0.05 was considered significant.\n\nResults\nIn total, 92 cases were followed up for a median of 15.5 months [interquartile range (IQR), 9–22 months]. Median patient age was 64.5 and 62.5 years in discontinuation and continuation cases, respectively (P = 0.35). The initial symptom was muscle weakness in almost all cases (discontinuation: 19/20; continuation 70/72), and cervical area was the most common site of symptoms (discontinuation: 9/20; discontinuation, 23/72; P = 0.5). Frequency of ALS/frontotemporal dementia was 20% (4/20) in the discontinuation cases (P = 0.77) and 12.5% (10/72) in the continuation cases. No patient characteristics were significantly associated with drug discontinuation (Table 1).Table 1 Profiles of the ALS cases examined in this study\n\n\tDiscontinued\tContinued\tP value\t\nn\t20\t72\t\t\nSex (male, n, %)\t12, 60\t34, 47.2\t0.31\t\nAge (Median, IQR, years old)\t64.5 (58.3–72.8)\t62.5 (56.5–69.3)\t0.35\t\nInitial symptom, n\tMuscle weakness: 19\tMuscle weakness: 70\t\t\nMuscle cramp: 1\tMuscle cramp: 1\t\t\n\tFTD: 1\t\t\nOnset site of weakness (n, %)\tB: 5, 25.0\tB: 23, 31.9\t0.4\t\nC: 9, 45.0\tC: 23, 31.9\t0.5\t\nT: 0, 0\tT: 2, 2.8\t0.5\t\nL:6, 30.0\tL: 22, 30.6\t0.63\t\nFTD (n, %)\t5, 20\t10, 12.5\t0.77\t\nB bulbar, C cervical, FTD Frontotemporal dementia, L lumbar, T: thoracic, P values are obtained by the Wald chi-square test, based on the null hypothesis that the characteristic contributes to the discontinuation more than the other reasons in the discontinued group. P value of age is obtained by t-test, compared discontinued group with continued group\n\nNo patient characteristics were significantly associated with drug discontinuation\n\n\n\nThe most frequent cause of discontinuation was elevation of liver enzymes (n = 5/92, 5.4%) followed by interstitial pneumonia (IP), nausea or appetite loss, dizziness, general malaise, tongue paresthesia, or urinary urgency. In two cases, the drug was discontinued because of progression of bulbar palsy. Median disease duration was 2 years (IQR, 1–3; range, 0–20). All adverse events occurred within 6 months of riluzole initiation, with half of the events occurring within 14 days (Tables 2 and 3). Median duration of drug administration in continuation cases was 15.5 months (IQR, 9–22 months), with the longest duration of 4 years (Data not shown).Table 2 Characteristics of the discontinued cases\n\nNo.\tSex\tOnset\tDementia\tDisease type\tThe reason of discontinuation of riluzole\tDuration from the beginning of riluzole (days)\tDuration of ALS at withdrawing riluzole (years)\tPast histories\t\nAge, site\t\n1\tM\t60, L\t–\tALS\tNausea\t0–3\t3\tBPH, Depressive status, HT\t\n2\tM\t77, C\t–\tALS\tIP\t60\t1\tPast smoker, HT\t\n3\tF\t75, B\t–\tALS\tProgression of bulbar palsy\t\t3\tDiabetes\t\n4\tF\t64, C\t+\tALS/FTD\tAppetite loss\t0–3\t5\t\t\n5\tM\t77, C\t+\tALS/FTD\tUrinary urgency\t0–3\t2\tOMI, Chronic gastritis\t\n6\tM\t53, C\t–\tALS\tProgression of bulbar palsy\t\t3\t\t\n7\tM\t63, B\t–\tALS\tRefusal\t\t1\tVentricular aneurism, HT\t\n8\tM\t75, L\t–\tALS\tDizziness\t90–120\t20\tEmphysema, BA, HT, CAVB\t\n9\tF\t72, B\t+\tALS/FTD\tIP\t150\t1\tHT, HL\t\n10\tF\t67, L\t–\tALS\tGeneral malaise\t90\t3\tnone\t\n11\tF\t43, L\t–\tALS\tChlamydia pneumonia s/o, IP n/r/o\t14\t4\tnone\t\n12\tM\t53, L\t–\tALS\tParesthesia of tongue\t180\t1\tPsoriasis vulgaris\t\n13\tM\t54, L\t–\tALS\tElevated liver enzymes\t3\t2\tDiabetes, HL\t\n14\tM\t56, B\t–\tALS\tElevated liver enzymes / dizziness\t14\t1\tReflux esophagitis, Heavy drinker\t\n15\tF\t63, C\t–\tALS\tDizziness\t4\t2\tnone\t\n16\tF\t67, C\t–\tALS\tElevated liver enzymes / General malais\t30\t5\tHL\t\n17\tF\t78, B\t+\tALS/FTD\tAppetite loss\t9\t1\tHT, HL, Depressive status\t\n18\tM\t68, C\t–\tALS\tElevated liver enzymes\t2–14\t1\tDiabetes, HT\t\n19\tM\t65, C\t–\tALS\tElevated liver enzymes / dizziness\t0–14\t1\tDiabetes, HL\t\n20\tM\t59, C\t–\tALS\tIP\t60\t2\tPast smoker, HT\t\nBA bronchial asthma, BPH Benign prostatic hyperplasia, CAVB complete arterial-ventricular block, F: female, HT Hypertension, HL Hyperlipidemia, IP interstitial pneumonia, M male, N/R/O not ruled out, OMI old myocardial infarction, S/O suspected of\n\n+: having dementia, −: not having dementia\n\nAll cases with elevated liver enzymes that discontinued riluzole presented a history of medication for diabetes or hyperlipidemia\n\nTable 3 Characteristics of the discontinued cases, categorized into events\n\nThe reason of discontinuation of riluzole\tn (rate vs. all, %)\tSex (Male, %)\tOnset of ALS\tDuration from the beginning of riluzole (days, median, IQR)\tDuration of ALS at withdrew riluzole (years, median, IQR)\tPast histories (n)\t\nAge (years old, median, IQR)\t\nElevated liver enzymes\t5 (5.4)\t80\t65 (56–67)\t11 (7.3–14)\t1 (1–2)\tDiabetes/HT/HL (4), Reflux esophagitis (1), Heavy drinker (1)\t\nIP\t4 (4.3)\t50\t65.5 (55–73.3)\t60 (48.5–82.5)\t2 (1.8–2.5)\tpast smoker (2)\t\nAppetite loss / Nausea\t3 (3.3)\t33\t64 (62–71)\t2 (2–5.5)\t3 (2–4)\tDepressive status (2)\t\nDizziness\t2 (2.2)\t50\t69 (66–72)\t4 and 90–120, respectively\t2 and 20 years, respectively\t\t\nGeneral malaise\t1 (1.1)\t0\t67\t90\t3\t\t\nParesthesia of tongue\t1 (1.1)\t100\t53\t180\t1\tPsoriasis vulgaris\t\nUrinary urgency\t1 (1.1)\t100\t70\t0–3\t2\t\t\nThe most frequent cause of discontinuation was elevation of liver enzymes (n = 5/92, 5.4%) followed by IP, nausea or appetite loss, dizziness, general malaise, tongue paresthesia, or urinary urgency. In two cases, the drug was discontinued because of progression of bulbar palsy. Median disease duration was 2 years (IQR, 1–3; range, 0–20). All adverse events occurred within 6 months of riluzole initiation, with half of the events occurring within 14 days\n\n\n\nIn this study, ALS patients who showed ALT and AST levels > 3× of the upper limit of the normal level [2, 12] and presented with accompanying subjective symptoms, such as anorexia, nausea, and dizziness, were considered cases/patients with abnormal elevated liver enzymes. In discontinuation cases, biochemical analyses revealed abnormally elevated liver enzymes in five cases and elevated Krebs von den Lungen-6 (KL-6) and surfactant protein (SP)-D levels in four pneumonia cases. All cases with abnormal elevated enzymes presented with a medical history of diabetes, hyperlipidemia, or hypertension and received medication for these conditions (Table 2). Furthermore, in two cases with elevated liver enzymes, biochemical analyses before riluzole administration showed moderately elevated γ-GTP levels (Tables 2 and 3). Two continuation cases showed slightly elevated liver enzyme levels. Overall, 8 of the 72 continuation cases showed mildly elevated liver enzyme levels (< 70 U/L) after drug administration, but there were no accompanying symptoms.\n\nAdverse events improved soon after drug discontinuation, except in three cases of IP that required steroid treatment to achieve a good response. Two cases with elevated liver enzymes and severe IP are reported below.\n\nCase1\nThe patient complained of weakness in her left (Lt.) upper limb at the age of 68 years, which gradually spread to the other side. Moreover, she experienced cramps in her Lt. upper and lower limbs at the age of 70 years and was admitted to our hospital. She presented no relevant family history. She presented a medical history of hyperlipidemia and received medication for it. Neurological examination revealed moderate muscle atrophy and weakness in her Lt. upper and lower limbs and fasciculation in her upper limbs. Electromyography revealed fasciculation in the thoracic area. We diagnosed the patient with ALS and initiated treatment with 50 mg riluzole twice daily. After 2 weeks of riluzole initiation, a skin rash appeared and riluzole was withdrawn. Riluzole was resumed 3 weeks after day 1 of treatment. Then, she complained of general malaise. Biochemical analysis at day 30 of riluzole treatment revealed elevated AST from 21 to 50 U/L and elevated ALT from 25 to 88 U/L (Table 4). We suspected drug-induced hepatic injury and discontinued the medication. Her liver enzyme levels worsened at 1 month after drug discontinuation (AST, 65 U/L; ALT, 132 U/L) but gradually improved; her malaise disappeared within 2 months after riluzole discontinuation (Table 4).Table 4 The course of biochemical analyses data of case1 with elevated liver enzymes\n\n\tAST\tALT\tALP\tγ-GTP\tLDH\tT-Bil\t\nBefore riluzole treatment\t21\t25\t189\t15\t187\t0.8\t\nWhen abnormality occurred\t50\t88\t259\t17\t213\t0.7\t\nThe worst biochemical data\t65\t132\t238\t37\t229\t0.8\t\nAfter discontinuation\t25\t37\t259\t21\t175\t0.6\t\nALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, γ-GTP gamma-glutamyl transpeptidase, T-bil total bilirubin\n\nT-bil: mg/dL, Others: U/L\n\nBiochemical analysis at day 30 of riluzole treatment revealed elevated AST from 21 to 50 U/L and elevated ALT from 25 to 88 U/L. The liver enzyme levels worsened at 1 month after drug discontinuation but gradually improved; the symptom disappeared within 2 months after riluzole discontinuation\n\n\n\nCase 2\nThe patient complained of fasciculation and muscle weakness in his upper limbs at the age of 59 years and was admitted to our hospital at the age of 60 years. He presented no relevant family history. He presented a medical history of proton pump inhibitor use. He was a past smoker of 30 cigarettes per day for 25 years. Neurological examination revealed hypertonus in his four extremities and muscle atrophy and weakness in his upper limbs. Electromyography revealed active denervation potentials in the cervical, thoracic, and lumbar areas. We diagnosed the patient with ALS and initiated treatment with 50 mg riluzole twice daily. The patient complained of shortness of breath and dry cough 2 months after treatment initiation. Physical examination revealed blood pressure of 105/75 mmHg and heart rate of 77 beats per minute. His SpO2 in room air was 92%. Routine biochemical analyses revealed increased KL-6 (1151 U/mL), SP-D (414 ng/mL), lactate dehydrogenase (354 U/L), C-reactive protein (0.9 mg/dL), and serum amyloid A (68.8 μg/mL) levels. Arterial blood gas analysis revealed hypoxemia with pO2 of 68.2 mmHg (Table 5). Chest X-ray and computed tomography (CT) revealed consolidation in the bilateral lower lung lobes (Fig. 1a). Pulmonary function test revealed diffusion impairment, with percent vital capacity (%VC) of 79.8%, forced expiratory volume percent in one second (FEV1.0%) of 70.4%, and diffusing capacity of the lung carbon monoxide (DLCO) of 49.2%. Drug-induced pneumonia was suspected, and riluzole treatment was withdrawn at day 80 of riluzole initiation. Bronchoalveolar lavage showed 57.8% increase in the lymphocyte counts. Transbronchial lung biopsy was performed from the right upper and lower segmental bronchi. Pathological analysis revealed organizing pneumonia—a subtype of IP. As the clinical course was acute and different from that of food microaspiration-induced idiopathic pulmonary fibrosis [19], we diagnosed the patient with drug-induced IP. and initiated oral prednisolone at 0.5 mg/kg body weight per day. Immediately, the symptoms and respiratory failure improved, with DLCO increasing to 105.3% and consolidation disappearing in 30 days (Table 5, Fig. 1b).Table 5 The course of biochemical analyses and pulmonary function data of our IP case\n\nBiochemical analysis\t\tLDH\tCRP\tSAA\tKL-6\t\nonset\t354\t0.9\t68.8\t1152\t\nafter treatment\t272\t0.1\t7.3\t469\t\nBlood gas analysis\t\tpH\tpCO2\tpO2\tHCO3\t\nonset\t7.41\t36.9\t68.2\t22.3\t\nPulmonary function test\t\t% VC\tFEV1.0%\tDLCO\t\t\nonset\t79.8\t70.4\t49.2\t\t\nafter treatment\t95.9\t73.3\t105.3\t\nCRP C-reactive protein, mg/dL, DLCO Diffusing capacity of the lung carbon monoxide, ml/min/mmHg, FEV1.0% Forced expiratory volume percent in one second, %, KL-6 Krebs von den Lungen-6, U/mL, LDH lactate dehydrogenase, U/L, pCO2: mmHg, pO2: mmHg, SAA Serum amyloid A, mg/mL, SP-D surfactant proteins D, ng/mL, %VC Percent vital capacity, %,\n\nOn his admission, routine biochemical analyses revealed increased levels related to IP. Arterial blood gas analysis revealed hypoxemia. Pulmonary function test revealed diffusion impairment. The symptoms and respiratory failure improved, with DLCO increasing after discontinuation and steroid treatment\n\nFig. 1 (a) Chest X-ray and CT radiography of the 61-year-old man of IP show consolidation in bilateral lungs, dominantly in the lower and right side (arrows). (b) On the 24th day after treatment with oral PSL, the consolidations are improved. R: right\n\n\n\nDiscussion and conclusion\nRiluzole is a presynaptic glutamate release inhibitor, which protects motor neuron from toxic neural excitation. The most common adverse events due to riluzole is elevated liver enzyme levels, specifically ALT (6.9%), AST (6.6%), and γ-GTP (3.8%), as well as nausea (3.8%), according to a treatment outcome study in the pharmaceutical reference. In a previous study, ALT levels elevated 2–4 times the normal range in 7.8% of the cases and AST levels elevated 4 times the normal range in 14.2% of the cases were reported, with 6.5% of the cases showing elevation of both enzymes; 6.5% cases resulted in drug withdrawal in that study, and enzyme levels returned to normal within 2 months after riluzole discontinuation [4]. Another study reported elevated ALT in 6.7% cases and elevated AST in 3.8% cases [15]. In addition to liver enzyme levels, asthenia prevalence of 8.5% (versus 7.0% in placebo) and nausea prevalence of 4.9% (versus 3.5% in placebo) has been reported [3]. All adverse events, except for urinary urgency, noted in this study have been reported in previous research studies or pharmaceutical references (Table 3). All five cases with elevated liver enzyme (5.4%) showed elevated ALT and AST levels, whereas only two cases showed elevated γ-GTP levels; this trend is consistent with previously reported trends [4, 15]. A study investigating dose-dependent effects of riluzole has suggested that hepatotoxicity reflects metabolic toxicity of riluzole [15, 17]. In this study, all cases with elevated liver enzymes that discontinued riluzole presented a history of medication for diabetes or hyperlipidemia (Tables 2 and 3); this may reflect increased metabolic ability. In addition, in some cases, biochemical analyses before riluzole administration revealed elevated γ-GTP; this also suggests that metabolic ability before medication is important. Since biochemical analysis does not always indicate asthenia and symptoms sometimes resemble disease progression, repeated interviews to assess general fatigue would be useful for making decision to discontinue riluzole considering patient’s quality of life (QOL).\n\nAlthough the incidence of riluzole-induced IP is 0.1% in Japan according to a pharmaceutical reference, the incidence rate in our study was much higher at 4.3%. Because ALS patients complain of dyspnea with disease progression, IP might be overlooked sometimes. The proposed mechanism underlying IP in riluzole-administered patients includes dosage-dependent cell-mediated allergy along with increased CD8-positive lymphocytes in bronchoalveolar lavage and DLST [5]. We speculate that IP in our cases was caused by riluzole-induced allergy. In case 2, prolonged history of smoking may have triggered IP. Therefore, conducting repeated interviews and chest X-rays, as required, are important to differentiate adverse events from disease progression.\n\nA double-blind trial of riluzole has shown that AST levels increased after 42 to 267 days of treatment initiation [4]. A dose-ranging study of riluzole has reported that the median duration of AST increase was 51 days in the 100 mg-dosing group [15]. Some case reports have shown elevated liver enzymes after 3 weeks, 4 weeks, and 6 months of riluzole initiation [6, 17], while in some other case reports of IP, this duration was 3 weeks, 4 weeks, and 2 months [13, 20]. Based on a phase III clinical trial and drug-use survey performed for 18 months [15] and the abovementioned reports of adverse events occurring from 7 days to 9 months, we considered our follow-up period of a median of 15.5 months to be sufficiently long. Indeed, in our cases, all adverse events occurred within 6 months after riluzole initiation, suggesting that careful follow-up for the first 6 months after riluzole initiation is important. Despite a sufficiently long follow-up, this report was retrospective and duration of drug administration was variable. Further investigations including prospective data and cases with comparable starting points and follow-up periods are warranted. Moreover, a selection bias existed because of the single-center nature of this study, and studies including more patients from multiple centers are imperative.\n\nAll but three cases of IP, which required steroid treatment, showed improvement soon after drug discontinuation. Only one IP case not require steroid treatment was diagnosed as IP with ground glass opacity (GGO) on chest X-ray and represented a very early stage of the event. Although responses to steroids were good, the three IP cases could have been mild. Furthermore, the need for steroids could have been eliminated if patients had earlier detection, as in the GGO case.\n\nRiluzole has been reported to be well tolerated for long periods of up to 7 years or more in the real-world setting [10, 14]. However, recurrent pancreatitis in two ALS patients associated with riluzole treatment has been reported recently [9]; both patients were diagnosed with pancreatitis within 3 months after riluzole initiation. Once again, these reports emphasize the importance of careful observation of adverse events in the first 6 months after riluzole administration.\n\nAlthough survival benefits of riluzole are debatable, some reports have suggested early benefits such that riluzole induced partial normalization of cortical and peripheral axonal hyperexcitability in the early stage of ALS [11] or increased survival in the last clinical stage of ALS [10]. In the light of these reports, it is advisable to continue riluzole as long as possible unless QOL is affected by the adverse events. When QOL is affected due to adverse events, riluzole should be discontinued rather than tapering administration, which is supported by the fact that all but three cases of IP in this study showed improvement simply with riluzole discontinuation [7, 9, 14, 16].\n\nIP could be treated and lethal in most cases. Therefore, all ALS patients should be carefully followed up through interviews after riluzole initiation, especially for the first 6 months. When patients complain of respiratory problems, such as dyspnea or dry cough, chest X-ray should be recommended.\n\nRiluzole was discontinued in 20 ALS patients (20/92) in this study. Moreover, incidence of IP was higher in this study than that reported in past studies, and strategies to differentiate IP from disease progression are warranted. Finally, careful follow-up for the first 6 months after the initiation of riluzole treatment is crucial, including thorough interviews, chemical analyses, and chest X-ray, as required.\n\nAbbreviations\n%VCPercent vital capacity\n\nALSAmyotrophic lateral sclerosis\n\nALTAlanine aminotransferase\n\nASTAspartate aminotransferase\n\nCTComputed tomography\n\nDLCODiffusing capacity of the lung carbon monoxide\n\nFEV1.0%Forced expiratory volume percent in one second\n\nFTDFrontotemporal dementia\n\nFVCForced vital capacity\n\nGGOGround glass opacity\n\nIPInterstitial pneumonia\n\nIQRInterquartile range\n\nKL-6Krebs von den Lungen-6\n\nLDHLactate dehydrogenase\n\nLt.Left\n\nN/R/ONot ruled out\n\nNa+Sodium\n\nPPIProton pump inhibitors\n\nPSLPrednisolone\n\nQOLQuality of life\n\nS/OSuspected of\n\nSPSurfactant proteins\n\nWe would like to thank all who are participating in treatment of ALS patients in our Tohoku regional community.\n\nFunding\nNo funding was obtained for the preparation of this case report.\n\nAvailability of data and materials\nThe source data supporting our data are stored in the archive of our center and are contained within the manuscript. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAll authors were involved in the clinical care of the patient. KH and TY were primary physician of the two patients in case reports. SN made substantial contributions to conception and design. KM and KY collected the clinical data. I-SA analyzed data and drafted the manuscript. IR, KJ, SN and WH helped interpreting the data, gave input into the discussion and participated in the conception and design of the report. AM gave final approval of the version to be published. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe study was submitted to and approved by the Ethics Committee of Tohoku University Graduate School of Medicine (2010–253, 2017–1-005). Consent to participate was directly provided by patients or their families.\n\nConsent for publication\nThe written consents for publication were obtained from patients, including two individuals for case reports, or their families.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Bellingham MC A review of the neural mechanisms of action and clinical efficiency of Riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther 2011 17 1 4 31 20236142 \n2. Bensimon G A D The tolerability of riluzole in the treatment of patients with amyotophic lateral sclerosis Expert Opinion Drug Saf, Nov 2004 3 6 525 534 \n3. Bensimon G Lacomblez L Delumeau JC Bejuit R Truffinet P Meininger V Riluzole/ALS Study Group II A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis J Neurol 2002 249 5 609 615 12021952 \n4. Bensimon G Lacomblez L Meininger V A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole study group N Engl J Med 1994 330 9 585 591 8302340 \n5. Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation. Respiration; International Review of Thoracic Diseases. n.d.;71(4):301–26.\n6. Castells LI Gámez J Cervera C J G Icteric toxic hepatitis associated with riluzole outcome of raising blood pressure in patients with penetrating trunk Lancet 1998 351 648 \n7. Cetin H, Rath J, Füzi J, Reichardt B, Fülöp G, Koppi S, et al. Epidemiology of amyotrophic lateral sclerosis and effect of riluzole on disease course. Neuroepidemiology. 2015;44(1):6–15.\n8. Chen L Liu X Tang L Zhang N Fan D Long-term use of riluzole could improve the prognosis of sporadic amyotrophic lateral sclerosis patients: A real-world cohort study in China Front Aging Neurosci 2016 8 OCT 1 8 26858637 \n9. Falcão de Campos C de Carvalho M Riluzole-induced recurrent pancreatitis J Clin Neurosci 2017 45 153 154 28867362 \n10. Fang T Al Khleifat A Meurgey JH Jones A Leigh PN Bensimon G Al-Chalabi A Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: A retrospective analysis of data from a dose-ranging study The Lancet Neurology 2018 17 5 416 422 29525492 \n11. Geevasinga N Menon P Özdinler PH Kiernan MC Vucic S Pathophysiological and diagnostic implications of cortical dysfunction in ALS Nat Rev Neurol 2016 12 651 27658852 \n12. Introna A D’Errico E Modugno B Scarafino A Fraddosio A Distaso E Adherence to riluzole in patients with amyotrophic lateral sclerosis: an observational study Neuropsychiatr Dis Treat 2018 14 193 203 29379292 \n13. Kakuta T Hirata H Soda S Shiobara T Watanabe M Tatewaki M Riluzole-induced lung injury in two patients with amyotrophic lateral sclerosis Intern Med 2012 51 14 1903 1907 22821110 \n14. Lacomblez L Bensimon G Leigh PN Debove C Bejuit R Truffinet P Meniinger V ALS Study Groups I and II Long-term safety of riluzole in amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases 2002 3 1 23 29 \n15. Lacomblez L Bensimon G Leigh PN Guillet P Meininger V Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II Lancet 1996 347 9013 1425 1431 8676624 \n16. Miller, R. G., Rosenberg, J. A., Gelinas, D. F., Mitsumoto, H., Newman, D., Sufit, R., Kalra S, Katz JS, Mitsumoto H, Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC. Oppenheimer, E. A. (1999). Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the quality standards Subcommittee of the American Academy of neurology. Neurology, 52(7), 1311–1311.\n17. Remy AJ Camu W Ramos J Blanc P Larrey D Acute hepatitis after riluzole administration J Hepatol 1999 30 3 527 530 10190739 \n18. Shaw PJ Ince PG Glutamate, excitotoxicity and amyotrophic lateral sclerosis J Neurol 1997 244 2 3 14 \n19. Sweet MP Patti MG Hoopes C Hays SR Golden JA Gastro-oesophageal reflux and aspiration in patients with advanced lung disease Thorax 2009 64 2 167 173 19176842 \n20. Takeshima S Neshige S Himeno T Takamatsu K Shimoe Y Kuriyama M Riluzole-induced interstitial pneumonia in a case with amyotrophic lateral sclerosis Rinsho Shinkeigaku 2015 55 11 840 843 26399668\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "19(1)",
"journal": "BMC neurology",
"keywords": "Adverse events; Amyotrophic lateral sclerosis; Interstitial pneumonia; Liver dysfunction; Riluzole; Side-effect",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000328:Adult; D000690:Amyotrophic Lateral Sclerosis; D056486:Chemical and Drug Induced Liver Injury; D018450:Disease Progression; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents; D012189:Retrospective Studies; D019782:Riluzole",
"nlm_unique_id": "100968555",
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"pages": "72",
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"pmid": "31029113",
"pubdate": "2019-04-27",
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"title": "Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study.",
"title_normalized": "interstitial pneumonia and other adverse events in riluzole administered amyotrophic lateral sclerosis patients a retrospective observational study"
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"abstract": "To present a case of fungal endophthalmitis with a novel organism and our management.\nA 46 year old male presented with delayed-onset acute endophthalmitis 6 weeks after routine phacoemulsification and intraocular lens implantation. Initial treatment with intravitreal antibiotics did not improve his condition. With repeated vitreal taps, the causative organism was eventually identified as a fungus, Pseudozyma aphidis. Treatment with oral and intravitreal voriconazole, as well as pars plana vitrectomy, led to resolution of the endophthalmitis and recovery of vision to 20/25.\nFungal endophthalmitis is a rare, potentially blinding complication of cataract surgery. We report our approach to this previously unreported organism, that led to an excellent visual outcome. There are no specific guidelines for fungal endophthalmitis. The management approach has to be tailored to the clinical response and emerging laboratory data from the microbiologist. Identification of the organism will require specialist laboratory references that may not be available in all hospitals. Ophthalmologists must work closely with microbiologists in order to ensure an optimal outcome.",
"affiliations": "Department of Ophthalmology, Dunedin Public Hospital, 201 Great King Street, Dunedin, 9016, Otago, New Zealand.;Southern Community Laboratories, Dunedin, 9016, Otago, New Zealand.;Department of Ophthalmology, Dunedin Public Hospital, 201 Great King Street, Dunedin, 9016, Otago, New Zealand.",
"authors": "Voon|Shong Min|SM|;Upton|Arlo|A|;Gupta|Deepak|D|",
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"doi": "10.1016/j.ajoc.2019.100475",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30402-X10.1016/j.ajoc.2019.100475100475Case ReportPseudozyma aphidis endophthalmitis post-cataract operation: Case discussion and management Voon Shong Min shongmin.voon@southerndhb.govt.nza∗Upton Arlo bGupta Deepak aa Department of Ophthalmology, Dunedin Public Hospital, 201 Great King Street, Dunedin, 9016, Otago, New Zealandb Southern Community Laboratories, Dunedin, 9016, Otago, New Zealand∗ Corresponding author. shongmin.voon@southerndhb.govt.nz31 5 2019 9 2019 31 5 2019 15 1004756 10 2018 24 1 2019 27 5 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo present a case of fungal endophthalmitis with a novel organism and our management.\n\nObservations\nA 46 year old male presented with delayed-onset acute endophthalmitis 6 weeks after routine phacoemulsification and intraocular lens implantation. Initial treatment with intravitreal antibiotics did not improve his condition. With repeated vitreal taps, the causative organism was eventually identified as a fungus, Pseudozyma aphidis. Treatment with oral and intravitreal voriconazole, as well as pars plana vitrectomy, led to resolution of the endophthalmitis and recovery of vision to 20/25.\n\nConclusions and importance\nFungal endophthalmitis is a rare, potentially blinding complication of cataract surgery. We report our approach to this previously unreported organism, that led to an excellent visual outcome. There are no specific guidelines for fungal endophthalmitis. The management approach has to be tailored to the clinical response and emerging laboratory data from the microbiologist. Identification of the organism will require specialist laboratory references that may not be available in all hospitals. Ophthalmologists must work closely with microbiologists in order to ensure an optimal outcome.\n\nKeywords\nPseudozyma aphidisFungal endophthalmitisExogenousManagement\n==== Body\n1 Introduction\nEndophthalmitis is a rare, potentially sight threatening complication post intraocular surgery, with a reported incidence of 0.04–0.2%.1, 2, 3,13,17 Amongst the causative organisms of endophthalmitis, fungi account for about 3–8% of reported cases, depending on geographic variation, with Candida, Aspergillus and Fusarium species being the more common fungal isolates.5, 6, 7,13,14 Rare fungal isolates are becoming increasingly recognised as a cause for ocular mycoses due to the ubiquity of fungi in nature, as well as increasingly sophisticated molecular diagnostic techniques.6,10 In this paper, we present the first reported case of post cataract-surgery endophthalmitis from Pseudozyma aphidis.\n\n2 Case report\nA 46-year-old New Zealand European male underwent cataract extraction for persistent appositional closure despite patent peripheral iridotomies. Surgery was routine with standard aseptic precautions; a toric intraocular lens was inserted; intra-cameral cefuroxime was administered at the end of the procedure. Day-one visual acuity was 20/30 unaided with a normal slit lamp examination and no wound leak. He had routine follow-up at 4 weeks’ post-operation. He presented to the acute eye clinic 6 weeks post-operatively with a one-day history of a painful, red right eye with reduced vision.\n\nOn examination, visual acuity was 20/40. He had diffuse conjunctival injection and was noted to have grade 4 + inflammation in his anterior chamber with <1 mm hypopyon, as well as 1 + vitreous cells on slit lamp examination. Intraocular pressures were 13 mmHg bilaterally. Fundus examination appeared normal with no retinal lesions. An initial diagnosis of an acute post-operative endophthalmitis was made.\n\nAn anterior chamber and a vitreous tap was performed under sterile conditions with Betadine solution used with aseptic techniques. He received intravitreal injections of Vancomycin 1mg/0.1 ml and Ceftazidine 2.25mg/0.1 ml, a five-day oral course of moxifloxacin 400 mg, and topical dexamethasone drops hourly. Initial follow up post treatment showed reduced hypopyon, pain and injection over the first few days. The anterior chamber tap showed moderate polymorphs but no organisms, and was reported culture negative. Topical dexamethasone was weaned to every 2 h as his anterior chamber inflammation improved to 2 + cells.\n\nOn review 10-days post intravitreal-injection, he was noted to have increased anterior chamber cells up to 4 + and trace hypopyon again. A white plaque was noted on the posterior capsule at the three o'clock position (see Fig. 1). Fundus examination and OCT confirmed optic nerve head and macular oedema. A low-grade P Acnes type endophthalmitis was clinically suspected.Fig. 1 Posterior capsular plaque evident on dilated examination.\n\nFig. 1\n\nA vitreo-retinal consult was obtained with recommendations for a 5-day course of further treatment with intravitreal Vancomycin 1mg/0.1 ml and Ceftazidine 2.25mg/0.1 ml. He also received subconjunctival Dexamethasone and started on Prednisolone 1% hourly.\n\nThe next day, the patient underwent another anterior chamber tap prior to his repeat course of intravitreal antibiotics. The Gram stain of the aspirate demonstrated oblong Gram-variable structures (see Fig. 2). During the fourth day of his 5-day course, the Microbiology department reported a light growth of yeast. Our lab also reported scanty growth of Propiobacterium acnes in one of the three growth cultures from the samples taken. Due to the prolonged incubation period of the culture and growth in only one plate out of three cultured, this was presumed to be a contaminant. Additionally, the Gram-positive organisms seen in the initial aspirate Gram stain did not resemble P. acnes.Fig. 2 Organisms on initial Gram stain.\n\nFig. 2\n\nThe yeast colonies on blood agar were white and wrinkled. Microscopically, it appeared as fusiform budding yeast. The isolate was identified as P. aphidis using the MALDI biotyper (Brucker Daltonics, Bremen, Germany) with a score of 1.7. In addition, the national mycology reference laboratory (LabPLUS) also identified it as P. aphidis using phenotypic methods. It was described as a flat cream-coloured yeast, going slightly pink with age. Gram stain of the isolates demonstrated oblong Gram-positive structures (Fig. 3). It grew a ‘dirty pink’ colour on Candid CHROM agar, and there was growth at 27 °C and 37 °C. Urea and nitrate were positive, and esculin was negative. Identification was confirmed using the key in “The Yeasts: A Taxonomic Study (4th Ed) by Kurtzman C., Fell JW”. Susceptibilities to fluconazole (MIC = 4.0 mg/L), voriconazole (MIC = 0.06 mg/L), and amphotericin (MIC = 1.0 mg/L) were done using Sensititre Y10 panels.Fig. 3 Organisms with Gram stain from culture plate.\n\nFig. 3\n\nWith this information, the patient was then commenced on oral voriconazole 200 mg twice a day on advice from our Infectious Diseases consultant. He was also reviewed by the medical team and found not to have any pre-existing endogenous or exogenous fungal infections or other medical co-morbidities.\n\nThe patient did not have much appreciable improvement over the next 2 weeks. He had ongoing disc swelling and further developed central macular oedema. The decision was made to undergo a pars plana vitrectomy, vitreous biopsy, posterior capsulotomy, and intravitreal voriconazole 0.05mg/0.1 ml. During the procedure, the patient had a small retinal tear from an infusion line, requiring endolaser and an SF6 gas fill. The vitreous aspirate examined on this occasion had occasional polymorphs and no organisms seen on microscopy and was culture negative as well.\n\nPost operatively he continued to have prednisolone drops and oral voriconazole at 200 mg twice a day. His anterior chamber cells slowly decreased, with gradual resolution of his macular and disc oedema, and complete resolution recorded at 3 months after initial presentation. The final visual acuity was 20/25.\n\n3 Discussion\nPseudozyma aphidis (Fig. 4) is an environmental yeast belonging in the Ustilaginomycetes class, and is commonly isolated from leaves, flowers, and soil.8,10 It is thought to have low pathogenicity but has been implicated in a few cases of invasive infection in humans, most of whom were immunocompromised.8, 9, 10, 11 First described as a possible human pathogen in 2008, P. aphidis had since been the primary pathogen in 8 cases of human infection.8, 9, 10, 11 Due to the rare occurrence of this pathogen in human infections, this species cannot be identified using commercial systems that are available in routine laboratories.8 To our knowledge, this is the first reported episode of ocular infection involving P. aphidis in medical literature.Fig. 4 Pseudozyma aphidis. Image from A Herb et al. (10).\n\nFig. 4\n\nThe typical presentation of post-surgical fungal endophthalmitis is that of indolent inflammation with relatively mild symptoms, but with findings of fibrinopurulent anterior chamber reaction, corneal opacities or a localized reaction at the intraocular lens.3,4,7,13 Substantial corneal involvement can occur, with keratitis, oedema, and exudates portending poorer outcomes if present.3,4,13 Posterior chamber inflammation with vitreous snowballs and opacities are also a feature.3,4,7,13 Examination findings tend to become evident after several weeks, as they are sometimes masked by topical corticosteroids.4,5 Nevertheless, post-surgical fungal endophthalmitis can also manifest acutely and patients had been recorded to present anywhere between 3 and 50 days after surgery but can present up to 210 days later.3,6,7,13,14 This was evident in our patient, who had a delayed presentation at 6 weeks post cataract surgery with features of acute endophthalmitis: namely a painful eye, reduced vision; an anterior chamber hypopyon with vitreal cells on examination.\n\nMost patients present with visual acuities ranging from 20/80 on the Snellen chart to light perception only.3,4,13,14 Initial presenting visual acuities have not been an independent predictor of final visual outcomes.13\n\nPost-surgical fungal endophthalmitis managed aggressively tends to have a better final visual acuity outcome compared to endophthalmitis caused by open globe trauma or external ocular infections.14 Nevertheless, outcome of fungal endophthalmitis tend to be poor, including serious visual impairment, permanent vision loss and other complications which may require enucleation.3,13,14\n\nSources of exogenous post-surgical fungal endophthalmitis are varied, including but not limited to: intraocular lenses, contaminated irrigation fluids, hospital ventilation or construction activities.6, 7, 8,13 In this case, we were unable to find any predisposing causes to account for his endophthalmitis. Potential colonization during the surgery or post-operative self-inoculation could have occurred. This does raise the possibility that the isolate of p. aphidis could be a contaminant rather than an infective pathogen. However, factors mitigating against this point include the clear clinical abnormality, the unusual looking organisms seen in the aspirate Gram stain (Fig. 2), and the lack of other pathogens isolated (except for very scanty growth of P. acnes on one occasion after prolonged incubation, and in only one of three growth cultures). P. Acnes was thought to be the likely culprit initially, especially with the initial response to treatment followed by a relapse, but mitigating against this was the response to oral voriconazole after vitrectomy. We surmise that the vitrectomy would have had the effect of reducing the organism load in the vitreous.\n\nAs fungal endophthalmitis is quite rare, guidelines for treatment in this case were limited. The European Society of Cataract and Refractive Surgeon (ESCRS) guidelines provide a general approach to undifferentiated endophthalmitis and treatment for bacterial causes but no specific recommendation on management of fungal endophthalmitis.1 The Infectious Diseases Society of America (IDSA) suggest amphotericin B for Candida sp and voriconazole for Aspergillus species, but there were no recommendations from Pseudozyma species.12\n\nIn treating our patient, we consulted previous literature on previous human infection with P. aphidis and laboratory susceptibility data, with the assumption that the treatment modality of choice will provide adequate concentration of the correct antifungal into infected tissue to achieve therapeutic levels. Previous literature had shown isolates of P. aphidis with low MIC (mg/L) to voriconazole (0.03–0.06 mg/L), amphotericin B (0.03–0.25 mg/L), and itraconzole (0.03–0.25 mg/L).8,9,15, 16, 17, 18 A high MIC was noted with fluconazole (4->64 mg/L), caspofugin (4->32 mg/L) and flucytosine (>32 mg/L).8,9,15, 16, 17, 18 This was reasonably consistent with the MIC values in our local laboratory: voriconazole (MIC = 0.06 mg/L), amphotericin (1.0 mg/L), and fluconazole (4.0 mg/L).\n\nAmphotericin B is mainly used to treat candida endophthalmitis, and previous research has shown poor penetration of the drug from systemic administration.12,14,15,18 Treatment of endophthalmitis therefore requires intravitreal injections, however amphotericin B had previously been known to cause retinal necrosis.14,16,18 Doses of between 20 μg and 100 μg had been administered intravitreally without toxicity, although typically administered doses ranges from 5 to 10 μg.12,16 It is important to note that doses of intravitreal amphotericin B for management of fungal endophthalmitis are not standardised, and usually dependant on the clinical response.14\n\nVoriconazole was predominantly used to treat an outbreak of Fusarium contact lens keratitis in 2005, and as a result, many studies have been done on the distribution of the drug with human rather than animal models.12,15 Voriconazole is known to have excellent oral bioavailability and intraocular penetration.12,14,15 Intraocular concentration after two doses of 400 mg oral voriconzole can achieve up to 38% of plasma levels 3 h post administration (0.81±0.31 μg/mL) which is equivalent to MIC of 0.81±0.31 mg/L.8,12,15,16,18 Intravitreal injection of voriconazole has been shown to be safe, with concentrations of <250 μg/ml showing no toxicity to retinal pigment epithelial cells in vitro.12,14,16 Common side effects present in third of patients are reversible photopsia and blurring of vision.14, 15, 16,18\n\nPars plana vitrectomy is recommended treatment for sight threatening endophthalmitis with vitritis.1,2,4,12 A vitrectomy allows for removal of infected vitreous that would normally not respond to systemic antifungal agents, and also decreases the overall burden of the pathogenic organism, as well as providing culture material to guide treatment.1,4,12 Vitrectomies are usually combined with administration of intravitreal antifungal agents; however, it is important to note that the half-life of antifungal agents administered post vitrectomy will be shorter, and that multiple treatments may be required.1,4,12 Previous research had showed eyes that have undergone vitrectomies tend to have better final visual outcome.13 In our case, a vitrectomy was performed as the patient had ongoing deterioration in spite of oral voriconzole, and we did not want to delay treatment. The vitrectomy also allowed us the opportunity to obtain samples and to exclude other causative organisms.\n\n4 Summary and conclusion\nIn summary, our patient had a delayed presentation at 6-weeks with acute symptoms and signs of endophthalmitis following routine cataract surgery. This was initially clinically suspected to be a low grade bacterial endophthalmitis, but later found to be caused by P. aphidis. The endophthalmitis responded well to oral and intravitreal voriconazole, pars plana vitrectomy and capsulotomy. This resulted in definitive treatment and excellent final visual acuity.\n\nThere exist guidelines for bacterial endophthalmitis but none that are specific for fungal endophthalmitis. The approach to infective post-operative endophthalmitis remains similar in fungal cases but management has to be tailored to clinical response and emerging laboratory data from the microbiologist.\n\nIdentification of the organism will require specialist laboratory references that may not be available in all hospitals. Ophthalmologists must work closely with microbiologists in order to ensure an optimal outcome.\n\nPatient consent\nConsent to publish the case report was obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nFunding\nNo funding or grant support.\n\nConflicts of interest\nThe authors have no financial disclosures to declare.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Barry P. Cordovés L. Gardner S. ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery: Data, Dilemmas and Conclusions 2013 European Society of Cataract and Refractive Surgeons Dublin, Ireland https://www.escrs.org/downloads/Endophthalmitis-Guidelines.pdf Available at: \n2 Hashemian H. Mirshahi R. Khodaparast M. Jabbarvand M. Post-cataract surgery endophthalmitis: brief literature review J Curr Ophthalmol 28 3 2016 101 105 27579452 \n3 Bourcier T. Scheer S. Chaumeil C. Morel C. Borderie V. Laroche L. Fungal and bacterial chronic endophthalmitis following cataract surgery Br J Ophthalmol 87 3 2003 Mar 372 373 12598469 \n4 Sunaric-Megevand G. Pournaras C.J. Current approach to postoperative endophthalmitis Br J Ophthalmol 81 1997 1006 1015 9505828 \n5 Yildiran S.T. Murlu F.M. Saracli M.A. Fungal endophthalmitis caused by Aspergillus ustus in a patient following cataract surgery Med Mycol 44 2006 Nov 665 669 17071563 \n6 Tarkannen A. Raivio V. Anttila V.-J. Fungal endophthalmitis caused by Paecilomyces variotii following cataract surgery: a presumed operating room air-conditioning system contamination Acta Ophthalmol Scand 82 2004 232 235 15043549 \n7 Esgin H. Bulut E. Orum C. Candida pelliculosa endophthalmitis after cataract surgery: a case report BMC Res Notes 7 2014 169 24656053 \n8 Joo H. Choi Y.-G. Cho S.-Y. Pseudozyma aphidis fungaemia with invasive fungal pneumonia in a patient with acute myeloid leukaemia: case report and literature review Mycoses 59 1 2015 56 61 26608844 \n9 Orecchini L.A. Olmos E. Taverna C.G. First case of fungemia due to Pseudozyma aphidi s in a pediatric patient with osteosarcoma in Latin America J Clin Microbiol 53 4 2015 Nov 3691 3694 11 26292313 \n10 Herb A. Sabou M. Delhorme J.-B. Pseudozyma aphidis fungemia after abdominal surgery: first adult case Med. Mycol. Case Rep. 8 2015 37 39 25870786 \n11 Parahym A.M. da Silva C.M. Domingos Ide F. Gonçalves S.S. Rodrigues M. de Morais V.L. Pulmonary infection due to Pseudozyma aphidis in a patient with Burkitt lymphoma: first case report Diagn Microbiol Infect Dis 75 2013 104 106 23182077 \n12 Riddell J. Comer G.M. Kauffman C.A. Treatment of endogenous fungal endophthalmitis: focus on New antifungal agents Clin Infect Dis 52 5 2011 Mar 648 653 21239843 \n13 Narang S. Gupta A. Gupta V. Fungal endophthalmitis following cataract surgery: clinical presentation, microbiological spectrum, and outcome Am J Ophthalmol 132 5 2001 609 617 11704021 \n14 Wykoff C.C. Flynn H.W. Miller D. Scott I.U. Alfonso E.C. Exogenous fungal endophthalmitis: microbiology and clinical outcomes Ophthalmology 115 9 2008 1501 1507 18486220 \n15 Hariprasad S.M. Mieler W.F. Holz E.R. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans Arch Ophthalmol 122 1 2004 42 47 14718293 \n16 Gao H. Pennesi M.E. Shah K. Intravitreal voriconazole: an electroretinographic and histopathologic Study Arch Ophthalmol 122 11 2004 1687 1692 15534131 \n17 Lin R.C. Sanduja N. Hariprasad S.M. Successful treatment of postoperative fungal endophthalmitis using intravitreal and intracameral voriconazole J Ocul Pharmacol Ther 24 2 2008 Apr 245 248 18321199 \n18 Hariprasad S.M. Mieler W.F. Lin T.K. Sponsel W.E. Graybill J.R. Voriconazole in the treatment of fungal eye infections: a review of current literature Br J Ophthalmol 92 7 2008 Jul 871 878 18577634\n\n",
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"issn_linking": "2451-9936",
"issue": "15()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Exogenous; Fungal endophthalmitis; Management; Pseudozyma aphidis",
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"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "11704021;12598469;14718293;15043549;15534131;17071563;18321199;18486220;18577634;21239843;23182077;24656053;25870786;26292313;26608844;27579452;9505828",
"title": "Pseudozyma aphidis endophthalmitis post-cataract operation: Case discussion and management.",
"title_normalized": "pseudozyma aphidis endophthalmitis post cataract operation case discussion and management"
} | [
{
"companynumb": "PHHY2019NZ150295",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Clozapine is the only approved treatment for Treatment-Refractory Schizophrenia. Here we describe a case series of three hospitalized patients with clozapine nonresponse. One of them responded to clozapine after dose adjustments were made for an interaction between clozapine and ciprofloxacin. The other two cases remained clozapine nonresponders despite optimizing clozapine treatment. However, both these patients responded to other antipsychotic medications (APMs) with better tolerability than observed with clozapine treatment. This case series focuses on diagnosing a genuine from a pseudo-nonresponse to clozapine and to consider other APMs in genuine nonresponse before switching to invasive interventions, such as ECT.",
"affiliations": "School of Medicine, Oregon Health & Science University, Portland, Oregon, United States; Department of Psychiatry, Oregon State Hospital, Salem, Oregon, United States; Samaritan Mental Healthcare System, Corvallis, Oregon, United States. Electronic address: shad@ohsu.edu.;School of Medicine, Oregon Health & Science University, Portland, Oregon, United States.;School of Medicine, Oregon Health & Science University, Portland, Oregon, United States; Department of Psychiatry, Oregon State Hospital, Salem, Oregon, United States.;Department of Psychiatry, Oregon State Hospital, Salem, Oregon, United States.",
"authors": "Shad|Mujeeb U|MU|;Felzien|Emma|E|;Roy|Kamalika|K|;Sethi|Simrat|S|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ajp.2019.08.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "45()",
"journal": "Asian journal of psychiatry",
"keywords": "Clozapine; Identify; Manage; Non-response",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D005260:Female; D006801:Humans; D008875:Middle Aged; D012559:Schizophrenia; D017211:Treatment Failure",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "50-52",
"pmc": null,
"pmid": "31494348",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "How to identify and manage non-response to clozapine?",
"title_normalized": "how to identify and manage non response to clozapine"
} | [
{
"companynumb": "US-ACCORD-155085",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Coccidioidomycosis is a systemic fungal infection first described in 1892. More than 95% of annual cases occur in Arizona and California. It is an opportunistic infection (OI) transmitted via inhalation of airborne spores (arthroconidia) and rarely via percutaneous inoculation into a tissue or solid organ transplantation in patients who are immunocompromised and with HIV. With the advent of antiretroviral therapy (ART), the incidence of OIs has markedly reduced; however, OIs continue to occur, particularly in patients who present late for medical care or delay ART initiation. In rare cases, immunodeficient individuals may experience a paradoxical worsening or unmasking of OI symptoms, known as the immune reconstitution inflammatory syndrome (IRIS). We present a case of a 31-year-old man with disseminated coccidioidomycosis affecting the spleen, lymph nodes, lungs, bone marrow, and adrenals who developed IRIS after the initiation of ART.",
"affiliations": "Internal Medicine, Howard University Hospital, Washington, DC, USA.;Internal Medicine, Howard University Hospital, Washington, DC, USA.;Internal Medicine, Howard University Hospital, Washington, DC, USA.;Internal Medicine, Howard University Hospital, Washington, DC, USA a_deonarine@howard.edu.",
"authors": "Yaqoob|Hamid|H|;Munawar|Muhammad Mohsin|MM|;Salih|Omer|O|;Deonarine|Anand|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(4)",
"journal": "BMJ case reports",
"keywords": "HIV / AIDS; immunology; infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D003047:Coccidioidomycosis; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D016867:Immunocompromised Host; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33846175",
"pubdate": "2021-04-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated coccidioidomycosis in a patient who is immunocompromised in the setting of immune reconstitution inflammatory syndrome.",
"title_normalized": "disseminated coccidioidomycosis in a patient who is immunocompromised in the setting of immune reconstitution inflammatory syndrome"
} | [
{
"companynumb": "US-BAUSCH-BL-2021-029076",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Anti-glomerular basement membrane (GBM) disease is a rarely described entity in the pediatric population, especially in those less than 3 years old. Even rarer, is double seropositive disease, consisting of anti-GBM antibody plus anti-neutrophil cytoplasmic antibodies. Both single and double antibody positive diseases are characterized by rapidly progressive glomerulonephritis, often without pulmonary involvement in the pediatric population. We report the case of a 2-year-old child with double seropositive anti-GBM disease, the youngest in the current literature, along with the role of therapeutic plasma exchange and rituximab in disease treatment.",
"affiliations": "ClinImmune Labs, Aurora, Colorado, USA.;School of Medicine, University of Colorado, Aurora, Colorado, USA.;Children's Hospital Colorado, Aurora, Colorado, USA.",
"authors": "Helander|Louise|L|;Hanna|Melisha|M|;Annen|Kyle|K|https://orcid.org/0000-0002-7192-5057",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21886",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "36(3)",
"journal": "Journal of clinical apheresis",
"keywords": "ANCA; Goodpasture's disease; anti-GBM; kidney; pediatrics",
"medline_ta": "J Clin Apher",
"mesh_terms": null,
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "505-510",
"pmc": null,
"pmid": "33629780",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pediatric double positive anti-glomerular basement membrane antibody and anti-neutrophil cytoplasmic antibody glomerulonephritis-A case report with review of literature.",
"title_normalized": "pediatric double positive anti glomerular basement membrane antibody and anti neutrophil cytoplasmic antibody glomerulonephritis a case report with review of literature"
} | [
{
"companynumb": "US-ROCHE-2860597",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "For many years, methotrexate has been used in the treatment of certain chronic medical disorders e.g. rheumatoid arthritis and psoriasis as well as a number of malignant disorders e.g. acute lymphoblastic leukemia, certain types of lymphoma and breast carcinoma. Its use has been associated with various systemic toxicities and complications. The association between methotrexate therapy and the development of lymphoma and pseudolymphoma is well established. In patients treated with methotrexate, the development of leukemia has been attributed to either the primary disorder e.g. rheumatoid arthritis or to other drugs used concomitantly e.g. cyclophosphamide. Reported here are two patients with rheumatoid arthritis and one patient with psoriasis treated with low dose methotrexate for variable periods of time. Two of these patients developed acute myeloid leukemia on myelodysplastic syndrome background, while the third patient developed pre-B acute lymphoblastic leukemia that expressed few myeloid markers and had a positive philadelphia chromosome. To our knowledge, these are the first reported cases of methotrexate-induced acute leukemia.",
"affiliations": "Section of Adult Hematology and Hematopoietic Stem Cell Transplant, Oncology Centre, King Fahad Specialist Hospital, Dammam, Saudi Arabia.",
"authors": "Al-Anazi|Khalid A|KA|;Eltayeb|Khalid I|KI|;Bakr|Mohammed|M|;Al-Mohareb|Fahad I|FI|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.4137/ccrep.s3078",
"fulltext": "\n==== Front\nClin Med Case RepClin Med Case RepClinical Medicine. Case Reports1178-6450Libertas Academica ccrep-2-2009-043Case ReportMethotrexate-Induced Acute Leukemia: Report of Three Cases and Review of the Literature Al-Anazi Khalid A. 1Eltayeb Khalid I. 2Bakr Mohammed 2Al-Mohareb Fahad I. 21 Section of Adult Hematology and Hematopoietic Stem Cell Transplant, Oncology Centre, King Fahad Specialist Hospital, Dammam, Saudi Arabia.2 Section of Adult Hematology and Hematopoietic Stem Cell Transplant, King Faisal Cancer Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Email: kaa_alanazi@yahoo.com2009 31 7 2009 2 43 49 © 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/).For many years, methotrexate has been used in the treatment of certain chronic medical disorders e.g. rheumatoid arthritis and psoriasis as well as a number of malignant disorders e.g. acute lymphoblastic leukemia, certain types of lymphoma and breast carcinoma. Its use has been associated with various systemic toxicities and complications. The association between methotrexate therapy and the development of lymphoma and pseudolymphoma is well established. In patients treated with methotrexate, the development of leukemia has been attributed to either the primary disorder e.g. rheumatoid arthritis or to other drugs used concomitantly e.g. cyclophosphamide. Reported here are two patients with rheumatoid arthritis and one patient with psoriasis treated with low dose methotrexate for variable periods of time. Two of these patients developed acute myeloid leukemia on myelodysplastic syndrome background, while the third patient developed pre-B acute lymphoblastic leukemia that expressed few myeloid markers and had a positive philadelphia chromosome. To our knowledge, these are the first reported cases of methotrexate-induced acute leukemia.\n\nmethotrexaterheumatoid arthritisacute lymphoblastic leukemiaacute myeloid leukemiamyelodysplastic syndrome\n==== Body\nIntroduction\nCertain systemic inflammatory disorders, such as rheumatoid arthritis (RA), may have an increase in the risk of malignancy, predominantly lymphoproliferative disorders. Immunosuppressive therapies and cytotoxic agents employed in the treatment of such diseases also increase the risk of development of malignant tumors. Studies have shown that tumor-associated antigens may be produced by inflammatory cells and that their production may be increased in RA and other autoimmune disorders.1 Moreover, the number of lymphomas reported in patients with RA treated with methotrexate (MTX) is increasing. The majority of these cases have features of lymphoproliferative disorders that are associated with immunosuppression.2–4 The risk factors for the development of lymphoma in these patients are: severe disease, intense immunosuppression, genetic predisposition and an increase in the frequency of latent infections with pro-oncogenic viruses. The spontaneous remission of these lymphomas after the withdrawal of MTX highlights the likely role of the drug in the evolution of these malignancies.3,4\n\nLong-term use of the traditional systemic agents, including MTX, in the treatment of psoriasis is not recommended due to the potential of: organ toxicity, myelosuppression and carcinogenesis. The increased risk of lymphoproliferative disorders and squamous cell carcinoma in patients with psoriasis, treated with these agents, is well documented.5–7\n\nCase Reports\nCase 1\nA 73 years old Bahraini lady, who is known to have: RA, hypertension, aortic stenosis, hyperlipidemia, bronchiectasis and bilateral knee replacement was referred from Sulaimaniyah Medical Centre in Bahrain to King Faisal Specialist Hospital and Research Centre (KFSH & RC) in Riyadh on 4/10/2008 as a case of acute leukemia for further evaluation and management. She presented with 2 week history of: fatigue, mucosal bleeding and low grade pyrexia. Her RA had been treated with MTX: 7.5 mg once weekly for 15 years. Physical examination revealed: a fairly well old lady with normal vital signs apart from temperature of 37.8 °C. There was pallor but no external palpable lymph nodes. Hand examination revealed typical rheumatoid changes. An ejection systolic murmur was heard over the aortic area and bilateral basal lung crackles were audible. She had no palpable abdominal organomegaly and her neurological examination did not show any abnormality. Complete blood count (CBC) revealed: WBC: 2.2 × 109/L, Hb: 92 g/L and PLT: 123 × 109/L. Differential cell count (DCC) showed: neutrophils: 4%, lymphocytes: 30%, monocytes: 9% and 54% blast cells. Peripheral blood film (PBF) showed: leucopenia, dysplastic neutrophils and platelets in addition to blast cells with occasional auer rods. Bone marrow examination (BME) showed: cellular marrow with 50% blasts with some auer rods, occasional dysplasia of the myeloid cells and prominent dysplasia of the megakaryocytic series. Immunophenotyping revealed positive myeloid markers and cytogenetic analysis revealed no abnormality. Renal, hepatic and coagulation profiles were all within normal limits. Rheumatoid factor and antinuclear antibodies were negative. Erythrocyte sedimentation rate, C-reactive protein and complements were all normal. Chest X-ray and high resolution CT scan of chest showed evidence of bilateral lower lobe bronchiectasis with superadded chest infection.\n\nAfter confirming the diagnosis of AML on background of myelodysplastic syndrome (MDS) and after commencing her on IV ceftriaxone for her bronchopneumonia and taking into consideration: her old age and her co-morbidities, it was decided not to subject her to intensive chemotherapy and to give her palliative chemotherapy in the form of cytosine arabinoside:10 mg/m2 subcutaneously twice daily (BID) for 20 days. Echocardiogram was done and it showed aortic stenosis without any other abnormality. The patient was reviewed by rheumatologists who believed that her rheumatoid arthritis was controlled and inactive. She tolerated the initial doses of chemotherapy rather well and she remained clinically stable. After improvement of her general condition and control of her chest infection, she was sent home on 15/10/08 on: cytosine arabinoside 20 mg subcutaneously BID for 10 more days, omeprazole 20 mg daily, fluconazole 200 mg daily, fosamax 70 mg weekly, calcium caltrate 600 mg BID, vitamin D 400 units daily, amlodipine 5 mg daily and cefuroxime 500 mg BID for 5 days. She was then followed up regularly at the out patient clinic. After completing her course of cytosine arabinoside, it was noted that her blood counts normalized and she became transfusion-independent for almost 3 months. Blasts also disappeared from peripheral blood and no new infective episodes were encountered. She was last seen on: 30/4/09 and her blood counts were: WBC: 4.82 × 109/L, Hb: 12.3g/L and PLT: 223 × 109/L. DCC showed: neutrophils of 3.8 and no blasts. Her renal and hepatic profiles were normal. She was kept on: omeprazole, amlodipine, calcium caltrate, vitamin-D, fosamax and fluconazole and she was given a new follow up appointment.\n\nCase 2\nA 35 years old Saudi lady, a known case of RA for 3 years treated with MTX 7.5 mg weekly was transferred to RFSH & RC in Riyadh from King Khalid General Hospital in Hafr Albaten on 5/10/2006 as a case of acute leukemia for further evaluation and management. She gave 1 month history of: fatigue, malaise and easy bruising. Physical examination revealed: pallor, no joint deformity or external lymphadenopathy. Chest was clear. There was no palpable abdominal organomegaly. Cardiovascular and neurological examinations were normal. CBC showed: WBC: 2.98 × 109/L, Hb: 83 g/L and PLT: 44 × 109/L. DCC showed: neutrophils: 45%, lymphocytes: 40%, monocytes: 2% and 3% blasts. PBF showed: pancycopenia, dysplasia in the neutrophils and platelets and few blast cells. BME showed: cellular marrow, dysplastic changes that were prominent in the megakaryocytic series and diffuse infiltration with myeloblasts. Immunophenotyping was consistent with AML (M4 type). Cytogenetic analysis did not reveal any abnormality. After confirming the diagnosis of AML on MDS background, the patient was commenced on an induction course of chemotherapy (ICE protocol) composed of: idarubicin, cytosine arabinoside and etoposide. During the neutropenic period following this course of chemotherapy, she developed septic shock due to multi-drug resistant (MDR) Stenotrophomonas maltophilia bacreremia. The septic shock was complicated by: acute respiratory distress syndrome, acute renal failure (ARF), disseminated intravascular coagulation (DIC) and bleeding diathesis. Management of the septic episode required admission to the intensive care unit, inotropic support for 3 days, removal of the central venous catheter, 21 sessions of hemodialysis, IV colistin and transfusion of blood products. Day 14 BME showed dilute marrow with no evidence of leukemia and day 28 BME revealed evidence of first complete remission (CR) of the AML. On 12/12/06, the patient was discharged on omeprazole 20 mg twice daily. Serum creatinine was still elevated (246 umol/L), blood counts were normal and blood film did not show any blasts. Because of prolonged hospitalization due to difficulty in controlling infection and due to management of complications specially ARF, the consolidation course of chemotherapy was delayed. On 20/1/2007, she was readmitted for a consolidation course of chemotherapy. She was asymptomatic and her physical examination revealed no new abnormality. CBC showed: WBC: 8.8 × 109/L, Hb: 87 g/L and PLT: 115 × 109/L. DCC showed: neutrophils: 58%, lymphocytes: 25% and 3% blast cells. BME revealed: hypercellular marrow with 50% myeloblasts. After confirming the relapse of her leukemia, the patient was commenced on MEC (mitoxantrone, etoposide and cytosine arabinoside) re-induction course of chemotherapy. Day 14 BME showed hypocellular marrow with no evidence of leukemia. The second neutropenic period was complicated by: disseminated Candida tropicalis infection; MDR Klebsiella pneumoniae infection; acute on chronic renal impairement and cardiac decompensation. The patient was managed with: liposomal amphotericn-B; amBisome; and voriconazole for the candida infection, piperacillin-tazobactam for the Klebsiella pneumoniae infection in addition to digoxin, captopril and frusemide for the cardiac decompensation. Due to the new complications and the lengthy recovery, it was not possible to subject her to a consolidation course of chemotherapy or to hematopoietic stem cell transplant (HSCT). Two months later, she developed a second relapse of her AML. Due to the repeated infections with MDR organisms, the organ decompensations encountered and the aggressive nature of her leukemia, it was decided to give her supportive measures and symptomatic treatment and not to subject her to further chemotherapy.\n\nCase 3\nA 52 years old Saudi male, a known case of hypertension, hyperlipidemia, recurrent gout and psoriasis, was commenced on oral MTX 7.5 mg weekly in July 2003 at Riyadh Armed Forces Hospital to control his psoriasis. Three months later, he presented with 2 week history of: fatigue, exertional dyspnea, dizziness and palpitations. Physical examination revealed: pallor, few psoriatic skin lesions over limbs but no external palpable lymphadenopathy and no palpable abdominal organomegaly. Chest, cardiovascular and neurological examinations revealed no abnormality. CBC showed: WBC: 10.1 × 109/L, Hb: 56 g/L and PLT: 18 × 109/L. DCC revealed: neutrophils: 14% lymphocytes: 24%, monocytes: 1% and 49% blasts. PBF showed: moderate leucocytosis and several blasts. BME revealed: hypercellular marrow with 80% blast cells. Immunophenotyping was consistent with ALL with coexpression of CD13 and CD33 myeloid markers. Cytogenetic analysis revealed no abnormality. The patient was transferred to KFSH & RC in Riyadh in November 2003 for further management. After confirming the diagnosis of pre-B ALL with CD13 CD33 co-expression, the patient was commenced on 1423 ALL induction course of chemotherapy composed of: daunorubicin cytosine arabinoside, vincristine, L-asparaginase and prednisone in addition to intrathecal methotrexate and hydrocortisone. Day 14 BME showed hypocellular marrow without evidence of leukemia and day 28 BME revealed cellular and regenerating marrow i.e. first CR. Thereafter, the patient received a consolidation course of chemotherapy composed of high dose cytosine arabinoside. As the patient had no compatible sibling donor, he received an autologous HSCT on 15/03/2004. The conditioning protocol was composed of: cyclophosphamide and total body irradiation. In the early post-transplant period, he developed: febrile neuotropenia empirically treated with cefepime and gentamicin and cytomegalovirus infection treated with IV ganciclovir. He engrafted his neutrophils on day 15 and his platelets on day 12 post-HSCT. On 4/4/2004, the patient was well and asymptomatic and his physical examination revealed no abnormality. His CBC results were: WBC: 3.7 × 109/L (neutrophils: 1.32), Hb: 102 g/L and PLT: 46 × 109/L. He was sent home on: bactrim, zantac and magnesium oxide. Thereafter, he had regular follow up at HSCT clinic and he was kept on maintenance chemotherapy with dexamethasone, vincristine and 6-mercaptopurine till March 2006. Three months later, the patient had relapse of his ALL. He presented this time with epistaxis, pancytopenia and 20% blasts on BME. Cytogenetic analysis showed presence of t 9,22 which was not revealed previously. The patient was commenced on imatinib and palliative chemotherapy (vincristive, 6-mercaptopurine and dexamethasone). Later on, he developed repeated infections and progressive disease. On 23/3/2008, he was transferred to palliative care. He continued to have supportive care and symptomatic treatment till he died on 9/4/2008.\n\nDiscussion\nFolate is an essential factor in DNA synthesis, stability and integrity. It may modulate DNA methylation which is vitally important in: gene expression, maintenance of DNA stability and integrity, chromosomal modification and development of mutations.8 Folate has been implicated in the development of cancer. Folate deficiency in normal epithelial tissues appears to predispose them to malignant transformation by two mechanisms: (1) hypomethylation of DNA, thus leading to inappropriate acivation of proto-oncogenes and induction of malignany transformation. (2) imbalance between normal DNA synthesis and repair leading ultimately to breakage and damage of chromosomes. However, modest folate supplements can reduce DNA instability in folate deficient individuals and consequently suppress the development of tumors in healthy tissues.8,9\n\nEpidemiologic, human as well as animal studies strongly suggest that folate status modulates the risk of cancer development in selected body tissues.8–10 Recently, the role of a common polymorphism of the gene encoding for methylenetetrahydrofolate reductase (MTHFR) enzyme has also been implicated.10 Animal studies on MTX have shown that: (1) administration of the drug under unfavorable conditions, e.g. stress or other diseases, diminishes the tolerance to the drug and increases its toxicity. (2) the use of MTX in combination with cyclophosphamide and 5-fluorouacil evokes carcinogenic responses in several organ systems including hematopoietic and lymphatic tissues.11–13\n\nThe etiology of most types of leukemia remains unknown, as the established causes of this malignancy; e.g. ionizing radiation, benzene and cytotoxic chemotherapy; account for only a small proportion. Leukemias are most likely the result of an adverse gene-environment interaction with susceptibility being related to polymorphisms in multiple genes.14 Leukemias commonly arise as a result of DNA translocations, inversions or deletions in genes that regulate blood cell development and homeostasis.15 As leukemias are derived from rapidly proliferating hematopoietic cells that are particularly sensitive to changes in the intracellular folate and have the greatest requirements for DNA synthesis, they are likely to be affected by the metabolic rate of folic acid.14,15 MTHFR is a key enzyme involved in folate metabolism, DNA methylation and synthesis.16 Two common polymorphisms, C677T and A1298C, in the gene coding for MTHFR enzyme have been shown to reduce MTHFR activity and thus modify the susceptibility to various malignancies including lymphoid and myeloid leukemia.14,15 Recent studies have also shown that individuals having various forms of MTHFR polymorphisms generally have a decreased risk of acute leukemia development.14–18\n\nTherapy-related MDS and AML (t-MDS and t-AML) are serious and rather frequent complications of immunosuppressive therepy, cytotoxic chemotherapy and radiotherapy.19 They were first recognized in the late 1970s and now they account for 10%–20% of all cases of MDS and AML. They have been reported in patients with several malignant disorders treated with various chemotherapeutic agents including: etoposide, anthracyclins, alkylating agents, fludarabine and procarbazine. In patients with t-MDS and t-AML, several chromosomal abnormalities have been described including: deletions and monosomies of chromosomes 5 and 7, 11q23, 21q22, t(15,17), t(8,21) and inversion 16. Two distinct syndromes have been described: (1) t-MDS and t-AML induced by alkylating agents: characterized by an antecedent dysplasia and a long latency period of 5–7 years. (2) t-MDS and t-AML induced by anthracyclins and etoposide: characterized by absence of antecedent dysplasia, presentation with AML, short latency period of 1–3 years and specific chromosomal abnormalities eg: 11q23 and 21q22.19 Despite the fact that t-MDS and t-AML and de novo MDS and AML seem to share genetic pathways, recent studies have shown that genetic mutations in general were not more frequent in patients with t-MDS or t-AML than in patients with de novo MDS or AML.20\n\nThere is no standard therapy for patients with t-MDS and t-AML. Treatment can be aggressive with curative intent, particularly for young and fit individuals. Aggressive chemotherapeutic protocols e.g. ICE and 3 + 7 (daunorubicin and cytosine arabinoside) have produced CRs in 20%–100% of patients, but short-lived remissions, early relapses and resistance to chemotherapy were frequently encountered. In patients who are unable to withstand curative regimens; low dose chemotherapy is an alterative option and in elderly or infirm patients, supportive care is a legitimate choice.19 HSCT offers the best chance of cure and has markedly reduced non-relapse mortality in patients with t-MDS and t-AML. However, not being in CR at the time of transplantation, abnormal cytogenetics and old age are the most significant factors for survival.21 Myeloablative HSCT has yielded long term survival in 30% of patients but transplant-related mortality has been reported to reach 49% while non-myeloablative HSCT has been associated with: frequent relapses, short survival and graft versus host disease (GVHD). On the other hand, autologous HSCT has resulted in short survival and high rates of relapse.19 The prognosis of patients with t-MDS and t-AML depends on: age of the patient, karyotype (cytogenetic abnormalities) and response to the initial chemotherapy given.21\n\nThe first patient developed MDS that transformed into AML 15 years after starting low dose MTX therapy for RA. The total dose of MTX given prior to the development of AML was 5.49 grams. Because of her advanced age and other comorbidities which did not allow intensive chemotherapy to be administered, low dose cytosine arabinoside was considered and it did bring her acute leukemia under control. In the second patient, MDS followed by AML transformation occurred 3 years after initiating low dose MTX treatment for RA. The total dose of MTX received prior to the development of AML was 1.11 grams. As the patient was much younger and as she had good performance status without other comorbidities, intensive chemotherapy was offered and the disease was controlled. The development of therapy-related complications e.g. serious infections and organ dysfunction did not allow curative therapy e.g. allogeneic HSCT to be given. The third patient developed ALL three months following the initiation of MTX therapy for psoriasis. The total dose of MTX received prior to the development of ALL was only 97.5 mg. His disease responded well to chemotherapy and he received an autologous graft, but he relapsed four years later and his response to the re-induction chemotherapy was poor. The latter course of his illness was complicated by clinical deterioration due to recurrent infections and progressive disease.\n\nThe three patients developed acute leukemia after the use of MTX to treat their primary medical disorders. The duration of MTX use and the total doses given were very variable. In the two patients with RA who developed AML, clear evidence of myelodysplasia was noted not only on the blood film, but also in the bone marrow. However, no cytogenetic abnormality, e.g. consistent with t-MDS or t-AML, was found. None of the three patients presented had received any other immunosuppressive or cytotoxic agent prior to the evolution of acute leukemia. The absence of prior therapy with another immunosuppressive agent in the three patients, the presence of MDS phase prior to the development of AML in the first two patients and the increasing reports of various types of malignancy in patients treated with MTX, for various reasons, make us conclude that MTX is the most likely cause of acute leukemia in the patients presented. We believe that acute leukemia may either be a direct consequence of MTX therapy or may be related to the changes in folate metabolism induced by MTX treatment.\n\nConclusion\nFor many years, MTX has been an integral part in the treatment of a number of malignancies including: breast cancer, lymphomas and ALL. It appears that its use, like many other chemotherapeutic agents e.g. alkylating agents and etoposide, is associated with the development of lymphomas, pseudolymphomas and even acute leukemias. Therefore, close monitoring for the evolution of malignancy is recommended once the drug is chronically used, even in low dose, particularly in patients with other risk factors for malignant disorders.\n\nAknowledgements\nWe are grateful to all medical, nursing and technical staff who participated in the management of the patients presented, at King Faisal Specialist Hospital and Research centre in Riyadh, Saudi Arabia.\n\nDisclosure\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n1 Szekanecz E Andras C Sandor Z Malignancies and soluble tumor antigens in rheumatoid arthritis Autoimmun Rev 2006 6 42 7 17110316 \n2 Mariette X Cazals-Hatem D Warszawki J Liote F Balandraud N Sibilia J Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France Blood 2002 99 3909 15 12010788 \n3 Georgescu L Paget SA Lymphoma in rheumatoid arthritis: what is the evidence of a link with methotrexate Drug Saf 1999 20 475 8 10392665 \n4 Kono H Inokuma S Matsuzaki Y Two cases of methotrexate induced lymphomas in rheumatoid arthritis: an association with increased serum IgE J Rheumatol 1999 26 2249 53 10529149 \n5 Ortiz A Yamauchi PS A treatment strategy for psoriasis: transitioning from systemic therapy to biologic agents Skinmed 2007 5 285 90 17085995 \n6 Patel RV Clark LN Lebwohl M Weinberg JM Treatments for psoriasis and the risk of malignancy J Am Acad Dermatol 2009 60 1001 17 19344980 \n7 Stern RS Laird N The carcinogenic risk of treatment for severe psoriasis. Phototherapy follow-up study Cancer 1994 73 2759 64 8194017 \n8 Kim YI Folate, colorectal carcinogenesis and DNA methylation: lessons from animal studies Environ Mol Mutagen 2004 44 10 25 15199543 \n9 Duthie SJ Folic acid deficiency and cancer: mechanisms of DNA instability Br Med Bull 1999 55 578 92 10746348 \n10 Choi SW Mason JB Folate and carcinogenesis: an integrated scheme J Nutr 2000 130 129 32 10720158 \n11 Zimecki M Artym J Effect of methotrexate on the immune response in selected expeimental models Postepy Hig Med Dosw 2004 58 226 35 \n12 Kolli VK Abraham P Rabi S Methotrexate-induced nitrosative stress may play a critical role in small intestinal damage in the rat Arch Toxicol 2008 82 763 70 18253714 \n13 Habs M Schmahl D Lin PZ Carcinogenic activity in rats of combined treatment with cyclophosphamide, methotrexate and 5-fluorouacil Int J Cancer 1981 28 91 6 7309284 \n14 Skibola CF Smith MT Kane E Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults Proc Natl Acad Sci 1999 96 12810 5 10536004 \n15 Robien K Ulrich CM 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview Am J. Epidemiol 2003 157 571 82 12672676 \n16 Hur M Park JY Cho HC Lee KM Shin HY Cho HI Methylenetetrahydrofolate reductase A1298C genotypes are associated with the risks of acute lymphoblastic leukemia and chronic myelogenous leukemia in the korean population Clin Lab Hematol 2006 28 154 9 \n17 Pereira TV Rudnicki M Pereira AC Pombo-Oliveira MS Franco RF 5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis Cancer Epidemiol. Biomarkers Prev 2006 15 1956 63 17035405 \n18 Skibola CF Smith MT Hubbard A Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphoblastic leukemia Blood 2002 99 3786 91 11986237 \n19 Rund D Ben-Yehuda D Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment Hematology 2004 9 179 87 15204099 \n20 Pedersen-Bjergaard J Christiansen DH Desta F Andersen MK Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia Leukemia 2006 20 1943 9 16990778 \n21 Kröger N Brand R van Biezen A For the Myelodysplastic Syndromes Subcommittee of The Chronic Leukemia Working Party of The Europian Group for Blood and Marrow Transplantation (EBMT) Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation Haematologica 2009 10.3324/haematol.2008.00097\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1178-6450",
"issue": "2()",
"journal": "Clinical medicine. Case reports",
"keywords": "acute lymphoblastic leukemia; acute myeloid leukemia; methotrexate; myelodysplastic syndrome; rheumatoid arthritis",
"medline_ta": "Clin Med Case Rep",
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"pages": "43-9",
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"references": "19278968;15114258;17035405;7309284;10746348;15204099;10536004;8194017;12010788;10392665;16990778;17085995;15199543;11986237;10529149;16706930;17110316;12672676;18253714;19344980;10720158",
"title": "Methotrexate-induced acute leukemia: report of three cases and review of the literature.",
"title_normalized": "methotrexate induced acute leukemia report of three cases and review of the literature"
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"abstract": "Streptococcal toxic shock syndrome (STSS) is a rapidly progressive infection, with potentially rapid patient deterioration in a very short period. We experienced a rare case of STSS during anticancer chemotherapy, and we continuously measured presepsin (P-SEP) and evaluated its usefulness.\nA 60-year-old woman with pulmonary metastasis from cervical cancer began anticancer chemotherapy. A fever of >40°C and right lower leg swelling developed on day 3. Symptoms worsened despite cefmetazole treatment (1.0 g/day). Blood culture was performed without suspecting STSS. On day 5, symptoms worsened and acute disseminated intravascular coagulation (DIC) and sequential organ failure assessment (SOFA) scores increased. C-reactive protein (CRP) increased from 28.8 mg/dl to 35.5 mg/dl and P-SEP also increased from 1,635 to 2,350 pg/mL. STSS was suspected due to the rapid progression of brown discoloration of the entire right lower leg. Ceftriaxone 2 g/day and clindamycin 1,200 mg/day were begun. On the evening of day 5, blood culture revealed rapidly progressive group A streptococci. After that, symptoms improved rapidly with treatment, and SOFA and DIC scores also decreased. While CRP remained at about 0.5 mg/dl, P-SEP remained slightly elevated at about 400 pg/mL. A residual infection focus was suspected. Contrast-enhanced computed tomography (CT) revealed a capsule-enclosed abscess in the right lower leg soleus muscle on day 32. Debridement was performed and antibiotics were continued until P-SEP was 88 pg/mL. CT confirmed the disappearance of the abscess.\nPrompt diagnosis by blood culture and a sufficiently early, appropriate change in antibiotic therapy led to successful recovery from STSS during anticancer chemotherapy without lower limb amputation. P-SEP was useful in assessment of the residual infection focus and suspending treatments.",
"affiliations": "Department of Critical Care, Disaster and General Medicine, School of Medicine, Iwate Medical University, Japan.",
"authors": "Takahashi|Gaku|G|0000-0002-5947-6295",
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"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi 10.1155/2019/3240501Case ReportA Patient of Using Presepsin to Diagnose Streptococcal Toxic Shock Syndrome during Anticancer Drug Treatment http://orcid.org/0000-0002-5947-6295Takahashi Gaku gakut@iwate-med.ac.jpDepartment of Critical Care, Disaster and General Medicine, School of Medicine, Iwate Medical University, JapanAcademic Editor: Ricardo Jorge Dinis-Oliveira\n\n2019 16 4 2019 2019 324050110 12 2018 18 3 2019 2 4 2019 Copyright © 2019 Gaku Takahashi.2019This 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.Background\n Streptococcal toxic shock syndrome (STSS) is a rapidly progressive infection, with potentially rapid patient deterioration in a very short period. We experienced a rare case of STSS during anticancer chemotherapy, and we continuously measured presepsin (P-SEP) and evaluated its usefulness.\n\n Case Presentation\n A 60-year-old woman with pulmonary metastasis from cervical cancer began anticancer chemotherapy. A fever of >40°C and right lower leg swelling developed on day 3. Symptoms worsened despite cefmetazole treatment (1.0 g/day). Blood culture was performed without suspecting STSS. On day 5, symptoms worsened and acute disseminated intravascular coagulation (DIC) and sequential organ failure assessment (SOFA) scores increased. C-reactive protein (CRP) increased from 28.8 mg/dl to 35.5 mg/dl and P-SEP also increased from 1,635 to 2,350 pg/mL. STSS was suspected due to the rapid progression of brown discoloration of the entire right lower leg. Ceftriaxone 2 g/day and clindamycin 1,200 mg/day were begun. On the evening of day 5, blood culture revealed rapidly progressive group A streptococci. After that, symptoms improved rapidly with treatment, and SOFA and DIC scores also decreased. While CRP remained at about 0.5 mg/dl, P-SEP remained slightly elevated at about 400 pg/mL. A residual infection focus was suspected. Contrast-enhanced computed tomography (CT) revealed a capsule-enclosed abscess in the right lower leg soleus muscle on day 32. Debridement was performed and antibiotics were continued until P-SEP was 88 pg/mL. CT confirmed the disappearance of the abscess.\n\n Conclusion\n Prompt diagnosis by blood culture and a sufficiently early, appropriate change in antibiotic therapy led to successful recovery from STSS during anticancer chemotherapy without lower limb amputation. P-SEP was useful in assessment of the residual infection focus and suspending treatments.\n==== Body\n1. Background\nStreptococcal toxic shock syndrome (STSS) is a sudden septic shock state caused by group A hemolytic streptococcus. The condition results in rapid multiple organ failure or death and is an extremely serious disease with a mortality rate of more than 30% [1, 2]. While in some cases, STSS is reported as a complication of other underlying diseases in middle or advanced age, or in immunocompromised patients, no underlying disease or significant medical history can be identified in 40% of cases. We encountered a female patient who suffered STSS during anticancer chemotherapy.\n\n2. Case Presentation\nA 60-year-old woman was admitted to the gynecology ward at our hospital to undergo anticancer chemotherapy for pulmonary metastatic uterine cervical cancer. On day 1, she received cisplatin plus irinotecan infusions. On day 2, fever >40°C, diarrhoea, haematuria, and right lower leg swelling developed. Blood culture was performed, and cefmetazole (CMZ) 1.0 g/day was begun. On day 4, the right lower leg swelling worsened. A blood test revealed increased serum inflammatory markers, and acute disseminated intravascular coagulation [3] (DIC) and sequential organ assessment [4] (SOFA) scores increased to 6 and 7, respectively. The patient was transferred to our department on day 5 at 00:30 hours. At the initial examination at our department (Table 1), the serum CRP and P-SEP level were 28.8mg/dl nad 1,635 mg/mL, respectively. The Glasgow Coma Scale was 14, blood pressure 88/52 mmHg, and heart rate 90 beats/minute. Although severe swelling was observed in the posterior aspect of the right lower leg, there was no warmth or redness anywhere on the right lower leg. A 9-cm2 patch of brown skin discoloration was noted on the anterior surface of the tibia. Because the right popliteal artery was compressed significantly by the severe swelling in the lower leg soleus muscle, and the image quality was poor, no apparent abscess formation could be confirmed by contrast-enhanced computed tomography (CT) at this time. The popliteal vein was completely occluded, and deep venous thrombosis developed. To prevent potential progression to compartment syndrome, a relaxing incision was made on the medial right lower leg, and no distinct signs of infection were observed in the subcutaneous tissues or muscles. The patient was transferred to the intensive care unit (ICU), and nafamostat mesylate 150 mg/day and recombinant thrombomodulin 19,000 U/day were begun, along with low-molecular-weight heparin 15,000 E/day for venous thrombosis. At this point, STSS was not suspected, and CMZ was continued. A blood test on the morning of day 5 revealed a further exacerbation of the inflammatory markers, a further increase in the acute DIC score, and no improvement in the SOFA score. The brown discoloration progressed rapidly to the entire right lower leg. At this point, STSS was suspected for the first time, and antibiotic therapy was switched to ceftriaxone 2 g/day plus clindamycin (CLDM) 1,200 mg/day, and γ-globulin 15 g/day was initiated. On the evening of day 5, blood culture (in the day 3 specimen) was positive for rapidly progressive group A streptococci. After day 6, while the skin discoloration expanded to above the right knee (Figure 1), blood tests showed a trend towards improved. On day 14, the patient was transferred from the ICU to our general ward (Figure 2). The mild swelling and feverishness of the right lower leg continued. Contrast-enhanced CT on day 32 revealed an encapsulated abscess in the right lower leg soleus muscle (Figure 3). Debridement was performed with the patient under general anesthesia on day 34, close to the site of the relaxation incision. No organisms were isolated from the tissue culture of a specimen collected during debridement. After that, CRP remained at 0.4–0.6 mg/dL except during perioperative period, but P-SEP fluctuated between 350 and 380 pg/mL. We considered that local infections remained. And we continued to take oral minocycline (MINO) 200 mg/day. On day 50, CT revealed a residual abscess (Figure 4). Therefore, we performed the second debridement on day 60. After that, P-SEP gradually decreased and CT confirmed the disappearance of the abscess and swelling on day 100 (Figure 5). Oral MINO was discontinued after confirming that the P-SEP level had improved to 88 pg/mL (Figure 6). Subsequently, the patient was returned to the gynecological ward without recurrent infection.\n\n3. Discussion\nIt is speculated that 5-12% of STSS infections are related to the medical environment [5, 6], especially related to surgery and childbirth [7]. In our case, the infection route could not be definitively identified; however, the patient presented with a 3-day history of sore throat before hospitalisation, and blood test at admission showed a slightly increased serum CRP of 2.8 mg/dL. Based on these findings, the infection was thought to be acquired via the pharyngeal mucosa, and the strain accumulated in the right lower leg muscle due to the patient's immunocompromised state.\n\nAmong the diagnostic criteria reported by the Centers for Disease Control and Prevention in 1993 [8], a positive blood culture, hypotension with systolic blood pressure <90 mmHg, and multiorgan failure were the factors for final diagnosis of STSS in our case.\n\nIn Japan, Nogami et al. [9] reported one case of STSS in 2014 in a patient with cervical cancer who suffered peritonitis after receiving cisplatin. In the same year, Fukumori et al. reported on a patient with hepatocellular carcinoma with soft tissue inflammation in the left thigh while receiving cisplatin and 5-fluorouracil chemotherapy as a Japanese paper. Nogami et al. [9] indicated the possibility of delayed STSS diagnosis in such patients due to influenza-like symptoms often observed as an adverse reaction of cisplatin infusion. Fukumori et al. also underscored the usefulness of early diagnosis using kits, because initial STSS symptoms often involve the upper respiratory tract, such as sore throat or fever, and some patients die before blood culture results become available. In our case, the blood culture specimen was collected on day 3, as soon as the high fever was noted, so as to obtain a definitive diagnosis at an early stage. In fact, if we had delayed switching the antibiotic therapy by a few days, the patient may have required lower extremity amputation or, worse, may not have been saved at all.\n\nIn addition to antibiotics, intravenous immunoglobulin (IVIG) was used to treat our patient. In the current sepsis guidelines [10], IVIG is not particularly recommended. However, Jessica et al. [11] reported that STSS treatment with IVIG and CLDM showed significant improvements in 28-day survival rates. In addition, Hamano et al. [12] compared single-dose administration of IVIG 15 g/day versus IVIG 5 g/day for 3 days and reported that single-dose IVIG 15 g yielded significantly greater improvements in features of systemic inflammatory response syndrome and serum interleukin-6 and lactate levels. We considered that administration of 5 g/day for 3 days is probably less effective because of the long half-life of IVIG (18–32 days). At our hospital, a single 15-g dose has been actively adopted. However, we acknowledge that improvement in just one case is not sufficient to demonstrate the efficacy of IVIG. In regard to the mechanism underlying the efficacy, Horstmann et al. [13] reported that group A streptococci suppress opsonization, which is potentially overcome, at least to some degree, by IVIG.\n\nP-SEP is reported to be a novel infection marker indicating a higher diagnostic capability than CRP and also reflecting severity [14]. To our knowledge, this is the first report of the serial measurement of P-SEP in a case of STSS. In this case, the level of P-SEP increased with the exacerbation of symptoms and fell below the diagnostic cutoff level earlier than CRP with improved symptoms. However, there are reports that presepsin is affected by renal function [15, 16]. It has been confirmed that no decline in diagnostic accuracy was observed in patients with sepsis complicated with acute kidney injury [17], but in such patients it is considered that reexamination of the diagnostic cutoff value is necessary. On the other hand, in this case, P-SEP was very effective in the evaluation of the residual infection focus after AKI improved. The 95% confidence level of P-SEP for healthy persons is reportedly 314 pg/mL [13]. If the P-SEP level is >314 and <500 pg/mL, we think that some local infection may still remain. In fact, the right lower leg abscess remained as long as the P-SEP level was maintained around 400mg/dl, and the level decreased to 88 pg/mL after the abscess disappeared. During this period, CRP remained around 0.5 mg/dl and did not fluctuate so much, so it may be that P-SEP is superior in the evaluation of the residual infection focuses.\n\nBecause this patient was hospitalised, we could closely observe the course of disease progression, including changes in the skin lesion, over time. Furthermore, prompt diagnosis by blood culture, appropriate change of antibiotic therapy at a sufficiently early stage, and recurrence evaluation by P-SEP were effective in this case.\n\n4. Conclusions\nWe experienced a rare case of STSS during anticancer chemotherapy. Prompt diagnosis by blood culture and appropriate change in antibiotic therapy at a sufficiently early stage led to successful recovery from STSS during anticancer chemotherapy without lower limb amputation. P-SEP was useful to evaluate the residual infection focuses.\n\nData Availability\nThe data generated and analyzed in this study are included in this published article and its additional files. The original datasets used for this study are not publicly available due to the existing regulation and only can be shared upon the approval of the directors of the corresponding hospitals.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editor of this journal.\n\nDisclosure\nWe have not obtained funds related to this case report from anywhere.\n\nConflicts of Interest\nThe author declares that they have no conflicts of interest.\n\nAuthors' Contributions\nGaku Takahashi managed the case and redaction and correction of the manuscript.\n\nFigure 1 On day 6, the skin discoloration expanded to above the right knee.\n\nFigure 2 Time course of changes in P-SEP, WBC, CPR, and platelet count.\n\nFigure 3 Contrast-enhanced CT on day 32.\n\nFigure 4 Contrast-enhanced CT on day 50; CT revealed a residual abscess.\n\nFigure 5 CT on day 100. Swelling was alleviated and disappearance of abscess was confirmed.\n\nFigure 6 Time course of changes in P-SEP and CPR after the transfer to the general ward. Debridement was performed on day 34. Later, C-reactive protein (CRP) was 0.4–1.1 mg/dL, but P-SEP fluctuated between 350 and 380 pg/mL. On day 50, CT revealed a residual abscess. Therefore, we performed the second debridement on day 60. After that, P-SEP gradually decreased.\n\nTable 1 Laboratory data at 0:30am on day 5.\n\nBlood cell count\tBlood biochemistry\t\n\n\n\t\nWBC\t19.49×103/μL\tAST\t66 IU/l\t\n\n\n\t\nHb\t12.4 g/dL\tALT\t52 IU/l\t\n\n\n\t\nHt\t34.7%\tT-Bil\t1.7 mg/dl\t\n\n\n\t\nPLT\t7.4×104/μL\t\nγGT\t89 IU/l\t\n\n\n\t\nBlood gas analysis\tBUN\t30.5 mg/dl\t\n\n\n\t\npH\t7.440\tCr\t1.56 mg/dl\t\n\n\n\t\nPaO2\t109.0 mmHg\tCK\t1514 IU/l\t\n\n\n\t\nPaCO2\t38.2 mmHg\tNa\t133 mEq/l\t\n\n\n\t\n HCO3−\t24.4 mmol/L\tK\t3.8 mEq/l\t\n\n\n\t\nLactate\t2.4 mmol/L\tCl\t100 mEq/l\t\n\n\n\t\nCoagulation test\tCRP\t28.87 mg/dl\t\n\n\n\t\nPT-INR\t1.63\tP-sep\t1645 ng/dl\t\n\n\n\t\nARTT\t41.5 s\t \t\n\n\n\t\nD-D\t222.3 ng/mL\tDICscore\t6\t\n\n\n\t\nATIII\t71%\tSOFAscore\t7\n==== Refs\n1 Hiroshi T. Michihiko F. Kunihiko K. A case of streptococcal toxic shock syndrome presented as primary peritonitis The Japanese Society of Intensive Care Medicine 2003 10 213 214 \n2 Shigeru I. Masakazu A. Shinsuke M. A case of fulminant infection with streptococcus pyogenes presented with primary peritonitis Journal of Japan Surgical Association 2003 64 2879 2882 10.3919/jjsa.64.2879 \n3 Gando S. Iba T. Eguchi Y. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria Critical Care Medicine 2006 34 3 625 631 10.1097/01.ccm.0000202209.42491.38 2-s2.0-33644589346 16521260 \n4 Vincent J.-L. Moreno R. Takala J. The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine Intensive Care Medicine 1996 22 7 707 710 10.1007/s001340050156 2-s2.0-0030015661 8844239 \n5 Lamagni T. L. Neal S. Keshishian C. Predictors of death after severe Streptococcus pyogenes infection Emerging Infectious Diseases Journal 2009 2009 1304 1307 \n6 O’Loughlin R. E. Roberson A. Cieslak P. R. The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000-2004 Clinical Infectious Diseases 2007 45 853 862 17806049 \n7 Lamagni T. L. Neal S. Keshishian C. Streptococcus pyogenes infection, United Kingdom, 2003-2004 Emerging Infectious Diseases 2008 4 2 202 209 10.3201/eid1402.070888 \n8 Robert F. Jeffrey P. Richard R. Defining the group A streptococcal toxic shock syndrome JAMA 1993 269 390 391 8418347 \n9 Nogami Y. Tsuji K. Banno K. Case of streptococcal toxic shock syndrome caused by rapidly progressive group A hemolytic streptococcal infection during postoperative chemotherapy for cervical cancer Journal of Obstetrics and Gynaecology Research 2014 40 1 250 254 2-s2.0-84897062245 10.1111/jog.12126 23937219 \n10 Nishida O. Ogura Y. Inoue S. The Japanese clinical practice guidelines for management of sepsis and septic shock 2016 The Japanese Society of Intensive Care Medicine 2016 24 1 232 \n11 Darenberg J. Ihendyane N. Sjölin J. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial Clinical Infectious Diseases 2003 37 3 851 857 10.1086/376630 2-s2.0-0041402681 \n12 Hamano N. Nishi K. Onose A. Efficacy of single-dose intravenous immunoglobulin administration for severe sepsis and septic shock Journal of Intensive Care 2013 1 1 10.1186/2052-0492-1-4 \n13 Horstmann R. D. Sievertsen H. J. Knobloch J. Fischetti V. A. Antiphagocytic activity of streptococcal M protein: Selective binding of complement control protein factor H Proceedings of the National Acadamy of Sciences of the United States of America 1988 85 5 1657 1661 2-s2.0-0343017792 10.1073/pnas.85.5.1657 2964038 \n14 Shozushima T. Takahashi G. Matsumoto N. Kojika M. Okamura Y. Endo S. Usefulness of presepsin (sCD14-ST) measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome Journal of Infection and Chemotherapy 2011 17 6 764 769 2-s2.0-84855279657 10.1007/s10156-011-0254-x 21560033 \n15 Nakamura Y. Ishikura H. Nishida T. Usefulness of presepsin in the diagnosis of sepsis in patients with or without acute kidney injury BMC Anesthesiology 2014 4 14 p. 88 2-s2.0-84922244491 \n16 Nakamura Y. Hoshino K. Kiyomi F. Comparison of accuracy of presepsin and procalcitonin concentrations in diagnosing sepsis in patients with and without acute kidney injury Clinica Chimica Acta 2019 490 200 206 10.1016/j.cca.2018.09.013 \n17 Takahashi G. Shibata S. Fukui Y. Okamura Y. Inoue Y. Diagnostic accuracy of procalcitonin and presepsin for infectious disease in patients with acute kidney injury Diagnostic Microbiology and Infectious Disease 2016 86 2 205 210 10.1016/j.diagmicrobio.2016.07.015 2-s2.0-84989813301 27489118\n\n",
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"issue": "2019()",
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"title": "A Patient of Using Presepsin to Diagnose Streptococcal Toxic Shock Syndrome during Anticancer Drug Treatment.",
"title_normalized": "a patient of using presepsin to diagnose streptococcal toxic shock syndrome during anticancer drug treatment"
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"abstract": "BACKGROUND\nIt has been suggested that the risk for cerebral venous sinus thrombosis (CVST) may be greater among users of the contraceptive patch than among users of oral contraceptives (OCs).\n\n\nMETHODS\nFrom the PharMetrics database, we identified women aged 15-44 years who filled at least one prescription for either the contraceptive patch or desogestrel-containing, norgestimate-containing or levonorgestrel-containing OCs to assess the risk of CVST. The person-time of current exposure to each study drug, as well as the incidence rates (IRs) and incidence rate ratios (IRRs) of CVST, was calculated.\n\n\nRESULTS\nWe identified over 1 million users of the four study drugs. There were five cases of CVST among current users of desogestrel, seven cases among current users of norgestimate, two cases among current users of levonorgestrel and none among current users of the contraceptive patch. The IRs per 100,000 woman-years were 2.7 [95% confidence interval (95% CI)=0.9-6.3], 1.6 (95% CI=0.7-3.3), 0.7 (95% CI=0.1-2.4) and 0.0 (95% CI=0.0-4.8), respectively, in users of desogestrel, norgestimate, levonorgestrel and the contraceptive patch. There were two women who had CVST while not currently taking a hormonal contraceptive (IR=0.4 per 100,000 woman-years; 95% CI=0.1-1.3). The IRRs were 4.0 (95% CI=0.7-42.4) for desogestrel-containing versus levonorgestrel-containing OCs, and 2.4 (95% CI=0.5-24.0) for norgestimate-containing versus levonorgestrel-containing OCs. The IRR for the patch could not be calculated.\n\n\nCONCLUSIONS\nThere is no evidence of an increased risk of CVST in users of the contraceptive patch compared to users of levonorgestrel-containing OCs.",
"affiliations": "Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, Lexington, MA 02421, USA. sjick@bu.edu <sjick@bu.edu>",
"authors": "Jick|Susan S|SS|;Jick|Hershel|H|",
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"title": "Cerebral venous sinus thrombosis in users of four hormonal contraceptives: levonorgestrel-containing oral contraceptives, norgestimate-containing oral contraceptives, desogestrel-containing oral contraceptives and the contraceptive patch.",
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"abstract": "Psychiatric disorders are increasingly understood as dysfunctions of hyper- or hypoconnectivity in distributed brain circuits. A prototypical example is obsessive compulsive disorder (OCD), which has been repeatedly linked to hyper-connectivity of cortico-striatal-thalamo-cortical (CSTC) loops. Deep brain stimulation (DBS) and lesions of CSTC structures have shown promise for treating both OCD and related disorders involving over-expression of automatic/habitual behaviors. Physiologically, we propose that this CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP). Here we report the results from the pilot patient in an Early Feasibility study (https://clinicaltrials.gov/ct2/show/NCT03184454) in which we use the Medtronic Activa PC+ S device to simultaneously record and stimulate in the supplementary motor area (SMA) and ventral capsule/ventral striatum (VC/VS). We hypothesized that frequency-mismatched stimulation should disrupt coherence and reduce compulsive symptoms. The patient reported subjective improvement in OCD symptoms and showed evidence of improved cognitive control with the addition of cortical stimulation, but these changes were not reflected in primary rating scales specific to OCD and depression, or during blinded cortical stimulation. This subjective improvement was correlated with increased SMA and VC/VS coherence in the alpha, beta, and gamma bands, signals which persisted after correcting for stimulation artifacts. We discuss the implications of this research, and propose future directions for research in network modulation in OCD and more broadly across psychiatric disorders.",
"affiliations": "Department of Psychiatry, Medical School, University of Minnesota Twin Cities, Minneapolis, MN, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;McLean Institute for Technology in Psychiatry and Harvard Medical School, Belmont, MA, United States.;McLean Institute for Technology in Psychiatry and Harvard Medical School, Belmont, MA, United States.;McLean Institute for Technology in Psychiatry and Harvard Medical School, Belmont, MA, United States.;McLean Institute for Technology in Psychiatry and Harvard Medical School, Belmont, MA, United States.;Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States.;McLean Institute for Technology in Psychiatry and Harvard Medical School, Belmont, MA, United States.;Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States.;Department of Psychiatry, Medical School, University of Minnesota Twin Cities, Minneapolis, MN, United States.",
"authors": "Olsen|Sarah T|ST|;Basu|Ishita|I|;Bilge|Mustafa Taha|MT|;Kanabar|Anish|A|;Boggess|Matthew J|MJ|;Rockhill|Alexander P|AP|;Gosai|Aishwarya K|AK|;Hahn|Emily|E|;Peled|Noam|N|;Ennis|Michaela|M|;Shiff|Ilana|I|;Fairbank-Haynes|Katherine|K|;Salvi|Joshua D|JD|;Cusin|Cristina|C|;Deckersbach|Thilo|T|;Williams|Ziv|Z|;Baker|Justin T|JT|;Dougherty|Darin D|DD|;Widge|Alik S|AS|",
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"doi": "10.3389/fnhum.2020.569973",
"fulltext": "\n==== Front\nFront Hum Neurosci\nFront Hum Neurosci\nFront. Hum. Neurosci.\nFrontiers in Human Neuroscience\n1662-5161 Frontiers Media S.A. \n\n10.3389/fnhum.2020.569973\nNeuroscience\nClinical Trial\nCase Report of Dual-Site Neurostimulation and Chronic Recording of Cortico-Striatal Circuitry in a Patient With Treatment Refractory Obsessive Compulsive Disorder\nOlsen Sarah T. 1* Basu Ishita 23 Bilge Mustafa Taha 23 Kanabar Anish 23 Boggess Matthew J. 23 Rockhill Alexander P. 23 Gosai Aishwarya K. 23 Hahn Emily 23 Peled Noam 2 Ennis Michaela 4 Shiff Ilana 4 Fairbank-Haynes Katherine 4 Salvi Joshua D. 4 Cusin Cristina 3 Deckersbach Thilo 23 Williams Ziv 5 Baker Justin T. 4 Dougherty Darin D. 23† Widge Alik S. 1† 1Department of Psychiatry, Medical School, University of Minnesota Twin Cities, Minneapolis, MN, United States\n2Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States\n3Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States\n4McLean Institute for Technology in Psychiatry and Harvard Medical School, Belmont, MA, United States\n5Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States\nEdited by: Michael S. Okun, University of Florida Health, United States\n\nReviewed by: Sameer A. Sheth, Baylor College of Medicine, United States; Ludvic Zrinzo, University College London, United Kingdom\n\n*Correspondence: Sarah T. Olsen, olsen378@umn.edu†These authors share senior authorship\n\nThis article was submitted to Brain Imaging and Stimulation, a section of the journal Frontiers in Human Neuroscience\n\n\n23 10 2020 \n2020 \n14 56997305 6 2020 15 9 2020 Copyright © 2020 Olsen, Basu, Bilge, Kanabar, Boggess, Rockhill, Gosai, Hahn, Peled, Ennis, Shiff, Fairbank-Haynes, Salvi, Cusin, Deckersbach, Williams, Baker, Dougherty and Widge.2020Olsen, Basu, Bilge, Kanabar, Boggess, Rockhill, Gosai, Hahn, Peled, Ennis, Shiff, Fairbank-Haynes, Salvi, Cusin, Deckersbach, Williams, Baker, Dougherty and WidgeThis 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.Psychiatric disorders are increasingly understood as dysfunctions of hyper- or hypoconnectivity in distributed brain circuits. A prototypical example is obsessive compulsive disorder (OCD), which has been repeatedly linked to hyper-connectivity of cortico-striatal-thalamo-cortical (CSTC) loops. Deep brain stimulation (DBS) and lesions of CSTC structures have shown promise for treating both OCD and related disorders involving over-expression of automatic/habitual behaviors. Physiologically, we propose that this CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP). Here we report the results from the pilot patient in an Early Feasibility study (https://clinicaltrials.gov/ct2/show/NCT03184454) in which we use the Medtronic Activa PC+ S device to simultaneously record and stimulate in the supplementary motor area (SMA) and ventral capsule/ventral striatum (VC/VS). We hypothesized that frequency-mismatched stimulation should disrupt coherence and reduce compulsive symptoms. The patient reported subjective improvement in OCD symptoms and showed evidence of improved cognitive control with the addition of cortical stimulation, but these changes were not reflected in primary rating scales specific to OCD and depression, or during blinded cortical stimulation. This subjective improvement was correlated with increased SMA and VC/VS coherence in the alpha, beta, and gamma bands, signals which persisted after correcting for stimulation artifacts. We discuss the implications of this research, and propose future directions for research in network modulation in OCD and more broadly across psychiatric disorders.\n\nneurostimulationcortico-striatal circuitryobsessive compulsive disorderventral capsule/ventral striatumsupplementary motor areaneural oscillationssynchronylocal field potentialNational Institutes of Health10.13039/100000002UH3-NS100548-01National Institutes of Health10.13039/100000002U01MH116925\n==== Body\nIntroduction\nObsessive compulsive disorder (OCD) is a chronic and severe psychiatric condition characterized by recurrent and intrusive thoughts, images, or fears which produce marked distress or anxiety (obsessions), and the performance of repetitive mental or physical rituals in response to that anxiety (compulsions). Individuals with OCD experience frequent and significant social impairments (Koran et al., 1996). Roughly 40% of individuals living with OCD report being unable to work (Mancebo et al., 2008). Standard treatments include exposure and response prevention therapy (ERP; e.g., Foa et al., 2005), and pharmacological interventions (e.g., Fineberg and Gale, 2005). Unfortunately, 30–60% of individuals will fail to respond adequately to treatment. Even those who do respond to treatment are often left with some level of residual symptoms (Pallanti et al., 2002; Foa et al., 2005; Dougherty et al., 2018).\n\nFor those treatment refractory individuals, neurostimulation, and in particular deep brain stimulation (DBS), is an option. Current neurostimulation therapies arose from the success of psychiatric neurosurgery procedures in which areas of the internal capsule were lesioned, with modern versions of those surgeries having open-label response rates as high as 80% (Brown et al., 2016; Dougherty et al., 2018; Rasmussen et al., 2018; Spatola et al., 2018). Given the irreversible nature of lesion surgeries, neurostimulation was proposed as a reversible option, which has greater customizability than the one-size-fits-all lesion surgeries (Nuttin et al., 1999). Early approaches in the internal capsule evolved into the current ventral capsule/ventral striatum target (VC/VS; Greenberg et al., 2010; Karas et al., 2019; for reports using different names for a similar target see: Luyten et al., 2016; Raymaekers et al., 2017). The VC/VS target is located at a putative junction of the anterior commissure, internal capsule, and striatum (Greenberg et al., 2010). Positive outcomes seen in early open label studies (Greenberg et al., 2010) led the VC/VS target to receive Humanitarian Device Exemption (HDE) approval for OCD in 2009 (approval H050003).\n\nResponse and symptom improvement rates with VC/VS DBS are promising, but there is much room for improvement. Reported (Luyten et al., 2016) and non-reported (NCT00640133) randomized controlled trials, as well as open-label trials (Menchón et al., 2019) have shown response rates of around 67% (response is considered a 35% drop in Yale-Brown Obsessive Compulsive Scale – YBOCS). This means that over 30% of individuals did not respond. These studies also found median improvement in YBOCS of 40–60 percent, with a median score of 20 with active stimulation. Critically, a YBOCS of 20 represents a level of symptom severity that often prevents the individual from working (Mancebo et al., 2008). In a qualitative survey of patient perspectives on VC/VS DBS, the majority of patients (86%) cited incomplete or unreliable symptom relief as their primary dissatisfaction with VC/VS DBS (Klein et al., 2016). Therefore, there is a need to advance neurostimulation to produce a more consistent response, and a higher level of effectiveness.\n\nImproving Neurostimulation for OCD: Potential for Targeted Network Disruption Through Dual-Site Stimulation\nObsessive compulsive disorder is thought to be a network disorder. There is some consensus that dysfunction of the cortico-striatal-thalamo-cortical loops (CSTC loops; e.g., Alexander et al., 1986; Parent and Hazrati, 1995), of which VC/VS (and the striatum, more generally) is a hub (Alexander et al., 1986; Obeso et al., 2008; Krack et al., 2010; Lapidus et al., 2013; Dougherty et al., 2018), is involved in the etiology of OCD (see Dougherty et al., 2018; Robbins et al., 2019 for reviews). Structures outside these loops (e.g., amygdala) also likely play key roles in OCD in at least some patients (Milad and Rauch, 2012; Gürsel et al., 2018; Hazari et al., 2019; Robbins et al., 2019). That said, CSTC loop dysfunction almost certainly plays at least a partial role in OCD. Further, individuals with OCD show deficits in cognitive domains (e.g., cognitive flexibility; Robbins et al., 2012; Shin et al., 2014; Voon et al., 2015; Vaghi et al., 2017) that are thought to involve CSTC loop function (Haber, 2003; Robbins et al., 2012, 2019; Vaghi et al., 2017).\n\nThe dominant narrative of CSTC dysfunction in OCD emphasizes CSTC hyper-connectivity (e.g., Dougherty et al., 2018; Calzà et al., 2019). There are many functional neuroimaging studies showing heightened connectivity between regions within CSTC loops (Graybiel and Rauch, 2000; Maia et al., 2008; Milad and Rauch, 2012; Brennan and Rauch, 2017; Dougherty et al., 2018). These have been considered to be further supported by robust results showing striatal hyper-activations in OCD (Robbins et al., 2019), but it is important to recognize that activity and connectivity are entirely separate constructs. A given region may have radically disrupted connectivity without any change in its overall level of activity. In that vein, some studies have linked OCD pathology to hypo- rather than hyper-connectivity within CSTC loop components (Göttlich et al., 2014; Posner et al., 2014; Vaghi et al., 2017). A recent meta-analysis concluded that there is evidence of general aberrant activity in CSTC loops, but that that disconnectivity was not in any specific direction- hypo or hyper (Gürsel et al., 2018). Hyper- versus hypoconnectivity seems to be, in part, a function of which functionally distinct CSTC loop the regions are in Harrison et al. (2009); Göttlich et al. (2014), Posner et al. (2014), and Vaghi et al. (2017), as well as the specifics of the experiment and patient population (Göttlich et al., 2014; Robbins et al., 2019). Despite differences, one common thread through the literature is the presence of a complex pattern of aberrant brain network communication in individuals with OCD. VC/VS DBS is believed to alter this pathological CSTC circuit function. For example, it alters cerebral glucose use in individuals with OCD (Rauch et al., 2006; Dougherty et al., 2016), and those alterations correlate with depressive (but not OCD) symptoms (Dougherty et al., 2016). Other groups have reported changes in cortico-striatal connectivity on functional MRI (Figee et al., 2013) or improvement in CSTC-related cognitive function after VC/VS DBS (Widge et al., 2019).\n\nThus, it may be possible to make VC/VS DBS more effective by identifying ways of more strongly disrupting targeted CSTC loops. Physiologically, this may mean disruption of abnormal oscillatory synchrony in the local field potential (LFP). LFP oscillations are argued to underlie many processes, including working memory, and even cognition in general (e.g., Miller et al., 2018). Oscillatory activity can be synchronous, or coherent, between brain regions, and this synchrony has been proposed to be a primary means by which regions in a circuit communicate (Fries, 2005, 2015). If this model holds and oscillatory synchrony is an index of communication between brain regions, then there may be CSTC hypersynchrony in individuals with OCD. High theta and beta subthalamic nucleus (STN) to cortical coherence has been reported in an individual with OCD (Wojtecki et al., 2017; using cortical MEG), but the synchrony theory has not been investigated within CSTC circuitry. In this way, establishing whether CSTC hypersynchrony exists in OCD may be a critical next step in understanding the disorder, improving treatments, and identifying useful biomarkers.\n\nSimilarly, disruption of oscillatory synchrony may be a mechanism of clinical DBS (Widge and Miller, 2019). For instance, in Parkinson’s disease, there is increased beta band activity in the STN, that beta power decreases with active DBS (Wingeier et al., 2006; Bronte-Stewart et al., 2009), and this decrease is in turn correlated with symptom improvement (Kühn et al., 2006, 2008; Ray et al., 2008). DBS in Parkinson’s specifically alters network-level LFP synchrony. For example, De Hemptinne et al. (2015) found a reduction in phase-amplitude coupling in the cortex with STN DBS in Parkinson’s patients, while Oswal et al. (2016) reported a reduction in cortico-STN coherence. In animal models, optogenetic neurostimulation increased oscillatory synchrony between brain regions, which was in turn causally linked to both changes in behavior and neurotransmission (Padilla-Coreano et al., 2019). To the degree that CSTC hyper-connectivity is reflected in hyper-synchrony, new stimulation methods to disrupt that synchrony may significantly improve the effectiveness of DBS (Widge and Miller, 2019).\n\nTherefore, we proposed that delivering frequency mismatched stimulation to multiple areas within a CSTC circuit would disrupt OCD-related hypersynchrony/hyperconnectivity more effectively than single site simulation. Stimulation resets the phase of neural oscillations (e.g., Rosanova et al., 2018). Stimulating two regions at mismatched frequencies should thus disrupt synchrony, by preventing the phase of the oscillations in the two regions from aligning. The supplementary motor area (SMA) is a particularly promising second target for this mismatched stimulation. While traditionally associated with the motor CSTC loop (e.g., Nakano et al., 2000; Obeso et al., 2008), the SMA (and medial prefrontal cortex, more generally) also participates in decision-making linked to limbic/associative CSTC loops (Milad and Rauch, 2012; Dougherty et al., 2018). Further, transcranial magnetic stimulation (TMS) of the SMA is an effective treatment for individuals with severe OCD (Mantovani et al., 2010; Gomes et al., 2012; Carmi et al., 2018, 2019), implicating this area in the neuropathology of the disorder. Given the CSTC hyperconnectivity hypothesis, we hypothesized that OCD symptoms would be reflected in heightened coherence between these two regions. Further, we hypothesized that mismatched stimulation would break this hyper-coherence between VC/VS and SMA.\n\nHere, we report the first patient in an early feasibility study1 combining VC/VS DBS with frequency mismatched stimulation of SMA in an effort to disrupt CSTC synchrony in treatment refractory OCD. The patient first received open-label VC/VS only stimulation, followed by a blinded phase of combined cortical and VC/VS stimulation, and finally an open-label combined stimulation phase. During the course of the study, daily LFP recordings from VC/VS and SMA were taken, allowing for the first known chronic recording of a cortico-striatal circuit in human. Using these recordings, we tested the hypersynchrony hypothesis, as well as the hypothesis that frequency mismatched stimulation could disrupt that hypersynchrony. These results are an important proof-of-principle toward understanding the mechanism of action for OCD neurostimulation, identifying biomarkers, and improving treatment.\n\nPatient History: Diagnoses, Symptoms, and Previous Treatment\nThe patient was a male in his 20s, who had previously received VC/VS DBS for treatment refractory OCD. Prior to the initial DBS surgery, the patient’s YBOCS was 29. He reported onset of OCD symptoms at approximately age 12–13, primarily of a mental ritualizing/obsessional type. Obsessions have included his symptoms themselves, counting, and symmetries. The patient had a past history of object-touching/rearranging compulsions, but at the time of his first course of DBS, he reported only mental rituals. Further, his OCD symptoms had sometimes been body-focused in ways that raised questions of body dysmorphic disorder (BDD).\n\nPrior to beginning the first course of DBS, the patient was also diagnosed with treatment-resistant depression, with a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) of 36. He reported substantial low mood and anhedonia, for the prior several years, combined with substantial anxiety. Symptoms also included difficulty concentrating when not using stimulants, low energy, some psychomotor slowing, and profound emotional numbing. The patient denied frank suicidality but had frequent thoughts/wishes of being dead. He had also previously carried the diagnosis of bipolar disorder, with past clinicians stating there were brief periods of hypomania. However, clinicians at the time of his first DBS surgery felt that symptoms previously labeled as hypomania were more correctly attributable to OCD/anxiety related racing thoughts. There were no identifiable distinct episodes of impulsivity, goal-directed activity, or decreased need for sleep.\n\nThe patient had been receiving weekly or biweekly cognitive behavioral therapy (CBT) and exposure with response prevention (ERP) for five years prior to the onset of his first course of DBS, conducted in a private practice. At the time of surgery, the patient continued that therapy with the same clinician, and was able to display numerous mindfulness and distress tolerance techniques.\n\nThe patient had also tried numerous serotonergic and dopaminergic medications: Paroxetine (four weeks), citalopram (2 weeks), mirtazapine (unknown time frame), fluoxetine (several weeks), lorazepam (unknown time frame), clomipramine (unknown time frame) were all trialed and discontinued due to intolerability of side effects. At the time of surgery the patient’s medications included: Fluvoxamine (400 mg), lithium (900 mg), amphetamine salt (20 mg), levomefolic acid (22.5 mg), lamotrigine (300 mg), olanzapine (27.5 mg) and levothyroxine (150 mcg). Additionally, the patient had undergone a course of rTMS for depression that he had not found helpful. At the time of his first DBS surgery, the patient had been undergoing bi-weekly maintenance electroconvulsive therapy (ECT) for depression, and had received around 50 sessions over the course of 2 years. The patient had found ECT to give him a slight mood lift. Despite these treatments, the patient continued to experience significant functional impairment, unable to attend community college, maintain significant employment, or live independently.\n\nRoughly 3 years prior to enrollment in the present study the patient began his first course of bilateral VC/VS DBS treatment for OCD and depression. He showed initial improvement reaching his lowest YBOCS, 14, about 6 months after implantation. The patient’s MADRS dropped significantly as well, with his lowest score of 18 recorded over 2 years after surgery. However, this improvement was not sustained. Generally, his YBOCS was in the mid-to-high 20 s, and his MADRS in the high 20 s, to low 30 s. By the time of enrollment in the present study, his YBOCS and MADRS were back to baseline levels (27 and 37, respectively). Given that the patient was still experiencing significant functional impairment, a multidisciplinary review committee (Widge and Dougherty, 2015) felt that the patient met criteria for inclusion in the present study (full criteria are at https://clinicaltrials.gov/ct2/show/NCT03184454).\n\nMaterials and Methods\nAll study procedures described below were reviewed and approved by the Institutional Review Board at Massachusetts General Hospital. The study was conducted under an Investigational Device Exemption from the US Food & Drug Administration (FDA).\n\nSurgery and Electrode Placement\nThe patient was implanted with bilateral electrodes targeting the VC/VS and SMA. VC/VS electrodes were implanted first, followed by SMA electrodes through the same burr hole. For VC/VS, the patient’s previously implanted leads (Medtronic model 3387 lead) were first removed, as we sought to use larger contacts to more efficiently activate capsular white matter and reach fibers running in the dorsal capsule. Using standard stereotactic surgery procedures, and coregistration of MRI and CT images, Medtronic model 3391 leads were implanted bilaterally targeting VC/VS. We sought to place contact 0 within the gray matter of the ventral striatum, 2 mm anterior to the posterior border of the anterior commissure. The lead trajectory was aligned with the internal capsule, so that contact 3 would be in the capsular white matter immediately adjacent to the caudate nucleus. Before securing the lead, we tested bipolar stimulation at up to 6 V (130 Hz, 150 μs pulse width) between all pairs of contacts, without adverse effects. There was no intraoperative hedonic or mirthful response.\n\nCortical paddles (Medtronic model 3986, Resume 4-contact paddle lead) were placed under direct visualization through the burr holes used to place the VC/VS electrodes. The surgeon (ZW) retracted the underlying cortex inferiorly and placed the paddles on the dorsal surface of the superior frontal gyrus (SFG). In this first patient, cortical lead placement was purely empirical, targeting the SFG just anterior to the motor strip, guided by the cortical landmarks visible to the surgeon. As with the deep leads, we performed test stimulations (50 and 130 Hz, 150 μs) at up to 4V through the cortical electrode to verify lack of adverse events. Before securing the electrodes, we recorded local field potentials (LFP) from both the deep and surface leads in each hemisphere through the intraoperative monitoring system (NeuroOmega, Alpha-Omega Systems, Nazareth, Israel; see Data Collection section below for more details). DBS and paddle electrodes were then secured using sutures on the dural edge, and burr holes were sealed with cranioplasty material. Final lead placement was confirmed by intraoperative x-ray, and post-operative CT scan. See Figure 1 for final lead locations.\n\nFIGURE 1 Images of the DBS and paddle leads rendered with the Multi-Modality Visualization Tool (Felsenstein and Peled, 2017; Felsenstein et al., 2019). Position of left (red) and right (blue) SMA leads, and left (green) and right (yellow) VC/VS leads. Brodmann Area 6 is colored in turquoise. (A) coronal slice showing position of VC/VS leads (subcortical regions not colored). (B) Angled view with cortical coronal slice. Caudate nucleus colored in green, nucleus accumbens (Nacc) in blue, and putamen in pink. (C) Superior view (left on top) showing cortical lead positions. Note: the right VC/VS lead is in the caudate nucleus and NAcc whereas the left VC/VS lead is more laterally placed in the putamen. No adverse effects of lead placement were observed with the patient.\n\nIn a subsequent surgery on the following day, two infraclavicular pulse generators (IPG; Medtronic Activa PC + S) were implanted bilaterally in the patient’s chest. The PC + S system was selected for it’s sensing/recording capabilities (discussed below). Given that the IPGs were only able to deliver pulses at one frequency to leads attached to the same device, the two VC/VS electrodes were attached to one device, and cortical electrodes were attached to the second device.\n\nStudy Phases and Stimulation Parameters\nOver the course of almost 2 years, the patient progressed through several phases of a single-blind randomized cross-over study (see Figure 2 for timing of each study phase). In the VC/VS optimization phase (study days 0 to 172, as measured by the days since operation), he only received VC/VS stimulation. We identified the initial most effective contact and titrated VC/VS stimulation voltage according to the algorithm in Widge and Dougherty (2015). This also served as a baseline period in which cortical-striatal synchrony was measured in the absence of combined, mismatched stimulation. The original protocol called for a 2-week baseline phase after IPG implant, and preceding the VC/VS optimization phase, in which the pattern of LFP oscillations in the absence of stimulation could be established. However, on the day after the IPG was implanted, while recovering in the hospital, the patient reported depression and suicidality. He stated that this was due to withdrawal of his prior DBS therapy, that he was certain it would not be tolerable, and that he could not maintain his personal safety for any period of time. Consistent with the study protocol’s directives that suicidality was a reason to escape a patient from any given phase/procedure, his VC/VS leads were thus activated early. Thereafter, the patient declined to permit deactivation of VC/VS stimulation, even if only for a few moments, making stimulation-off recordings impossible to obtain.\n\nFIGURE 2 Figure depicts the timeline of study phases, changes in stimulation or recording parameters, and collection of clinical measures and LFP recordings. The x-axis values are days since the operation, and the ticks/labels denote days of clinical programming sessions. Note that there was no chronic cortical stimulation until day 235.\n\nIn the blinded cortical crossover phase (days 172–270) the patient had biweekly clinical visits with the unblinded programmer (DDD). During one of these sessions (day 235), cortical stimulation was activated, unknown to the patient or to the researchers obtaining rating scales. At the onset of this phase (day 172), we performed an acute cortical optimization in which we identified cortical stimulation parameters. During the cortical optimization, the VC/VS electrodes remained on, using the same contact as previously programmed for clinical therapy, but set to a frequency of 135, 55, or 15 Hz. For each of those VC/VS frequencies, we programmed the ipsilateral cortical stimulation to a corresponding (slightly mismatched) frequency of 130, 50, or 10 Hz, respectively. The 5 Hz difference between frequencies was selected because this was the only spacing that could be achieved consistently at all three frequency bands given the limits of the pulse generator (at higher frequencies, only steps of 5 Hz were possible).\n\nWe then tested each contact of the cortical electrode, in a monopolar configuration, at 2, 4, and (if tolerated) 6 V. At each setting, the patient rated the change in his mood, anxiety, and overall energy level on a 1–10 scale. The settings producing the best clinical effect were retained, but the cortical electrodes/IPG remained inactive until the actual crossover at day 235. During the cortical optimization procedure, no evidence of seizure activity was detected by clinicians. This is unsurprising, as chronic epicortical stimulation has been trialed in psychiatric patients in multiple studies without epileptic complications (Kopell et al., 2011; Williams et al., 2016). In the open label, unblinded cortical phase (days 270–606) the blind was broken on the cortical stimulation while the patient continued to receive combined stimulation. The full course of the study ranged from day 0, or the day of surgery, to day 606, at which point the battery for the VC/VS IPG reached the cut-off for minimum battery life required to take recordings.\n\nVC/VS stimulation parameters can be seen in Figure 2. The patient received constant unipolar stimulation at contact 0 (left hemisphere) and contact 2 (right hemisphere). VC/VS stimulation frequency was 135 Hz. VC/VS stimulation pulsewidth was 150 and 90 μs for left and right hemispheres, respectively. VC/VS stimulation voltage was gradually increased to 2.5 and 4.5 V for left and right hemispheres, respectively, during the VC/VS optimization phase.\n\nCortical stimulation parameters can be seen in Figure 2. From day 235 until day 403, the patient received constant unipolar stimulation at contact 1 (left hemisphere) and contact 2 (right hemisphere) of the cortical paddles. Cortical stimulation frequency was 130 Hz during the blinded cortical phase, until approximately 2 weeks after the patient was unblinded (from day 235 to 291). Due to patient complaints of what he described as “overstimulation,” the stimulation frequency was reduced to 100 Hz at day 291, where it remained for the remainder of the study. Complaints of “overstimulation” also resulted in the patient beginning day-night cycling of his cortical stimulation (turning it off at night) at day 403. See section “Clinical outcomes with deep brain and combined stimulation” for a more detailed description of the patient’s feelings of overstimulation. Cortical stimulation pulsewidth was 90 μs. Voltage ranged from 4 to 5.1 V for the left hemisphere, and from 2 to 3.1 V for the left hemisphere, limited in both cases by anxious distress at higher voltages.\n\nImpedances were measured during clinical visits, and were within normal ranges. Mean (SD) impedance was 777.46 (18.54) Ω for the left VC/VS lead, 761.12 (42.89) Ω for right VC/VS, 757.64 (22.25) Ω for left cortical, and 1144.46 (79.22) Ω for the left cortical lead. There were no dramatic shifts in impedance throughout the study, and changes in impedance did not correspond to changes in power spectra.\n\nData Collection\nClinical Outcome Measures\nClinical sessions occurred approximately every 2 weeks (see Figure 2). Stimulation settings were adjusted only during these sessions. The primary outcome variable was the YBOCS (Goodman et al., 1989). Key secondary outcomes were MADRS (Montgomery and Åsberg, 1979) and patient global impression of improvement (PGI-I; Yalcin and Bump, 2003). All were collected during the biweekly clinical sessions.\n\nEcological Momentary Assessment (EMA)\nMidway through the present study, the patient enrolled in a separate study. The purpose of that study was to use data from the patient’s smartphone to obtain a more continuous measure of functioning than the sporadic clinical ratings. Among other measures, this study collected ecological momentary assessments (EMAs; Shiffman et al., 2008). Data collection for the EMA study began 151 days following surgery, with the first EMA collected 235 days following surgery. The EMA contained eight questions regarding the patient’s motivation and ability to perform tasks (e.g., “In the past 24 h; it was difficult for me to get anything done,” or “It was difficult for me to complete my morning routine”). These prompts were derived from the patient’s report of his primary symptoms. Questions were scored on a scale from 0 to 4, with 0 indicating the highest level of functioning (e.g., “extremely easy”) and 4 indicating the lowest level of functioning (e.g., “extremely difficult”). The scores for the eight questions were averaged to create a summary EMA score. The patient was prompted to take the EMA at least once a day but could choose not to participate.\n\nMulti-Source Interference Task (MSIT)\nDuring several clinical sessions (on days 13, 104, 216, 335, and 448, see Figure 2) the patient performed the Multi-Source Interference Task (MSIT; Bush et al., 2003; Bush and Shin, 2006). Considered to measure cognitive control, the MSIT produces robust subject-level behavioral and neural effects (Bush et al., 2003, preprint; Bush and Shin, 2006; González-Villar and Carrillo-de-la-Peña, 2017; Widge et al., 2019), which can be modulated through DBS of CSTC circuitry (Basu et al., preprint; Widge et al., 2019).\n\nDuring an MSIT trial three numbers (between 0 and 3) were presented on the screen. Two of these numbers had the same value, and the other was different (e.g., 020 or 233). The patient’s task was to identify, via button press, the identity of the number that was unique, not its position. Trials were either congruent or incongruent. In congruent trials (e.g., 020), the unique number was in the same position as it’s corresponding keyboard position, and the other numbers were always ‘0’, which was never a valid response. In incongruent trials (e.g., 233) the unique number was in a different position than its corresponding position, and the non-unique numbers were always one of the other valid responses, such that incongruent trials contained multiple types of interference (position and response). Congruent and incongruent trials were presented together in a pseudo-randomized fashion, such that no more than two trials in a row ever shared the same condition or correct response finger. The patient performed 8 blocks of 48 trials each, for a total of 384 trials per run of the MSIT. The task was run using the Psychophysics Toolbox (Kleiner et al., 2007).\n\nWe analyzed MSIT response time (RT), as task accuracy is very high, and previous effects of DBS on MSIT performance have been shown in response time data. We grouped MSIT runs based on the stimulation phase/condition: VC/VS only stimulation with non-optimized settings (non-optimized VC/VS), VC/VS only stimulation after settings had been optimized (optimized VC/VS), and combined VC/VS and cortical stimulation (combined). Note that we only have MSIT runs during 100 Hz cortical stimulation. Trials were removed from analysis based on the criteria used in Widge et al. (2019). Namely, error and post-error (i.e., trials following an incorrect response) trials, as well as trials with RTs with a likelihood of less than 0.005 based on a fitted gamma distribution. We excluded 130 trials (0.07% of total trials), leaving 1790 trials in the analysis. Following Widge et al. (2019), we analyzed trial-wise RT in a generalized linear model (GLM) using a gamma distribution and identity link function, with conflict (congruent and incongruent) and stimulation condition (non-optimized VC/VS, optimized VC/VS, and combined) condition as the fixed effects. Collinearity between day since operation and stimulation condition was high. Further, adding day to the model containing conflict condition and stimulation condition (i.e., adding day to RT ∼ conflict condition + stimulation condition) did not add significant explanatory power (F = 2.32, p = 0.13), whereas doing the same for stimulation condition (i.e., adding stimulation condition to RT ∼ conflict condition + day since operation) did add significant explanatory power (F = 24.23, p < 0.0001). For these reasons we opted not to include day since operation in the reported model.\n\nConflict adaptation, or Gratton effect (Gratton et al., 1992), has been shown to be modulated by CSTC connected regions (Sheth et al., 2012). The patient failed to show the typical effect (slower RT when switching from a low conflict to a high conflict condition versus no switch), and therefore we did not examine changes in this effect across treatment.\n\nIntraoperative Local Field Potential (LFP) Recordings\nAs stated previously, the high resolution intraoperative monitoring system (NeuroOmega, Alpha-Omega Systems, Nazareth, Israel) was used to record LFPs intraoperatively, after the electrodes had been implanted. We recorded simultaneously from all cortical and striatal contacts, with separate recordings for the left and right hemispheres. Two recordings per hemisphere were taken. Each recording was 2.25–2.5 min, with a sampling rate of 1000 Hz. LFP recordings were referenced against a needle electrode in the scalp.\n\nDaily Local Field Potential (LFP) Recordings\nDaily timer triggered recordings were taken by the cortical and VC/VS Activa PC + S devices throughout the course of the study. Recordings were taken every 6 h, yielding four recordings per day. Recordings were from a pair of contacts (bipolar montage) not used for stimulation. Recordings were 1 min long, at a sampling rate of 200 Hz (see Figure 2 for other recording parameters). Recordings were downloaded at least every 2 weeks. Note on Figure 2 that there are brief periods during the course of the study with missing LFP data, the largest of which occurred when the patient took an extended vacation. Given the potential for drift, the internal clocks of the cortical and VC/VS IPGs were re-synchronized with the programming device at each data download.\n\nSaline Bath Testing and Artifact Subtraction\nThe recording/sensing capabilities of the Activa PC + S system have been utilized in preclinical (e.g., Connolly et al., 2015) and clinical (e.g., Swann et al., 2017; Huang et al., 2019; Veerakumar et al., 2019) studies. However, while the sensing capabilities in the PC + S system were designed to minimize the influence of stimulation artifacts, small artifacts remain (Stanslaski et al., 2012). Additionally, these original tests focused on measuring LFPs in the spectral domain; Stanslaski et al. (2012) state that results do not transfer easily to time domain, making phase-related analyses less reliable. For example, Swann et al. (2017) found broadband stimulation artifacts, as well as narrow band artifacts (with stimulation off) that were influenced by the sampling rate of recordings. Stimulation artifacts have caused some recent PC + S studies to analyze only stimulation-off recordings (e.g., Huang et al., 2019; Veerakumar et al., 2019).\n\nGiven that the recording and artifact removal capabilities of the PC + S device were not designed for our configuration (two IPGs delivering different frequency stimulation at the same time; Stanslaski et al., 2012), we specifically characterized the artifacts in our configuration in the absence of brain signal. We tested the recording and stimulation setting configurations used in the experiment in a saline preparation. We rejected the resulting artifact from the patient recordings (see LFP preprocessing and analysis below).\n\nSaline testing used two Activa PC + S IPGs, with one electrode per IPG (Medtronic model 3387 and 3391). Settings were tested by taking simultaneous recordings, with the recording and stimulation settings used for the patient’s VC/VS leads in one IPG, and the settings used for the patient’s cortical leads in the other. Due to limited availability of leads, we were able to mimic only one hemisphere of the brain with a cortical and a VC/VS lead at one time. That is, this testing captured intra-hemispheric but not cross-hemispheric artifacts. Each lead had 4 contacts and were immersed in a saline bath. Each IPG was grounded through an alligator clip that was taped to the IPG body on one end via a metal foil and a resistor on the other end that was suspended in the same saline bath as the leads. Each IPG was connected via an antenna to a Nexus-D telemetry head which was in turn connected to a laptop (Figure 3). The recording settings on the IPGs were changed using a sensing programmer (SP) while the stimulation settings were changed using a clinician programmer (CP). Before starting any recordings, we first measured the impedances of both the electrodes with the CP. We ensured good contact on all leads, with impedance below 1000 Ω on at least 3 of the 4 contacts. We verified impedances again between recordings.\n\nFIGURE 3 Schematic of saline bath preparation.\n\nWe manipulated frequency (cortical only), pulsewidth (150 μs for left VC/VS channel, 90 μs for other channels), configuration of the recording contacts (whether or not recording contacts directly flanked the stimulation contact), centering frequency, and gain (see Figure 2 for list of possible values). Sampling rate (200 Hz), and VC/VS channel frequency (135 Hz) did not vary over the course of the patient experiment, and thus were not varied in the saline test. To reduce the number of tests, only configurations used in the study were used in the saline test. We also took baseline (stimulation off) recordings, in which we assessed the change in the signal while varying only recording settings.\n\nWe took at least two recordings per setting configuration, on two separate days. Each recording was 2 min in length. We used custom written code in MATLAB to manually trigger recording in both the IPGs. Before sending the trigger command, we changed the recording settings (centering frequency, recording contact pair, gain) using the SP and the stimulation settings (stimulation current, frequency, pulse width, and lead contact) using the CP.\n\nThe saline bath recordings were preprocessed and power and synchrony were calculated using the same steps and criteria used for the patient recordings. See the LFP preprocessing and analysis section below for these criteria, and for a description of the methods used for artifact subtraction.\n\nIntraoperative LFP Preprocessing and Analysis\nWe calculated cortical-striatal synchrony for the left and right side, as a function of VC/VS depth. For the purposes of clarity/brevity and alignment with previous studies exploring cortical-striatal connectivity, we use the term cortical-striatal here, though at least one of the contacts is not technically in the striatal gray matter (but in VC/VS, more broadly). Data from the four contacts on each lead were first bipolar referenced, yielding 3 pairs. Intraoperative recordings were then epoched into one second segments, and bad epochs were identified and removed by visual inspection for artifacts. Epochs for the two recordings (from a given hemisphere) were concatenated.\n\nWe used the debiased weighted phase lag index (WPLI) as the measure of cortical-striatal synchrony. This measure was selected as a way to minimize stimulation artifacts in the daily LFP recordings from the device. Volume conduction of stimulation artifacts could create artificial synchrony between brain regions. We selected the debiased weighted phase lag index (WPLI) because it is less sensitive to this artifactual synchrony caused by volume conduction (Vinck et al., 2011). The WPLI, and other similar measures, use the principles proposed by the imaginary part of coherency (Nolte et al., 2004), which operates on the assumption that volume conduction has essentially no time lag (e.g., Stinstra and Peters, 1998), and therefore effects due to volume conduction will have zero phase lag. By using the imaginary components of the cross-spectral density, which are themselves phase shifted, phase synchrony with zero phase lag is removed (Nolte et al., 2004). The WPLI builds on the phase lag index (PLI; Stam et al., 2007), which is a measure of the asymmetry of the phase leads and lags between two signals, by weighting the contribution of phase asymmetries based on the magnitude of the imaginary component of the cross-spectral density (Vinck et al., 2011). Given that the WPLI can be positively biased (Vinck et al., 2011), the debiased estimator or squared WPLI was used.\n\nTo calculate WPLI each epoch was decomposed to its time-frequency representation (TFR) using Morlet wavelet convolution, with wavelet base frequencies from 5 to 50 Hz, in 32 logarithmically spaced steps, and the number of cycles characterizing a wavelet ranging from 3 to 7, in 32 logarithmically spaced steps. WPLI was calculated between the ipsilateral cortical and VC/VS leads.\n\nDaily LFP Preprocessing and Analysis\nLocal field potentials from the two recording contacts were bipolar re-referenced by the device internally prior to download from the IPG. All other LFP pre-processing and analysis was conducted using the MNE-Python suite (Gramfort et al., 2013).\n\nCortical and VC/VS recordings were temporally aligned using each IPG’s internal timestamp, which was reset during each data download session to reduce the amount of temporal drift. Given the reliance on the accuracy of the two devices’ timestamps, which do not have millisecond level precision, there is some uncertainty regarding the synchrony of the timing of the cortical and VC/VS signals. However, the temporal offset of the signals remains consistent within each pair of 1-min recordings. Phase synchrony is defined as a consistent phase difference, and thus can be calculated regardless of a constant shift/offset between two recordings. Only the portions of the recordings that overlapped temporally between the cortical and VC/VS IPGs were used in analysis. Therefore, while timer triggered recordings were each 1 min, the portion of the recording used in analysis was slightly less than 1 min in length. Recordings were band pass filtered between 5 and 50 Hz, in an effort to reduce the influence of stimulation artifacts. Additionally, given variations in the scale across recordings, each recording (within a channel) was normalized by scaling the band passed data to the interval from −1 to 1.\n\nSpectral Analysis\nSingle recordings (5–50 Hz bandpass, normalized) were decomposed to their time-frequency representation (TFR) using Morlet wavelet convolution, and then averaged within the approximately 1-min recording to arrive at the power spectral density (PSD) for a given recording within each channel (VC/VS left, VC/VS right, cortical left, and cortical right). TFRs were calculated with wavelet base frequencies of 5–50 Hz, in 32 logarithmically spaced steps, and the number of cycles characterizing a wavelet ranging from 3 to 7, in 32 logarithmically spaced steps. These same TFR parameters were used for the synchrony analysis.\n\nWe then subtracted the artifact signal from the recording. This was done by subtracting the PSD from the saline bath recording matching the recording/stimulation settings used in the patient recording (PSD averaged across at least two saline recordings) from the PSD of a given channel for the corresponding 1-min patient recording.\n\nFinally, for analysis of changes in power across the course of the study, we averaged the PSDs within each channel across the recordings for a single day to arrive at the average PSD for each day for the VC/VS left and right, and cortical left and right channels.\n\nCortical-Striatal Synchrony: Weighted Phase Lag Index\nTo calculate the WPLI the time-aligned, band-pass filtered, normalized recordings were epoched into one second segments. Within recording, each epoch was then decomposed to its TFR as above. WPLI was calculated between the ipsilateral cortical and striatal leads (separately for left and right hemispheres), then averaged across time to get the WPLI at each base frequency and hemisphere for a single minute recording. WPLI was calculated using the spectral connectivity function in the MNE python suite, with the wpli2_debiased option.\n\nWe then subtracted the artifactual WPLI from the left and right hemisphere WPLI of a given recording, by subtracting the WPLI across frequency from the saline bath recording matching the recording/stimulation settings used in the patient recording from the WPLI values for that 1-min patient recording.\n\nTo assess changes across the study, the WPLI from recordings on a single day were then averaged to get the average WPLI for that day for the left and right hemispheres.\n\nClinical Outcomes and WPLI Correlations\nBased on our initial hypotheses, we explored the relationship between the clinical outcome measures (YBOCS, MADRS, PGI, EMA) and cortical-striatal synchrony (WPLI) in each frequency band. We calculated the mean WPLI (left and right hemispheres averaged) within each frequency band (theta, alpha, beta, gamma) for the nearest recording day that occurred prior to the day of the corresponding clinical outcome measurement. The day prior was used for clinical outcomes (YBOCS, MADRS, PGI), as on many occasions there were also stimulation settings changes that occured on the day the measure was taken (i.e., the recordings for that day reflected the stimulation settings, not the symptom burden over the prior week). In cases where the EMA did not occur on a clinical session day, the recordings from the day the EMA was taken were used to calculate WPLI. We then correlated the WPLI in each band to the clinical measures. Given multiple comparisons for each clinical outcome, a Bonferroni corrected p-value of 0.0125 was used to determine significance.\n\nRandom Forests Using LFP Features to Predict Clinical Outcomes\nWe conducted five-fold cross validated (using five equally sized groups) random forest regressions to predict each clinical outcome measure (YBOCS, MADRS, PGI, EMA) using features of the LFP recordings, as well as some recording and stimulation settings features. The number of dependent data points for each regression depended on the instances of the given outcome (total of 39 for YBOCS and MADRS, 38 for PGI, and 215 for EMA).\n\nWe created power and WPLI features from the LFP recordings. Power and WPLI for each recording, in each band (theta, alpha, beta, or gamma) were either averaged across a full day of recording (full day), or binned into the time of day they occurred (night: 12:00am to 6:00am; morning: 6:00am to 12:00pm; afternoon: 12:00pm to 6:00pm; evening 6:00pm to 12:00am). Within each of those groups, features were then created based on whether recordings contributing to the features were from the day prior (for clinical outcomes; day of for EMA only days) to the day a given outcome measure was taken, or were the average of the recordings across all the days in the 2 weeks prior the outcome measure. The total number of LFP features was 280. Features also included 12 recording and stimulation parameters that varied throughout the experiment (for a total of 292 features): cortical stimulation (on vs. off), cortical stimulation frequency, cortical and VC/VS (left and right separately) stimulation voltage, and left and right cortical recording channel names. Missing values were possible, as there was not always a recording that occurred during a given time of day when only a single day of data was used. Missing values were imputed using the mean from that feature.\n\nWe used the scikit-learn package in Python (Pedregosa et al., 2011) to perform the random forest analyses. The random forest was conducted using 2000 estimators, with 2 samples required to split the group (a low sample to split was chosen because of the low number of instances of the clinical outcomes). All possible features were used at each split. The model was calculated first with all the features, and then again using only the top 5 features (based on importance scoring) from the first model. We report model accuracy, R2, and feature importances for the model using the top five features only. Model accuracy is 100 minus the mean absolute percentage error (MAPE) in prediction of the outcome variable on the held-out test set. R2, or coefficient of determination, is essentially a measure of whether the model created using the training set is performing better than a constant model (i.e., using the training set mean) for predicting the values in the test set. R2, in this case, ranges from −1 to 1, with an R2 of 1 indicating perfect prediction, R2 > 0 indicating the model is performing better than the constant model, and an R2 < 0 indicating that the model is performing worse than the constant model at predicting the test set values. Feature importances are a normalized estimate of predictive power for each feature, based on the fraction of samples a feature contributes to, combined with decrease in error by splitting. Reported values for all measures are calculated as the average of the values for each of the five cross-validated test sets.\n\nResults\nClinical Outcomes With Deep Brain and Combined Stimulation\nChanges in clinical outcomes over the course of the study are displayed in Figure 4B (with the timing of study events, for reference in Figure 4A). The patient’s OCD symptoms changed modestly throughout the study (Figure 4B). The patient’s YBOCS was 27 at the pre-surgery baseline, at which point he was already receiving VC/VS DBS (he had a YBOCS of 29 prior to his first course of DBS). His mean YBOCS during the VC/VS optimization phase was 25.13 (SD = 2.13), dropping 13.34% from his score prior to any DBS. With the addition of cortical stimulation, his YBOCS dropped another point (M = 24.25, SD = 1.92), dropping a further 3% from his initial YBOCS of 29 (i.e., 16.38% change). YBOCS consistently fell below the criteria for severe OCD (YBOCS < 24) during his last four clinical sessions. There was no difference in mean YBOCS between the blinded and unblinded cortical phases. During acute cortical optimization the patient reported that with the addition of cortical stimulation he felt that he was more easily able to focus attention away from the OCD thoughts, and that it was as if the OCD was on the other side of a door or barrier, trying to get through, but that he was able to keep it behind the barrier. These subjective self-reports did not, however, translate to YBOCS improvement with chronic cortical stimulation.\n\nFIGURE 4 (A) Timing of important study events, for reference. (B) Clinical outcomes (from top to bottom YBOCS, MADRS, PGI, EMA) by days since operation.\n\nThe patient’s depressive symptoms appeared to improve with VC/VS stimulation, but did not improve further with the addition of cortical stimulation. By the end of his first course of VC/VS DBS, the patient continued to suffer from severe depression (MADRS > 34), with a MADRS of 37 at his pre-surgery baseline. During the VC/VS optimization phase, the MADRS dropped almost ten points (M = 27.33, SD = 4.61, 26.14% drop from baseline), with the patient no longer meeting criteria for severe depression. The MADRS rose slightly with the addition of cortical stimulation (M = 28.58, SD = 3.24, 22.76% drop from baseline).\n\nThe change in formal rating scales did not meet the standard criteria for YBOCS (35% drop) or MADRS (50% drop) response. Despite this, the patient felt that he was much improved with the addition of cortical stimulation. During the VC/VS optimization phase the patient’s PGI-I averaged somewhere between minimally and much improved (M = 2.47, SD = 0.64). With the addition of cortical stimulation, the patient consistently rated his symptoms as very much improved (PGI-I = 1).\n\nAt the time of this writing, the patient continues to live with family, does not maintain significant employment or volunteer activities, and has not returned to complete his education.\n\nThe patient did not experience any significant side-effects from either the VC/VS or cortical stimulation. He did report experiences of being “overstimulated” with the 130 Hz cortical stimulation. Due to these, his cortical stimulation was changed to 100 Hz at day 291, and he began cycling his cortical stimulation off at night beginning at day 403. The patient described this experience as an overfocused, anxious, or agitated state, with the patient also using terms like “racing thoughts” and “tunnel vision” to describe the feeling. The attending clinicians did not believe these represented a hypomanic state, given that they were not accompanied by impulsivity, euphoria, or pleasure-seeking. In theory, this “overstimulation” could be akin to the anxiety effects reported from VC/VS stimulation, except that VC/VS-related anxiety tends to have a very acute onset and the patient’s “overstimulation” feelings arose gradually. Moreover, even prior to this study, the patient’s obsessions often focused on his current mood state and his stimulation settings, i.e., the possibility that his settings were incorrect and that he might feel bad as a result. Thus, some of this might not reflect actual side effects, but his usual obsessional content. Indeed, the patient only began reporting feelings of overstimulation after being unblinded to the cortical stimulation, indicating that it may be more psychological than physiological.\n\nMulti-Source Interference Task (MSIT)\nBoth conflict condition (congruent and incongruent; f = 117.76, p < 0.0001) and stimulation condition (VC/VS non-optimized, VC/VS optimized, and combined; f = 1231.32, p < 0.0001) contributed significantly to the final model. RT was faster for congruent (M = 0.507 s, SEM = 0.004) than for incongruent (M = 0.691 s, SEM = 0.004) trials (β = 0.18, z = 34.36, p < 0.001), replicating the robust subject-level effects seen in the literature.\n\nRT also differed as a function of stimulation condition (see Figure 5). RT was faster when the patient was receiving optimized VC/VS stimulation (M = 0.596 s, SEM = 0.005) compared to non-optimized VC/VS stimulation (M = 0.676 s, SEM = 0.009; β = −0.08, z = −10.33, p < 0.001). RT was fastest during combined stimulation (M = 0.564 s, SEM = 0.005), differing from both non-optimized (β = 0.11, z = 14.54, p < 0.001) and optimized (β = 0.03, z = 5.60, p < 0.001) VC/VS only stimulation.\n\nFIGURE 5 Mean response time (in seconds) for each MSIT run as a function of day since operation the patient performed the task, collapsed across congruent and incongruent trials. Color of points indicates the stimulation phase: VC/VS only prior to setting optimization, VC/VS only after optimization, and combined VC/VS and cortical (100 Hz) stimulation.\n\nDaily LFP Recordings: Power and Cortical-Striatal Synchrony With Single-Site and Combined Stimulation\nIntraoperative Cortical-Striatal Synchrony\nA prominent alpha WPLI peak was detected intraoperatively using the high resolution OR rig (Figure 6). Alpha WPLI was more pronounced in the right hemisphere at each VC/VS depth. Right hemisphere alpha WPLI was relatively constant across VC/VS depth, whereas left hemisphere alpha WPLI was stronger more dorsally (near the head of the caudate). There was also a small gamma band WPLI peak, particularly in the left mid and dorsal striatum.\n\nFIGURE 6 Intraoperative WPLI as a function of VC/VS depth.\n\nSaline Bath Test and Artifact Subtraction Results\nWhen separated by the “cortical” stimulation frequency, there are noticeable artifacts in the “cortical,” but not “VC/VS,” saline recordings (Figure 7A). The spectrum of these artifacts differs depending on cortical stimulation frequency. For the patient recordings (Figures 7B,C), spectra also differ as a function of cortical stimulation frequency, particularly in the cortical recordings. These fluctuations largely remain after artifact subtraction, though the theta/beta peak appears to be much reduced. The 10 Hz peak in the cortical/right lead (Figure 7C, bottom right), at 130 Hz cortical stimulation is over-corrected, i.e., the saline artifact was larger than the same peak in the actual recording. Given this, 130 Hz cortical recordings showing a pronounced decrease in power in the 10 Hz range will not be interpreted as reflecting changes in brain signal.\n\nFIGURE 7 Average PSDs for: (A) the saline bath test (artifact) recordings; (B) the patient recordings prior to the removal of artifacts; and (C) the patient recordings after the subtraction of artifacts. For the patient recordings (B,C), each plot represents the recordings from each of the patient’s four leads, labeled by the brain region (cortical or VC/VS) and hemisphere. Plots in (A) (saline recordings) are labeled by which region and hemisphere a given recording matched in terms of recording and stimulation settings. Lines in each plot are the average PSD for all recordings, separated by the cortical stimulation frequency. Cortical stimulation frequency of 0 Hz indicates that no cortical stimulation was on during that recording. Lines represent means for all saline bath (A) or patient (B,C) recordings in each group. Error bands represent 95% confidence intervals, calculated from 1000 bootstrapped samples.\n\nWhile there are some marked artifacts in the power spectra, the synchrony spectra appear relatively artifact-free, as expected from a measure that is insensitive to volume conducted artifact (Figure 8A). In the patient recordings (Figure 8B), there are differences in WPLI with the type of cortical stimulation, which largely remain after artifact subtraction (Figure 8C). Contrary to our initial hypothesis, cortical-striatal synchrony increased with cortical stimulation, especially for 130 Hz stimulation. There is overcorrection in the lower frequencies of the right hemisphere, 0 Hz stimulation recordings (Figure 8C, top plot), therefore this will not be interpreted as hyposynchrony in the absence of cortical stimulation.\n\nFIGURE 8 WPLI across frequency for: (A) the saline bath test (artifact) recordings; (B) the patient recordings prior to the removal of artifacts; and (C) the patient recordings after the subtraction of artifacts. Plots of patient recordings (B,C) indicate the cortical-striatal WPLI for the left and right hemispheres, with colored lines indicating the cortical stimulation frequency at the time of recording. Saline test plots (A) indicate whether the recording and stimulation settings for the IPGs matched those of the left or right hemisphere of patient recordings. Error bands represent 95% confidence intervals, calculated from 1000 bootstrapped samples.\n\nDaily LFP Spectral Analysis: Power Changes Over Time\nVC/VS power spectra were relatively constant across stimulation settings, with a consistent peak in the theta range, and no other discernible peaks in the higher frequency bands (Figure 9B, upper panels, Figure 9A displays the timing of study phases for reference). Additionally, spectra were largely consistent across the left and right hemispheres.\n\nFIGURE 9 (A) Timing of important study events for reference. (B) Heatmaps denoting the artifact corrected power (5–50 Hz) across the course of the study. (C) Artifact corrected cortical-striatal synchrony (WPLI) across the frequencies tested, as a function of days since operation. To better show subtle changes in WPLI, the range used for the color map is –0.1 to 0.2. Dotted lines on heatmaps (B,C) indicate clinical sessions, during which stimulation and recording settings changed and clinical outcomes were taken (see Figure 2 above for timing of important settings changes). Areas with missing LFP recordings have been interpolated (e.g., between days 138 and 151).\n\nCortical power spectra, on the other hand, changed with study phases. Prior to turning on the cortical stimulation full-time, power for the cortical leads was relatively consistent across frequency and time (with some minor fluctuation in the theta band, Figure 9B lower panels). At day 235, when 130 Hz cortical stimulation was turned on, there was a dramatic shift in cortical power spectra. Interestingly, this shift resulted in increased power in the theta range, with an overall shift that looked much like the spectra of the DBS-on VC/VS recording. This change at approximately 5 Hz corresponds to the difference in frequencies between the cortical (130 Hz) and VC/VS (135 Hz) leads. The spectra shift again at day 291, when cortical stimulation is changed from 130 to 100 Hz. This shift results in the end of the increased theta power seen with 130 Hz stimulation, and some subtle banding in the alpha and beta/low gamma bands. These may correspond to the 35 Hz difference between the cortical and VC/VS stimulation.\n\nThere were also large shifts in cortical power spectra from day 172 to 202 and 216 to 235, which were more pronounced in the left hemisphere. No recording or stimulation parameter changes occurred at those times, other than the acute cortical optimization at day 172. Inspection of the non-normalized recordings indicated that the voltage values for those recordings were greatly increased relative to other recordings (by almost 100 fold). This may reflect a physical change in the contacts due to being stimulated for the first time, e.g., removal of accumulated protein deposits. However, the fact that these changes (including shifts in the scale of recordings) disappear between day 202 and 216, and then reappear between day 216 to 235, may indicate that there is also a neural component.\n\nDaily LFP Cortical-Striatal Synchrony: Weighted Phase Lag Index\nConsistent with our initial hypothesis, cortico-striatal synchrony changed more strongly than power across the study phases (Figure 9C). There were minimal differences between the left and right hemispheres. However, there does appear to be lower theta synchrony in the right hemisphere in the absence of cortical stimulation, which is not present in the left hemisphere. Given that this low theta synchrony only emerged after artifact subtraction (see Figure 8), and does not appear in the left hemisphere, its significance is uncertain.\n\nPrior to the addition of cortical stimulation, WPLI was fairly equal across all frequency bands. This is in contrast to the intraoperative recordings (Figure 6), which showed WPLI peaks in the theta and alpha/low beta ranges. It is possible that this is a function of differences in the resolution of the recordings, but it may also indicate changes in synchrony when VC/VS stimulation is on (as is the case for the daily PC + S recordings) versus off (as is the case for the intraoperative recordings). Those changes would be consistent with our hypothesis that DBS disrupts cortico-striatal synchrony. The patient declined even temporary interruption of VC/VS stimulation, and thus we are unable to disentangle these possibilities at this time.\n\nThere is a dramatic increase in WPLI in the theta, alpha, beta, and low gamma bands when cortical stimulation is turned on full-time at 130 Hz (day 235). When stimulation is reduced to 100 Hz (day 291) this increase abates, although WPLI in the alpha, beta, and low gamma bands remains high relative to the other frequencies. Given the absence of WPLI artifacts in saline testing, these synchrony changes likely reflect true physiologic change. Contrary to our initial expectation, there was an increase in synchrony with combined VC/VS and cortical stimulation, and this increase was greatest when cortical stimulation was 130 Hz.\n\nRelationship of Power and Cortical-Striatal Synchrony to Clinical Outcomes\nClinical Outcomes and WPLI Correlations\nWe correlated WPLI in each band (theta, alpha, beta, and gamma) to the clinical measures (Figure 10). Raw p-values are reported here; only p-values below the Bonferroni threshold of 0.0125 were considered significant. YBOCS improvement was correlated with higher WPLI in the theta band, but this did not reach significance (r = −0.30, p = 0.06) and may be driven by outliers. Improvement in MADRS was significantly correlated with lower WPLI in the gamma band (r = 0.40, p = 0.01). PGI correlations echoed the YBOCS, with improvement associated with increased WPLI in the alpha (r = −0.63, p < 0.001), beta (r = −0.46, p = 0.004), and gamma (r = −0.47, p = 0.003) bands. There were no significant correlations between EMA and WPLI in any band.\n\nFIGURE 10 Correlations between YBOCS (A), MADRS (B), PGI (C), and EMA (D) and WPLI in the theta (leftmost column), alpha (second from the left), beta (second from the right), and gamma (rightmost column) bands. Data points are colored by the cortical stimulation frequency. Linear regressions (gray lines) were fit to the full data set for that measure (i.e., not separated by cortical stimulation frequency), with the error bands indicating the 95% confidence interval. Pearson correlations were also calculated, and the corresponding r and p-values are displayed.\n\nRandom Forests Using LFP Features to Predict Clinical Outcomes\nTable 1 contains the results of the random forest regressions predicting the clinical outcomes using LFP features. The models predicting MADRS (R2 = −0.14 ± 1.39) and EMA score (R2 = −0.01 ± 0.40) failed to perform better than a constant model. While average R2 for the model predicting YBOCS was positive, the 2 SD confidence interval included 0. We therefore concluded that the model did not meet performance criteria (R2 = 0.23 ± 0.28). This was likely due to a lack of variability in YBOCS scores across the course of the study; the mean predicted YBOCS scores with 94% accuracy, calculated as the average across the 5 cross validated test sets. In line with the correlation results, the model predicting PGI did perform better than the constant model (R2 = 0.77 ± 0.37), and was able to predict PGI of the test sets with 92% accuracy. Cortical-striatal synchrony in the gamma and theta bands appeared as important features in the model.\n\nTABLE 1 Baseline accuracy indicates prediction accuracy for a constant model (i.e., using the mean to predict values), averaged across the 5 test sets.\n\nMeasure\tBaseline accuracy\tModel accuracy\tModel R2\tTop feature properties\tTop feature importance’s\t\n\t\t\t\tMeasure\tBand\tRecording time of day\tRecording time period\t\t\nYBOCS\t93.75%\t94.25%\t0.23 (±0.28)\tSR Power\tGamma\tFull Day\t14 days prior\t0.2870\t\n\t\t\t\tCL Power\tTheta\tNight\t14 days prior\t0.1945\t\n\t\t\t\tLeft WPLI\tTheta\tMorning\t1 day prior\t0.1798\t\n\t\t\t\tSL Power\tTheta\tEvening\t1 day prior\t0.1723\t\n\t\t\t\tSL Power\tGamma\tEvening\t1 day prior\t0.1665\t\nMADRS\t89.26%\t89.06%\t−0.14 (±1.39)\tCL Power\tTheta\tAfternoon\t14 days prior\t0.2276\t\n\t\t\t\tAvg WPLI\tGamma\tEvening\t1 day prior\t0.2165\t\n\t\t\t\tRight WPLI\tGamma\tFull Day\t1 day prior\t0.2157\t\n\t\t\t\tRight WPLI\tGamma\tMorning\t14 days prior\t0.2047\t\n\t\t\t\tRight WPLI\tGamma\tMorning\t1 day prior\t0.1354\t\nPGI\t54.96%\t91.80%\t0.77 (±0.37)\tAvg WPLI\tTheta\tFull Day\t14 days prior\t0.2360\t\n\t\t\t\tCL Power\tGamma\tAfternoon\t14 days prior\t0.2250\t\n\t\t\t\tCR Power\tGamma\tEvening\t14 days prior\t0.2051\t\n\t\t\t\tLeft WPLI\tGamma\tMorning\t14 days prior\t0.1922\t\n\t\t\t\tRight WPLI\tTheta\tMorning\t1 day prior\t0.1417\t\nEMA\t76.10%\t77.48%\t−0.01 (±0.40)\tCL Power\tAlpha\tEvening\tDay of\t0.2240\t\n\t\t\t\tSR Power\tBeta\tFull day\tDay of\t0.2083\t\n\t\t\t\tCL Power\tAlpha\tAfternoon\t14 days prior\t0.1992\t\n\t\t\t\tLeft WPLI\tGamma\tNight\tDay of\t0.1849\t\n\t\t\t\tAvg WPLI\tTheta\tAfternoon\tDay of\t0.1836\t\nModel accuracy indicates the accuracy of the model using only the top five features. Model R2 (±2 SD), is the average test set coefficient of determination of the final model. R2 values > 0 indicate that the model is performing better than a constant model, and values < 0 indicate the model is performing worse. The top five features (from an initial model using all possible features) are broken apart here into their component parts. The measure column indicates which LFP measure the feature contains (SL power, striatal left power; SR power, striatal right power; CL power, cortical left power; CR power, cortical right power; left WPLI, right WPLI, or average of left and right WPLI); Band indicates the frequency band of the feature; Recording time of day indicates which time of day the recordings contributing to the feature were from (morning, afternoon, evening, night, or the full day); Recording time period indicates how many days of recordings preceding the day the clinical measure was taken were used in the analysis (14 days preceding, one day prior to outcome measure day- YBOCS, MADRS, PGI, or day of the outcome measure day - EMA only). Top feature importances indicates the feature importance (normalized estimate of the predictive power of each feature) of each of the top features, averaged across the 5-fold cross-validated models.Discussion\nWe examined targeted CSTC network disruption with combined cortical (SMA) and VC/VS neurostimulation in one patient with treatment refractory OCD in a blinded crossover study. Chronic recording of the cortical-striatal circuit for almost 2 years allowed us to test the hypothesis that frequency mismatched stimulation would disrupt CSTC hypersynchrony, leading to a greater improvement in symptoms with combined stimulation compared to VC/VS stimulation alone. The patient is the first known case of chronic SMA stimulation, and of chronic combined cortical and VC/VS stimulation. The patient experienced no significant side-effects or adverse events with the addition of cortical stimulation. While this will need to be confirmed in future patients, these findings are a first step in establishing the safety of a combined cortical-subcortical approach to neurostimulation.\n\nThe patient experienced positive effects with acute combined cortical-striatal stimulation. Specifically, he reported an increase in the ability to divert focus away from OCD thoughts, which he did not feel with VC/VS-only stimulation. Throughout the study, the patient described cortical stimulation as the “icing on the cake” to traditional DBS. These positive effects did not translate into improvement in clinical outcomes with chronic combined stimulation, however. The patient did not respond to his initial course of standard DBS at the VC/VS target. Cortical and combined stimulation did not rescue this non-response. The patient’s YBOCS dropped 13% from baseline with striatal stimulation, and 16% from baseline with the addition of cortical stimulation. The patient’s MADRS dropped 26% with VC/VS stimulation, and 23% from baseline with the addition of cortical stimulation. While a single case cannot define a therapy’s potential, the lack of response to chronic combined stimulation was surprising, given the positive acute effects.\n\nDespite the lack of significant movement in formal rating scales, the patient felt as though his symptoms had greatly improved with the addition of combined stimulation, as measured by the PGI. However, it should be noted that the shift to “very much improved” occurred in the session where the patient was unblinded to the cortical stimulation. In this way, the most parsimonious explanation of subjective improvement with cortical stimulation is a placebo effect. Additionally, despite subjective feelings of improvement, at the time of this writing the patient continued to show significant impairment in functioning, as well as moderate OCD and depressive symptoms. Nevertheless, the patient’s feelings of improvement may be important, given that they represent a change from previous treatments, and that the PGI-I has been shown to be related to more objective measures of symptom improvement in larger samples (e.g., Yalcin and Bump, 2003). Overall satisfaction with DBS therapy, despite a lack of response to the treatment has been described before (e.g., Denys et al., 2020). It is possible that this effect represents changes in overall mood, or the limitations of the YBOCS in terms of sensitivity to change at extremes of pathology (van Westen et al., 2020). It is also possible, however, that this is simply a subjective sense of, “I had brain surgery, so it must be doing something.” Regardless, overall satisfaction with the treatment even in the absence of response may serve a protective function, as it may represent a decrease in hopelessness, which is correlated with long-term adverse outcomes such as suicide (Papakostas et al., 2005; Beck et al., 2006).\n\nThe patient’s cognitive control, as measured by performance on the MSIT, also appeared to improve with combined stimulation. In line with previous research showing improved performance with VC/VS DBS (Basu et al., preprint; Widge et al., 2019), the patient’s response speed improved when he was receiving optimized VC/VS stimulation. With the addition of cortical stimulation he showed an additional quickening of response time, compared to optimized VC/VS stimulation alone. It should be noted, though, that the patient did appear to show an effect of time, such that he improved as day since operation increased (see Figure 5). Our study design meant that stimulation condition and day since operation were highly collinear. Therefore, we are unable to dissociate the improvement seen with stimulation condition from an improvement with time. However, Widge et al. (2019) found no differences in RT between multiple MSIT runs conducted an average of 88 min apart. It is unlikely that such effects would emerge at much longer time delays, such as those seen in our study. Therefore, differences between VC/VS only stimulation and combined stimulation may reflect an additional boost to cognitive control with the addition of cortical stimulation. This finding tracks with our finding of subjective symptom improvement with combined stimulation, and the possibility that the YBOCS may not have been sensitive enough to detect changes in our patient’s OCD pathology. Namely, there may have been subtle shifts in some of the cognitive deficits thought to underly OCD (e.g., Robbins et al., 2012; Shin et al., 2014; Voon et al., 2015; Vaghi et al., 2017) which resulted in the subjective improvement felt by the patient, but which were too subtle to produce significant changes in traditional rating scales. This finding also tracks with prior studies implicating medial prefrontal cortex in the cognitive deficits seen in OCD (Haber, 2003; Cocchi et al., 2012; Robbins et al., 2012; Vaghi et al., 2017; Robbins et al., 2019).\n\nThis study represents the first chronic recording of the cortical-striatal circuit in a human. Using these recordings we were able to measure cortical-striatal synchrony continuously for nearly 2 years. In line with our initial prediction, frequency mismatched stimulation did in fact alter cortical-striatal synchrony. However, this alteration was in the opposite direction of our initial prediction - frequency mismatched stimulation actually increased cortical-striatal synchrony. Further, the increase in synchrony was greater when the two frequencies were closer together (130 and 135 Hz), versus when they were farther apart (100 and 135 Hz). While there were power changes with acute cortical stimulation, synchrony changes only emerged with chronic stimulation. These findings remained even after the removal of stimulation artifacts. Additionally, the increase in cortical-striatal synchrony (in the alpha, beta, and gamma bands) was associated with an increase in the patient’s subjective feelings of improvement, with LFP features (especially synchrony) predicting PGI with 92% accuracy in a random forest regression. Synchrony was not significantly related to either OCD or MDD symptoms. Importantly, given the n of 1 and the absence of baseline and stimulation off recordings, any conclusions regarding changes in synchrony are extremely tentative. Future research is needed to elucidate the influence of combined (and arguably, single-site) stimulation on the synchrony of neural oscillations, and its relationship to symptom improvement.\n\nIf the finding holds, one possibility for the unexpected increase in synchrony with combined stimulation is that neural elements may have imprecise or broadly tuned frequency responses, or responses that become insensitive to mismatch at high driving currents (Fröhlich, 2015). At the relatively high stimulation intensities used in clinical DBS, a small mismatch between driving frequencies may essentially be zero mismatch from the biological system’s perspective. Another possibility is that the DBS frequency may entrain the endogenous frequency, as was observed for narrowband gamma in Swann et al. (2016). Finally, rather than causing disruption (by forcing two oscillators out of phase), it may be that the separation between frequencies can actually entrain activity at the difference between the two driving frequencies, an effect that some have proposed could be exploited therapeutically (Grossman et al., 2017).\n\nSubjective symptom improvement with increases in cortico-striatal synchrony was not in line with our initial hypothesis that OCD arises from CSTC hypersynchrony. While this finding clearly requires replication, one explanation is that the hyperconnectivity hypothesis represents an oversimplified view of the neurobiology of OCD. As discussed previously, there is evidence of both hyper and hypoconnectivity (Gürsel et al., 2018), which may be partially a function of which CSTC loop (e.g., motor, associative, or limbic loops: Obeso et al., 2008; Krack et al., 2010; Milad and Rauch, 2012; Lapidus et al., 2013) the regions showing aberrant connectivity are in Harrison et al. (2009); Göttlich et al. (2014), Posner et al. (2014), and Vaghi et al. (2017). In this way, it is possible that our patient’s specific pattern between VC/VS and SMA was one of hypoconnectivity, and combined stimulation did move his networks toward a more normal/healthy connectivity pattern.\n\nEstablishing an individual’s specific pattern of connectivity, therefore, may be a critical step in developing personalized treatments for OCD. However, establishing this pattern does no good if there is no means of restoring the communication to “normal” levels. Neurostimulation, and in particular combined stimulation, offers a unique means of directly influencing connectivity between regions. Despite the direction, our results suggest that the communication between CSTC regions, as measured by phase synchrony, may be altered by neurostimulation. Further, our results indicate that these alterations can potentially be sustained across long periods of time, while the patient is receiving stimulation. Thus, this case supports the possibility of using DBS to deliver personalized, network-level therapy.\n\nLimitations, Lessons Learned, and Future Considerations\nThe results of the present study are limited in that it is difficult to assess whether changes in power and synchrony are a result of actual changes in brain signal, or are artifacts of stimulation. This is in part a result of the imperfect artifact rejection from the device recordings (Stanslaski et al., 2012; Swann et al., 2017), amplified in this case by the fact that some of our optimal stimulation contacts did not permit the use of the preferred “flanking dipole” recording configuration. Further, while we attempted to subtract the artifact signal from our recordings using saline bath test recordings, these methods were imperfect. Most notably, we did not have enough leads to test the full four lead configuration in saline, potentially missing artifacts that only emerge with that full configuration. Despite imperfections, we do feel that the process of establishing the signal in the absence of brain signal (which to our knowledge has not been reported before in the DBS literature) may be an important check when making claims about the effect of DBS on neural oscillations in the presence of potential stimulation artifacts. Further, effective artifact subtraction/removal will almost certainly be critical for developing closed-loop therapies, which are a critical next step in advancing neurostimulation (Bilge et al., 2018; Widge et al., 2018).\n\nTo the prior point, we believe this study is the first to report an attempt at multi-structure chronic recording through two implanted PC + S systems. One of our unpleasant surprises was that this implant configuration could not be combined with real-time data streaming. The two implanted neurostimulators exhibited cross-talk during streaming attempts, whether using the base PC + S system (Sensing Programmer) or the more advanced Nexus-D toolkit. Starting streaming sessions from a second IPG immediately ended the streaming from whichever IPG we had contacted first. It is unclear whether this will continue to be a limitation in future generations of sensing systems, which may benefit from continued advances in medical implant communication infrastructure. There is a move toward wireless programming even for clinical applications, which necessitates the development of devices that can flexibly switch bands to prevent cross talk.\n\nOne solution to the problem of stimulation artifacts is simply taking recordings with stimulation off. This is the approach that has been taken in previous studies (Huang et al., 2019; Veerakumar et al., 2019), and will be our approach moving forward. However, taking stimulation off recordings presents potential challenges/drawbacks. The first is the potential unblinding of the participant during a randomized protocol. There is also the potential that the changes in synchrony due to combined stimulation only occur while stimulation is on. One indication that this may be the case comes from studies showing that the beneficial effects of VC/VS DBS for OCD are not sustained when stimulation is turned off in a blinded fashion (Luyten et al., 2016), and from our own studies showing rapid cognitive change from DBS discontinuation (Widge et al., 2019). Therefore, we also plan to take recordings with stimulation on. While this brings us back to the issue of stimulation artifacts, we believe that having corresponding stimulation on and off recordings would only be beneficial.\n\nThe data from this specific patient are limited in that there were no baseline recordings taken prior to turning on VC/VS stimulation. Baseline recordings would have helped establish the level of cortical-striatal synchrony in our patient in the absence of an intervention. The original protocol called for 2-weeks of baseline recordings. However, as discussed previously, while recovering in the hospital the patient reported suicidality, which he attributed to cessation from his prior DBS therapy. From then on, the patient declined any deactivation of VC/VS stimulation, and as such, we were unable to obtain any recordings in the absence of stimulation. This is also the reason we were unable to obtain stimulation off recordings throughout the course of the study. Psychiatric DBS patients generally tolerate turning the device off [e.g., 14 out of 14 participants in Widge et al. (2019) tolerated having their stimulation turned off], so DBS on/off comparisons will likely be possible in the future, and will clarify the baseline, non-stimulation recording characteristics.\n\nThe results are also potentially limited in the specific patient selected as the first participant. Given that the patient did not respond to his initial course of VC/VS DBS, the approving physicians felt that there was hope of improvement with the addition of combined stimulation. In hindsight, the lack of response to prior VC/VS DBS may instead have been an indication that the patient would also be more likely to be a non-responder to other types of neurostimulation. Further, the presentation of the patient’s OCD symptoms is particularly challenging, in that his compulsions are largely mental and thus difficult to target for exposure. It is very hard to distinguish some of these compulsions from ruminative preoccupation. This pattern may have made it less likely that the patient would respond to treatment, and is an important caution for DBS patient selection generally.\n\nMoving forward, we also plan on implementing EMA style assessments of OCD and other symptoms, which are an important way of capturing more frequent variability in symptoms [see Walz et al. (2014) for a review of their use in anxiety disorders]. We will also attempt take corresponding LFP recordings in an effort to more successfully model changes in symptoms using the features of the LFP. The EMA used in the present study was limited in that it did not specifically measure OC symptoms, but instead was an assessment of motivation and the ability to perform daily tasks. Further, the EMA only began being collected mid-way through the study, meaning that important baseline levels were not established. For the next patient, we plan to collect a wide range of baseline questionnaires and EMAs prior to initiating treatment. Theoretically, it should also be possible to then titrate future EMAs to just the areas in which the patient shows the most impairment, making the EMAs more user friendly. As previously discussed, there are significant nuances and (likely) individual differences in the complex pattern of aberrant connectivity in individuals with OCD. Therefore, establishing an individual’s specific pattern of connectivity may help improve neurostimulation therapies for psychiatric disorders through targeting brain regions which show dysfunctional connectivity. While there are almost certainly others, we see two methods of implementing this type of targeting. The first is the use of diffusion tensor imaging (DTI) and tractography. This type of MRI was not possible in the first patient due to his chronic indwelling hardware, but we anticipate collecting it in future patients. Using the patient’s tractography between certain CSTC seed regions, we may be able to more specifically target both sub-cortical and cortical electrodes. The second is the through measuring cortical-striatal synchrony intraoperatively, in real-time. Electrodes (especially cortical) could be placed in areas showing the most pronounced synchrony patterns (either high or low synchrony, depending on the patient).\n\nConclusion\nPsychiatric disorders, including OCD, are network disorders. We have shown that those networks can potentially be safely manipulated with multi-site continuous stimulation, and measured over periods of years with currently available technologies. Although the patient was not relieved of his psychiatric symptoms to the extent expected, our results are important safety and feasibility evidence toward a more network-oriented and personalized approach to DBS.\n\nData Availability Statement\nPreprocessed data and analysis script are available at: https://github.com/tne-lab/Olsen-et-al-2020. Raw data and preprocessing scripts can be made available upon request.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Institutional Review Board of Massachusetts General Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAW conceived, developed, and supervised all aspects of the study, with significant input from DD. SO wrote the manuscript with support from AW and IB and performed the final data analysis with significant input from MTB, IB, and AW. AW, DD, CC, and TD performed the clinical care aspects of the study. ZW performed the study surgical procedures. MTB, IB, AK, MJB, AR, AG, and EH carried out the study procedures and collected the data. IB performed the saline bath test study. MTB conceptualized and created the data analysis procedures. IB, AK, MJB, AR, AG, and EH provided the data analysis support. NP and AR performed the MRI analysis and developed the MMVT software. JB conceived of and carried out the separate study of which the ecological momentary assessments are reported here. ME, IS, KF-H, and JS performed the data collection and some analysis of the ecological momentary assessment study. All the authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nAW, DD, and TD are named inventors on patent applications related to deep brain stimulation and oscillations, including at least one application related to the subject of this paper. AW and DD have received consulting income and/or research support from Medtronic, which manufactured the devices used in this study. Medtronic had no financial or technical involvement with this specific research. TD discloses honoraria, consultation fees, and/or royalties from the MGH Psychiatry Academy, BrainCells Inc., Clintara, LLC., Systems Research and Applications Corporation, Boston University, the Catalan Agency for Health Technology Assessment and Research, the National Association of Social Workers Massachusetts, the Massachusetts Medical Society, Tufts University, NIDA, NIMH, and Oxford University Press. None of those entities manufactures technology or products used in the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SS declared a past co-authorship with several of the authors DD, and AW to the handling editor.\n\nFunding. This study was supported by the NIH (UH3-NS100548-01), NIH (U01MH116925), the MnDRIVE Brain Conditions Program, and the University of Minnesota Medical Discovery Team on Addictions.\n\n1 https://clinicaltrials.gov/ct2/show/NCT03184454\n==== Refs\nReferences\nAlexander G. E. DeLong M. R. Strick P. L. (1986 ). Parallel organization of functionally segregated circuits linking basal ganglia and cortex.\n\nAnnu. Rev. Neurosci. \n9 \n357 –381\n. 10.1146/annurev.ne.09.030186.002041 \n3085570 \nYousefi A. Crocker B. Zelmann R. Paulk A. C. Peled N. (Preprint ). Closed Loop Enhancement and Neural Decoding of Human Cognitive Control. 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"issn_linking": "1662-5161",
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"journal": "Frontiers in human neuroscience",
"keywords": "cortico-striatal circuitry; local field potential; neural oscillations; neurostimulation; obsessive compulsive disorder; supplementary motor area; synchrony; ventral capsule/ventral striatum",
"medline_ta": "Front Hum Neurosci",
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"pubdate": "2020",
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"title": "Case Report of Dual-Site Neurostimulation and Chronic Recording of Cortico-Striatal Circuitry in a Patient With Treatment Refractory Obsessive Compulsive Disorder.",
"title_normalized": "case report of dual site neurostimulation and chronic recording of cortico striatal circuitry in a patient with treatment refractory obsessive compulsive disorder"
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"abstract": "Histoplasma capsulatum causes pneumonia and multisystemic disease in humans. Musculoskeletal involvement in histoplasmosis is most often tenosynovitis and rarely septic arthritis. Even more uncommon is the involvement of prosthetic joints. Here, we report a series of 3 cases of prosthetic joint failures caused by infection due to H capsulatum. Together with a review of 4 previously reported cases, we summarize host characteristics, clinical presentation, surgical approaches, antifungal management, and outcomes of this rare orthopedic joint infection.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN.",
"authors": "Berbari|Hadi E|HE|;Gurram|Pooja|P|;Mahmood|Maryam|M|;Deziel|Paul J|PJ|;Walker|Randall C|RC|;Razonable|Raymund R|RR|",
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"doi": "10.1016/j.mayocpiqo.2020.07.008",
"fulltext": "\n==== Front\nMayo Clin Proc Innov Qual Outcomes\nMayo Clin Proc Innov Qual Outcomes\nMayo Clinic Proceedings: Innovations, Quality & Outcomes\n2542-4548\nElsevier\n\nS2542-4548(20)30143-0\n10.1016/j.mayocpiqo.2020.07.008\nCase Report\nProsthetic Joint Infections Due to Histoplasma capsulatum: A Report of 3 Cases\nBerbari Hadi E. MS\nGurram Pooja MBBS\nMahmood Maryam MBChB\nDeziel Paul J. PAC\nWalker Randall C. MD\nRazonable Raymund R. MD Razonable.raymund@mayo.edu\n@RazonableMD\n@MayoClinicINFD\n∗\nDivision of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN\n∗ Correspondence: Address to Raymund R. Razonable, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 Razonable.raymund@mayo.edu@RazonableMD@MayoClinicINFD\n21 1 2021\n2 2021\n21 1 2021\n5 1 225229\n© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.\n2020\nMayo Foundation for Medical Education and Research\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHistoplasma capsulatum causes pneumonia and multisystemic disease in humans. Musculoskeletal involvement in histoplasmosis is most often tenosynovitis and rarely septic arthritis. Even more uncommon is the involvement of prosthetic joints. Here, we report a series of 3 cases of prosthetic joint failures caused by infection due to H capsulatum. Together with a review of 4 previously reported cases, we summarize host characteristics, clinical presentation, surgical approaches, antifungal management, and outcomes of this rare orthopedic joint infection.\n\nAbbreviations and Acronyms\n\nPJI, prosthetic joint infection\nTKA, total knee arthroplasty\n==== Body\nHistoplasma capsulatum is a dimorphic fungus that is endemic throughoutthe Ohio and Mississippi river valleys and in certain pockets around the world. Although the fungus primarily causes lung infection, extrapulmonary histoplasmosis may involve the bone marrow, liver, brain, spleen, and the gastrointestinal tract.1,2 Osteomyelitis and septic arthritis are uncommon forms of histoplasmosis, while the involvement of joint prosthesis is even much more uncommon.2,3 In our review of the medical literature, we found only 4 cases of H capsulatum infection involving a prosthetic joint.4, 5, 6 Here, we present the clinical outcomes of 3 additional cases of prosthetic joint infection (PJI) due to H capsulatum.\n\nCase Report\n\nCase 1\n\nA 77-year-old diabetic woman from Wisconsin presented to our clinic in 2019 with a 2-day history of right knee pain. She was a recipient of a deceased donor kidney transplant for end-stage renal disease due to autosomal dominant polycystic kidney disease in 1991, followed by a living-related donor kidney transplant due to allograft failure from calcineurin inhibitor nephrotoxicity in 2009. She was receiving maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone. She also had bilateral total knee arthroplasties (TKAs) in 1998 (right) and 2012 (left) for degenerative joint disease. She did not have fever, chills, rigors, or other signs and symptoms of systemic illness. On physical examination, her right knee was erythematous, swollen, warm, and tender. Right knee synovial fluid analysis was suggestive of infection (Table). She had an elevated C-reactive protein level (23.1 mg/L; normal range, <8 mg/L). However, the synovial fluid cultures for bacteria were negative at 14 days.Table Clinical Characteristics and Outcomes of 7 Cases of Prosthetic Joint Infection Due to Histoplasma capsulatum\n\nCase number (author; patient location)\tAge (y)/sex\tComorbidity\tPresenting symptoms\tJoint involvement\tSynovial fluid cell count\tSynovial fluid or tissue culture\tBlood culture\tSerology\tUrine Histoplasma antigen\tSurgical treatment\tAntimicrobial treatment\tOutcome\t\n1 (Berbari; Wisconsin)\t77/F\tKidney transplant\tRight knee pain and swelling\tRight knee joint\t2530 cells (88% neutrophils)\tH capsulatum on surgical culture after 15 d of incubation\tNegative\tNegative\tNegative\tDebridement and retention\tItraconazole (lifelong plan)\tGood function at last follow-up (12 mo)\t\n2 (Berbari; Iowa)\t69/F\tRheumatoid arthritis, previous breast cancer\tLeft shoulder pain\tLeft shoulder joint\t3512 cells (85% neutrophils)\tH capsulatum on surgical cultures after 12 d of incubation\tNegative\tNegative\tNegative\tResection arthroplasty\tItraconazole (ongoing)\tReimplanted at 7 mo after resection\t\n3 (Berbari; Nebraska)\t75/M\tHypertension\tRight knee wound drainage\tRight knee joint\tNot done\tH capsulatum on surgical cultures\tNegative\tImmunodiffusion M band positive\tNegative\tResection arthroplasty\tItraconazole (heart failure) → posaconazole × 1 y\tReimplanted at 10 mo after the initiation of antifungal treatment\t\n4 (Fowler; North Carolina)\t84/F\tPolymyalgia rheumatica\tSinus track over the left hip, pain and swelling\tLeft hip joint\t192,500 cells (88% granulocytes)\tH capsulatum on cultures 6 wk after surgery\tNot reported\tNot reported\tNot reported\tDebridement and retention\tItraconazole (lifelong plan)\tGood function at the time of the last report (3 y)\t\n5 (Meiyappan; travel to Ethiopia)\t57/F\tVasculitis\tRight knee pain and swelling\tRight knee joint\t1800 cells (31% neutrophils)\tHistoplasma capsulatum on surgical and synovial fluid cultures\tNot reported\tNegative\tNegative\tResection arthroplasty\tAmphotericin B + posaconazole (prolonged)\tReimplanted at 11 mo; good function at 3.8 y\t\n6 (Nowbakht; Wisconsin, Guatemala)\t77/F\tCardiac disease, diabetes mellitus\tRight knee pain\tRight knee joint\tNot reported\tH capsulatum on synovial fluid culture\tNegative\tNot reported\tNot reported\tResection arthroplasty\tItraconazole × 9 mo\tReimplanted at 9 mo; good function at 2 y\t\n7 (Foo; Singapore)\t68/M\tEnd-stage renal disease receiving hemodialysis\tRight knee pain and swelling\tRight knee joint\t9600 cells (56% neutrophils)\tH capsulatum on tissue culture\tNot reported\tNot reported\tNot reported\tRevision with implantation of prosthesis\tItraconazole (ongoing at the time of the report)\tNo recurrence of symptoms at 8 mo\t\nF = female; M = male.\n\nFrom references 4-7.\n\nShe underwent irrigation and debridement of the right knee joint. Intraoperatively, the right knee joint and prosthesis did not look grossly infected, and because the components were well-seated, they were retained. Fifteen days later, multiple cultures of intraoperative tissue specimens grew H capsulatum. Histoplasma serology and urinary Histoplasma antigen were negative. The chest radiograph was normal. Oral itraconazole was initiated. The dose of mycophenolate mofetil was reduced. Twelve months later, she was tolerating itraconazole and she had a pain-free functional right knee joint. There were no symptoms of immune reconstitution inflammatory syndrome. Because of the retained components and her immunocompromised status, chronic long term itraconazole suppression is planned.\n\nCase 2\n\nA 69-year-old woman from Iowa with rheumatoid arthritis taking etanercept and prednisone had multiple prosthetic joints implanted for painful destructive arthritis, including a left shoulder reverse arthroplasty in 2019. Eight months after her left shoulder arthroplasty, she complained of progressive lingering pain in her left shoulder. The C-reactive protein level was 13.8 mg/L. The radiograph of the shoulder revealed lucency about the glenoid component, which was suggestive of loosening. Left shoulder synovial fluid analysis revealed 3512 cells/μL with predominance of neutrophils. The culture of the synovial fluid was negative at 14 days.\n\nOver concerns of underlying infection and component loosening, she underwent resection of left shoulder prosthesis. On histopathology, there was no evidence of acute inflammation. However, after 12 days of incubation, the intraoperative tissue cultures were positive for H capsulatum. The chest radiograph was normal. Histoplasma serology and urine antigen were negative. Oral itraconazole therapy was initiated. She has completed 7 months of itraconazole treatment before shoulder reimplantation. She continued receiving itraconazole treatment at the time of this report, with reassessment planned at 1 year. Despite not resuming etanercept treatment of her underlying rheumatoid arthritis, there were no symptoms related to immune reconstitution inflammatory syndrome.\n\nCase 3\n\nA 75-year-old man from Nebraska with hypertension underwent a right TKA in 2019 for degenerative joint disease at his local hospital. Two weeks later, he developed redness, swelling, and drainage of the surgical wound. He did not have a fever or other systemic symptoms of disseminated infection. During surgical debridement of the right knee, the wound was found to track deep into the knee joint prosthesis. Thus, resection TKA was performed. Multiple intraoperative tissue cultures grew H capsulatum. A computed tomography scan of the chest revealed mediastinal and hilar adenopathy. Histoplasma M band serology was positive, whereas urinary antigen was negative. Oral itraconazole therapy was initiated but later complicated by congestive heart failure. His antifungal regimen was subsequently changed to posaconazole.\n\nThree months after resection arthroplasty, he presented to our hospital because of recurrence of right knee pain. Radiographic studies revealed a fractured knee spacer. He underwent irrigation, debridement, and exchange of the spacer. Intraoperative cultures were negative. The chest radiograph was normal. Histoplasma serology and urine Histoplasma antigen were negative. He continued receiving posaconazole therapy to complete 1 year of antifungal treatment. Right TKA reimplantation was performed 10 months after initial resection arthroplasty.\n\nDiscussion\n\nOur case series of PJI due to H capsulatum add to 4 previously reported cases.4, 5, 6, 7 The clinical details of all 7 cases are summarized in the Table. One common characteristic of these cases is the delayed growth of H capsulatum in cultures, which led to the initial use of broad-spectrum antibacterial therapy for presumed culture-negative PJI.8,9 About 7% to 10% of PJIs are culture-negative, which is most often due to the recent intake of antibiotics.8,9 However, as highlighted in this report, it may be due to an unusual organism such as fungi.10 To diagnose unusual infections, one may need to prolong culture incubation, use special culture medium, obtain serology, or perform molecular testing. In addition, one should consider unusual infection when there is a history of exposures, such as residence or travel to endemic areas. Our 3 cases reside in the Midwest United States and were at risk of histoplasmosis. In all the reported cases, H capsulatum eventually grew in cultures, albeit delayed (among the cases in which time to growth was reported [at least 12 days]).5 Notably, Histoplasma serology and urinary Histoplasma antigen were negative in all except 1 case in which the M band was positive, suggesting that cases were localized infections involving only joint arthroplasty. This finding is consistent with a study reporting that most bone and joint infections due to H capsulatum are localized.3 Our third case, however, could have been a component of a systemic disease because of the reported presence of mediastinal and hilar adenopathy on the chest computed tomography scan. Histoplasma M band serology was also positive, although urine antigen and blood cultures were negative in this case. A detailed review of this third case did not identify unusual exposures that could have predisposed him to acquire a high burden of infection.\n\nOverall, PJI due to fungi is extremely rare.11 All fungi accounted for only 1% of 3525 PJI cases at Mayo Clinic during 1996 to 2014, and most are due to Candida species.11 As mentioned, bone and joint infections due to H capsulatum are rare.3,12 None of the fungal PJIs in our institution from 1996 to 2014 were due to H capsulatum.11 In a review of 222 osteoarticular infections due to dimorphic fungi from 1970 to 2012, only 18 cases of H capsulatum were observed.3 Most cases of osteoarticular infections due to H capsulatum (89%) were described as a solitary bone lesion or joint infection.3 The clinical presentation in our cases is consistent with this report—PJI due to H capsulatum appear to be mostly isolated without other active focus of infection.\n\nFactors that predispose patients to develop PJI due to H capsulatum is unknown. Although many of the cases are residents in endemic regions, there are no unifying host characteristics in the 7 patients. Although the infection has occurred in immunocompetent patients, it is possible that an underlying immunosuppression may predispose a patient to develop PJI due to H capsulatum.5 However, in a case-control study of immunocompromised transplant patients with PJI, no case of histoplasmosis was reported.13 In another report on 152 transplant patients with histoplasmosis, none involved bones or joints.14 In addition, the time to infection in relation to initial joint implantation was highly variable (from weeks to many years), suggesting that there is no unifying factor that predisposes to this rare orthopedic infection.\n\nThe antifungal treatment of histoplasmosis depends on the immune status and disease severity.15 Because of the localized nature of joint infection in our patients, oral itraconazole alone was used. In one of the previously reported cases, amphotericin B was also used over concerns of disseminated histoplasmosis, although this was not conclusively proven. The duration of treatment of PJI due to H capsulatum is not clear; however, all cases were treated with more than 7 months of antifungal therapy after resection arthroplasty. Longer (anticipated lifelong) courses were given to 2 immunocompromised individuals with retained joint components.\n\nIn general, a 2-stage exchange surgery (in which the infected joint prosthesis is removed during debridement, followed by antimicrobial treatment, and implantation of new prosthesis once the infection has cleared) is the recommended curative therapy for PJI.16 Because H capsulatum is efficient in forming a biofilm,17 a 2-stage exchange approach may also be needed for the complete eradication of PJI due to H capsulatum. Resection arthroplasty was used in 5 cases in this report, but the time to prosthesis reimplantation was highly variable. In addition to microbial and pharmacological factors, the decision on the timing of reimplantation considers host and social considerations, such as the desire to resume activities of daily living and the availability of caretakers during the debilitating periods related to surgical joint explantation. In 2 immunocompromised patients, resection arthroplasties were not performed because prostheses were well fixed and patients were functional without pain. Because of retained prostheses, both patients were receiving maintenance indefinite itraconazole suppression.5\n\nConclusion\n\nHistoplasma capsulatum is a rare cause of PJI. The diagnosis of histoplasmosis was initially not suspected, and most patients were receiving antibacterial therapy for presumed culture-negative PJI until cultures surprisingly grew H capsulatum. Resection arthroplasty was performed in 5 of 7 cases, whereas debridement and retention strategy was used in 2 immunocompromised cases. All the cases were treated initially or fully with itraconazole for prolonged durations; one was also given amphotericin B over concerns of disseminated infection, while another one was transitioned to posaconazole after he developed heart failure attributed to itraconazole therapy.\n\nPotential Competing Interests: The authors report no competing interests.\n==== Refs\nReferences\n\n1 Hage C.A. Azar M.M. Bahr N. Loyd J. Wheat L.J. Histoplasmosis: up-to-date evidence-based approach to diagnosis and management Semin Respir Crit Care Med 36 5 2015 729 745 26398539\n2 Nel J.S. Bartelt L.A. van Duin D. Lachiewicz A.M. Endemic mycoses in solid organ transplant recipients Infect Dis Clin North Am 32 3 2018 667 685 30146029\n3 Rammaert B. Gamaletsou M.N. Zeller V. Dimorphic fungal osteoarticular infections Eur J Clin Microbiol Infect Dis 33 12 2014 2131 2140 24939620\n4 Meiyappan A. Villa J.M. Sabesan V.J. Patel P.D. Suarez J.C. Histoplasma capsulatum periprosthetic knee infection complicated by autoimmune-mediated systemic inflammatory response syndrome Arthroplast Today 5 2 2019 135 138 31286031\n5 Fowler V.G. Jr. Nacinovich F.M. Alspaugh J.A. Corey G.R. Prosthetic joint infection due to Histoplasma capsulatum: case report and review Clin Infect Dis 26 4 1998 1017 9564509\n6 Nowbakht C. Garrity K. Webber N. Eraso J. Ostrosky-Zeichner L. Prosthetic joint infection due to Histoplasma capsulatum complicating a total knee arthroplasty Open Forum Infect Di 4 3 2017 ofx118\n7 Foo R.M. Putta Subramanyam N. Chan D. Photo quiz: an unusual knee infection J Clin Microbiol 57 4 2019 e00207 e00218 30923077\n8 Berbari E.F. Marculescu C. Sia I. Culture-negative prosthetic joint infection Clin Infect Dis 45 9 2007 1113 1119 17918072\n9 Malekzadeh D. Osmon D.R. Lahr B.D. Hanssen A.D. Berbari E.F. Prior use of antimicrobial therapy is a risk factor for culture-negative prosthetic joint infection Clin Orthop Relat Res 468 8 2010 2039 2045 20401555\n10 Marculescu C.E. Berbari E.F. Cockerill F.R. III Osmon D.R. Fungi, mycobacteria, zoonotic and other organisms in prosthetic joint infection Clin Orthop Relat Res 451 2006 64 72 16906078\n11 Brown T.S. Petis S.M. Osmon D.R. Periprosthetic joint infection with fungal pathogens J Arthroplasty 33 8 2018 2605 2612 29636249\n12 Mathews D.M. John R. Verghese V. Histoplasma capsulatum infection with extensive lytic bone lesions mimicking LCH J Trop Pediatr 62 6 2016 496 499 27329388\n13 Vergidis P. Lesnick T.G. Kremers W.K. Razonable R.R. Prosthetic joint infection in solid organ transplant recipients: a retrospective case-control study Transpl Infect Dis 14 4 2012 380 386 22260428\n14 Assi M. Martin S. Wheat L.J. Histoplasmosis after solid organ transplant Clin Infect Dis 57 11 2013 1542 1549 24046304\n15 Wheat L.J. Freifeld A.G. Kleiman M.B. Infectious Diseases Society of America Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America Clin Infect Dis 45 7 2007 807 825 17806045\n16 Osmon D.R. Berbari E.F. Berendt A.R. Infectious Diseases Society of America Executive summary: diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America Clin Infect Dis 56 1 2013 1 10 23230301\n17 Pitangui N.S. Sardi J.C.O. Silva J.F. Adhesion of Histoplasma capsulatum to pneumocytes and biofilm formation on an abiotic surface Biofouling 28 7 2012 711 718 22784100\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2542-4548",
"issue": "5(1)",
"journal": "Mayo Clinic proceedings. Innovations, quality & outcomes",
"keywords": "PJI, prosthetic joint infection; TKA, total knee arthroplasty",
"medline_ta": "Mayo Clin Proc Innov Qual Outcomes",
"mesh_terms": null,
"nlm_unique_id": "101728275",
"other_id": null,
"pages": "225-229",
"pmc": null,
"pmid": "33718797",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "30146029;31286031;23230301;24939620;24046304;16906078;22260428;26398539;27329388;9564509;29636249;22784100;17918072;20401555;17806045;30923077;32793759",
"title": "Prosthetic Joint Infections Due to Histoplasma capsulatum: A Report of 3 Cases.",
"title_normalized": "prosthetic joint infections due to histoplasma capsulatum a report of 3 cases"
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"abstract": "OBJECTIVE\nA case of a nortriptyline overdose complicated by delayed ventricular arrhythmias necessitating prolonged sodium bicarbonate infusion is presented, along with a review of tricyclic antidepressant (TCA) toxicology and key concepts for massive overdose management.\n\n\nCONCLUSIONS\nA 61-year-old man presented after an intentional nortriptyline overdose with a possible consumption of up to 2500 mg of nortriptyline. Electrocardiogram on presentation demonstrated QRS widening to 240 milliseconds. Despite treatment with a sodium bicarbonate infusion and further narrowing of his QRS interval, his course was complicated by repeated episodes of wide complex tachycardia. Given these episodes, an elevated quantitative serum nortriptyline level of 468 μg/L on hospital day 6 and persistently positive TCA urine screens, the patient was continued on a sodium bicarbonate infusion until hospital day 14. Based on our patient's quantitative serum nortriptyline levels, we calculated an elimination half-life of 184 hours, 6 days post ingestion as compared to the reported half-life of nortriptyline of 14 to 51 hours.\n\n\nCONCLUSIONS\nThis case demonstrates that at toxic levels of ingestion, routine TCA pharmacokinetics may be unreliable due to delayed absorption, enterohepatic recirculation, large volume of distribution, and saturable kinetics. Therefore, in these cases, pharmacokinetic values derived from routine dosing should not be used to make clinical decisions (such as timing of discontinuation of sodium bicarbonate infusion). We found that urine TCA screens provided similar information to quantitative nortriptyline levels and can be used to guide therapy along the QRS duration.",
"affiliations": "Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA.;Department of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.;Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA.",
"authors": "Elsamadisi|Pansy|P|https://orcid.org/0000-0003-0302-6006;Sclafani|Alyssa|A|;Eche|Ifeoma Mary|IM|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D009661:Nortriptyline",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190019838700",
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"issn_linking": "0897-1900",
"issue": "33(4)",
"journal": "Journal of pharmacy practice",
"keywords": "cardiotoxicity; nortriptyline; sodium bicarbonate; toxicokinetics; toxicology",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000929:Antidepressive Agents, Tricyclic; D066126:Cardiotoxicity; D062787:Drug Overdose; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D009661:Nortriptyline",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "543-547",
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"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Delayed Cardiotoxicity From a Massive Nortriptyline Overdose Requiring Prolonged Treatment.",
"title_normalized": "delayed cardiotoxicity from a massive nortriptyline overdose requiring prolonged treatment"
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"abstract": "BACKGROUND\nExpert consensus panels have recommended risperidone as first-line treatment for agitation of psychiatric origin. However, there are few if any studies on this medication in the emergency setting.\n\n\nOBJECTIVE\nTo assess the hemodynamic effects of risperidone in an emergency department (ED) setting, stratified by age.\n\n\nMETHODS\nThis is a structured chart review of all patients who received oral risperidone over a 6-year period in an ED setting, excluding patients who received this medication as a prescription refill. Vital signs were analyzed for this subset prior to and after medication administration, and changes in vital signs were stratified by age.\n\n\nRESULTS\nThe median dose of risperidone was less in patients aged > 65 years. However, the median drop in systolic blood pressure was larger in this age group compared with younger patients.\n\n\nCONCLUSIONS\nClinicians tend to be more cautious with dosing of risperidone to geriatric patients in the ED. Despite this, decreases in systolic blood pressure are larger and more frequent in this age group. When possible, clinicians should consider or attempt nonpharmacologic methods of agitation treatment prior to administering medications such as risperidone to elderly patients.",
"affiliations": "Department of Emergency Medicine Behavioral Emergencies Research (DEMBER), University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Department of Emergency Medicine Behavioral Emergencies Research (DEMBER), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Psychiatric Emergency Services, Denver Health Medical Center; University of Colorado at Denver, Denver, Colorado.;Department of Emergency Medicine Behavioral Emergencies Research (DEMBER), University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Arkansas Department of Health, Little Rock, Arkansas; Department of Epidemiology, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas.;Department of Emergency Medicine Behavioral Emergencies Research (DEMBER), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Department of Emergency Medicine, UC San Diego Health System, University of California San Diego, San Diego, California.;Department of Emergency Medicine Behavioral Emergencies Research (DEMBER), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Department of Emergency Medicine, UC San Diego Health System, University of California San Diego, San Diego, California.",
"authors": "Wilson|Michael P|MP|;Nordstrom|Kimberly|K|;Hopper|Austin|A|;Porter|Austin|A|;Castillo|Edward M|EM|;Vilke|Gary M|GM|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2017.06.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "53(5)",
"journal": "The Journal of emergency medicine",
"keywords": "agitation; geriatric patients; risperidone",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D015331:Cohort Studies; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007022:Hypotension; D008297:Male; D008875:Middle Aged; D011595:Psychomotor Agitation; D012189:Retrospective Studies; D018967:Risperidone; D055986:Vital Signs",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "735-739",
"pmc": null,
"pmid": "28987309",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risperidone in the Emergency Setting is Associated with More Hypotension in Elderly Patients.",
"title_normalized": "risperidone in the emergency setting is associated with more hypotension in elderly patients"
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report a case of acute transient myopia with anterior chamber shallowing induced by sulfamethoxazole in a patient with pseudoxanthoma elasticum (PXE).\n\n\nMETHODS\nObservational case report.\n\n\nMETHODS\nA case report of a 45-year-old woman who presented with bilateral acute myopia, anterior chamber shallowing, and intraocular hypertension induced by sulfamethoxazole and was found to have PXE. Initial and follow-up examination findings were reviewed.\n\n\nRESULTS\nOn first examination, bilateral myopic shift of 4.25 D, bilateral narrowed angles, and ocular hypertension (36 mm Hg right eye and 38 mm Hg left eye) were found. Pentacam images documented the anterior displacement of the iris-lens diaphragm. Undilated fundus examination disclosed bilateral angioid streaks radiating from the papilla. Several redundant skin folds on the neck and axillae were found on external examination. With sulfamethoxazole discontinuation and administration of topical intraocular pressure-lowering drops, there was complete clinical resolution within 1 week. The diagnosis of PXE was confirmed by biopsy of the skin lesions.\n\n\nCONCLUSIONS\nAcute myopia with angle narrowing is an extremely rare sulfamethoxazole side effect, and its relationship, if any, with PXE is unknown. As far as we know, this is the first reported case of PXE presenting with bilateral angle narrowing induced by sulfamethoxazole.",
"affiliations": "*Ophthalmology Department, S. João Hospital †Department of Sense Organs, University of Porto, Porto, Portugal.",
"authors": "Araújo|Joana R|JR|;Silva|Sérgio E|SE|;Cruz|Francisco|F|;Falcão-Reis|Fernando|F|",
"chemical_list": "D000890:Anti-Infective Agents; D000959:Antihypertensive Agents; D013420:Sulfamethoxazole",
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000000074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "23(6)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000208:Acute Disease; D000284:Administration, Oral; D000867:Anterior Chamber; D000890:Anti-Infective Agents; D000959:Antihypertensive Agents; D001706:Biopsy; D003556:Cystitis; D005260:Female; D006801:Humans; D007429:Intraocular Pressure; D008875:Middle Aged; D009216:Myopia; D009798:Ocular Hypertension; D011561:Pseudoxanthoma Elasticum; D013420:Sulfamethoxazole",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "415-7",
"pmc": null,
"pmid": "25075463",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Acute transient myopia with shallowing of the anterior chamber induced by sulfamethoxazole in a patient with pseudoxanthoma elasticum.",
"title_normalized": "acute transient myopia with shallowing of the anterior chamber induced by sulfamethoxazole in a patient with pseudoxanthoma elasticum"
} | [
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"companynumb": "PHHY2014PT130712",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": n... |
{
"abstract": "The additional sex combs like 3 gene is considered to be causative for the rare Bainbridge-Ropers syndrome (BRPS), which is characterized by severe intellectual disability, neonatal hypotonia, nearly absent development of speech and language as well as several facial dysmorphisms. Apart from disruptive autistiform behaviors, sleep disturbances and epileptic phenomena may be present. Here, a 47-year-old severely intellectually disabled male is described in whom exome sequencing disclosed a novel heterozygous frameshift mutation in the ASXL3 gene leading to a premature stopcodon in the last part of the last exon. Mutations in this very end 3' of the gene have not been reported before in BRPS. The phenotypical presentation of the patient including partially therapy-resistant epilepsy starting in later adulthood shows overlap with BRPS, and it was therefore concluded that the phenotype is likely explained by the identified mutation in ASXL3.",
"affiliations": "Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, the Netherlands.;Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, the Netherlands.;ASVZ, Centre for People with Intellectual Disabilities, Sliedrecht, the Netherlands.;Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.;Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.;Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.",
"authors": "Verhoeven|Willem|W|;Egger|Jos|J|;Räkers|Emmy|E|;van Erkelens|Arjen|A|;Pfundt|Rolph|R|;Willemsen|Marjolein H|MH|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S153511",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S153511ndt-14-867Case ReportPhenotypic characterization of an older adult male with late-onset epilepsy and a novel mutation in ASXL3 shows overlap with the associated Bainbridge-Ropers syndrome Verhoeven Willem 12Egger Jos 13Räkers Emmy 4van Erkelens Arjen 5Pfundt Rolph 5Willemsen Marjolein H 5\n1 Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, the Netherlands\n2 Department of Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands\n3 Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands\n4 ASVZ, Centre for People with Intellectual Disabilities, Sliedrecht, the Netherlands\n5 Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the NetherlandsCorrespondence: Willem Verhoeven, Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, PO Box 5, 5800AA Venray, the Netherlands, Tel +31 47 852 7339, Fax +31 47 858 4765, Email wmaverhoeven@planet.nl2018 27 3 2018 14 867 870 © 2018 Verhoeven 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.The additional sex combs like 3 gene is considered to be causative for the rare Bainbridge-Ropers syndrome (BRPS), which is characterized by severe intellectual disability, neonatal hypotonia, nearly absent development of speech and language as well as several facial dysmorphisms. Apart from disruptive autistiform behaviors, sleep disturbances and epileptic phenomena may be present. Here, a 47-year-old severely intellectually disabled male is described in whom exome sequencing disclosed a novel heterozygous frameshift mutation in the ASXL3 gene leading to a premature stopcodon in the last part of the last exon. Mutations in this very end 3′ of the gene have not been reported before in BRPS. The phenotypical presentation of the patient including partially therapy-resistant epilepsy starting in later adulthood shows overlap with BRPS, and it was therefore concluded that the phenotype is likely explained by the identified mutation in ASXL3.\n\nKeywords\nBainbridge-Ropers syndromeASLX3frameshift mutationepilepsyintellectual disabilityarray analysiswhole exome sequencingautism spectrum disorder\n==== Body\nIntroduction\nBainbridge-Ropers syndrome (BRPS) [OMIM #615485] is a novel syndromal entity that is caused by a mutation in the additional sex combs like 3 (ASLX3) gene located at 18q12.1. In 2013, the syndrome was first described in four patients.1 The ASLX3 gene has a functional role in the process of deubiquitination and is expressed in several organ systems including the central nervous system.2 At present, <30 patients with this syndrome, children and adolescents only, have been published.1,3–6 The phenotype typically includes severe intellectual disability, nearly absent speech and language, hypotonia, and feeding difficulties at young age as well as distinct craniofacial features such as prominent forehead, arched eyebrows, and hypertelorism. Regarding behavior, in addition to aggressive and autistic traits with rocking and hand flapping, periodic agitation and sleep disturbances are frequently described. In a minority of the patients, tonic-clonic seizures or absences occur in childhood.5–7\n\nHere, the first middle-aged male patient with a mutation in ASXL3 and a phenotype reminiscent of BRPS is described. He developed tonic-clonic epilepsy at the end of his fourth decade.\n\nPatients and methods\nCase description\nThe patient is a 47-year-old male with one older sister by 4 years from the same parents, two half-brothers and one half-sister from other fathers. All siblings, including most probably also their mother, were intellectually disabled and developed within a very poor pedagogic family context. Apart from minimal to absent speech and language development, no information is available about his early years. From the age of 6, the patient needed a specialized child day care facility. Two years later, he had to be institutionalized because of severe behavioral problems, particularly continuous extreme screaming, also nocturnal. From his early adolescence on, anxious, aggressive, self-injurious, and compulsive behaviors occurred intermittently contingent upon environmental changes for which various psychotropics were prescribed symptomatically. Social maturity was established at a developmental level of ~5 years. At his mid-thirties, the behavioral pattern was attributed to an autism spectrum disorder for which he was moved to a specialized ward. This resulted in a significant amelioration of his behavioral repertoire. Aged 38, the patient developed erythema migrans due to a borrelia infection that was proven by seroconversion in blood with normal cerebrospinal fluid parameters for which he was adequately treated with antibiotics.\n\nAt the age of 45 years, the patient’s actions became increasingly disruptive with progressive repetitive and compulsive behaviors. In addition, intensified sensitivity to sensory stimuli as well as severe sleep problems developed for which risperidone and lorazepam were prescribed. In this period, generalized epilepsy with three tonic-clonic seizures occurred and treatment with carbamazepine was started (800 mg; 8.7 mg/L). Subsequently, two consecutive 24 h video-EEG registrations disclosed no epileptic configurations. CT and MRI scanning of the brain, the latter under general anesthesia because of his disinhibited behaviors, disclosed no abnormalities. Because of accumulation of severe challenging behaviors and sleep disturbances necessitating nearly permanent individualized care, the patient was referred for expert consultation.\n\nRelevant family context\nThe patient’s older sister, with about a similar history and later staying at the same institute, was institutionalized from early age on because of severe challenging behaviors. She was also suffering from tonic-clonic seizures, most probably starting in infancy, for which she was initially treated with phenytoine, which was changed to carbamazepine (1,000 mg) in her early twenties. There were no neurological abnormalities or notable dysmorphic features. Development of speech and language was restricted to single words and sounds. She displayed autistic traits with periodic screaming, crying, and anxiety-driven aggressive behaviors. At that time, mean developmental age was 2.5 years. Because of persistent epileptic phenomena, occurring also at night, 10 years later valproic acid was added (1,200 mg), which, however, could not prevent further tonic-clonic seizures. Aged 35 years, she underwent bilateral mastectomy because of carcinoma. One year later, she died during a nocturnal tonic-clonic epileptic status.\n\nThe mother of both siblings deceased 4 years later (unknown cause). Their father died many years before. Similar to the early years of the patient and his sister, no additional information is available for both parents.\n\nResults\nAt examination by a clinical geneticist, a severe intellectually disabled, middle-aged male patient was seen with only mild facial dysmorphisms (Figure 1). Height, weight, and head circumference were 168 cm (−2 SD), 54 kg (BMI: 19), and 53.5 cm (−2.5 SD), respectively. Somatic and neurological examination disclosed no abnormalities. Relevant hematological and biochemical parameters were all normal. His behavior repertoire was evaluated by a neuropsychiatrist and could be best typified by autistic-like repetitive and compulsive behaviors such as rubbing/stroking and licking with increase in unknown situations. Hardly any communication was possible but, based on nonverbal instructions, the patient was able to perform very simple daily activities, for example, bringing his plate to the table and taking his meal.\n\nSince etiological investigation was not performed as yet, first, chromosomal analysis using the CytoScan HD array (Applied Biosystems™, Foster City, CA, USA) was done, which disclosed no abnormalities. Fragile-X syndrome was also excluded by DNA diagnostics. Subsequently, whole exome sequencing was performed essentially as described before.8 Target regions were enriched using the Agilent SureSelectXT Human All Exon 50Mb Kit. Whole-exome sequencing was performed on the Illumina HiSeq platform (BGI, Copenhagen, Denmark) followed by analysis of the variants in genes involved in neurodevelopmental diseases. Data were analyzed with Burrows-Wheeler Aligner (read alignment) and Genome Analysis Toolkit (variant calling) software packages. Variants were annotated using an in-house developed pipeline. Prioritization of variants was done by an in-house designed “variant interface” and manual curation. This revealed a heterozygous frameshift mutation in the ASXL3 gene: (Chr18(GRCh37):g.31326509_31326522du p; NM_030632.1:c.6697_6710dup(p.(Ser2238fs)).\n\nIt concerns a duplication of 14 base pairs leading to a frameshift and premature stop in the 3′-part of the last exon of the ASXL3 gene. This will probably lead to the presence of a truncated protein, rather than nonsense-mediated decay and haploinsufficiency. Other reported mutations in patients with BRPS are most likely leading to haploinsufficiency, although the vast majority of the mutations that have been described so far are located in the last two exons of the ASXL3 gene (The Human Gene Mutation Database).9 Pathogenic mutations in this very end 3′ of the gene have not been reported before. Also, the mutation has been reported neither in the previous literature nor in the Exome Aggregation Consortium (ExAC; http://exac.broadinstitue.org) or Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org). It was classified as possibly pathogenic since the phenotype of the patient, although not highly specific but including intellectual disability, the above-described speech/language impairment, sleep disturbances, behavioral phenomena, and epilepsy, could fit within the spectrum of BRPS. Thus, the ASXL3 mutation was concluded to be a likely explanation. In addition, it is possible that mutations in ASXL3 with another effect than haploinsufficiency may lead to phenotypes with intellectual disabilities that are not typically fitting into the phenotype of BRPS.\n\nTo further specify the phenotypic presentation, extensive neuropsychological assessment was performed showing a discrepant profile with a developmental age ranging from ≤1 year (social and communicative skills; Vineland Screener,10 SRZ-P,11) to maximally 2.5 years (visuomotor functioning; Beery VMI12). Due to major impairments in communication, formal testing of attention, memory, and executive functioning could not be performed. Instead, relevant domains were objectivated by proxy-ratings of attention/executive functioning (DEX13 and EFI14: severely disturbed) and psychopathology (PIMRA15: anxiety bound symptoms).\n\nSince no appropriate plasma concentration of risperidone could be achieved due to enzymatic induction by the previously mentioned antiepileptic carbamazepine, the latter was replaced by valproic acid. Also, zopiclone was added to lorazepam, which to some extent improved his sleep pattern. Concerning epilepsy, since the start of antiepileptic drugs, tonic-clonic seizures did no longer occur although regular daytime absences were still noticed. At present, the patient is treated with 1,200 mg valproic acid (60 mg/L), 5 mg risperidone (2.8/29 μg/L), 3.5 mg lorazepam (28 μg/L), and 7.5 mg zopiclone.\n\nDiscussion\nIn this paper, the first middle-aged male patient is described in whom whole exome sequencing demonstrated a never reported novel frameshift mutation in the ASXL3 gene (c.6697_6710dup). Although never reported before and located in the very 3′ end of the gene, this mutation was considered to be likely pathogenic since the phenotype shows overlap with the phenotypic spectrum of BRPS, including severe intellectual disability, autistic-like behavioral problems, and epilepsy that is reported in a minority of the patients diagnosed with BRPS. The facial phenotype is not typically recognizable as BRPS but the phenotype in other patients with this syndrome is variable and not highly specific.6 There are, however, some similarities, for example, in the shape of the nose that can also be recognized in the present patient (Figure 1). It might be that the mutation in the very 3′ end of the ASXL3 gene leads to a less “typical” presentation of BRPS which, however, is not an easily recognizable syndrome per se.6 Furthermore, since individuals with BRPS, in particular adults, are relatively rare, the clinical spectrum may be actually much broader than reported up to now. In contrast to his deceased sister, his epilepsy started not at an early age but in his fourth decade and is partially therapy resistant since absences still persist. However, given the developmental issues, presentation, and course of disease including severe epilepsy, his deceased sister could have had the same genetic disorder. In both, social interaction could be characterized as predominantly anxiety-driven disruptive autistiform behaviors. Since intellectual disability was reported in the mother as well, the mutation in ASXL3 might be inherited from her. Perhaps, she was more mildly affected due to the presence of the mutation in mosaic state. However, half-siblings with the same father were also reported to have intellectual disability. Since segregation analysis was not possible and detailed clinical data are lacking, it remains unclear whether this mutation is inherited and if so, from whom.\n\nConclusion\nExtensive genetic analysis including whole exome sequencing is mandatory in patients with unexplained developmental delay and intellectual disability, also in adulthood and older age. The latter not only to detect the genetic etiology of syndromic intellectual disability, but especially also to further elucidate course into adulthood and prognosis of newly discovered disorders like Bainbridge-Ropers syndrome.\n\nAcknowledgments\nWritten informed consent was obtained from the legal representative (manager of the institute; since no family members are alive) for publication of this paper on the patient and his family and to include a picture of the face of the patient. The patient was referred by the Centre of Consultation and Expertise, region West. The authors are indebted to Mrs Anneke Baselier, consultant psychologist, and to the staff members of the ASVZ-institute for intellectual disabilities for their careful assessment of the behavior status of the patient. Thanks are extended to Mrs Linde van Dongen, psychologist from the Centre of Excellence for Neuropsychiatry of the Vincent van Gogh Institute for Psychiatry, who performed neuropsychological testing.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Clinical photograph of the present patient showing mild facial dysmorphic features, including deeply set eyes and a prominent nose with high nasal bridge, possibly fitting within the spectrum of facial dysmorphic features in BRPS.\n\nNote: They are, however, neither very specific nor easily recognizable.\n\nAbbreviation: BRPS, Bainbridge-Ropers syndrome.\n==== Refs\nReferences\n1 Bainbridge MN Hu H Muzny DM De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome Genome Med 2013 5 2 11 23383720 \n2 Srivastava A Ritesh KC Tsan YC De novo dominant ASXL3 mutations alter H2A deubiquination and transcription in Bainbridge-Ropers syndrome Hum Mol Genet 2016 25 3 597 608 26647312 \n3 Dinwiddle DL Soden SE Saunders CJ De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies BMC Med Genomics 2016 6 32 \n4 Hori I Miya F Ohashi K Novel splicing in the ASXL3 gene causing Bainbridge Ropers syndrome Am J Med GenetA 2016 170 7 1863 1867 \n5 Kuechler A Czeschik JC Graf E Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3 : a recognizable condition Eur J Hum Genet 2017 25 2 183 191 27901041 \n6 Balasubramanian M Willoughby J Fry AE Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo heterozygous, loss-of-function mutations in ASXL3 and review of the published literature J Med Genet 2017 54 8 537 543 28100473 \n7 Contreras-Capetillo SN Vilchis-Zapata ZH Ribbón-Conde J Pinto-Escalante D Global developmental delay and postnatal microcephaly: Bainbridge-Ropers syndrome with a new mutation in ASXL3 Neurología Epub 2017 4 18 \n8 Neveling K Feenstra I Gilissen C Post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases HumMutat 2013 34 12 1721 1726 \n9 Stenson PD Mort M Ball EV The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies Hum Genet 2017 136 6 665 677 28349240 \n10 Scholte E Van Duijn E Dijkxhoorn Y Vineland Screener 0-6 Years: Manual of the Dutch Adaptation Leiden, The Netherlands PITS 2008 \n11 Kraijer DW Kema GN Sociale Redzaamheidsschaal Voor Verstandelijk Gehandicapten Van Hoger Niveau (SRZ-P) Amsterdam, The Netherlands Pearson 2004 \n12 Beery KE Buktenica NA Beery NA The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) 5th ed San Antonio, Texas Pearson 2004 \n13 Wilson B Alderman N Burgess P Emslie H Evans J Behavioural Assessment of the Dysexecutive Syndrome (BADS) London, UK Pearson 1997 \n14 Janssen GT De Mey HR Egger JI Executive functioning in college students: evaluation of the Dutch executive function index (EFI-NL) Int J Neurosci 2009 119 6 792 805 19326285 \n15 Matson JL Kazdin AE Senatore V Psychometric properties of the psychopathology instrument for mentally retarded adults Appl Res Ment Retard 1984 5 1 81 89 6721483\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "14()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "ASLX3; Bainbridge-Ropers syndrome; array analysis; autism spectrum disorder; epilepsy; frameshift mutation; intellectual disability; whole exome sequencing",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "867-870",
"pmc": null,
"pmid": "29628764",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19326285;23383720;24044690;24123792;26647312;27075689;27901041;28100473;28349240;28431838;6721483",
"title": "Phenotypic characterization of an older adult male with late-onset epilepsy and a novel mutation in ASXL3 shows overlap with the associated Bainbridge-Ropers syndrome.",
"title_normalized": "phenotypic characterization of an older adult male with late onset epilepsy and a novel mutation in asxl3 shows overlap with the associated bainbridge ropers syndrome"
} | [
{
"companynumb": "NL-MYLANLABS-2022M1002607",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Colorectal cancer is the third most common cancer diagnosed in the USA each year. Oxaliplatin, a platinum-based chemotherapy agent, is part of the standard adjuvant chemotherapy regimen FOLFOX (oxaliplatin with 5-fluorouracil [5-FU] and leucovorin [LV]) for the treatment of stage III and some high-risk stage II colorectal cancers. Although oxaliplatin is generally well tolerated, certain side effects such as nausea, vomiting, and peripheral neuropathy are common. We report a case of oxaliplatin-induced capillary-leak syndrome in a 63-year-old man undergoing his 12th and final cycle of FOLFOX for stage III colorectal cancer. To our knowledge, this is the first case of systemic capillary leak syndrome (SCLS) reported in association with oxaliplatin. Currently, there is no prevention for SCLS. Documenting future cases of SCLS attributed to oxaliplatin is vital, as SCLS is associated with significant morbidity and mortality and no standard treatments beyond supportive care measures exist. Early recognition and diagnosis are therefore essential to improving patient outcomes.",
"affiliations": "Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.;Department of Medicine, Medical University of South Carolina, Charleston, SC, USA petersll@musc.edu.",
"authors": "Anderson|Brandon J|BJ|;Peterson|Lindsay L|LL|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1177/1078155215591388",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "22(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "FOLFOX; Oxaliplatin; colorectal cancer; systemic capillary leak syndrome",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D019559:Capillary Leak Syndrome; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "725-8",
"pmc": null,
"pmid": "26071595",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic capillary leak syndrome in a patient receiving adjuvant oxaliplatin for locally advanced colon cancer.",
"title_normalized": "systemic capillary leak syndrome in a patient receiving adjuvant oxaliplatin for locally advanced colon cancer"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201502993",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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{
"abstract": "OBJECTIVE\nSeveral studies have reported that itraconazole-induced inhibition of vincristine (VCR) metabolism might result in neurological impairment and syndrome of inappropriate antidiuretic hormone (SIADH). However, there are few reports concerning adverse drug reactions (ADRs) resulting from concomitant use of vindesine (VDS) and itraconazole. Here, we report the first case of adverse drug interactions (ADIs) between itraconazole and VDS in a Chinese child with acute lymphocytic leukaemia (ALL).\n\n\nMETHODS\nA 4-year-old boy was diagnosed with standard-risk ALL and was receiving VDS (3 mg/m2 ) for maintenance therapy and itraconazole for IFI recurrence. Severe neurotoxicity, consisting mainly of trismus and SIADH, was noticed after 7 days of VDS administration. After discontinuation of itraconazole and its replacement with caspofungin, the patient recovered from neurological signs and symptoms. The ADIs can be explained by VDS accumulation owing to inherent loss of CYP3A5 (*3/*3) function, and inhibition of CYP3A4 activity by itraconazole.\n\n\nCONCLUSIONS\nSyndrome of inappropriate antidiuretic hormone from co-administration of itraconazole and VDS has not previously been reported to our knowledge. We suggest that the concomitant use of these drugs should be avoided if possible. The use of alternative antifungal drugs (AFDs) should be considered, and ADRs should be closely monitored when the combination of itraconazole and VDS is unavoidable.",
"affiliations": "Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"authors": "Zhou|H|H|;Li|L|L|;Zhou|Y|Y|;Han|Y|Y|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole; D014751:Vindesine",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12598",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "drug interaction; itraconazole; syndrome of inappropriate antidiuretic hormone; vindesine",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000935:Antifungal Agents; D002675:Child, Preschool; D004347:Drug Interactions; D006801:Humans; D007177:Inappropriate ADH Syndrome; D017964:Itraconazole; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014751:Vindesine",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "137-140",
"pmc": null,
"pmid": "28782144",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Syndrome of inappropriate antidiuretic hormone secretion from concomitant use of itraconazole and vindesine.",
"title_normalized": "syndrome of inappropriate antidiuretic hormone secretion from concomitant use of itraconazole and vindesine"
} | [
{
"companynumb": "CN-JNJFOC-20170819712",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VINDESINE"
},
"drugadditional": "1",
"d... |
{
"abstract": "Oral phenylephrine is a commonly used over-the-counter nasal decongestant drug. It is usually taken for symptomatic relief (in combination drug products) for upper respiratory tract infections, allergic rhinitis, or sinusitis. Adverse cardiovascular effects of intravenous phenylephrine, including organ ischemia, are well known; however, oral phenylephrine is rarely associated with significant adverse effects. We describe the first case of acute ischemic colitis in a young patient due to over-the-counter oral phenylephrine, which was taken as a nasal decongestant. We reviewed the literature of colonic ischemia related to the use of systemic nasal decongestants phenylephrine and pseudoephedrine.",
"affiliations": "Department of Medicine, Anne Arundel Medical Center, Annapolis, MD.;Promedica Digestive Health Care (affiliated with ProMedica Toledo Hospital, Toledo, OH), Sylvania, OH.",
"authors": "El-Alali|Emran|E|;Alhmoud|Tarik|T|",
"chemical_list": null,
"country": "United States",
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"doi": "10.14309/crj.0000000000000459",
"fulltext": "\n==== Front\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253 Wolters Kluwer Maryland, MD \n\nACGCR-20-0285\n10.14309/crj.0000000000000459\n00012\nCase Report\nColon\nAcute Ischemic Colitis due to Oral Phenylephrine\nEl-Alali Emran MD1 Alhmoud Tarik MD, MS2 1 Department of Medicine, Anne Arundel Medical Center, Annapolis, MD\n2 Promedica Digestive Health Care (affiliated with ProMedica Toledo Hospital, Toledo, OH), Sylvania, OH\nCorrespondence: Emran El-Alali, MD (eelalali@aahs.org).\n9 2020 \n29 9 2020 \n7 9 e0045927 3 2020 10 7 2020 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nOral phenylephrine is a commonly used over-the-counter nasal decongestant drug. It is usually taken for symptomatic relief (in combination drug products) for upper respiratory tract infections, allergic rhinitis, or sinusitis. Adverse cardiovascular effects of intravenous phenylephrine, including organ ischemia, are well known; however, oral phenylephrine is rarely associated with significant adverse effects. We describe the first case of acute ischemic colitis in a young patient due to over-the-counter oral phenylephrine, which was taken as a nasal decongestant. We reviewed the literature of colonic ischemia related to the use of systemic nasal decongestants phenylephrine and pseudoephedrine.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nIschemic colitis (IC) is caused by sudden reduction in colonic perfusion leading to ischemic injury. IC is most commonly caused by nonocclusive colonic ischemia and less often due to acute arterial occlusion or mesenteric venous thrombosis.1 The prevalence of acute intestinal vascular insufficiency, including IC, is 406 of 100,000.2 Various medications can cause IC through vasoconstriction, hypotension, thrombogenic/procoagulant effect, or direct colonic toxicity.1,3,4 Over-the-counter (OTC) systemic nasal decongestants include the alpha-adrenergic agonists pseudoephedrine and oral phenylephrine, which are used for symptomatic relief of nasal congestion in common cold, allergic rhinitis, and sinusitis. Alpha-adrenergic agonists work via arterial vasoconstriction, which can potentially lead to tissue ischemia of various organs. Pseudoephedrine is a more potent decongestant compared with phenylephrine and has been linked to IC in several case reports. Intravenous phenylephrine is used to treat shock and hypotension and is known to cause cardiovascular adverse effects and tissue ischemia. Such side effects are rare with oral phenylephrine.\n\nCASE REPORT\nA 34-year-old White man with no significant medical history presented to the emergency department with a 2-day history of lower abdominal pain. Pain was associated with watery diarrhea, which had progressed to hematochezia. The patient had no nausea, vomiting, fever, or chills. He was admitted to the hospital for further management.\n\nThe patient used multiple OTC DayQuil LiquiCaps (containing phenylephrine 10 mg per LiquiCaps) over 2 days before symptoms onset to relieve nasal congestion and cold symptoms. He did not use other OTC or prescription medications. The patient reported no family history of hypercoagulation disorders. He chews tobacco occasionally and does not drink alcohol or use illicit drugs.\n\nVital signs were normal. Body mass index was 43 kg/m2. Heart rate and rhythm were normal and regular. Bowel sounds were normal. Abdomen was distended and showed left lower quadrant tenderness, no peritoneal signs, and no hepatosplenomegaly. White blood cell count was elevated (11.9 × 109/L), and hemoglobin was normal (15.0 g/dL). Serum creatinine, electrolytes, and liver enzymes were normal. Enteric pathogen panel was negative. Urine drug screen was negative for illicit drugs. Abdominal and pelvic computed tomography showed mural thickening of the descending colon with infiltrative changes in the mesentery compatible with left-sided colitis.\n\nDuring hospital stay, the patient was started on intravenous fluids and he maintained normal blood pressure, heart rate, and hemoglobin level. Gastroenterology consultation was requested, and colonoscopy demonstrated segmental moderate inflammation of the descending and sigmoid colon, characterized by mucosal congestion, erythema, erosions, friability, loss of vascularity, serpentine, and shallow ulcerations suggestive of IC vs, less likely, Crohn's disease (Figure 1).\n\nFigure 1. Endoscopy showing edema, erythema, friability, loss of vascularity, erosions, and ulcerations in the sigmoid colon (A and B) and descending colon (C).\n\nHistologic examination confirmed the diagnosis of IC. The patient was managed conservatively and was subsequently discharged from the hospital after resolution of symptoms. He was advised to avoid all phenylephrine-containing OTC products and to quit tobacco use. Outpatient mesenteric duplex study revealed no impairment to visceral circulation. He remained asymptomatic and was doing well after 2 months, during an outpatient office visit.\n\nDISCUSSION\nWe report a case of IC in a young man after the use of oral phenylephrine that was taken as a decongestant for common cold. IC was likely induced by the vasoconstrictive effect of the alpha-adrenergic receptor agonist phenylephrine, probably aggravated by coexisting smokeless tobacco use. Although the patient had obesity (body mass index of 43 kg/m2), he had no hypertension, heart disease, diabetes, or previous thromboembolic events, and his drug screen was negative for illicit drugs that are associated with IC (cocaine or amphetamines). A mesenteric duplex showed no vascular occlusions or impairment to visceral circulation. The episode resolved after discontinuing the offending drug.\n\nWe performed a literature search on PubMed and Google Scholar databases for IC related to oral phenylephrine use. Only 1 case report linking acute IC to oral phenylephrine use was found.5 Table 1 shows the characteristics of our patient compared with the previously reported case by Ward et al (similar word count).\n\nTable 1. Clinical characteristics of current case and previously reported case of ischemic colitis due to oral Phenylephrine\n\n\tCurrent case\tWard et al case5\t\nAge, yr\t34\t70\t\nGender\tMale\tFemale\t\nRace\tWhite\tAfrican American\t\nComorbidities\tSmokeless tobacco use, BMI 43 kg/m2\tHypertension, hyperlipidemia, and diverticulosis. Remote 5-pack-year smoking\t\nYear of presentation\t2019\t2014\t\nClinical presentation\tLower abdominal pain (cramping) and hematochezia\tNausea, vomiting, lower abdominal pain (cramping), and hematochezia\t\nNormal vital signs\tElevated blood pressure\t\nLLQ tenderness\tLLQ tenderness\t\nOTC phenylephrine containing product\tPhenylephrine HCl 5 mg, acetaminophen 325 mg, and dextromethorphan hydrobromide 10 mg\tPhenylephrine bitartrate 7.8 mg, aspirin 325 mg, and chlorpheniramine maleate 2 mg\t\nAbnormal laboratory findings\tLeukocytosis (WBC 11.9 × 109/L)\tLeukocytosis (WBC 22.3 × 109/L)\t\nAffected colon\tSplenic flexure, sigmoid and descending colon\tSplenic flexure, sigmoid and descending colon\t\nOutcome\tSelf-limited, no complications\tSelf-limited, no complications\t\nBMI, body mass index; LLQ, left lower quadrant; OTC, over-the-counter; WBC, white blood cell.\n\nPseudoephedrine—in contrast to phenylephrine—was reported to cause IC in 11 case reports.6–13 Pseudoephedrine is a more potent decongestant compared with oral phenylephrine, largely because of its higher systemic bioavailability.14 Pseudoephedrine was more widely used before restrictions were placed on its sale to limit its illicit conversion to methamphetamines.15 As a result, phenylephrine has largely replaced pseudoephedrine in many OTC cold and allergy medicines.\n\nWe conclude that our patient is the first reported case of acute IC due to oral phenylephrine use in a young person. The occurrence of IC with the less potent systemic decongestant phenylephrine in a patient with limited risk factors, and the fact that henylephrine became the more prevalent decongestant, suggests the call for extra caution with OTC decongestants use. Onset of abdominal pain and diarrhea should alarm individuals to promptly discontinue the drug and seek medical attention. Finally, a detailed medication history including the use of OTC products is crucial and can significantly contribute to the patient's management.\n\nDISCLOSURES\nAuthor contributions: E. El-Alali and T. Alhmoud wrote the manuscript and reviewed the literature. E. El-Alali is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Brandt LJ Feuerstadt P Longstreth GF Boley SJ ; American College of Gastroenterology . ACG clinical guideline: Epidemiology, risk factors, patterns of presentation, diagnosis, and management of colon ischemia (CI)\n. Am J Gastroenterol . 2015 ;110 (1 ):18 –45\n.25559486 \n2. Elkafrawy AA Chauhan M Elkaryoni A \nNational trends, outcomes and predictors of mortality in patients with ischemic colitis and acute mesenteric venous thrombosis. A Nationwide Inpatient Sample Study from 2002 to 2014\n. Gastroenterology . Suppl \n2019 ;156 (6 ):S-1067 (Abstract).\n3. Hass DJ Kozuch P Brandt LJ \nPharmacologically mediated colon ischemia\n. Am J Gastroenterol . 2007 ;102 (8 ):1765 –80\n.17488249 \n4. Tapia C Schneider T Manz M \nFrom hyperkalemia to ischemic colitis: A resinous way\n. Clin Gastroenterol Hepatol . 2009 ;7 (8 ):e46 –7\n.19281864 \n5. Ward PW Shaneyfelt TM Roan RM \nAcute ischaemic colitis associated with oral phenylephrine decongestant use\n. BMJ Case Rep . 2014 ;2014 :bcr2013202518 .\n6. Schneider RP \nIschemic colitis caused by decongestant?\n\nJ Clin Gastroenterol . 1995 ;21 (4 ):335 –6\n.8583118 \n7. Dowd J Bailey D Moussa K Nair S Doyle R Culpepper-Morgan JA \nIschemic colitis associated with pseudoephedrine: Four cases\n. Am J Gastroenterol . 1999 ;94 (9 ):2430 –4\n.10484004 \n8. Lichtenstein GR Yee NS \nIschemic colitis associated with decongestant use\n. Ann Intern Med . 2000 ;132 (8 ):682 .\n9. Klestov A Kubler P Meulet J \nRecurrent ischaemic colitis associated with pseudoephedrine use\n. Intern Med J . 2001 ;31 (3 ):195 –6\n.11478350 \n10. Traino AA Buckley NA Bassett ML \nProbable ischemic colitis caused by pseudoephedrine with tramadol as a possible contributing factor\n. Ann Pharmacother . 2004 ;38 (12 ):2068 –70\n.15522982 \n11. Sherid M Samo S Husein H Sulaiman S Vainder JA \nPseudoephedrine-induced ischemic colitis: Case report and literature review\n. J Dig Dis . 2014 ;15 (5 ):276 –80\n.24612436 \n12. Ambesh P Siddiqui S Obiagwu C \nPseudoephedrine associated ischemic colitis\n. Am J Ther . 2018 ;25 (5 ):e604 –6\n.28786857 \n13. Aziz M Pervez A Fatima R Bansal A \nPseudoephedrine induced ischemic colitis: A case report and review of literature\n. Case Rep Gastrointest Med . 2018 ;2018 :8761314 .30050703 \n14. Horak F Zieglmayer P Zieglmayer R \nA placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber\n. Ann Allergy Asthma Immunol . 2009 ;102 (2 ):116 –20\n.19230461 \n15. Eccles R \nSubstitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse\n. Br J Clin Pharmacol . 2007 ;63 (1 ):10 –4\n.17116124\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2326-3253",
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"journal": "ACG case reports journal",
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"medline_ta": "ACG Case Rep J",
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"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00459",
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"pmid": "33062792",
"pubdate": "2020-09",
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"references": "24895387;17488249;24612436;30050703;10484004;8583118;17116124;10766702;28786857;19230461;25559486;15522982;19281864;11478350",
"title": "Acute Ischemic Colitis due to Oral Phenylephrine.",
"title_normalized": "acute ischemic colitis due to oral phenylephrine"
} | [
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"abstract": "OBJECTIVE\nNonconvulsive status epilepticus (NCSE) is relatively common in older people. Although NCSE is a known cause of delirium, diagnosis is often delayed or missed.\n\n\nMETHODS\nWe report three cases where NCSE was identified as the cause of delirium in older people that illustrate the challenge of diagnosis.\n\n\nRESULTS\nThe cases illustrate that clinical manifestations such as slight twitching of the eyelids or periorally, eye signs, automatisms and disorders of speech and language are often very subtle. Electroencephalography (EEG), and monitoring the clinical and EEG effects of intravenous anticonvulsants, are crucial to diagnosis. Increased availability of portable EEG machines will facilitate early diagnosis. In situations where an EEG is not easily available, a trial of treatment is warranted. Hypoactive delirium is the main variant seen in NCSE but psychosis may also occur.\n\n\nCONCLUSIONS\nClinicians should maintain a high index of suspicion for NCSE in patients with delirium especially when no other obvious cause is identified.",
"affiliations": "Department of Geriatric Medicine, Galway University Hospitals, Galway, Ireland.;Department of Medicine, Beaumont Hospital, Dublin, Ireland.;Department of Geriatric Medicine, Galway University Hospitals, Galway, Ireland. sokanc@iolfree.ie.",
"authors": "Mulkerrin|Patrick|P|;Gopinathan|Deepak|D|;O'Keeffe|Shaun T|ST|http://orcid.org/0000-0002-7682-5004",
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"country": "Switzerland",
"delete": false,
"doi": "10.1007/s41999-018-0092-9",
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"issue": "9(5)",
"journal": "European geriatric medicine",
"keywords": "Absence status epilepticus; Delirium; Electroencephalography; Nonconvulsive status epilepticus; Older people",
"medline_ta": "Eur Geriatr Med",
"mesh_terms": null,
"nlm_unique_id": "101533694",
"other_id": null,
"pages": "721-724",
"pmc": null,
"pmid": "34654226",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "15667410;29650639;14695868;7488492;24353033;1734289;26400582;23910220;20002146;24836528;24931690",
"title": "Challenge of diagnosing non-convulsive status epilepticus presenting as delirium.",
"title_normalized": "challenge of diagnosing non convulsive status epilepticus presenting as delirium"
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"companynumb": "IE-MICRO LABS LIMITED-BB2018-02397",
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"abstract": "OBJECTIVE\nProlactinomas are primarily treated with medical therapy. Given the efficacy of dopamine agonists (DAs), surgery has remained a second-line treatment option. Despite medical therapy, some tumors display resistance and/or patients maybe intolerant of DA and require alternative treatment options. We examined the indications, efficacy, and safety of pituitary surgery for the treatment of prolactinomas.\n\n\nMETHODS\nWe performed a retrospective analysis of all patients who had surgery for a prolactinoma at our institution from January 1993 to October 2014.\n\n\nRESULTS\nSeventy-eight patients (46 females, mean age 32 years) with a median follow-up of 12 months were analyzed. Macroprolactinomas accounted for 65% (51/78) of tumors. The most common indication for surgery in microprolactinomas was medication intolerance (37%, 10/27) and medication failure (33%, 17/51) in macroprolactinomas. DA therapy had been tried in 76% (59/78) patients prior to surgery. Following surgery, long-term remission was seen in 72% (18/25) of micro-adenomas and 20% (10/49) of macro-adenomas (32% [10/32] in those without cavernous sinus invasion). Despite persistent disease in those with macro-adenomas (34% [13/38]) were able to remain off medication. Early surgical failure was more common in males (P = .004) and those with large (P≤.001) or atypical (P = .003) adenomas.\n\n\nCONCLUSIONS\nSurgery can result in prolonged remission in 72% of microprolactinomas. Despite lower remission rates among macroprolactinomas, a third of patients with persistent disease did not require medical therapy. Therefore, surgery remains an alternative effective treatment option, particularly for those who are intolerant or resistant to medical therapy.\n\n\nBACKGROUND\nACTH = adrenocorticotropic hormone CI = confidence interval CSF = cerebrospinal fluid DA = dopamine agonist IQR = interquartile range MIB-1 = methylation inhibiting binding protein-1 VF = visual field.",
"affiliations": null,
"authors": "Donegan|Diane|D|;Atkinson|John L D|JL|;Jentoft|Mark|M|;Natt|Neena|N|;Nippoldt|Tod B|TB|;Erickson|Bradley|B|;Meyer|Fredric|F|;Erickson|Dana|D|",
"chemical_list": "D018491:Dopamine Agonists; D004873:Ergolines; D001971:Bromocriptine; D000077465:Cabergoline",
"country": "United States",
"delete": false,
"doi": "10.4158/EP161446.OR",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-891X",
"issue": "23(1)",
"journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists",
"keywords": null,
"medline_ta": "Endocr Pract",
"mesh_terms": "D000328:Adult; D001971:Bromocriptine; D000077465:Cabergoline; D018491:Dopamine Agonists; D004873:Ergolines; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures; D010911:Pituitary Neoplasms; D015175:Prolactinoma; D012074:Remission Induction; D012189:Retrospective Studies; D017211:Treatment Failure; D016896:Treatment Outcome; D047368:Tumor Burden; D055815:Young Adult",
"nlm_unique_id": "9607439",
"other_id": null,
"pages": "37-45",
"pmc": null,
"pmid": "27682355",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "SURGICAL OUTCOMES OF PROLACTINOMAS IN RECENT ERA: RESULTS OF A HETEROGENOUS GROUP.",
"title_normalized": "surgical outcomes of prolactinomas in recent era results of a heterogenous group"
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"abstract": "Immunomodulatory agents (IMiDs) are used to treat multiple hematologic malignancies. Their use is also associated with increased risk of venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) have been increasingly utilized but due to their relative novelty, their role in malignancy has only been recently investigated. The objective of this study was to assess the safety and efficacy of DOACs in patients receiving IMiDs. This was a retrospective study of patients at our institution treated with an IMiD and concomitant warfarin or DOAC between January 1, 2010 and December 31, 2015. Information on demographic and clinical characteristics was collected. Separate encounters were collected for each specific combination of IMiD and anticoagulant. Bleeding and thrombotic events were recorded. There were four bleeding events in the DOAC group; all were non-major. There were six bleeding events in the warfarin group, two of which were major (gastrointestinal bleeding (GIB) and subarachnoid hemorrhage (SAH)) and four of which were non-major. Of the two major bleeds in this group, neither event occurred with concomitant antiplatelet therapy. There was one thrombotic event in the DOAC group, which was a myocardial infarction, suspected to be related to carfilzomib. There were no thrombotic events in the warfarin group. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs as compared to warfarin in patients on IMiDs. DOACs may represent an attractive alternative to warfarin for VTE prophylaxis in patients on IMiDs but prospective studies in this population are warranted.",
"affiliations": "Department of Medicine Division of Hematology/Oncology, University of Virginia Health System, 1300 Jefferson Park Avenue, Room 6023, PO Box 800716, Charlottesville, VA, 22908, USA. LMM3R@hscmail.mcc.virginia.edu.;Department of Pharmacy Services, University of Virginia Health System, Charlottesville, VA, USA.;Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA.;Department of Pharmacy Services, University of Virginia Health System, Charlottesville, VA, USA.;Department of Medicine Division of Hematology/Oncology, University of Virginia Health System, 1300 Jefferson Park Avenue, Room 6023, PO Box 800716, Charlottesville, VA, 22908, USA.",
"authors": "Man|L|L|http://orcid.org/0000-0001-8053-5336;Morris|A|A|;Brown|J|J|;Palkimas|S|S|;Davidson|K|K|",
"chemical_list": "D000925:Anticoagulants; D007155:Immunologic Factors; D014859:Warfarin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-017-1534-9",
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"issue": "44(3)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Deep venous thrombosis; Direct oral anticoagulant; Immunomodulatory agents; Multiple myeloma; Thromboembolic event",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D005260:Female; D006470:Hemorrhage; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013927:Thrombosis; D016896:Treatment Outcome; D054556:Venous Thromboembolism; D014859:Warfarin",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "298-302",
"pmc": null,
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"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": "28316279;27476789;19626046;16365178;18094721;15842354;12853587;15701913;9521222",
"title": "Use of direct oral anticoagulants in patients on immunomodulatory agents.",
"title_normalized": "use of direct oral anticoagulants in patients on immunomodulatory agents"
} | [
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"companynumb": "US-CELGENEUS-USA-2016118057",
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"activesubstancename": "THALIDOMIDE"
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... |
{
"abstract": "BACKGROUND\nPregnancy complicated with adrenocortical carcinoma (ACC) is a sporadic syndrome that is characterized by hypertension, uncontrolled hypokalemia, severe heart failure, premature delivery and other adverse effects. The clinical presentation of adrenocortical carcinoma is vague and nonspecific, it is challenging to identify complications of pregnancy with adrenocortical carcinoma. Here we present a case of adrenocortical carcinoma during pregnancy. We describe how to distinguish secondary hypertension from other conditions and the importance of timely detection and treatment of such patients.\n\n\nMETHODS\nA 22-year-old woman 30 weeks pregnant was hospitalized with uncontrolled hypertension and hypokalemia. An ultrasound examination of the right adrenal gland revealed a large mass. She underwent transabdominal adrenalectomy, and histopathology from the sample removed revealed an adrenocortical carcinoma. Five days after surgery, the patient had a premature rupture of the fetal membranes and gave birth to a newborn girl via vaginal delivery at 32 weeks of gestation. The newborn was transferred to the neonatal pediatrics ward, and the woman started receiving chemotherapy.\n\n\nCONCLUSIONS\nPregnancy with adrenocortical carcinoma is a rare condition. This case alerts the obstetricians that analysis of hypertension, hypokalemia, the plasma level and circadian rhythm of plasma cortisol provides a strategy to diagnose adrenocortical carcinoma during pregnancy.",
"affiliations": "Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji'nan, Shandong, 250012, People's Republic of China.;Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji'nan, Shandong, 250012, People's Republic of China.;Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji'nan, Shandong, 250012, People's Republic of China.;Radiology Departments, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji'nan, Shandong, 250012, People's Republic of China.;Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji'nan, Shandong, 250012, People's Republic of China. yl_zhang0706@163.com.;Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji'nan, Shandong, 250012, People's Republic of China. fangyan7801@163.com.",
"authors": "Zhang|Yuanli|Y|;Yuan|Zeng|Z|;Qiu|Chunping|C|;Li|Shuyi|S|;Zhang|Shiqian|S|;Fang|Yan|Y|http://orcid.org/0000-0001-5291-7345",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12884-020-2737-1",
"fulltext": "\n==== Front\nBMC Pregnancy ChildbirthBMC Pregnancy ChildbirthBMC Pregnancy and Childbirth1471-2393BioMed Central London 273710.1186/s12884-020-2737-1Case ReportThe diagnosis and treatment of adrenocortical carcinoma in pregnancy: a case report Zhang Yuanli 1Yuan Zeng 1Qiu Chunping 1Li Shuyi 2Zhang Shiqian yl_zhang0706@163.com 1http://orcid.org/0000-0001-5291-7345Fang Yan fangyan7801@163.com 11 0000 0004 1761 1174grid.27255.37Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji’nan, Shandong 250012 People’s Republic of China 2 0000 0004 1761 1174grid.27255.37Radiology Departments, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Ji’nan, Shandong 250012 People’s Republic of China 21 1 2020 21 1 2020 2020 20 5017 10 2019 13 1 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPregnancy complicated with adrenocortical carcinoma (ACC) is a sporadic syndrome that is characterized by hypertension, uncontrolled hypokalemia, severe heart failure, premature delivery and other adverse effects. The clinical presentation of adrenocortical carcinoma is vague and nonspecific, it is challenging to identify complications of pregnancy with adrenocortical carcinoma. Here we present a case of adrenocortical carcinoma during pregnancy. We describe how to distinguish secondary hypertension from other conditions and the importance of timely detection and treatment of such patients.\n\nCase presentation\nA 22-year-old woman 30 weeks pregnant was hospitalized with uncontrolled hypertension and hypokalemia. An ultrasound examination of the right adrenal gland revealed a large mass. She underwent transabdominal adrenalectomy, and histopathology from the sample removed revealed an adrenocortical carcinoma. Five days after surgery, the patient had a premature rupture of the fetal membranes and gave birth to a newborn girl via vaginal delivery at 32 weeks of gestation. The newborn was transferred to the neonatal pediatrics ward, and the woman started receiving chemotherapy.\n\nConclusions\nPregnancy with adrenocortical carcinoma is a rare condition. This case alerts the obstetricians that analysis of hypertension, hypokalemia, the plasma level and circadian rhythm of plasma cortisol provides a strategy to diagnose adrenocortical carcinoma during pregnancy.\n\nKeywords\nPregnancyAdrenocortical carcinomaDifferential diagnosisCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAdrenocortical carcinoma (ACC) is a rare condition with an estimated annual incidence of 1–2 per 1 million [1]. The prognosis is poor with a 5-year survival of approximately 30% [2]. In ACC, excessive cortisol inhibits the pituitary secretion of gonadotropin, and this could cause ovulation disorders, hypomenorrhea, and irregular periods or menopause in the majority of female patients [3]. ACC is rarely diagnosed during pregnancy, mostly reported as isolated cases [4]. The clinical presentation of adrenocortical carcinoma are vague and nonspecific, and for these reasons, it is challenging to identify ACC during pregnancy. Here we present a case of ACC during pregnancy, and we describe how to distinguish secondary hypertension from other conditions and the importance of timely detection and treatment of such patients.\n\nCase presentation\nA 22-year-old woman with gestational age of 28 weeks and 4 days had a blood pressure of 161 /99 mmHg at a routine prenatal visit, and before that, her blood pressure was normal. The physical examination showed the following: Scattered ecchymosis in the neck skin, a purple ecchymosis of 5 × 4 cm size in the skin of the right forearm, and broad, dark, and thick striae in the skin of the lower abdomen (Fig. 1). The results of laboratory tests showed that concentrations of serum liver enzymes and creatinine were normal, suggesting that she did not have impaired liver function and renal insufficiency. Moreover, she did not have proteinuria. However, her serum potassium was 2.12 mmol/L, compared with non-pregnant values, serum potassium fell by 0.2–0.4 mmol/L, the rest of the serum electrolyte levels are in the normal range. After the administration of labetalol (300 mg, twice a day) and potassium, her blood pressure was remained in the range of 170 /100 mmHg and serum potassium maintained at 3.0–3.5 mmol/L. The electrocardiogram showed sinus tachycardia, while echocardiography indicated that her heart function was normal. Considering that the patient and her family had no previous history of hypertension and kidney disease, the liver and kidney function were normal, and the fetal ultrasound examination showed a fetus with a normal gestational age, the presence of uncontrolled hypertension and hypokalemia increased the suspicion that the problem was due to secondary hypertension rather than preeclampsia. The primary care physician ordered an ultrasound examination of the adrenal glands. The ultrasound showed a solid cystic mass (12.8 × 8.5 cm) in the right suprarenal gland region. Therefore, the patient was admitted to the endocrinology ward of Qilu Hospital of Shandong University with a diagnosis of “hypertension and hypokalemia of unknown origin” at 30 weeks gestation. Laboratory results showed the following values: glucose (−) in the urinalysis and her fasting blood glucose was 5.2 mmol/L, considering that she had no history of diabetes and had no polyuria and polydipsia recently, we ruled out the diagnosis of gestational diabetes. Plasma renin and aldosterone levels were in the normal range and the aldosterone/renin ratio (ARR) was 2.87 (normal range: 0–40). The 24-h urinary free cortisol level was 3357 μg/24 h (normal range: 21–110 μg/24 h), the serum cortisol level of 1246 nmol/L at 08:00 AM, 707 nmol/L at 04:00 PM (normal range: 112–288 nmol/L at 08:00 AM, < 128.7 nmol/L at 04:00 PM). The adrenocorticotropic hormone (ACTH) levels were 2.18 ng/L at 08:00 AM, 1.6 ng/L at 04:00 PM (normal range: 4.7–48.8 ng/L). The normal circadian rhythm of serum cortisol was lost, moreover, there was no significant inhibition in the low dose dexamethasone test. The above laboratory results supported a diagnosis of “ACTH-independent Cushing Syndrome,” therefore, a high dose dexamethasone test was requested.\nFig. 1 The patient’s lower abdominal skin was covered with broad, dark, thick striae (width is about 3.0 cm)\n\n\n\nIn order to localize the adrenal mass and its relationship with surrounding organs, we ordered an adrenal plain magnetic resonance imaging (MRI) without contrast agent 3 days after admission. The signal of the mass was slightly longer in T1 and T2-weighted image, and high signal intensity on diffusion-weighted imaging. In the T1-weighted image, multiple dot flake short signals were observed in the interior of the tumor, which had a size of approximately 10.1 × 10.5 × 12.8 cm. A short patchy hyperintensity in the T1-weighted image and a longer striate signal in the T2-weighted image were seen in the lesion. (Fig. 2). The above imaging features suggested the presence of hemorrhage in the lesion, and the location of the lesion was very close to the right adrenal gland. The imaging findings combined with the test results showing that a high dose of dexamethasone could not inhibit cortisol; therefore, we considered the possibility that an adrenal tumor was causing the Cushing syndrome.\nFig. 2 Coronal (a) and transverse (b) pelvic magnetic resonance imaging performed preoperatively demonstrates a soft tissue mass measuring 10.1 × 10.5 × 12.8 cm in the right retroperitoneal adrenal region, which oppressed the right kidney and liver\n\n\n\nThe hospital held a case discussion board to obtain a consensus regarding the diagnosis and treatment to follow in this patient. Participants in this discussion board belong to various specialties such as obstetrics, urology, and anesthesiology, and they considered that hypertension and hypokalemia were caused by the mass in the adrenal region, and the symptoms would be relieved after the mass was removed. The discussion was focused on the ideal timing of treatment and the best surgical approach. The discussion board concluded that adrenalectomy should be performed by the urological department as soon as possible.\n\nTransabdominal adrenalectomy was performed 12 days after admission. The abdominal cavity was opened using an inverted L-shaped incision 30 cm in length in the right lower abdomen. During the operation, a large mass (15x12x10 cm) was found in the right adrenal gland. The surface of this mass was hard in texture, and the surface envelope was intact and spread out all over the engorged blood vessels. The adhesions between the tumor and the superior, inferior vena cava, and surrounding tissues of the kidney was extreme. Also, the tumor squeezed the inferior vena cava, the right renal vein, and the right kidney, but it did not infiltrate the kidney and renal veins. The tumor were entirely resected during the operation and were sent to routine pathological examination. After tumor extraction, the urological surgeon closed the anterior sheath and placed a vacuum suction device subcutaneously, the skin at the wound was closed with skin staples. Postoperative day 1, ACTH increased to 78 ng/L, and plasma cortisol decreased to 172 nmol/L. Hydrocortisone was administered orally after the operation to prevent the occurrence of adrenal crisis. Unfortunately, the pathological results revealed that the tumoral mass was an ACC, and immunohistochemical staining of tissue specimens showed that: LH (−), HCG (−), and inhibin receptors (−).\n\nPostoperative day 2, the patient was transferred to the maternity ward and treated with magnesium sulfate and ritodrine to inhibit the uterine contractions. At 32 weeks of gestation, she experienced a premature rupture of membranes. Considering her physical condition and disease state, we decided to stop using magnesium sulfate and ritodrine; therefore, her uterus naturally started contractions and entered the labor process. She had a vaginal delivery, the female newborn weighted 1360 g and had Apgar scores of 10 at both 1 and 5 min. Immediately after birth, the infant was transferred to the neonatology ward. Unfortunately, the newborn developed abdominal distension 2 days after birth, and there was no significant improvement after gastrointestinal decompression. Plain abdominal x-ray film showed intestinal perforation. The neonatologist suggested a surgical treatment, but the parents of the newborn refused. The newborn died 1 week after birth. The father of the newborn refused to perform an autopsy, thus, it was difficult to determine whether the death of the newborn was due to the impact of the maternal disease on the newborn or due to premature birth or other effects. Considering the patient’s condition, the oncology department recommended chemotherapy. Therefore, she was transferred to the oncology department for intravenous chemotherapy 3 days after delivery. After 6 months of follow-up, the hypertension and hypokalemia disappeared and she has completed chemotherapy at another hospital and without any clinical evidence of disease recurrence.\n\nDiscussion and conclusions\nIn this case, the patient had elevated blood pressure at 28 weeks of gestation, so the main problem was differentiating the cause of hypertension. The four types of hypertension that are identified during pregnancy are gestational hypertension, preeclampsia or eclampsia, preeclampsia or eclampsia superimposed on chronic hypertension, and chronic hypertension (including primary and secondary hypertension). In 2019, the American College of Obstetricians and Gynecologists’ Committee (ACOG) defined gestational hypertension and pre-eclampsia as a systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure ≥ 90 mmHg, or both, after 20 weeks of gestation, in a woman with a normal blood pressure previously [5]. However, preeclampsia is usually accompanied by new-onset proteinuria. Even if the patient’s protein is negative, other signs such as thrombocytopenia, renal insufficiency, impaired liver function, and pulmonary edema may occur. The patient had uncontrollable hypertension and hypokalemia, and blood pressure was not reduced after oral antihypertensive drugs, her liver function and renal function are normal, so it was not considered as preeclampsia. At the same time, the presence of elevated serum cortisol and wide gestational marks of the skin increased the suspicion that the problem was due to secondary hypertension.\n\nSecondary hypertension during pregnancy includes chronic kidney disease, Pheochromocytoma, Primary aldosteronism, renovascular hypertension, Cushing’s Syndrome and obstructive sleep apnea causing hypertension. Pheochromocytoma and primary aldosteronism may also associated with severe hypokalemia. Persistent or paroxysmal hypertension is a typical symptom of pheochromocytoma, the diagnosis of it is established by measuring 24-h urinary fractionated metanephrines and catecholamines and plasma fractionated metanephrines. In addition to increasing aldosterone secretion, plasma renin activity is inhibited by increasing plasma aldosterone concentration in Primary aldosteronism. Given the adrenal mass with elevated plasma cortisol levels and the disappearance of circadian rhythm, we don’t think it is necessary to consider chronic kidney disease, pheochromocytoma, primary aldosteronism, renovascular hypertension as additional possible causes of hypertension and hypokalemia [6].\n\nIn a normal pregnancy, circadian cortisol rhythm still exists despite elevated cortisol levels. Currently, primary methods for diagnosing Cushing syndrome are 24-h free cortisol, midnight plasma or salivary cortisol levels, and low-dose dexamethasone suppression test (DSTs), as the HPA axis loses sensitivity to the effects of dexamethasone, more than 80% of DSTs in normal pregnant women produce false positive results [7]. Often, the diagnosis of pregnancy complicated with adrenal carcinoma is facilitated when the circadian rhythm of cortisol is lost [8]. Ultrasound and MRI are the recommended diagnostic imaging methods because both are safe for pregnant women and fetuses. Ultrasound is the preferred screening method, and if needed, MRI provides further diagnostic details [9]. Although ACC screening largely depends on biochemical and imaging studies, and the final diagnosis depends on histopathology.\n\nIn general, ACC is characterized by an increase in serum sodium and a decrease in serum potassium, which is related to the glucocorticoid effect on sodium and potassium excretion. It has been reported that the decrease of serum potassium in patients with adrenocortical carcinoma is more evident than those in patients with suprarenal cortical adenoma [10]. This finding is also supported by the patient’s persistent and uncontrolled hypokalemia. Some researchers suggested that pregnancy is a risk factor for the deterioration of ACC [11]. Therefore, this disease should be considered when there are typical pregnancy symptoms complicated with refractory hypokalemia.\n\nIn patients with adrenocortical carcinoma during pregnancy, if the condition is not controlled, the harm to the fetus could be severe. Fassnacht et al. [12] reviewed the survival results of 416 patients from the German Adrenocortical Carcinoma Registry. They found that the patients’ prognosis was related to the stage of the disease at the time of diagnosis. When the tumor was limited to the adrenal gland and less than 5 cm, the 5-year disease-free survival rate was about 82%. When the tumor exceeded 5 cm but was still limited to the adrenal gland, the 5-year disease-free survival rate was close to 61%. If the disease extends beyond the adrenal gland, the survival rate declines. There are several clinical and in vitro tests that show a link between adrenal cortical proliferation and pregnancy. In an in vitro experiment, researchers found that increased expression of Aberrant GPCR expression in adrenocortical cells led to the formation of adrenocortical hyperplasia and the development of Cushing syndrome characteristics in transplanted mice [12]. Abiven-Lepage G et al. [2] compared 12 women diagnosed with ACC during pregnancy or immediately after delivery with non-pregnancy-diagnosed ACC patients, and found that patients diagnosed during pregnancy or postpartum had larger tumor volumes. However, the survival rate of patients diagnosed during pregnancy was 50% at 1 year and only 13% at 5 years. A retrospective single-center study showed that older age at diagnosis and cortisol hypersecretion were prognostic factor [13]. Data on fetal survival in pregnancy with ACC are unknown; reported cases could be biased toward the publication of successful pregnancy outcomes. Abiven-Lepage G et al. [14] reported that two newborns died (one abortion for medical reasons and one stillbirth) in 12 cases and five children were born before 37 weeks. Excessive steroid secretion in pregnant women with adrenal cortex could affect fetal sex differentiation, as shown in a case report of a 46 XX baby girl with ambiguous genitalia [15].\n\nSurgical treatment is the first choice for patients during an early second trimester of pregnancy who have an apparent mass on the adrenal gland, medication is usually ineffective. It is relatively safe to perform surgery in the second trimester, any possible adverse events on the mother and fetus are minimal [16]. Unilateral or bilateral adrenalectomy has a good effect on alleviating hyper cortisol that is caused by an adrenal adenoma or adenocarcinoma and can also improve the perinatal outcome. After the operation, intravenous or oral administration of hydrocortisone is recommended to avoid adrenocortical insufficiency [17]. The laparoscopy approach is the preferred surgical technique due to the advantages of the short operation time, little interference to the abdominal cavity, and less bleeding. However, carbon dioxide (CO2) pneumoperitoneum during the operation could increase the blood CO2 partial pressure of the pregnant women, which might pose a potential threat to the fetus. Besides, the enlarged uterus could have an impact on the operation [18]. The tumor might not be completely removed through a laparoscopic approach considering the large volume of the adrenal gland. Therefore, we choose to perform transabdominal adrenalectomy.\n\nIn summary, ACC during pregnancy is sporadic and difficult to distinguish from other diseases that cause hypertension during pregnancy. Therefore, when hypertension and uncontrolled hypokalemia are present with adrenal masses, the possibility of secondary hypertension should be considered in the diagnosis, the analysis of plasma level and circadian rhythm of plasma cortisol provides a strategy to diagnose adrenocortical carcinoma during pregnancy.\n\nAbbreviations\nACCAdrenocortical carcinoma\n\nACOGThe American College of Obstetricians and Gynecologists’ Committee\n\nACTHAdrenocorticotropic hormone\n\nCO2Carbon dioxide\n\nDSTsDexamethasone suppression test\n\nMRIMagnetic resonance imaging\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank the Qilu Hospital, Shandong University for their assistance with this research.\n\nAuthors’ contributions\nYLZ, ZY, CPQ, SYL, SQZ and YF were involved in drafting the manuscript. All authors read and approved the final version of the manuscript.\n\nFunding\nNo funding was available.\n\nAvailability of data and materials\nDatasets used and/or analyzed in the current study are available from the corresponding author by request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent has been received from the patient for potentially descriptive information to be published in this article.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Fassnacht M Allolio B Clinical management of adrenocortical carcinoma Best Pract Res Clin Endocrinol Metab 2009 23 2 273 289 10.1016/j.beem.2008.10.008 19500769 \n2. Allolio B Fassnacht M Clinical review: Adrenocortical carcinoma: Clinical update J Clin Endocrinol Metab 2006 91 6 2027 2037 10.1210/jc.2005-2639 16551738 \n3. Lindsay JR Nieman LK The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment Endocr Rev 2005 26 6 775 799 10.1210/er.2004-0025 15827110 \n4. Brue T Amodru V Castinetti F Management of endocrine disease: Management of Cushing's syndrome during pregnancy: solved and unsolved questions Eur J Endocrinol 2018 178 6 R259 R266 10.1530/EJE-17-1058 29523633 \n5. Practice Bulletin No ACOG 202: gestational hypertension and preeclampsia Obstet Gynecol 2019 133 1 e1 e25 10.1097/AOG.0000000000003018 30575675 \n6. Malha L August P Secondary hypertension in pregnancy Curr Hypertens Rep 2015 17 7 53 10.1007/s11906-015-0563-z 26068655 \n7. Guignat L Bertherat J The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline: commentary from a European perspective Eur J Endocrinol 2010 163 1 9 13 10.1530/EJE-09-0627 20375177 \n8. Lekarev O New MI Adrenal disease in pregnancy Best Pract Res Clin Endocrinol Metab. 2011 25 6 959 973 10.1016/j.beem.2011.08.004 22115169 \n9. Lacroix A Feelders RA Stratakis CA Nieman LK Cushing’s syndrome Lancet 2015 386 9996 913 927 10.1016/S0140-6736(14)61375-1 26004339 \n10. Findling JW Kehoe ME Shaker JL Raff H Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome: early recognition of the occult ectopic ACTH syndrome J Clin Endocrinol Metab 1991 73 2 408 413 10.1210/jcem-73-2-408 1649842 \n11. Grubbs E Lee JE Limited prognostic value of the 2004 International Union against Cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification Cancer. 2009 115 24 5847 10.1002/cncr.24693 19827149 \n12. Mazzuco TL Chabre O Feige JJ Thomas M Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis Mol Cell Endocrinol 2007 265-266 23 28 10.1016/j.mce.2006.12.034 17250952 \n13. Abiven G Coste J Groussin L Anract P Tissier F Legmann P Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients J Clin Endocrinol Metab 2006 91 7 2650 2655 10.1210/jc.2005-2730 16670169 \n14. Abiven-Lepage G Coste J Tissier F Groussin L Billaud L Dousset B Adrenocortical carcinoma and pregnancy: clinical and biological features and prognosis Eur J Endocrinol 2010 163 5 793 800 10.1530/EJE-10-0412 20699382 \n15. Abbassy M Kshettry VR Hamrahian AH Johnston PC Dobri GA Avitsian R Avitsian R Surgical management of recurrent Cushing's disease in pregnancy: A case report Surg Neurol Int 2015 6 Suppl 25 S640 S645 26682090 \n16. Bornstein SR Allolio B Arlt W Barthel A Don-Wauchope A Hammer GD Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical Practice guideline J Clin Endocrinol Metab 2016 101 2 364 389 10.1210/jc.2015-1710 26760044 \n17. Borna S Akbari S Eftekhar T Mostaan F Cushing’s syndrome during pregnancy secondary to adrenal adenoma Acta Med Iran 2012 50 1 76 78 22267384 \n18. Morris LF Park S Daskivich T Churchill BM Rao CV Lei Z Virilization of a female infant by a maternal adrenocortical carcinoma Endocr Pract 2011 17 2 e26 e31 10.4158/EP10209.CR 21324830\n\n",
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"keywords": "Adrenocortical carcinoma; Case report; Differential diagnosis; Pregnancy",
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"mesh_terms": "D000306:Adrenal Cortex Neoplasms; D000315:Adrenalectomy; D018268:Adrenocortical Carcinoma; D000328:Adult; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D014057:Tomography, X-Ray Computed",
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"title": "The diagnosis and treatment of adrenocortical carcinoma in pregnancy: a case report.",
"title_normalized": "the diagnosis and treatment of adrenocortical carcinoma in pregnancy a case report"
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"abstract": "Rheumatoid arthritis (RA) is a common autoimmune disease most well-known for its inflammatory, destructive polyarthropathy. Extraarticular manifestations of the disease may involve the respiratory system, including interstitial lung disease, pleural disease, pulmonary vascular abnormalities, and airways disease. Smoking is highly prevalent in the RA population, and may even have a synergistic effect in disease development and progression. In the diagnosis of pulmonary disease, this presents a unique diagnostic and therapeutic challenge. We present a case of a woman in her 50s who presented for evaluation of dyspnea and was found to have obstructive lung disease. In addition to RA, she had a significant smoking history and also owned pet birds, making definitive diagnosis difficult. Ultimately, chest imaging was crucial in identifying RA-related lung disease as the root cause of her symptoms, leading to successful treatment and symptom management.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Department of Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, MD, USA.;Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.",
"authors": "Glick|Danielle R|DR|;Galvin|Jeffrey R|JR|;Deepak|Janaki|J|",
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"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30497-4\n10.1016/j.rmcr.2020.101283\n101283\nCase Report\nComplex obstructive lung disease – A diagnostic and management conundrum\nGlick Danielle R. a Galvin Jeffrey R. b Deepak Janaki jadeepak@som.umaryland.eduac∗ a Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA\nb Department of Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, MD, USA\nc Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA\n∗ Corresponding author. 110 S Paca Street, 2nd Floor, Baltimore, MD, 21201, USA. jadeepak@som.umaryland.edu\n06 11 2020 \n2020 \n06 11 2020 \n31 1012838 7 2020 23 10 2020 2 11 2020 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Rheumatoid arthritis (RA) is a common autoimmune disease most well-known for its inflammatory, destructive polyarthropathy. Extraarticular manifestations of the disease may involve the respiratory system, including interstitial lung disease, pleural disease, pulmonary vascular abnormalities, and airways disease. Smoking is highly prevalent in the RA population, and may even have a synergistic effect in disease development and progression. In the diagnosis of pulmonary disease, this presents a unique diagnostic and therapeutic challenge. We present a case of a woman in her 50s who presented for evaluation of dyspnea and was found to have obstructive lung disease. In addition to RA, she had a significant smoking history and also owned pet birds, making definitive diagnosis difficult. Ultimately, chest imaging was crucial in identifying RA-related lung disease as the root cause of her symptoms, leading to successful treatment and symptom management.\n\nKeywords\nRheumatoid arthritisObstructive lung diseases\n==== Body\n1 Background\nThe pulmonary manifestations of rheumatoid arthritis (RA) are many and varied. Rheumatoid nodules are common, as is follicular bronchiolitis [[1], [2], [3]]. It can affect the large and small airways alike. In fact, the small airways can often manifest changes on imaging despite normal pulmonary function testing in asymptomatic non-smokers with RA [4]. In addition to the wide variation of presentations, it can often be difficult to diagnose RA-related lung disease due to the presence of competing diagnoses. Smoking is known to be associated with and possibly even causative of RA, and many population-based cohort studies have shown confounding of the incidence of obstructive lung disease from smoking [[5], [6]]. However, some studies have shown increased incidence of obstructive pulmonary function testing in non-smoking RA patients [7]. In patients where there exist multiple exposures and potential etiologies for pulmonary disease, it can be difficult to isolate and treat a primary diagnosis [8] With the express consent of the patient, we present a case of complex obstructive lung disease with significant contribution of RA-related small airways disease, which created a diagnostic and therapeutic challenge.\n\n2 Case presentation\nA Caucasian woman in her late 50s with a known history of Rheumatoid Arthritis, celiac disease, diabetes mellitus type 1, childhood asthma, and a 70-pack-year smoking history presented to the pulmonary clinic for initial evaluation in late spring 2018 of cough and dyspnea. Her respiratory symptoms started roughly 4 years prior to presentation, following a hospitalization for epiglottitis reportedly related to ACE-inhibitors. She thereafter developed increasing shortness of breath and cough, which were persistent. This resulted in two subsequent hospitalizations, during which time she was incorrectly diagnosed with COPD (no evidence of obstruction on spirometry in 2014) and started on supplemental oxygen therapy (2L by nasal cannula). At the time of her initial consultation, she was using budesonide and formoterol nebulizers, with rescue inhaler use about once daily. She reported using 4L of oxygen continuously while at home only. With regard to her current symptoms, she reported continued cough productive of yellow sputum, which did not improve with the addition of every other day azithromycin. She also endorsed shortness of breath made worse by exertion (with tolerance of about 100 feet), humidity, grass, pollen, and strong odors.\n\nWith regard to other past medical history, the patient was diagnosed with Rheumatoid Arthritis (RA) about 10 years prior to presentation. Her treatment for RA had been sporadic – she had taken methotrexate (discontinued due to persistent RA flare), mycophenolate mofetil (discontinued for unclear reasons, perhaps disease stability), hydroxychloroquine, and prednisone, but had never had rituximab. She also had stem cell therapy at some point.\n\nThe patient had a significant smoking history, having smoked 3 packs per day for 24 years, but quit roughly 20 years prior to presentation. She used alcohol socially but denied illicit drug use. She worked in a managerial position at a horse racetrack, but denied animal exposure. In the past, she had worked as a bank teller. Her home environment was notable for the possession of 4 pet birds. There was no mold exposure in the home, no one else was a smoker, and there were minimal carpets.\n\nHer initial physical examination revealed a thin, frail, chronically ill-appearing middle-aged woman in no acute distress. Her oxygen saturation was 92% on 2L NC with normal respiratory rate, heart rate, and blood pressure. While her cardiac exam was unremarkable, her pulmonary exam revealed diffuse crackles with a prominent inspiratory squawk in the upper lung fields bilaterally. No wheezing was noted and her respiratory effort was normal. Her joint examination revealed swelling of the PIP and DIP joints of the bilateral second and third fingers without erythema, and discoloration of the finger pads consistent with mechanic's hands.\n\n3 Investigations\nInitial work-up included pulmonary function testing (PFTs), lab work, and imaging. Her first PFTs from 2014 revealed a restrictive pattern on spirometry (forced expiratory volume in 1 second, FEV1, 40% predicted and forced vital capacity, FVC, 41% predicted) in the setting of a normal total lung capacity (TLC) (Table 1). Her TLC may have been falsely elevated due to hyperinflation, as evidenced by an elevated RV which suggests the presence of obstructive disease despite a normal ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). Over time, she did develop overt obstruction, with an FEV1/FVC ratio of 68% in 2018. At that time, her TLC again remained within the normal range but with a persistently elevated RV. Over that four year time period, her diffusion capacity (DLCO), which was initially low at 58%, worsened as well.Table 1 Pulmonary Function Tests (spirometry, lung volumes, and diffusion capacity) from 2014 to 2020. Values from December 2014 and June 2018 are pre-treatment. Values from September 2018 reflect two months of therapy on mycophenolate 500 mg twice daily and prednisone 15 mg daily. Spirometry from January 2020 reflects lung performance while on mycophenolate 1500 mg twice a day only. There was no reversibility demonstrated on any bronchodilator testing.\n\nTable 1\tDecember 2014\tJune 2018\tSeptember 2018\tJanuary 2020\t\nFEV1, L (% pred)\t1.12 (40%)\t0.83 (36%)\t1.09 (47%)\t1.08 (43%)\t\nFVC, L (% pred)\t1.46 (41%)\t1.24 (39%)\t1.74 (56%)\t1.79 (56%)\t\nFEV1/FVC, %\t77%\t68%\t63%\t61%\t\nTLC, L (% pred)\t4.99 (97%)\t5.01 (99%)\t4.94 (97%)\t\t\nRV, L (% pred)\t3.40 (182%)\t3.67 (190%)\t3.22 (165%)\t\t\nDLCO, mL/min/mmHg (% pred)\t11.3 (58%)\t8.6 (39%)\t13.4 (61%)\t\t\n\n\nLaboratory testing was remarkable for an elevated serum bicarbonate of 34 mmol/L suggesting chronic respiratory acidosis and mild peripheral eosinophilia of 4.7% with otherwise normal chemistries and complete blood count. Her rheumatologic work-up revealed a positive rheumatoid factor, anti-nuclear antibody (ANA), SSA, and aldolase, but negative CCP. A myositis panel was negative, however a hypersensitivity panel was positive for reaction to pigeon antigen.\n\nA chest x-ray from 2014 was remarkable only for flattening of the diaphragms consistent with hyperinflation. Computed tomography imaging of the chest from 2015 again showed hyperinflation with diffuse mosaic attenuation, worse during expiration (Fig. 1). This was persistent on repeat imaging in 2018 (Fig. 2). Notably absent was any evidence of emphysematous changes, focal infiltrates, upper lobe predominance, or nodularity.Fig. 1 Axial images from a 2015 CT chest, shown here in both inspiration and expiration, demonstrating mosaic attenuation especially during the expiratory phase, a finding consistent with air-trapping and small airways disease.\n\nFig. 1Fig. 2 Coronal images from a 2018 CT chest on inspiration, demonstrating mosaic attenuation in a diffuse distribution.\n\nFig. 2\n\n4 Differential diagnosis\nBased upon the constellation of symptoms and imaging, a number of diagnoses were considered (Fig. 3). First, a range of rheumatoid arthritis-related lung disease were considered, with interstitial lung disease, small airways disease, and bronchiolitis being of chief concern. Given her exposure to birds and positive pigeon antigen, hypersensitivity pneumonitis was also considered. Prior treatment with methotrexate raised concern for delayed drug toxicity. While chronic obstructive pulmonary disease was a possibility, absence of emphysema on imaging and her pattern of symptoms made this less likely. Infection was considered less likely given the duration of her symptoms. This was a complicated case, and there were likely several concomitant diagnoses, which contributed to our treatment decisions below. However, based upon the dramatic amount of mosaic attenuation observed on CT chest imaging (particularly on expiration), lack of nodularity, and diffuse rather than upper lobe predominance on imaging, the principal diagnosis pursued was RA-related small airways disease after a multidisciplinary discussion during an institutional Interstitial Lung Disease conference. Hypersensitivity pneumonitis was also strongly considered, though imaging was rather diffuse to be entirely explained by this. Similarly, lack of emphysematous changes argued against COPD as the main diagnosis. Although there was evidence of obstruction and hyperinflation on PFTs, these could have also been a consequence of obstructive disease caused by RA rather than purely COPD. This is further supported by the fact that restrictive disease with suggestion of developing obstructive disease was present 4 years prior to presentation.Fig. 3 Visual flowchart of potential causes of obstructive lung disease in this complex patient.\n\nFig. 3\n\n5 Treatment\nA treatment approach to address the likely multifactorial disease process described above was enacted, starting with mycophenolate mofetil 250 mg, then up-titrated to 1500 mg, twice daily as immunosuppressive treatment of RA-related small airways disease. Prednisone was also included at an initial dose of 20 mg daily to treat any component of hypersensitivity pneumonitis. Over the course of a year, while increasing mycophenolate, the prednisone was tapered and eventually stopped. To treat obstructive airways disease, a combination inhaled corticosteroid and long-acting bronchodilator were also started. Additionally, the patient was educated on the importance of antigen exposure by removal of birds from the home and rehab of the existing ductal systems.\n\n6 Outcome and follow-up\nAfter two months on mycophenolate and prednisone, the patient returned for repeat pulmonary function testing which showed improvement of her FEV1 by 200 mL (to 1.03 L, 44% predicted) and FVC of 300 mL (1.72L 55% predicted), with stable TLC and reduced RV (3.22 L from 3.67L), as well as improvement also of her DLCO to 13.4 mL/mmHg/min (61% predicted) (Table 1). Her spirometry has remained stable now a year and a half later. Symptomatically, she has noted respiratory symptom improvement as well, and is no longer requiring day-time oxygen therapy. Her joint pains have also improved. She has successfully rehomed her cockatiels, though at the time of first follow-up she still retained one of the four birds. In spite of having the birds at home she still had remarkable symptomatic improvement which again points towards the majority of her disease being explained by RA-related obstructive lung disease.\n\n7 Discussion\nThat the diagnosis of Rheumatoid arthritis-related obstructive lung disease is challenging and often confounded in the RA population has been discussed previously. A 2013 study from the Mayo Clinic of a cohort of patients with and without RA found that the risk of RA-related obstructive disease was higher in men, current or former smokers, and in those with more severe RA [5]. However, those individuals with RA who were non-smokers did not have an increased risk of obstructive disease. In a Taiwanese retrospective cohort study, the incidence of COPD in individuals with RA was found to be 1.74 fold higher than the non-RA population; however because they used a national database that did not include information regarding tobacco use, they could not assess the effect of smoking (Shen). A prospective study of 52 non-smoking patients with “active” RA (as defined by the current use of DMARD therapy) in the United Kingdom found that there was an increased prevalence of obstructive pattern found on PFTs which did not worsen over a 10-year follow-up period [7]. These individuals did demonstrate a decline in DLCO over the same time period, which may have been attributable to their RA therapy. Even the definition of obstruction varies among these studies, with some using the traditional definition of FEV1/FVC <70% while others focused on the FEF 25–75% instead. Impulse oscillometry may be useful, where obstruction can be identified as increased resistance values at lower oscillatory frequencies. This pattern was shown to be present in a retrospective cohort of RA patients in Japan [[8], [9]]. Overall, there is no consensus on what defines RA-related obstructive lung disease, and it should be taken into account that confounders are abundant. When the diagnosis of obstruction is made, treatment should reasonably be tried for obstructive disease with bronchodilators. If this therapy fails, or there is progression despite adequate therapy, consideration for treatment of underlying RA with DMARDs such as steroids or other immunosuppressants should be considered.\n\n8 Learning points/take home messages\n1. Rheumatoid arthritis has many different pulmonary manifestations, and can be a primary and common cause of obstructive lung disease in this patient population.\n\n2. The high incidence of smoking in RA makes exclusion of other pulmonary diseases challenging.\n\n3. Imaging can be helpful in distinguishing between differential diagnoses.\n\n\n\nCRediT author statement\nDanielle Glick: Conceptualization, Visualization, Writing – Original Draft; Jeffrey Galvin: Resources, Writing – Review and Editing; Janaki Deepak: Supervision, Writing – Review and Editing.\n\nDeclaration of competing interest\nNone.\n==== Refs\nReferences\n1 Shaw M. Collins B.F. Ho L.A. Raghu G. Rheumatoid arthritis-associated lung disease Eur. Respir. Rev. 24 135 2015 Mar 1 16 10.1183/09059180.00008014 25726549 \n2 Sirajuddin A. Primary pulmonary lymphoid lesions: radiologic and pathologic findings Radiographics 36 1 2016 Jan 12 53 70 10.1148/rg.2016140339 [Internet] 26761531 \n3 Massey H. Darby M. Edey A. Thoracic complications of rheumatoid arthritis Clin. Radiol. 68 2013 293 301 10.1016/j.crad.2012.07.007 22998801 \n4 Perez T. Remy-Jardin M. Cortet B. Airways involvement in Rheumatoid Arthritis: clinical, functional, and HRCT findings Am. J. Respir. Crit. Care Med. 157 1998 1658 1665 9603152 \n5 Nannini C. Incidence and mortality of obstructive lung disease in rheumatoid arthritis: a population-based study Arthritis Care Res. 65 8 2013 Aug 1243 1250 10.1002/acr.21986 \n6 Shen T.C. Increased risk of chronic obstructive pulmonary disease in patients with rheumatoid arthritis: a population-based cohort study Q. J. Med. 107 2014 537 543 10.1093/qjmed/hcu027 \n7 Fuld J.P. A longitudinal study of lung function in nonsmoking patients with rheumatoid arthritis Chest 124 4 2003 Oct 1224 1231 14555550 \n8 Sokai R. Respiratory mechanics measured by forced oscillation technique in rheumatoid arthritis-related pulmonary abnormalities: frequency-dependence, heterogeneity, and effects of smoking SpringerPlus 5 2016 335 10.1186/s40064-016-1952-8 [Internet] 27064652 \n9 Mori S. Yukinori K. Sugimoto M. Small airway obstruction in patients with rheumatoid arthritis Mod. Rheumatol. 21 2 2011 Apr 164 173 10.1007/s10165-010-0376-5 21136133\n\n",
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"journal": "Respiratory medicine case reports",
"keywords": "Obstructive lung diseases; Rheumatoid arthritis",
"medline_ta": "Respir Med Case Rep",
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"title": "Complex obstructive lung disease - A diagnostic and management conundrum.",
"title_normalized": "complex obstructive lung disease a diagnostic and management conundrum"
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"abstract": "OBJECTIVE\nThe Veterans Health Administration (VHA) is the largest cancer care provider in the United States, with the added challenge of serving more than twice the percentage of patients with cancer in rural areas than the national average. The VHA established the National Precision Oncology Program in 2016 to implement and standardize the practice of precision oncology across the diverse VHA system.\n\n\nMETHODS\nTumor or peripheral blood specimens from veterans with advanced solid tumors who were eligible for treatment were submitted for next-generation sequencing (NGS) at two commercial laboratories. Annotated results were generated by the laboratories and independently using IBM Watson for Genomics. Levels-of-evidence treatment recommendations were based on OncoKB criteria.\n\n\nRESULTS\nFrom July 2016 to June 2018, 3,698 samples from 72 VHA facilities were submitted for NGS testing, of which 3,182 samples (86%) were successfully sequenced. Most samples came from men with lung, prostate, and colorectal cancers. Thirty-four percent of samples were from patients who lived in a rural area. TP53, ATM, and KRAS were among the most commonly mutated genes. Approximately 70% of samples had at least one actionable mutation, with clinical trials identified as the recommended option in more than 50%. Mutations in genes associated with a neuroendocrine prostate cancer phenotype were expressed at increased frequency among veterans than in the general population. The most frequent therapies prescribed in response to NGS testing were immune checkpoint inhibitors, EGFR kinase inhibitors, and PARP inhibitors.\n\n\nCONCLUSIONS\nClinical implementation of precision oncology is feasible across the VHA health care system, including rural sites. Veterans have unique occupational exposures that might inform the nature of the mutational signatures identified here. Importantly, these results underscore the importance of increasing clinical trial availability to veterans.",
"affiliations": "Department of Veterans Affairs, Durham, NC.;Department of Veterans Affairs, Durham, NC.;Department of Veterans Affairs, Durham, NC.;Argonne National Laboratory, Lemont, IL.;Argonne National Laboratory, Lemont, IL.;Argonne National Laboratory, Lemont, IL.;Argonne National Laboratory, Lemont, IL.;Department of Veterans Affairs, Durham, NC.;Department of Veterans Affairs, Durham, NC.;Department of Veterans Affairs, Durham, NC.;Department of Veterans Affairs, Durham, NC.;Department of Veterans Affairs, Durham, NC.",
"authors": "Poonnen|Pradeep J|PJ|;Duffy|Jill E|JE|;Hintze|Bradley|B|;Shukla|Maulik|M|;Brettin|Thomas S|TS|;Conrad|Neal R|NR|;Yoo|Hyunseung|H|;Guertin|Christopher|C|;Looney|Jane A|JA|;Vashistha|Vishal|V|;Kelley|Michael J|MJ|;Spector|Neil L|NL|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1200/PO.19.00075",
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"issn_linking": "2473-4284",
"issue": "3()",
"journal": "JCO precision oncology",
"keywords": null,
"medline_ta": "JCO Precis Oncol",
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"nlm_unique_id": "101705370",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32914016",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "27413114;26325560;29985747;28890946;25596245;2199829;25925381;22730846;26822149;24132290;23550210;28007021;30293943;28481359;26822237;28683054;27798265;25998713;18710986;29466156;29375902;27245685;22588877;26014291;26855148;30413407;26544944;28810986",
"title": "Genomic Analysis of Metastatic Solid Tumors in Veterans: Findings From the VHA National Precision Oncology Program.",
"title_normalized": "genomic analysis of metastatic solid tumors in veterans findings from the vha national precision oncology program"
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"abstract": "Stem cell transplantation remains the curative option for many patients with hematological malignancies. The long-term effects of these treatments on the patients and their immune systems have been extensively investigated, but there remains a paucity of data regarding autoimmune manifestations post-transplant, although these effects are well recognized.Herein we present the clinical picture and therapeutic approach in three patients (cases 1-3), with varied presentations of autoimmune disease post-transplant. Case 1 exhibited autoimmune hemolytic anemia and other autoimmune manifestations (serositis, thyroiditis), that were probably linked to graft versus relapsed leukemia effect. Cases 2 and 3 had pure red white cell aplasia and pure red cell aplasia, respectively, which were associated with hyperglobulinemia and a clonal T cell expansion.",
"affiliations": "University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.;University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK.",
"authors": "Lloyd|Rebecca|R|;Nikolousis|Emmanouil|E|;Kishore|Bhuvan|B|;Lovell|Richard|R|;Shankara|Paneesha|P|;Zeid|Nervana Abou|NA|;Horgan|Claire|C|;Panteliadou|Alkistis Kyra|AK|;McIlroy|Graham|G|;Xenou|Evgenia|E|;Kaparou|Maria|M|;Holder|Kathleen|K|;Murthy|Vidhya|V|;Kanellopoulos|Alexandros|A|0000-0002-7400-5416",
"chemical_list": "D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": "10.1177/0963689720950641",
"fulltext": "\n==== Front\nCell Transplant\nCell Transplant\nCLL\nspcll\nCell Transplantation\n0963-6897 1555-3892 SAGE Publications Sage CA: Los Angeles, CA \n\n32806929\n10.1177/0963689720950641\n10.1177_0963689720950641\nCase Study\nAutoimmune Cytopenias Developing Late Post Alemtuzumab-Based Allogeneic Stem Cell Transplantation: Presentation of Short Case Series from a Transplant Center\nLloyd Rebecca 1 Nikolousis Emmanouil 1 Kishore Bhuvan 1 Lovell Richard 1 Shankara Paneesha 1 Zeid Nervana Abou 1 Horgan Claire 1 Panteliadou Alkistis Kyra 1 McIlroy Graham 1 Xenou Evgenia 1 Kaparou Maria 1 Holder Kathleen 1 Murthy Vidhya 1 https://orcid.org/0000-0002-7400-5416Kanellopoulos Alexandros 1 \n1 University Hospitals Birmingham NHS, Bone Marrow Transplant Unit Heartlands Hospital, Birmingham, UK\n\nAlexandros Kanellopoulos, MD, Consultant Hematologist, University Hospitals Birmingham Heartlands Hospital, 27 Rodbourne Rd, Birmingham, West Midlands, B17 0PN, UK. Emails: Alexandros.Kanellopoulos@nhs.net; akanell@hotmail.com\n18 8 2020 \nJan-Dec 2020 \n29 096368972095064125 3 2020 16 5 2020 27 7 2020 © The Author(s) 20202020SAGE Publications Inc, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Stem cell transplantation remains the curative option for many patients with hematological malignancies. The long-term effects of these treatments on the patients and their immune systems have been extensively investigated, but there remains a paucity of data regarding autoimmune manifestations post-transplant, although these effects are well recognized.\n\nHerein we present the clinical picture and therapeutic approach in three patients (cases 1–3), with varied presentations of autoimmune disease post-transplant. Case 1 exhibited autoimmune hemolytic anemia and other autoimmune manifestations (serositis, thyroiditis), that were probably linked to graft versus relapsed leukemia effect. Cases 2 and 3 had pure red white cell aplasia and pure red cell aplasia, respectively, which were associated with hyperglobulinemia and a clonal T cell expansion.\n\nautoimmune diseasehematopoietic stem cellst cellsgraft versus host diseasebone marrow transplantcover-dateJanuary-December 2020typesetterts3\n==== Body\nIntroduction\nHematopoietic stem cell transplantation (HSCT) remains the only curative option for many patients with hematological malignancies. Disease relapse, graft versus host disease (GvHD), and infective complications have been under intense study resulting in great advances in terms of their diagnosis and management. On the other hand, there is paucity for data with regard to autoimmune complications post-HSCT, such as pure red cell aplasia (PRCA), pure white cell aplasia (PWCA), autoimmune hemolytic anemia (AIHA), and serositis. These complications are recognized but underdiagnosed in both allo-HSCT and auto-HSCT settings. In this article, we aimed to convey our reflections on the clinical features of three allograft patients at our Center who developed the aforementioned complications post-Alemtuzumab HSCT.\n\nCase 1\nThe first case (case 1) refers to a 43-year-old man who underwent myeloablative Busulphan/Cyclophosphamide with Alemtuzumab 15 mg in the stem cell bag matched unrelated donor HSCT in first complete remission (CR1) for acute myeloid leukemia (AML) (FLT3 wild type, NPM1 wild type, normal karyotype). Recipient and donor blood group were O RhD+ and O RhD−, respectively. Apart from the high body mass index (BMI), there were no other comorbid conditions at transplant. As part of his workup for initial induction chemotherapy, he was found to have past hepatitis B infection (HBcAb+, HBsAg−) with negative hepatitis B virus (HBV) DNA and was set on lamivudine and later entecavir prophylaxis. Frequent HBV DNA assessments have ensued regularly. The early term post-HSCT period was complicated by repeated cytomegalovirus (CMV) reactivation, effectively treated with valganciclovir. At day +94 post-transplant, the patient had mixed chimerism (93% donor in post-transplant whole blood, 3% donor in CD3+ T cell fraction) and underwent his first donor lymphocyte infusion (DLI) at a dose 0.5 × 106 CD3 cells/kg on day +180. The second dose was given 12 weeks later at a dose of 1 × 106 CD3 cells/kg resulting in abrupt full donor conversion only 2 weeks later. On day +305, the patient presented to the clinic with sickness, early satiety, and fatigue. He was diagnosed with Warm Antibody Coombs positive AIHA and upper gastrointestinal tract GvHD. The patient was started on prednisolone oral initially (1 mg/kg) to good effect. He exhibited recurred AIHA and thyroiditis on day +505 upon initial steroid taper. The latter manifested with palpitations and fatigue, undetectable thyroid-stimulating hormone, raised free thyroxine, and free triiodothyronine (26.1 pmol/l [9–19] and 7.5 pmol/l [2.6–5.7], respectively), with negative thyroid peroxidase antibodies. Steroid reintroduction at 1 mg/kg resulted in rapid resolution of thyroid function test abnormalities within 4 weeks. On day +520, cyclosporine was relaunched to enable steroid taper, but on day +560 leukocytosis, anemia, and blasts on blood film ensued. Bone marrow confirmed relapsed AML albeit with abnormal karyotype and two apparent unrelated clones one with del 2q and one with trisomy 3 and der(3), that is, 46 XY del(2)(q2q3)[6]/47 XY +3 der(3) add (3) (p?1)add(3)(q?1) [3] /46xy(3). Donor chimerism was 30% in the bone marrow and no Flt-3, NPM1, or IDH1/2 mutants were identified. Chemotherapy with Fludarabine/Cytarabine/Lenograstim/Idarubicin (FLAG-IDA) × 2 cycles was deployed and resulted in morphological CR2. This was followed by single DLI at a dose of 1 × 106 CD3+ cells per kg on day +650. On day +945, he displayed HBV DNA reactivation (13,150 copies/ml) without a picture of biochemical hepatitis. He was few weeks off lamivudine prophylaxis suspension. At that time, he was also off on steroids and without AIHA. CD4+ T cell count exceeded 300/µl. He was then set on entecavir with complete response (null viral copies since day +1069). On a separate note, on day +1035, the patient was admitted with recurred AIHA, moderate pericardial effusion, and moderate pleural effusions suggesting GvHD serositis. Steroids (prednisolone initial dose 1 mg/kg) elicited a good response. Four rituximab weekly infusions at a dose of 375 mg/m2 were also administered at the time. Although the patient has responded well to steroid therapy and his AML has remained in second complete remission (CR2) as of now (day +1533), it has been difficult to wean steroids altogether (the current dose is 5 mg on alternate days). Mycophenolate mofetil has been added to enable prednisolone taper over the last 12 months.\n\nCase 2\nCase 2 refers to a 62-year-old woman who received a Busulphan/Fludarabine/Alemtuzumab 30 mg reduced intensity conditioning (RIC) stem cell transplant from a matched unrelated donor for therapy-related AML (patient had previously received anthracycline-based treatment for breast cancer). The patient attained morphological CR but had the cytogenetically active disease (del 7q) prior to transplant. Early post-transplant course was uneventful, only complicated by CMV reactivation. On day +160, she was admitted with neutropenic sepsis and mouth ulcers (white cell count 3.38 × 109/L, hemoglobin 114 g/l, platelet 285 × 109/l, and neutrophil count 0.02 × 109/l). The bone marrow aspirate was consistent with PWCA revealing (1) reduced cellularity, profoundly suppressed myeloid series that comprised less than 5% of total marrow nucleated cells with virtually absent mature forms (metamyelocytes, band forms, neutrophils) and (2) normal erythropoiesis and slightly reduced megakaryocytes. In addition, the aspirate showed 42% lymphoid cells having a phenotype consistent with CD8+ T cells and natural killer (NK) cells on flow cytometry. A dominant T cell clone was demonstrated on T cell receptor analysis. The patient denied having a bone marrow biopsy at the time. Epstein–Barr virus, CMV, human herpesvirus 6, adenovirus, parvovirus B-19 viral PCR, and autoimmune screening were negative. Monoclonal gammopathy had been identified from day +90, but at diagnosis of PWCA, the clonal immunoglobulin G (IgG) kappa surged at 16.5 g/l. The condition had excellent response to intermittent Lenograstim. The agent was suspended 7 months afterward without recurring neutropenia. The patient has since received DLI for mixed chimerism. She has also been complicated by a high level (>20,000 copies/ml) EBV reactivation twice (days +270, +635) that responded promptly to rituximab intravenously (375 mg/m2) repeated weekly until viral clearance. She remains in remission from AML with normal neutrophils and full donor chimerism. She has never exhibited any acute, chronic, or post-DLI GvHD. Bone marrow T cell large granular lymphocytosis (T-LGL) clone has disappeared. Monoclonal IgG has been dwindling and is now barely detectable on immunofixation.\n\nCase 3\nFinally, we describe a 60-year-old man (case 3) who received a Busulphan/Fludarabine/Alemtuzumab 50 mg RIC allograft from a matched unrelated donor for inv(16)/trisomy 8 relapsed AML in CR post-FLAG-IDA salvage. Early transplant complications were recurring CMV reactivation, skin acute GvHD (overall grade1), and mild hemorrhagic cystitis associated with BK virus infection. On day +266, pre-emptive DLI at a dose 0.5 × 106 CD3/kg for mixed T cell chimerism was administered (whole blood chimerism was 99%, and T-cell chimerism was 85% at the time). Very soon later, on day +277, the patient developed sudden onset, heavy hypoproliferative anemia with reticulocytes less than 5/µl (white blood cells 5.22 × 109/l, hemoglobin 59 g/l, platelets 262 × 109/l, neutrophils 2.03 × 109/l, lymphocytes 2.31 × 109/l, mean cell volume 95.6 fl, mean corpuscular hemoglobin 32.8 pg, mean corpuscular hemoglobin concentration 343 g/l, red cell distribution width 12.8%) without evidence of hemolysis, hematinic deficiency, or of disease relapse. Parvovirus, CMV, and EBV PCR were all negative. At that time, IgG peaked at 30 g/l with a monoclonal band 24.5 g/l, and no accompanying immunoparesis. Bone marrow aspirate revealed profoundly suppressed erythroid series (<1% on aspirate), whereas the trephine biopsy showed nearly aplastic erythropoiesis together with some hotspots of arrested erythroblast maturation and an excess of polyclonal plasma cells that comprised less than 10% of hematopoietic cells. On flow cytometry, CD8+ T cells comprised 7% of total marrow nucleated cells with confirmation of a dominant T cell clone from molecular diagnostics (T cell receptor PCR analysis). The diagnosis was of T-LGL-associated PRCA post-HSCT, and the patient was treated with the reintroduction of cyclosporine along with darbepoetin to good effect. The CD8+ T cell clone resolved in a subsequent bone marrow that was performed a few months later, whereas the monoclonal IgG has eventually subsided at 14.1 g/l. Over time, cyclosporine was successfully weaned off. The patient remains in remission with full donor chimerism some 5 years out from allograft.\n\nDiscussion\nIn this study, case 1 highlighted that AIHA might occur post-DLI in combination with rare, underdiagnosed forms of chronic GvHD, and this can potentially be linked to a somewhat unexpected Graft versus relapsed leukemia effect. Besides, through cases 2 and 3, we wanted to convey that clonal T cell (or NK-cell) expansions should be sought when isolated central cytopenias occur late post-allograft in the absence of viral/toxic causes (Table 1).\n\nTable 1. Salient Clinical and Treatment Details for Patients Under Study.\n\nPatient; age; disease; disease status at onset\tConditioning type; intensity\tType of transplant/stem cell source\tDLI/timing to episode\tCMV reactive/presence at onset\tGvHD and status at onset\tComplication\tTime (days [D]) from transplant at diagnosis of autoimmunecomplex\tTreatment for autoimmune complex\tResponse to treatment\t\nCase 1 male; 43; AML; CR2\tBu/Cy/Alemt 15 mg in the stem cell bag; MAC\tHLA 10/10 MUD/PBSC\tY/Pre\tY/Low level, recurring through Tx for AIHA\tUpper GI tract grade 2 post-DLI GvHD prior to AML relapse; CR\tWarm antibody; autoimmune hemolysis, pericarditis; pleuritis\tD +305 (AIHA) and D +1035 (AIHA and serositis)\tPrednisolone × last 16 months; rituximab 375 mg/m2 × 4 weekly twice months +12 and +23 post-BMT; MMF × last 12 months\tLow-dose steroid dependence. Currently on prednisolone 10 mg OD and MMF.\t\nCase 2 female;62; AML; CR1\tBu/Flu/Alemt 30 mg; RIC\tHLA 10/10 MUD/PBSC\tY/Post\tY/resolved\tN\tPure white cell aplasia associated with NK and T-LGL expansion\tD +160\tLenograstim weekly × 7 months\tComplete response—off treatment\t\nCase 3 male; 60; AML; CR1\tBu/Flu/Alemt 50 mg; RIC\tHLA 10/10 MUD/PBSC\tY/Pre\tY/resolved\tSkin stage 2, overall Gr.1 CR\tPure red cell aplasia associated with T-LGL expansion\tD +277\tCyclosporine × 8 months darbepoetin × 4 weeks\tComplete response—off treatment\t\nAIHA, autoimmune hemolytic anemia; Alemt, Alemtuzumab; AML, acute myeloid leukemia; Bu/Cy, busulphan/cyclophosphamide; Bu/Flu, busulphan/fludarabine; CMV, cytomegalovirus; CR, complete remission; CR1, first complete remission; CR2, second complete remission; DLI, donor lymphocyte infusion; GvHD, graft versus host disease; MAC; myeloablative; MUD, matched unrelated donor; MMF, mycophenolate mofetil; NK, natural killer; PBSC, peripheral blood stem cells; RIC, reduced intensity conditioned; T-LGL, T cell large granular lymphocytosis.\n\nAutoimmune cytopenias are encountered following allogeneic stem cell transplantation, but there have also been reports of thyroid dysfunction, myasthenia gravis, vitiligo, and autoimmune hepatitis1,2. The incidence and pathophysiology of autoimmune complications post-transplant have not been adequately studied, but they are perceived to be linked to dysregulation of autoreactive T cells3 not only from the transplant itself but from multiple previous chemotherapy treatments4. Treatment with highly immunosuppressive therapy, given primarily to eradicate disease and prevent GvHD, causes loss of regulatory T cells which can then lead to an expansion of recipient tissue reactive B and T cells5. Delayed immune reconstitution in patients receiving T cell depletes HSCT and may also predispose to autoimmune conditions4.\n\nIn case 1, the late onset of AIHA, thyroiditis, and serosal inflammation 1-year post-chemo-DLI salvage might have been linked to vigorous Graft versus leukemia effect as the patient has remained in remission more than 29 months now despite that his AML relapse post-transplant with new complex karyotype clonal evolution. AIHA and serositis (inflammation of body serosal epithelium in pleural cavities, peritoneum, and pericardium) are classified as “other” manifestations of chronic GvHD. Their occurrence has been described in conjunction with other more frequent chronic GvHD manifestations, but there is a striking scarcity of data about their prevalence, clinical features, and impact on transplant outcomes. Case 1 is also unique in that these two aforementioned manifestations together with transient thyroiditis manifested as post-DLI or de novo chronic GvHD6. At that time, serositis was far more steroid responsive than the AIHA to steroids, which is in line with study data showing the latter is difficult to treat in the post-HSCT setting7. Although prednisolone is initially effective in controlling AIHA/Evans syndrome episodes, the majority of patients develop steroid dependency and receive second-line or third-line therapies, including rituximab, sirolimus, mycophenolate mofetil, intravenous immunoglobulin, and the recently proposed anti-CD38 antibody (daratumumab), with varied efficacy, as shown in Table 2.\n\nTable 2. Key Studies on Autoimmune Hemolytic Anemia Following Allogeneic Stem Cell Transplantation.\n\nPatients analyzed\tCumulative incidence of AIHA\tMedian time to diagnosis\tNumber of patients/GvHD\tNumber of patients/CMV reactivation\tTreatment outcomes\tReference\t\n272 Adults. All had ATG\t4.4% at 3 years (n = 12 pts)\t147 days\t10\t6\tSteroids—no response; rituximab—17% alive; AIHA contributed to mortality\tSanz et al (2007)\t\n3 TYA patients. ALL, XLT/WAS, DNA-ligase IV deficiency\tAll patients had AIHA\t180 days\tNR\tNR\tSteroids, bortezomib—plasmapheresis no response; daratumumab CR in two-thirds; death to AIHA in one-third.\tSchuetz et al (2018)\t\n531 pediatric patients\t5% at 3 years (n = 26 patients)\t\t3\t14\tSteroids/IVIG—22% CR; rituximab—36% CR; bortezomib—57% CR; MMF, sirolimus—100% CR; stem cell boost—75% CR; overall CR—92%; overall OS—79%\tMatthijis et al (2018)\t\n530 adults and pediatric with AA, median age 21 years\t2.6% at 6.4 years (n = 14 patients) with AIHA or Evans, another n = 8 patients ITP and n = 4 patients AIN)\t10.6 months\tNo correlation with GvHD\tNR\tSteroids, IVIG, rituximab, G-CSF, AIHA—85% CR; Evans—14% CR; overall OS—85% at 5 years\n\n\tMiller et al (2019)\t\n380 pediatric patients\t6.3% at 35 months\n(n = 24 patients).\nMost had additional AIN, ITP, or both\t133 days\t15\tNR\tSteroids—13% CR\nMMF, sirolimus, rituximab—all patients responded to additional treatment.\nOverall OS—83%\tSzanto et al (2020)\t\nAA, aplastic anemia; AIHA; autoimmune hemolytic anemia; AIN, autoimmune neutropenia; CMV, cytomegalovirus; CR, complete remission; G-CSF, granulocyte colony stimulating factor; GvHD, graft versus host disease; ITP, immune thrombocytopenia; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; NR; not reported; OS, overall survival; WAS, Wiskott–Aldrich syndrome; XLT, X-linked thrombocytopenia.\n\nWith regard to the incidence and prognostic factors for autoimmune cytopenias post-allo-HSCT, a joint study of the Autoimmune Diseases and Severe Aplastic Anemia Working Parties (ADWP/SAAWP) of the European Society for Blood and Marrow Transplantation (EBMT) studied 530 adult and pediatric patients who underwent allo-HSCT for aplastic anemia8. Of these, n = 25 or 4.7% of patients were diagnosed with autoimmune cytopenia at a median 10.6 months post-allo-HSCT (32% with immune thrombocytopenia [ITP], 28% AIHA, 24% AIHA + ITP, and 16% autoimmune neutropenia). On multivariable analysis, the use of bone marrow and myeloablative conditioning was protective against autoimmune cytopenias. As the study was retrospective, the findings were limited by the absence of bone marrow biopsy and exhaustive differential diagnosis in some of the studied cases. Another large retrospective study from the Netherlands found that 30 out of 380 pediatric patients with both benign and malignant diseases developed autoimmune cytopenias post-allograft9. On univariate analysis, T cell depletion with ATG or Alemtuzumab, benign disease, and GvHD predisposed to autoimmunity. An interesting finding was that of a significant increase in IgG, IgA, and IgM levels shortly before autoimmune cytopenia onset. This is in line with cases 2 and 3 in this article, which displayed peaking IgG monoclonal gammopathy just before T-LGL-PWCA and PRCA, respectively.\n\nLGL post-HSCT is often associated with cytopenias and nonclonal hypergammaglobulinemia10. It has been observed that LGL is often associated with chronic CMV infection as well as patients with chronic GvHD through a process of chronic antigenic stimulation. LGL is a phenomenon estimated to affect between 0.5% and 18.4% of patients following HSCT11. The presentations can range from self-limiting polyclonal expansion to overt leukemia. Due to the lack of studies focusing on LGL, the data remain limited with interval between transplant and LGL estimated to be between 1 and 61 months. LGL is not always associated with cytopenias, but this is an important differential when investigating these cases in the post-transplant setting. Central cytopenias associated with an autoimmune mechanism to T-LGL expansion following an allograft are underreported, and they have been thought to complicate early post-transplant course due to unstable engraftment and evolving immune reconstitution. Therefore, cases 2 and 3 were notable because the autoimmune attack to bone marrow precursors causing PWCA and PRCA, respectively, was unraveled beyond day +150 following excellent engraftment with full donor status. In case 2, neutropenia was effectively controlled with Lenograstim, while case 3 patient had an excellent response to cyclosporine.\n\nFinally, this study highlights that Alemtuzumab used for primary GvHD prophylaxis might elicit autoimmunity in selected stem cell transplant recipients. Alemtuzumab has long been associated with the development of secondary autoimmune diseases, with studies suggesting up to 30% of multiple sclerosis patients treated with Alemtuzumab develop secondary autoimmune manifestations12. which can occur years after the treatment, such as thyroid disorders and immune thrombocytopenia. It has been postulated that patients with preponderance for higher levels of interleukin-21 are more likely to experience secondary autoimmune complications due to greater levels of T cell apoptosis and cell cycling, increasing the likelihood for autoreactive T cells.\n\nTo conclude, this study illustrated rare post-HSCT autoimmunity, in particular hypoproliferative unicytopenia associated with clonal T-cell expansion, as well as autoimmune constellation of AIHA, thyroiditis, and serosal inflammation. The necessity to decipher autoimmunity post-HSCT through prospective clinical studies cannot be overstated.\n\nEthical Approval: This study was approved by our institutional review board.\n\nStatement of Human and Animal Rights: This article does not contain any studies with human or animal subjects.\n\nStatement of Informed Consent: There are no human subjects in this article and informed consent is not applicable.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iD: Alexandros Kanellopoulos \nhttps://orcid.org/0000-0002-7400-5416\n\n\nStatements: This article does not contain any (experimental) studies with human or animal subjects. The article refers to a retrospective description of bone marrow transplant patients displaying unusual autoimmune manifestations.\n\nVerbal informed consent was obtained from the patients for their anonymized information to be published in this article.\n==== Refs\nReferences\n1 \nKhalil A Zaidman I Bergman R Elhasid R Ben-Arush MW \nAutoimmune complications after hematopoietic stem cell transplantation in children with nonmalignant disorders\n. Scientific World Journal . 2014 ;2014 :581657 .24574898 \n2 \nHolbro A Abinun M Daikeler T \nManagement of autoimmune diseases after haematopoietic stem cell transplantation\n. Br J Haematol . 2012 ;157 (3 ):281 –290\n.22360687 \n3 \nLoh Y Oyama Y Statkute L Quigley K Yaung K Gonda E Barr W Jovanovic B Craig R Stefoski D Cohen B , et al.\nDevelopment of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used\n. Blood . 2007 ;109 (6 ):2548 –2643\n.\n4 \nMarleau AM Sarvetnick N \nT cell homeostasis in tolerance and immunity\n. J Leukoc bio . 2005 ;78 (3 ):575 –584\n.15894586 \n5 \nZhyoyan L Rubinstein S Thota R Savani M Brissot E Shaw B Majhail N Mohty M Savani B \nImmune-mediated complications after hematopoietic stem cell transplantation\n. Biol Bone Marrow Transplant . 2016 ;22 (8 ):1368 –1375\n.\n6 \nLeonard J Newell L Meyers G Hayes-Lattin B Gajewski J Heitner S Nonas S Allen B Stentz A Frires R Maziarz R , et al.\nChronic GvHD-associated serositis and pericarditis\n. Bone Marrow Transplant . 2015 ;50 (8 ):1098 –1104\n.25961774 \n7 \nBarcellini W Fattizzo B Zaninoni A \nCurrent and emerging treatment options for autoimmune hemolytic anemia\n. Expert Rev Clin Immunol . 2018 ;14 (10 ):857 –872\n.30204521 \n8 \nSzanto CL Langenhorst J de Koning C Nierkens S Bierings M Huitema ADR Lindemans CA Boelens JJ \nPredictors for Autoimmune Cytopenias after Allogeneic Hematopoietic Cell Transplantation in Children\n. Biol Blood Marrow Transplant . 2020 ;26 (1 ):114 –122\n.31344451 \n9 \nMiller PDE Snowden JA De Latour RP Iacobelli S Eikema DJ Knol C Marsh JCW Rice C Koh M Fagioli F Chaganti S , et al.\nAutoimmune cytopenias (AIC) following allogeneic haematopoietic stem cell transplant for acquired aplastic anaemia: a joint study of the autoimmune diseases and severe aplastic anaemia working parties (ADWP/SAAWP) of the european society for blood and marrow transplantation (EBMT)\n. Bone Marrow Transplant . 2020 ;55 (2 ):441 –451\n.31554929 \n10 \nMohty M Faucher C Vey N Chabannon C Sainty D Arnoulet C Gaugler B Gastaut JA Maraninchi D Olive D Blaise D \nFeatures of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis\n. Leukemia \n2002 ;16 (10 ):2129 –2133\n.12357367 \n11 \nQiu ZY Tian GY Zhang Z Zhang YQ Xu W Li JY \nLarge granular lymphocytosis after transplantation\n. Oncotarget . 2017 ;8 (46 ):81697 –81708\n.29113425 \n12 \nJones JL Phuah C Cox A Thompson S Ban M Shawcross J Walton A Sawcer S Compston A Coles A \nIL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1 H)\n. J Clin Invest . 2009 ;119 (7 ):2052 –2061\n.19546505\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0963-6897",
"issue": "29()",
"journal": "Cell transplantation",
"keywords": "autoimmune disease; bone marrow transplant; graft versus host disease; hematopoietic stem cells; t cells",
"medline_ta": "Cell Transplant",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D001327:Autoimmune Diseases; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous",
"nlm_unique_id": "9208854",
"other_id": null,
"pages": "963689720950641",
"pmc": null,
"pmid": "32806929",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19546505;25961774;31554929;17119125;12357367;27095688;15894586;24574898;31344451;29113425;30204521;22360687",
"title": "Autoimmune Cytopenias Developing Late Post Alemtuzumab-Based Allogeneic Stem Cell Transplantation: Presentation of Short Case Series from a Transplant Center.",
"title_normalized": "autoimmune cytopenias developing late post alemtuzumab based allogeneic stem cell transplantation presentation of short case series from a transplant center"
} | [
{
"companynumb": "GB-SA-2020SA231538",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IDARUBICIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo report 2 cases of paclitaxel-related maculopathy manifesting as cystoid macular edema (CME) with late petaloid hyperfluorescence on indocyanine green angiography (IA).\n\n\nMETHODS\nA 74-year-old man (patient 1) undergoing paclitaxel chemotherapy for gastric and metastatic liver cancer and a 69-year-old man (patient 2) receiving paclitaxel for hypopharyngeal cancer presented with anorthopia in both eyes. Spectral domain-optical coherence tomography (SD-OCT) revealed macular edema in both eyes of each patient. Fluorescein angiography showed weak petaloid pooling around the fovea in the late phase. IA revealed CME with petaloid hyperfluorescence that matched the region of macular edema detected by SD-OCT. The CME was attenuated in the right eye but not in the left eye of patient 1 at 2 weeks after discontinuation of paclitaxel treatment, whereas it was no longer apparent in either eye at 3 months. The CME was no longer detected in either eye of patient 2 at 3 months after discontinuation of paclitaxel.\n\n\nCONCLUSIONS\nThese cases suggest that paclitaxel-induced CME may result from intraretinal accumulation of intracellular fluid and minimal impairment of the blood retinal barrier.",
"affiliations": "Japan Community Health Care Organization (JCHO) Shimonoseki Medical Center, Shimonoseki, Yamaguchi, Japan.;JA Shuto General Hospital, Yanai, Yamaguchi, Japan.;Japan Community Health Care Organization (JCHO) Shimonoseki Medical Center, Shimonoseki, Yamaguchi, Japan.;Japan Community Health Care Organization (JCHO) Shimonoseki Medical Center, Shimonoseki, Yamaguchi, Japan.;Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.;Ube-Kohsan Central Hospital, Ube, Yamaguchi, Japan.;Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan. yanai@yamaguchi-u.ac.jp.;Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.",
"authors": "Nomi|Nanami|N|;Ota|Manami|M|;Fukumura|Miho|M|;Nuno|Yoshihisa|Y|;Hatano|Makoto|M|;Wakuta|Makiko|M|;Yanai|Ryoji|R|;Kimura|Kazuhiro|K|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D007208:Indocyanine Green; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10384-017-0552-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5155",
"issue": "62(2)",
"journal": "Japanese journal of ophthalmology",
"keywords": "Cystoid macular edema; Indocyanine green angiography; Maculopathy; Paclitaxel",
"medline_ta": "Jpn J Ophthalmol",
"mesh_terms": "D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D007208:Indocyanine Green; D008266:Macula Lutea; D008269:Macular Edema; D008297:Male; D009369:Neoplasms; D017239:Paclitaxel; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "0044652",
"other_id": null,
"pages": "163-167",
"pmc": null,
"pmid": "29270811",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17502517;22484725;6910356;21708093;17763235;20112801;9779722;12692483;19001234",
"title": "Indocyanine green angiography findings of cystoid macular edema secondary to paclitaxel therapy.",
"title_normalized": "indocyanine green angiography findings of cystoid macular edema secondary to paclitaxel therapy"
} | [
{
"companynumb": "JP-PFIZER INC-2018003106",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "1",
... |
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