article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "5-Fluorouracil (5-FU) is combined with folinic acid (FA) for enhancing its cytotoxic effects in the colon cancer chemotherapy treatment. Folinic acid has rarely been involved in hypersensitivity reactions. Here, we report a case of FA hypersensitivity in an adult patient initially attributed to oxaliplatin administered concurrently. A 56-year-old male patient diagnosed with colon cancer received twelve cycles of FOLFOX4, one cycle of FOLFIRI plus cetuximab and nine cycles of FOLFOX6 uneventful. At the tenth cycle of FOLFOX6 chemotherapy, after 15 minutes of starting the infusion of oxaliplatin and FA, the patient reported flushing, pruritus and abdominal pain and erythema and oedema developed over the face and thorax. After progression, FOLFIRI plus aflibercept was scheduled and another reaction occurred. At this time, FA was discontinued and the patient received another cycle consisted on irinotecan plus 5-FU without incidences. This episode of hypersensitivity reaction following FA infusion with no oxaliplatin empirically confirmed that the hypersensitivity reaction was secondary to FA. Clinicians should be aware of hypersensitivity reaction with FA, especially when FA is administered concomitantly with oxaliplatin, despite its lower risk to cause hypersensitivity reactions. Furthermore, the similar signs and symptoms associated to the hypersensitivity reactions of each agent, highlight the importance of having a specialised allergist team for to make a prompt diagnose of the causative agent in order to prevent patient harm and proceed properly without unnecessary delays in the scheduled chemotherapy treatments.",
"affiliations": "a Department of Pharmacy , Hospital Universitari del Mar , Barcelona , Spain.;a Department of Pharmacy , Hospital Universitari del Mar , Barcelona , Spain.;c Department of Medical Oncology , Hospital Universitari del Mar , Barcelona , Spain.;b IMIM (Instituto de Investigación Hospital del Mar) , Barcelona , Spain.",
"authors": "Florit-Sureda|Marta|M|;Conde-Estévez|David|D|;Vidal|Joana|J|;Montagut|Clara|C|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1179/1973947815Y.0000000048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "28(6)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Chemotherapy; Colon cancer; Folinic acid; Hypersensitivity reaction",
"medline_ta": "J Chemother",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D004342:Drug Hypersensitivity; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "500-505",
"pmc": null,
"pmid": "26042586",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypersensitivity reaction caused by folinic acid administration: a case report and literature review.",
"title_normalized": "hypersensitivity reaction caused by folinic acid administration a case report and literature review"
} | [
{
"companynumb": "ES-PFIZER INC-2016402575",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "A 76-year-old man was admitted to hospital with a right-sided fractured neck of femur requiring repair via a cemented hemiarthroplasty. Intraoperatively he received 10 mg of intravenous morphine. Post-operatively he received a short course of low-dose oral opioids and subsequently developed myoclonic jerks and hyperalgesia. The opioids were discontinued and both adverse effects resolved. This case report discusses the concurrent development of myoclonus and hyperalgesia following a low dose of opioids and explores possible management options.",
"affiliations": "Arrowe Park Hospital, Wirral, UK.;Arrowe Park Hospital, Wirral, UK.;Arrowe Park Hospital, Wirral, UK.",
"authors": "Woodward|Owen Bleddyn|OB|;Naraen|Sangeeta|S|;Naraen|Akriti|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2049463716664371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-4637",
"issue": "11(1)",
"journal": "British journal of pain",
"keywords": "Pain perception; adverse effect; hyperalgesia; myoclonus; opioid",
"medline_ta": "Br J Pain",
"mesh_terms": null,
"nlm_unique_id": "101583844",
"other_id": null,
"pages": "32-35",
"pmc": null,
"pmid": "28386402",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "27247915;8278214;2475196;7525780;16414554;9223843;7892029;20864417;18574358;17047136;8573956;15911155;11401105;18443635;1784504;21412369;18715174;3620918;17065897;23556990;9809090;19594845;1690960;3400849;9514554;20870687;21676160;12906962",
"title": "Opioid-induced myoclonus and hyperalgesia following a short course of low-dose oral morphine.",
"title_normalized": "opioid induced myoclonus and hyperalgesia following a short course of low dose oral morphine"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-136042",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugad... |
{
"abstract": "We describe a 69-year-old woman with metastatic breast cancer who developed dyspnea on exertion, persistent cough, fever and fatigue while on everolimus and exemestane combination. The initial differentials included opportunistic infection such as pneumocystis jiroveci pneumonia (PJP) vs. pneumonitis. Bronchoalveolar lavage (BAL) from bronchoscopy revealed PJP. The patient recovered after appropriate treatment. We also correlated the progressive decrease in her absolute lymphocyte count with PJP infection and recovery. This is the second case that PJP has been described in patients with breast cancer receiving everolimus. Clinicians should be vigilant in their monitoring of patients on everolimus-based regimens and promptly institute appropriate therapy to reduce and prevent morbidity and mortality.",
"affiliations": "Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, U.S.A.;Touro University California, Vallejo, CA, U.S.A.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, U.S.A. hung.khong@hci.utah.edu.",
"authors": "Ray|Abhijit|A|;Khong|Brian|B|;Khong|Hung T|HT|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(12)",
"journal": "Anticancer research",
"keywords": "Pneumocystis jiroveci pneumonia; chemotherapy; everolimus; immunosuppression; metastatic breast cancer",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D011020:Pneumonia, Pneumocystis",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6673-6676",
"pmc": null,
"pmid": "27920001",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case Report of Pneumocystis Jiroveci Pneumonia in a Patient with Metastatic Breast Cancer.",
"title_normalized": "a case report of pneumocystis jiroveci pneumonia in a patient with metastatic breast cancer"
} | [
{
"companynumb": "PHHY2016US179620",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "1",
"druga... |
{
"abstract": "OBJECTIVE\nEmergence delirium after general anesthesia with sevoflurane has not been frequently reported in adults compared to children. This study aimed to determine the incidence of emergence delirium in adult patients who had anesthesia with sevoflurane as the volatile agent and the probable risk factors associated with its occurrence.\n\n\nMETHODS\nA prospective observational study was conducted in adult patients who had non-neurological procedures and no existing neurological or psychiatric conditions, under general anesthesia. Demographic data such as age, gender, ethnicity and clinical data including ASA physical status, surgical status, intubation attempts, duration of surgery, intraoperative hypotension, drugs used, postoperative pain, rescue analgesia and presence of catheters were recorded. Emergence delirium intensity was measured using the Nursing Delirium Scale (NuDESC).\n\n\nRESULTS\nThe incidence of emergence delirium was 11.8%. The factors significantly associated with emergence delirium included elderly age (>65) (p=0.04), emergency surgery (p=0.04), African ethnicity (p=0.01), longer duration of surgery (p=0.007) and number of intubation attempts (p=0.001). Factors such as gender, alcohol and illicit drug use, and surgical specialty did not influence the occurrence of emergence delirium.\n\n\nCONCLUSIONS\nThe incidence of emergence delirium in adults after general anesthesia using sevoflurane is significant and has not been adequately reported. Modifiable risk factors need to be addressed to further reduce its incidence.",
"affiliations": "Eric Williams Medical Sciences Complex, The University of the West Indies, Faculty of Medical Sciences, Mount Hope, Trinidad and Tobago.;Eric Williams Medical Sciences Complex, The University of the West Indies, Faculty of Medical Sciences, Mount Hope, Trinidad and Tobago. Electronic address: uwi.hariharan@gmail.com.;Eric Williams Medical Sciences Complex, The University of the West Indies, Faculty of Medical Sciences, Mount Hope, Trinidad and Tobago.",
"authors": "Ramroop|Renair|R|;Hariharan|Seetharaman|S|;Chen|Deryk|D|",
"chemical_list": "D018685:Anesthetics, Inhalation; D000077149:Sevoflurane",
"country": "Brazil",
"delete": false,
"doi": "10.1016/j.bjan.2018.12.003",
"fulltext": "\n==== Front\nBraz J Anesthesiol\nBraz J Anesthesiol\nBrazilian Journal of Anesthesiology\n0104-0014\n2352-2291\nElsevier\n\nS0104-0014(18)30171-4\n10.1016/j.bjane.2018.12.012\nScientific Article\nEmergence delirium following sevoflurane anesthesia in adults: prospective observational study\nDelirium do despertar após anestesia com sevoflurano em adultos: estudo observacional prospectivoRamroop Renair\nHariharan Seetharaman uwi.hariharan@gmail.com\n⁎\nChen Deryk\nEric Williams Medical Sciences Complex, The University of the West Indies, Faculty of Medical Sciences, Mount Hope, Trinidad and Tobago\n⁎ Corresponding author. uwi.hariharan@gmail.com\n14 1 2019\nMay-Jun 2019\n14 1 2019\n69 3 233241\n23 3 2018\n3 12 2018\n© 2018 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda.\n2018\nSociedade Brasileira de Anestesiologia\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground and objectives\n\nEmergence delirium after general anesthesia with sevoflurane has not been frequently reported in adults compared to children. This study aimed to determine the incidence of emergence delirium in adult patients who had anesthesia with sevoflurane as the volatile agent and the probable risk factors associated with its occurrence.\n\nDesign & methods\n\nA prospective observational study was conducted in adult patients who had non-neurological procedures and no existing neurological or psychiatric conditions, under general anesthesia. Demographic data such as age, gender, ethnicity and clinical data including ASA physical status, surgical status, intubation attempts, duration of surgery, intraoperative hypotension, drugs used, postoperative pain, rescue analgesia and presence of catheters were recorded. Emergence delirium intensity was measured using the Nursing Delirium Scale (NuDESC).\n\nResults\n\nThe incidence of emergence delirium was 11.8%. The factors significantly associated with emergence delirium included elderly age (>65) (p = 0.04), emergency surgery (p = 0.04), African ethnicity (p = 0.01), longer duration of surgery (p = 0.007) and number of intubation attempts (p = 0.001). Factors such as gender, alcohol and illicit drug use, and surgical specialty did not influence the occurrence of emergence delirium.\n\nConclusions\n\nThe incidence of emergence delirium in adults after general anesthesia using sevoflurane is significant and has not been adequately reported. Modifiable risk factors need to be addressed to further reduce its incidence.\n\nResumo\n\nJustificativa e objetivos\n\nO delirium do despertar após a anestesia geral com sevoflurano não tem sido relatado com frequência em adultos como nas crianças. Este estudo teve como objetivo determinar a incidência de delirium do despertar em pacientes adultos submetidos à anestesia com sevoflurano como agente volátil e os prováveis fatores de risco associados a sua ocorrência.\n\nDesenho e métodos\n\nUm estudo observacional prospectivo foi conduzido com pacientes adultos sem distúrbios neurológicos ou psiquiátricos que foram submetidos à anestesia geral para procedimentos não neurológicos. Dados demográficos como idade, sexo, etnia e dados clínicos, incluindo escore ASA, estado cirúrgico, tentativas de intubação, tempo de cirurgia, hipotensão intraoperatória, drogas utilizadas, dor pós-operatória, analgesia de resgate e presença de cateteres foram registrados. A intensidade do delirium do despertar foi medida usando a Escala de Triagem de Delirium em Enfermagem (Nursing Delirium Scale – NuDESC).\n\nResultados\n\nA incidência de delirium do despertar foi de 11,8%. Os fatores significativamente associados ao delirium do despertar incluíram idade avançada (>65) (p = 0,04), cirurgia de emergência (p = 0,04), descendência africana (p = 0,01), tempo maior de cirurgia (p = 0,007) e número de tentativas de intubação (p = 0,001). Fatores como sexo, uso de álcool e drogas ilícitas e especialidade cirúrgica não influenciaram a ocorrência de delirium do despertar.\n\nConclusões\n\nA incidência de delirium do despertar em adultos após a anestesia geral com sevoflurano é significativa e não tem sido relatada adequadamente. Fatores de risco modificáveis precisam ser abordados para reduzir ainda mais sua incidência.\n\nKeywords\n\nEmergence delirium\nSevoflurane\nAdult patients\nPost-anesthesia care\nPalavras-chave\n\nDelirium do despertar\nSevoflurano\nPacientes adultos\nCuidados pós-anestésicos\n==== Body\npmcIntroduction\n\nDelirium is a disturbance of consciousness with inattention accompanied by a change in cognition or perceptual disturbance that develops over a short period (hours to days) and fluctuates over time.1 The hallmark symptom of delirium is an impairment of consciousness, usually occurring in association with global impairments of cognitive functions.1 Delirium may be associated with a wide range of conditions.2, 3, 4\n\nDelirium during the postoperative period can be divided into Emergence Delirium (ED) and Postoperative Delirium (PD) based on its onset.2 ED is also referred to as Emergence Agitation (EA) or post-anesthetic excitement in the literature, and is a well-documented phenomenon occurring in children and adults during the immediate postoperative period and lasting for 5–15 min.2 ED is a clinical condition in which patients are ‘awake’ but experience alterations in disorientation and other mental status changes that range from confusion and lethargy to violent and harmful behavior.2 A direct association with the administration of a general anesthetic is likely because it occurs during the emergence process and mimics the excitation ‘Stage II’ of ether anesthesia as described by Guedel.3 ED has been categorized under the DSM-IV diagnostic criteria as a substance-induced delirium.3\n\nED may lead to serious consequences for a patient such as injury, increased pain, hemorrhage, self-extubation, removal of catheters or drains. It can also necessitate physically or pharmacologically restraining the patient, often requires additional nursing support and delays recovery time.3, 4, 5 ED can be disturbing to the anesthesiologists as well as Post Anesthesia Care Unit (PACU) staff and can lead to increased hospital costs.3, 6, 7\n\nEmergence Delirium in the PACU was also found to be a strong predictor of postoperative delirium long after surgery.8 Postoperative delirium in itself may be associated with increased morbidity, mortality, duration of hospital stay, technical, consultant and nursing costs.9 The incidence of ED varies widely with reports ranging from as low as 3% to as high as 21%.3, 4, 9, 10 Despite its common occurrence and serious sequelae, ED has not been frequently studied in adults, studies being done much more commonly in the pediatric population.6, 7, 8 The precise etiology of ED after general anesthesia remains unknown3; however, many factors may predispose a patient to agitation, which is frequently initiated by uncomfortable stimuli.11 Previous reports have found some risk factors that are associated with the development of ED. These include age, history of alcohol abuse, type of surgery, use of sevoflurane as the volatile agent, use of anticholinergic drugs, duration of surgery and presence of a urinary catheter.3, 4, 11\n\nTo our knowledge, there have not been many published studies from Caribbean, investigating the incidence and factors associated with emergence delirium in adult patients after sevoflurane anesthesia. With this background, this prospective study aimed to determine the incidence and identify modifiable risk factors in adult patients in the Caribbean, which could be considered in risk reduction strategies in day-to-day operating room practice.\n\nMethodology\n\nA prospective observational study was conducted over a 6 month period in the PACU at the Eric Williams Medical Sciences Complex, a tertiary care teaching hospital in Trinidad & Tobago. Approval of the study protocol was obtained from the Ethics Committee of the Faculty of Medical Sciences, The University of the West Indies, St. Augustine. The 5 bed PACU is located within the main ‘Block-of-8’ operating-rooms suite, where procedures in the specialties including general surgery, orthopedic, otorhinolaryngology (ENT), urology, plastic, thoracic and maxillofacial surgeries are performed. Each PACU nurse cares for 1–2 patients. An anesthesiologist is responsible for the discharge of patients.\n\nInclusion criteria for the study were patients aged 18 years and older, undergoing general anesthesia with sevoflurane as the volatile agent, and admitted to the PACU after extubation in the operating room. The study excluded those who have undergone a neurosurgical procedure, patients known to have pre-existing neurological disease, (such as a history of chronic dementia, psychosis, mental retardation, cerebrovascular accident with residual cognitive impairment), patients who had the procedure exclusively under local/regional anesthetic technique, patients admitted to the PACU with endotracheal tube in situ, and patient refusal to participate. Informed written consent was obtained by the anesthesiologist administering the general anesthetic prior to induction. Patients who met the inclusion criteria were assessed for delirium in the PACU. This was done using the Nurses Delirium Scale (Nu-DESC),12 10 min after entry into the PACU. The Nu-DESC score is based on the Confusion Rating Scale and has a sensitivity and specificity of 0.95 and 0.87 respectively for detecting delirium in the PACU when compared against the gold standard, the DSM-IV criteria.13, 14 The Nu-DESC consists of the following five criteria: disorientation, inappropriate behavior, inappropriate communication, illusions/hallucinations and psychomotor retardation. Each is graded from 0–2 with a maximum of score of 10 and a score of 2 or greater indicating presence of delirium. It is easy to use and has an average completion time of 1 min.13 In this study, a NuDeSc score of 2 and above was considered positive for the diagnosis Emergence Delirium, while those patients who scored less than 2, were considered not to have ED. The patients were categorized into two groups for the purpose of analysis, based on the presence and absence of delirium.\n\nThe sample size was calculated using the ED incidence of 4.7%, as reported by Lepouse et al.6 Although the calculated sample size required for this study was only 69 patients, all consented patients were included to increase the validity of the study.\n\nDemographic factors including age, gender, and ethnicity were recorded. Preoperative data included alcohol use (>3 times per week), illicit drug use, history of diabetes and/or hypertension, American Society of Anesthesiologists (ASA) score, type of surgical procedure, and surgical status (elective or emergency). The intra-operative clinical data recorded were episodes of hypotension (systolic blood pressure <20% of the baseline or requiring use of vasopressors), type of airway used, number of attempts at endotracheal intubation, volatile agent used, use of nitrous oxide, total morphine dose used intra-operatively, use of non-depolarising neuromuscular blockers, use of atropine and the length of surgery. Postoperatively, presence of a urinary catheter, postoperative pain and need for analgesics in the PACU were recorded.\n\nThe assessment of delirium in PACU using NuDESC scale was done by different personnel who were unaware of the details of the anesthesia management of the patient. The assessment and recording the score were done by a limited small number of personnel who had specific training in the use of the NuDESC scale. This was done in order to minimize bias in recording the data.\n\nThe Statistical Package for Social Sciences (SPSS) version 21 software was used to analyze the data. Continuous variables were analyzed with independent t-test; Pearson's Chi-square and Fisher's exact test analyses were done to determine the associations between the various perioperative variables and the presence of ED. After the initial analyses, a multivariate logistic regression was done to further determine the factors significantly associated with Emergence Delirium. Statistical significance was fixed at p < 0.05 level.\n\nResults\n\nFour hundred and seventeen (417) patients were enrolled in the study. The gender distribution was equal. Majority of the patients presented for elective surgery and belonged to all ASA categories. Different types of airways such as endotracheal tubes and laryngeal mask airways were used for the procedures. Anesthesia was maintained on sevoflurane as the volatile agent for all the patients, the dose adjusted by the individual anesthesiologists. Neuromuscular blocking agents, nitrous oxide and atropine were used in some patients. The preoperative characteristics of the patients including the prevalence of comorbidities, substance use, as well as the intra-operative and postoperative factors which could have possibly influenced ED are listed in Table 1.Table 1 Preoperative characteristics of patients and intra-and-postoperative factors.\n\nTable 1Variable\tNumber (%)\t\nPreoperative characteristics\t\nGender\tMale\t225 (54.0)\t\nFemale\t192 (46.0)\t\nComorbidities\tHypertension\t105 (25.2)\t\nDiabetes mellitus\t88 (21.1)\t\nSubstance Use\tIllicit drugs use\t43 (10.3)\t\nRegular alcohol use\t39 (9.4)\t\nASA Grade\tASA I\t207 (49.6)\t\nASA II\t159 (38.1)\t\nASA III\t50 (12.1)\t\nASA IV\t1 (0.2)\t\nSurgical status\tElective\t340 (81.5)\t\nEmergency\t77 (18.5)\t\n\n\n\t\nIntraoperative factors\t\nAirway\tEndotracheal tube\t269 (64.5)\t\nLaryngeal mask airway\t139 (33.3)\t\nOthersa\t9 (2.2)\t\nDrugs used\tNeuromuscular blocking agents\t323 (77.5)\t\nAtropine\t239 (57.3)\t\nNitrous Oxide\t42 (10.1)\t\nEvents\tHypotension\t124 (29.7)\t\n\n\n\t\nPostoperative factors\t\n Urinary catheter in situ\t78 (18.7)\t\t\n Requirement of analgesia in the Recovery Room\t120 (28.8)\t\t\na Facemask, rigid bronchoscope, tracheostomy.\n\nUsing the Nu-DESC, emergence delirium was diagnosed in 49 patients, giving an overall incidence of 11.8% in this setting. The scores recorded for each element of the Nu-DESC is shown in Fig. 1. Disorientation, inappropriate communication and psychomotor retardation were noted in patients who had a score of 1. Other elements noted included inappropriate behavior and illusions/hallucinations. As shown in Fig. 1, a relatively higher degree of inappropriate behavior and inappropriate communication were observed in patients who scored 2. Overall, psychomotor retardation appeared to be the most commonly observed element in the NuDesc score while illusions/hallucinations were the least recorded element in the score.Figure 1 The scores recorded by the Nursing Delirium Screening Scale.\n\nContinuous variables such as age, duration of surgery and intra-operative morphine dose were compared between the two groups. This is shown in Table 2. Only duration of surgery was significantly longer in patients who had delirium.Table 2 Age, surgical duration, morphine dose and emergence delirium.\n\nTable 2Variable\tRange\tOverall (n = 417)\nMean ± SD\tDelirium absent (n = 368)\nMean ± SD\tDelirium present (n = 49)\nMean ± SD\tp-valuea\t\nAge (y)\n\t18–93\t48.3 ± 16.7\t47.7 ± 16.5\t52.6 ± 17.5\t0.05\t\nSurgical duration (min)\t10–540\t102.7 ± 78.9\t98.9 ± 76.3\t131.3 ± 92.5\t0.007\t\nMorphine dose (mg)\nMean ± SD\t0–30\t5.7 ± 4.1\t5.5 ± 4.0\t6.6 ± 4.2\t0.08\t\nSD, Standard Deviation.\n\na p-value by independent t-test.\n\nThe comparison of preoperative categorical variables is shown in Table 3, while the comparison of intra-operative and postoperative factors is shown in Table 4.Table 3 Pre-operative factors and emergence delirium.\n\nTable 3Factor\tTotal\nn (%)\tDelirium absent\nn (%)\tDelirium present\nn (%)\tp-valuea\t\nAge\t\n ≤64\t342 (82.0)\t307 (83.4)\t35 (71.4)\t\t\n ≥65\t75 (18.0)\t61 (16.6)\t14 (28.6)\t0.04\t\n\n\n\t\nEthnicity\t\n African descent\t190 (45.6)\t158 (83.2)\t32 (16.8)\t\t\n Indian descent\t174 (41.7)\t160 (92.0)\t14 (8.0)\t\t\n Other\t53 (12.7)\t50 (94.3)\t3 (5.7)\t0.01\t\n\n\n\t\nGender\t\n Male\t225 (54.0)\t195 (86.7)\t30 (13.3)\t\t\n Female\t192 (46.0)\t173 (90.1)\t19 (9.9)\t0.277\t\n\n\n\t\nDiabetes mellitus\t\n Yes\t88 (21.1)\t77 (87.5)\t11 (12.5)\t\t\n No\t329 (78.9)\t291 (88.4)\t38 (11.6)\t0.806\t\n\n\n\t\nHypertension\t\n Yes\t105 (25.2)\t95 (90.5)\t10 (9.5)\t\t\n No\t312 (74.8)\t273 (87.5)\t39 (12.5)\t0.413\t\n\n\n\t\nAlcohol use\t\n Yes\t39 (9.4)\t34 (87.2)\t5 (12.8)\t\t\n No\t378 (90.6)\t334 (88.4)\t44 (11.6)\t0.795\t\n\n\n\t\nIllicit drug use\t\n Yes\t43 (10.3)\t38 (88.4)\t5 (11.6)\t\t\n No\t374 (89.7)\t330 (88.2)\t44 (11.8)\t0.979\t\n\n\n\t\nASA score\t\n I\t207 (49.6)\t182 (87.9)\t25 (12.1)\t\t\n II\t159 (38.1)\t142 (89.3)\t17 (10.7)\t\t\n III\t50 (12.0)\t43 (86.0)\t7 (14.0)\t\t\n IV\t1 (0.2)\t1 (100)\t0 (0)\t0.903\t\n\n\n\t\nSurgical status\t\n Elective\t341 (81.8)\t62 (81.6)\t306 (89.7)\t\t\n Emergency\t76 (18.2)\t14 (18.4)\t35 (10.3)\t0.04\t\na p-value using Fisher's Exact Test or Pearson Chi-Square Test.\n\nTable 4 Intra-operative and postoperative factors and emergence delirium.\n\nTable 4Factor\tTotal\nn (%)\tDelirium absent\nn (%)\tDelirium present\nn (%)\tp-valuea\t\nIntra-operative hypotension\t\n Yes\t124 (29.7)\t106 (85.5)\t18 (14.5)\t\t\n No\t293 (70.3)\t262 (89.4)\t31 (10.6)\t0.254\t\n\n\n\t\nAirway type\t\n LMA\t139 (33.3)\t127 (91.4)\t12 (8.6)\t\t\n ETT\t269 (64.5)\t233 (86.6)\t36 (13.4)\t\t\n Other\t9 (2.2)\t8 (88.9)\t1 (11.1)\t0.368\t\n\n\n\t\nNitrous oxide use\t\n Yes\t42 (10.1)\t38 (90.5)\t4 (9.5)\t\t\n No\t375 (89.9)\t330 (88.0)\t45 (12.0)\t0.803\t\n\n\n\t\nNumber of intubation attempts\t\n None\t141 (33.8)\t129 (91.5)\t12 (8.5)\t\t\n 1\t227 (54.4)\t197 (86.8)\t30 (13.2)\t\t\n 2\t40 (9.6)\t35 (87.5)\t5 (12.5)\t\t\n 3\t7 (1.7)\t7 (100)\t0 (0)\t\t\n >3\t2 (0.5)\t0 (0)\t2 (100)\t0.001\t\n\n\n\t\nNon-depolarising neuromuscular blockers\t\n Yes\t323 (77.5)\t282 (87.3)\t41 (12.7)\t\t\n No\t94 (22.5)\t86 (91.5)\t8 (8.5)\t0.268\t\n\n\n\t\nAtropine use\t\n Yes\t239 (57.3)\t205 (85.8)\t34 (14.2)\t\t\n No\t178 (42.7)\t163 (91.6)\t15 (8.4)\t0.069\t\n\n\n\t\nUrinary catheter in PACU\t\n Yes\t78 (18.7)\t67 (85.9)\t11 (14.1)\t\t\n No\t339 (81.3)\t301 (88.8)\t38 (11.2)\t0.474\t\n\n\n\t\nPACU analgesia\t\n Yes\t120 (28.8)\t102 (85.0)\t18 (15.0)\t\t\n No\t297 (71.2)\t266 (89.6)\t31 (10.4)\t0.190\t\nLMA, laryngeal mask airway; ETT, type of airway.\n\na p-value using Fisher's Exact Test or Pearson Chi-Square Test.\n\nPatients were categorized into younger and older age groups (≤64 and ≥65) and analyzed for the presence of delirium. Elderly age group patients did have a significantly higher risk of developing ED compared to younger patients (p = 0.04).\n\nAlthough male patients were more likely to develop ED (13.3%) than female patients (9.9%), this difference was not statistically significant (p = 0.277). Both diabetics and non-diabetics were found to have similar incidences of ED, 12.5% and 11.6% respectively (p = 0.806). ED was present in 12.5% in non-hypertensives compared to 9.5% in hypertensive patients (p = 0.413). The proportion of alcohol users in the study was only 9.4% compared to 90.6% non-users, although the incidences of ED were very similar between the 2 (12.8% and 11.6%, p = 0.795). Similarly, only 10.3% of patients admitted to use illicit drugs compared to 89.7% who did not; however the incidence of ED in patients who used illicit drugs was 11.6%, while it was 11.8% in the non-users (p = 0.979). The incidences of ED in the various ASA categories were also comparable: I (12.1%), II (10.7%), III (14.0%) and IV (0.0%), (p = 0.903).\n\nOf the 124 patients who developed intra-operative hypotension, 14.5% were noted to have ED. In comparison, 10.6% were diagnosed with ED in intra-operatively normotensive patients (p = 0.254). The number of patients with an endotracheal tube (64.5%) almost doubled those who had a LMA (33.3%). The incidence of ED in those with an endotracheal tube (13.4%) was also higher that of the LMA patients (8.6%). No statistically significant difference in the incidence of ED was found between the groups (p = 0.368).\n\nNitrous oxide was used in 10.1% of patients, however, similar incidences of ED were observed in those it was used (9.5%) and in those it was not used (12.0%) (p = 0.803). Similarly, 12.8% of the patients who had Neuromuscular Blocking Agents (NMBA) experienced ED, compared to 8.5% in patients who were not given NMBAs (p = 0.268). Patients who received atropine had an increasing trend of experiencing ED than those who did not (14.2% vs. 8.4%), but the difference was not statistically significant (p = 0.069).\n\nIn PACU, most patients (81.3%) did not have a urinary catheter in situ; the incidence of ED (11.2%) was comparable in those with a catheter (14.1%) (p = 0.474). Of those that required rescue analgesia in the PACU, 15% developed ED in comparison to 10.4% who did not require analgesia (p = 0.190). Although the proportion of patients scheduled for emergency surgery was smaller, the incidence of ED in emergency surgical patients was significantly higher (p = 0.04).\n\nThe presence of ED in patients belonging to each surgical specialty was analyzed. Table 5 depicts the distribution of the patients in each specialty and the comparison. Thoracic surgery had the highest incidence of ED (17.6%), followed by General Surgery and Urology, although there was no statistically significant difference between the groups.Table 5 Type of surgery and emergence delirium.\n\nTable 5\tType of surgery\t\n\tGeneral (n = 207)\tOrthopedic (n = 74)\n\tENT (n = 3)\tMaxillofacial (n = 16)\tPlastic (n = 7)\tThoracic (n = 68)\tUrology (n = 42)\t\nOverall (%)\t49.6\t17.7\t0.7\t3.8\t7.0\t16.3\t10.1\t\nDelirium absent (%)\t88.4\t90.5\t100\t93.8\t100\t82.4\t88.1\t\nDelirium present (%)\t11.6\t9.5\t0\t6.3\t0\t17.6\t11.9\t\nPearson Chi-Square value (4.459); df (6); p-value (0.615).\n\nMost patients either had an LMA or needed only 1 intubation attempt. The incidence of ED increased to 100%, when patients had more than 3 attempts at intubation.\n\nAfter initially analyzing individual factors for association with ED, a stepwise multivariate logistic regression analyses were done to determine the factors significantly associated with ED. The adjusted odds ratios, 95% Confidence Intervals and the p-values of the significant factors associated with ED are depicted in Table 6.Table 6 Multivariate analyses of the factors associated with emergence delirium.\n\nTable 6Variable\tOdds Ratio\t95% Confidence Intervals\tSignificance\t\n\t\tLower bound\tHigher bound\t\t\nAge (older)\t1.03\t1.01\t1.05\tp = 0.01\t\nGender\t1.58\t0.80\t3.10\tp = 0.187\t\nEthnicity (African)\t3.69\t1.02\t13.12\tp = 0.04\t\nIntubation attempts\t1.31\t0.52\t3.30\tp = 0.56\t\nType of airway (ETT)\t0.93\t0.22\t3.96\tp = 0.92\t\nIntra-operative hypotension\t1.19\t0.60\t2.40\tp = 0.62\t\nNMBA use\t0.65\t0.20\t2.10\tp = 0.47\t\nAtropine use\t1.51\t0.68\t3.36\tp = 0.31\t\nRescue analgesia in PACU\t1.57\t0.79\t3.13\tp = 0.19\t\nSurgical status (Emergency)\t2.31\t1.13\t4.74\tp = 0.02\t\nSurgical duration (longer)\t1.04\t1.01\t1.07\tp = 0.02\t\nNMBA, neuromuscular blocking agents.\n\nThe demographic factors significantly associated with ED were age and ethnicity, while emergency surgical status and longer surgical duration were the clinical factors significantly associated with ED. All other factors including gender, the number of attempts at intubation, the type of airway used, presence of intra-operative hypotension and the need for analgesia in PACU were not significantly associated with ED as denoted by the logistic regression analyses.\n\nDiscussion\n\nThe incidence of ED in adult surgical patients after general anesthesia using sevoflurane as the volatile agent in a Caribbean tertiary care teaching hospital is significant and comparable to the previously published reports from other regions. Internationally published studies show a widely varying incidence of ED ranging from 3% to 20%.3, 4, 9, 10 This wide variation may be perhaps due to the fact that a precise definition and timeline for ED does not exist so far. In addition, there are also wide variations in the protocols to diagnose and measure ED, which may render a direct comparison difficult.15 The present study did find some factors to be attributable to ED. These factors are ethnicity, older age, emergency surgical status and the length of surgery.\n\nEthnicity has not been identified in the previous literature to have a significant association with the incidence of ED. In Trinidad and Tobago, people of African and Asian Indian descent comprise the majority of the population, each contributing to almost 45%, while Caucasians, Middle Easterners, Chinese and mixed races contribute to the rest. The enrolled patients in the present study clearly reflected the nation's demographic pattern, with equal proportions of patients belonging to the African and Indian ethnicities, followed by other ethnicities. However, African ethnic patients had higher odds ratio of developing ED (Table 6). This may be explained in part by the anatomical differences related to stature and size of the patients. African descent patients are usually phenotypically larger than their Indian ethnic counterparts and require larger LMAs, endotracheal tubes, nasogastric tubes, urinary catheters and higher doses of anesthetic drugs based on weight. Lepouse et al. has suggested that awakening from anesthesia with foreign devices in situ may be linked to ED.6 Furthermore, cultural differences may also be influential for the manifestation of ED, including varying perceptions and attitudes toward surgery, pain and strange environments.\n\nDespite their smaller numbers, emergency surgical patients had a higher incidence of ED compared to elective patients. This is in contrast to the finding of Lepouse et al. where emergency surgical status had no influence on the occurrence of ED.6 Elective operations afford patients enough time to become both mentally and physically prepared for surgery. Fears regarding the surgical procedure, postoperative pain and the recovery period can also be addressed. In an emergent situation, this luxury of time may not be available to the patient and the healthcare provider. Often, patients only learn of the need for surgery within a few hours (or a few days) of the procedure. Patients in the height of their anxiety, imagining over the prospect of surgery, may not fully comprehend all the information conveyed by the healthcare provider, thus predisposing them for more anxiety. In addition, emergency patients may also have physiological derangements which are seldom seen in elective situations. These may include (but not limited to) electrolyte and metabolic disturbances, decreased oxygen carrying capacity, altered gas exchange etc., which, due to the involvement of the central nervous system, may also be hypothetically attributable to the increased incidence of ED.\n\nAnother risk factor identified in this study for ED, is the longer duration of surgery. More than two hours of surgical duration was positively associated with the incidence of ED. This finding corroborates with the results of many other studies, who also reported that longer the surgery, higher the risk of ED.6, 16, 17 Longer surgical procedures may predispose patients to have foreign bodies (e.g., airways) in situ for a longer period of time, relatively more consumption of anesthetic drugs, larger fluid shifts, blood loss, electrolyte imbalance, hypothermia etc., which may be again attributable to the development of ED.\n\nAlmost two-thirds of patients in the present study had general anesthesia with an endotracheal tube placement, and in patients who had more than three attempts at intubation, the incidence of ED was 100%. This can be easily explained by the fact that multiple attempts do predispose for trauma resulting in upper airway edema. Notwithstanding this, in the present study, the number of attempts for endotracheal intubation was not significantly associated with ED, according the logistic regression analyses. When there are multiple attempts at intubation, most patients in our setting do receive dexamethasone invariably.\n\nSanders et al. reported that ED tends to affect younger individuals.17 Radtke et al. also found age to be a significant factor for ED, with younger patients (<40 years) and older patients (>64 years) having a higher incidence of ED compared to middle aged patients.16 In the present study, although the mean ages for patients with and without ED were comparable, the elderly age was significantly associated with ED (Table 4).\n\nThere have been conflicting reports on the influence of gender on ED. While Sanders et al. reported a higher predisposition in male patients, Lepouse et al. did not find a significant association.6, 17 The present study also did not find a significant association between gender and presence of ED.\n\nSanders et al. also suggested that ED was more common in otherwise healthy patients.17 Patients with co-morbidities and a higher ASA grade should therefore be at risk of developing ED. In fact, Lepouse et al. showed ASA grade to be influential on the incidence of ED.6 The present study did not find co-morbidities such as diabetes mellitus and hypertension as well as ASA grades to be impacting on ED, which is similar to the conclusion drawn by Radtke et al.16\n\nThe detrimental effects on alcohol and illicit drug use on the brain are well recognized. However, Radtke et al. found no significant association between alcohol abuse and ED.16 Similarly, the present study also did not find a significant influence of and illicit drug usage on the development of ED.\n\nIntra-operative hypotension may predispose a patient to cerebral hypoperfusion. However, the effect of intra-operative hypotension on ED is not well documented in the literature. Again, presence of intra-operative hypotension did not influence ED in the present study. It may be possible that the duration of intra-operative hypotension might have been the key factor, which was not specifically recorded in the present study.\n\nPrevious studies have suggested that the type of surgical procedure predisposes a patient to developing ED. Oral cavity and ENT procedures were identified by Yu et al. as being significantly associated with ED.5 Lepouse et al. identified higher incidence of ED in breast and abdominal surgery.6 Radtke et al. reported a higher incidence in patients undergoing musculoskeletal surgery, than those having oral, ENT or intra-abdominal procedures.16 In the present study, thoracic surgery patients had the highest incidence of ED, although there was no statistically significant difference between the specialties. This may be due to smaller number of patients in the individual specialties.\n\nThe use of nitrous oxide and Neuromuscular Blocking Agents (NMBA) were not significant factors in the occurrence of ED. These findings are very similar to Radtke et al., who also found no significant association between ED and nitrous oxide or NMBA use.16\n\nSeveral authors have reported anticholinergic drugs such as atropine to be deliriogenic,17, 18, 19 whereas the current study could not find any impact.\n\nThe dose of intra-operative morphine did not have an impact on the incidence of ED in the present study, similar to Radtke et al.16\n\nYu et al. identified the presence of a urinary catheter as being a risk factor for ED.5 Lepouse et al. also suggested that various catheters may startle patients on awakening from general anesthesia.6 The present study however, did not find a significant relationship of ED with the presence of catheters in the postoperative period.\n\nPain may be a confounding factor when assessing ED in the PACU.8 Inadequately treated postoperative pain has been well recognized to be associated with ED. In fact, Radtke et al., did report that postoperative pain was strongly associated with ED.16 Patients who had a pain score of 6–10 in the Numerical Rating Scale (NRS), were twice as likely to develop ED as those with a score of 0–5. Davis et al. demonstrated that when fentanyl was given to children IV or intra-nasally for moderately painful procedures, the incidence of ED reduced.20 The present study although did not specifically assess pain scores, it did not find a significant relationship between ED and the need for rescue analgesics in the PACU. Other authors have suggested that ED may still occur even when postoperative pain is adequately treated.21, 22, 23 In pediatric patients, even in the absence of postoperative pain ED may still be present, indicating that ED may be a clinical phenomenon separate from pain.7\n\nThere are some limitations to the present study. Many other factors such as premedication with benzodiazepines have been shown to be associated with the development of ED.24 Some studies have shown a beneficial effect of benzodiazepines in children.25 This was not included in our study since it is an observational study and premedication is seldom used in our setting.\n\nAlthough preoperative anxiety has been suggested as a risk factor for ED, this was not assessed in the present study. Other limitations include patient-introduced errors by providing false information during the history taking. For example, many patients deny illicit drug use due to the social stigma. Also, in the present study, the number of patients enrolled within individual specialty was small, which could have influenced the results. The ideal time frame for assessing ED is unknown.6 This study chose to assess ED when the patient has been declared ‘ready for discharge’ by the anesthesiologist; which is usually by 10 min after admission to the PACU. However, based on the patient's clinical condition, the type and nature of the surgery and the course of intra-operative events, the time interval between admission to the PACU and discharge may vary widely between patients. Therefore, some patients might have fallen out of the optimum window for ED detection. Another major limitation of the study is that we did not assess and record the postoperative pain scores of patients in PACU.\n\nNevertheless, in conclusion, the study could reasonably determine the incidence of Emergence Delirium in adults after sevoflurane general anesthesia in our setting which was around 12%. Elderly age, African ethnicity, emergency surgery, and longer duration of surgery were found to be significantly associated with the incidence of ED. It is therefore important for clinicians to recognize those patients who may be at risk of developing ED, and other modifiable factors, so that appropriate measures can be taken to reduce ED and thus patient morbidity and improve patient satisfaction.\n\nConflicts of interest\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n\n1 Fricchione G.L. Nejad S.H. Esses J.A. Postoperative delirium Am J Psychiatry 165 2008 803 812 18593786\n2 Burns A. Gallagley A. Byrne J. Delirium J Neurol Neurosurg Psychiatry 75 2004 362 367 14966146\n3 Scott G.M. Gold J.I. Emergence delirium: a re-emerging interest Sem Anesth Perioperat Pain Med 25 2006 100 104\n4 Silverstein J.H. Timberger M. Reich D.L. Central nervous system dysfunction after non-cardiac surgery and anesthesia in the elderly Anesthesiology 106 2007 622 628 17325520\n5 Yu D. Chai W. Sun X. Emergence agitation in adults: risk factors in 2000 patients Can J Anesth 57 2010 843 848 20526708\n6 Lepouse C. Lautner C.A. Liu L. Emergence delirium in adults in the post-anesthesia care unit Br J Anaesth 96 2006 747 753 16670111\n7 Duffen A. Williams A. Should sevoflurane be used for maintenance of anesthesia in children? Br J Hosp Med (Lond) 72 2011 598 22041739\n8 Vlajkovic G.P. Sindjelic R.P. Emergence delirium in children: many questions, few answers Anesth Analg 104 2007 84 91 17179249\n9 Hudek K. Emergence delirium: a nursing perspective AORN J 89 2009 509 516 19326585\n10 Sharma P.T. Sieber F.E. Zakriya K.J. Recovery room delirium predicts postoperative delirium after hip-fracture repair Anesth Analg 101 2005 1215 1220 16192548\n11 Rose D.K. Recovery room problems or problems in the PACU Can J Anesth 43 1996 116 128\n12 O’Brien D. Acute postoperative delirium: definitions, incidence, recognition and interventions J Perianesth Nurs 17 2002 384 392 12476404\n13 Williams M.A. Ward S.E. Campbell E.B. Confusion: testing versus observation J Gerentol Nurs 14 1988 25 30\n14 Radkte F.M. Franck M. Schneider M. Comparison of three scores to screen for delirium in the recovery room Br J Anaesth 101 2008 338 343 18603528\n15 Gooden R. Tennant I. James B. The incidence of emergence delirium and risk factors following sevoflurane use in pediatric patients for day case surgery, Kingston, Jamaica Rev Bras Anestesiol 64 2014 413 418 25437698\n16 Radtke F.M. Franck M. Hagemann L. Risk factors for inadequate emergence after anesthesia: emergence delirium and hypoactive delirium Miner Anestesiol 76 2010 394 403\n17 Sanders R.D. Pandharipande P.P. Davidson A.J. Anticipating and managing postoperative delirium and cognitive decline in adults BMJ 343 2011 d4331 21775401\n18 Parikh S.S. Chung F. Postoperative delirium in the elderly Anesth Analg 80 1995 1223 1232 7762856\n19 Fong H.K. Sands L.P. Leung J.M. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a systematic review Anesth Analg 102 2006 1255 1266 16551934\n20 Davis P.J. Greenberg J.A. Gendelman M. Recovery characteristics of sevoflurane and halothane in preschool-aged children undergoing bilateral myringotomy and pressure equalization tube insertion Anesth Analg 88 1999 34 38 9895062\n21 Weldon B.C. Bell M. Craddock T. The effect of caudal analgesia on emergence agitation in children after sevoflurane versus halothane anesthesia Anesth Analg 98 2004 321 326 14742362\n22 Cravero J. Surgernor S. Whalen K. Emergence agitation in paediatric patients after sevoflurane anesthesia and no surgery: a comparison with halothane Paediatr Anaesth 10 2000 419 424 10886700\n23 Uezono S. Goto T. Teruik K. Emergence agitation after sevoflurane versus propofol in pediatric patients Anesth Analg 91 2000 563 566 10960377\n24 Kudoh A. Takase H. Takahira Y. Postoperative confusion increases in the elderly long-term benzodiazepine users Anesth Analg 99 2004 1674 1678 15562052\n25 Cho E.J. Yoon S.Z. Cho J.E. Comparison of the effects of 0.03 and 0.05 mg/kg midazolam with placebo on prevention of emergence agitation in children having strabismus surgery Anesthesiology 120 2014 1354 1361 24566243\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": null,
"issue": "69(3)",
"journal": "Brazilian journal of anesthesiology (Elsevier)",
"keywords": "Adult patients; Cuidados pós‐anestésicos; Delirium do despertar; Emergence delirium; Pacientes adultos; Post‐anesthesia care; Sevoflurane; Sevoflurano",
"medline_ta": "Braz J Anesthesiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000768:Anesthesia, General; D018685:Anesthetics, Inhalation; D000071257:Emergence Delirium; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D061646:Operative Time; D011446:Prospective Studies; D012307:Risk Factors; D000077149:Sevoflurane; D055815:Young Adult",
"nlm_unique_id": "101624623",
"other_id": null,
"pages": "233-241",
"pmc": null,
"pmid": "31076155",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Emergence delirium following sevoflurane anesthesia in adults: prospective observational study.",
"title_normalized": "emergence delirium following sevoflurane anesthesia in adults prospective observational study"
} | [
{
"companynumb": "TT-ABBVIE-19P-159-2893608-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
},
"drugadditional": "3",
... |
{
"abstract": "Cutaneous infection with rapidly growing mycobacteria is uncommon and diagnosis may be difficult. However, the histopathological features are distinctive and may aid diagnosis. The three pathogenic species, Mycobacterium fortuitum, M. chelonae and M. abscessus, show major differences in their antimicrobial sensitivities, and species identification is therefore important. We describe a case of infection with M. abscessus, and discuss the clinical and pathological features of such infections, and approaches to their treatment.",
"affiliations": "Department of Dermatology, Staffordshire General Infirmary, U.K.",
"authors": "Fitzgerald|D A|DA|;Smith|A G|AG|;Lees|A|A|;Yee|L|L|;Cooper|N|N|;Harris|S C|SC|;Gibson|J A|JA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2133.1995.tb00730.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "132(5)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D017192:Skin Diseases, Bacterial",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "800-4",
"pmc": null,
"pmid": "7772489",
"pubdate": "1995-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous infection with Mycobacterium abscessus.",
"title_normalized": "cutaneous infection with mycobacterium abscessus"
} | [
{
"companynumb": "ES-JNJFOC-20190122179",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "The last 3 decades have seen a shift in the epidemiology of epiglottitis. Epiglottitis was once most commonly associated with Haemophilus influenzae type B. However, with the implementation of the H. influenzae type B vaccine in 1985, the incidence has drastically declined. There are now new emerging pathogens-bacteria, viruses, and fungi-causing epiglottitis. Here, we report the first case of epiglottitis secondary to influenza A in a former full-term, vaccinated infant who presented with cough, fever, stridor, pursed lip breathing, and progressive respiratory distress and eventual respiratory failure. This case highlights the presentation and clinical course of epiglottitis and describes a rare clinical feature, pursed lip breathing, in an infant.",
"affiliations": "From the Department of Pediatrics, Texas Children's Hospital.;From the Department of Pediatrics, Texas Children's Hospital.;From the Department of Pediatrics, Texas Children's Hospital.;From the Department of Pediatrics, Texas Children's Hospital.",
"authors": "OʼBryant|Shelease C|SC|;Lewis|Jonathan D|JD|;Cruz|Andrea T|AT|;Mothner|Brent A|BA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001589",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "35(11)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000402:Airway Obstruction; D003937:Diagnosis, Differential; D004826:Epiglottitis; D005260:Female; D006801:Humans; D007223:Infant; D009980:Influenza A virus; D007251:Influenza, Human; D012131:Respiratory Insufficiency",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e213-e216",
"pmc": null,
"pmid": "30247455",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Influenza A-Associated Epiglottitis and Compensatory Pursed Lip Breathing in an Infant.",
"title_normalized": "influenza a associated epiglottitis and compensatory pursed lip breathing in an infant"
} | [
{
"companynumb": "NVSC2020US093889",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Dabigatran is a direct thrombin inhibitor used as an alternative to warfarin for long term anticoagulation. Warfarin-related nephropathy is an increasingly recognized entity, but recent evidence suggests that dabigatran can cause a WRN-like syndrome. We describe a case of a biopsy-proven anticoagulant nephropathy related to dabigatran in a patient with IgA nephropathy and propose that, despite the base glomerular disease, acute kidney injury was due to tubular obstruction by red blood cells and heme-associated tubular injury, and through a mechanism involving inhibition of anticoagulation cascade and barrier abnormalities caused by molecular mechanisms.",
"affiliations": "Department of Nephrology, Centro Hospitalar do Médio Tejo, 2350-754 Torres Novas, Portugal.;Department of Nephrology, Centro Hospitalar do Médio Tejo, 2350-754 Torres Novas, Portugal.;Department of Nephrology, Centro Hospitalar do Médio Tejo, 2350-754 Torres Novas, Portugal.;Department of Nephrology, Centro Hospitalar de Lisboa Central, Hospital Curry Cabral, 1069-166 Lisbon, Portugal.",
"authors": "Escoli|Rachele|R|;Santos|Paulo|P|;Andrade|Sequeira|S|;Carvalho|Fernanda|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/298261",
"fulltext": "\n==== Front\nCase Rep NephrolCase Rep NephrolCRINCase Reports in Nephrology2090-66412090-665XHindawi Publishing Corporation 10.1155/2015/298261Case ReportDabigatran-Related Nephropathy in a Patient with Undiagnosed IgA Nephropathy Escoli Rachele \n1\n\n*\nSantos Paulo \n1\nAndrade Sequeira \n1\nCarvalho Fernanda \n2\n1Department of Nephrology, Centro Hospitalar do Médio Tejo, 2350-754 Torres Novas, Portugal2Department of Nephrology, Centro Hospitalar de Lisboa Central, Hospital Curry Cabral, 1069-166 Lisbon, Portugal*Rachele Escoli: rachele_escoli@hotmail.comAcademic Editor: Yoshihide Fujigaki\n\n2015 5 8 2015 2015 29826125 5 2015 30 6 2015 14 7 2015 Copyright © 2015 Rachele Escoli et al.2015This 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.Dabigatran is a direct thrombin inhibitor used as an alternative to warfarin for long term anticoagulation. Warfarin-related nephropathy is an increasingly recognized entity, but recent evidence\nsuggests that dabigatran can cause a WRN-like syndrome. We describe a case of a biopsy-proven anticoagulant nephropathy related to dabigatran in a patient with IgA nephropathy and propose that,\ndespite the base glomerular disease, acute kidney injury was due to tubular obstruction by red blood cells and heme-associated tubular injury, and through a mechanism involving inhibition of anticoagulation\ncascade and barrier abnormalities caused by molecular mechanisms.\n==== Body\n1. Introduction\nAnticoagulant therapy plays a central role in the prevention and treatment of venous and arterial thromboembolic diseases. Recently, several oral anticoagulants were approved, including the direct thrombin inhibitors such as dabigatran. It has a quick onset of action, results in a predictable anticoagulation response, and does not require routine laboratory monitoring. However, concerns have been raised since there is no antidote for treatment of secondary hemorrhages. We report a case of a 69-year-old woman with a biopsy-proven anticoagulant nephropathy related to dabigatran and discuss the diagnostic and management approach.\n\n2. Case Presentation\nA 69-year-old white female with a past history of hypertension presented with nausea, vomiting, and oliguria. The patient had been in her usual state of health until 2 weeks earlier, when she developed palpitations that prompted her to seek medical care. New-onset atrial fibrillation was diagnosed. After reversing into sinus rhythm with amiodarone, she was discharged with a prescription of dabigatran 110 mg twice daily (Pradaxa Boehringer). At this time serum creatinine was 1,5 mg/dL (corresponding to an estimated glomerular filtration rate [eGFR] of 35,2 mL/min/1,73 m2 as calculated by the CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equation). Two weeks later she started vomiting and having oliguria and was sent to our medical facilities. She denied additional complaints and was on dabigatran 100 mg twice a day during the previous two weeks.\n\nThe patient's medical history included arterial hypertension medicated with ramipril. On admission blood pressure was 212/98 mmHg, pulse rate was 98 heart beats per minute, and she was oliguric. The physical examination revealed hydrated mucosa with no respiratory distress, crackles in bilateral lung fields, and mild lower-extremity edema. Laboratory results showed the following: serum urea was 230 mg/dL, serum creatinine was 8 mg/dL, hemoglobin was 9.1 g/dL, white blood cell count was 14.7 × 103/μL with 86% of PMN and 0.2% of eosinophils, platelet count was 369 × 103/μL, prothrombin time (PT) was 25.3 seconds with international normalized ratio (INR) of 2.3, activated partial thromboplastin time (aPTT) was 68 seconds, LDH was 531 IU/L, and C-reactive protein was 7.1 mg/dL. A random urine specimen revealed that leukocytes were 500/μL, proteins were 100 mg/dL, and hemoglobin was 1 mg/dL. Urine sediment had hematuria (>100 red blood cells (RBC)/high-power field) and leukocyturia (6 leukocytes/high-power field) without dysmorphic red blood cells or red blood casts. Renal ultrasound suggested globular kidneys with regular shape but hyperechogenic cortical parenchyma without hydronephrosis. The patient was then transferred to the Nephrology Department. Due to oliguric acute renal failure she started hemodialysis two days after being admitted and proceeding with investigation. A peripheral blood smear did not show schizocytes. C3 complement level was decreased (52 mg/dL). C4 and antistreptolysin were normal. Screening for antinuclear antibody, antineutrophil cytoplasmic antibody, anti-glomerular basement membrane antibody, cryoglobulins, and antiphospholipid antibody and VDRL test were negative. After an inconclusive Doppler renal ultrasound, a contrast enhanced computed tomography angiography was performed four days after admission and showed no abnormalities. A transthoracic echocardiogram was done and illustrated normal sized left chambers without intracardiac thrombus. After 3 sessions of hemodialysis a normal aPTT was accomplished and due to persistent oliguria a biopsy was performed.\n\nFive glomeruli appeared normal. The tubulointerstitium had large intratubular RBC casts, extensive tubular necrosis, and interstitial hemorrhage (Figures 1 and 2). By immunofluorescence there were mesangial deposits of IgA (++), C3 (++), K, and λ chains on 3 glomeruli (Figure 3).\n\nSo the diagnosis of IgA nephropathy, anticoagulant nephropathy with acute tubular necrosis, and interstitial hemorrhage was made. Following the kidney biopsy there were perirenal haematoma and hypotension. Three units of RBC were provided and resolution was achieved under tight follow-up. After intravenous fluid reposition she restored diuresis (hematuria). Two weeks later, renal function improved, urine cleared, and patient was discharged. Creatinine was 1.9 mg/dL in the last clinical evaluation.\n\n3. Discussion\nAnticoagulant-related nephropathy (ARN) is a form of acute kidney injury caused by excessive anticoagulation first described with warfarin, and because of that it is called warfarin-related nephropathy (WRN) [1]. Diagnosis should be suspected among patients who present with unexplained acute renal injury defined as a serum creatinine increase greater than 0.3 mg/dL within one week of an INR measurement greater than 3 in a patient treated with warfarin, excluding other causes of AKI and bleeding [1, 2]. Recent evidence suggests that WRN-like syndromes are not confined to anticoagulation with warfarin but may occur with other anticoagulants, such as acenocoumarol [3] and dabigatran [2].\n\nIn WRN AKI occurs through glomerular hematuria with subsequent widespread tubular obstruction [4]. Biopsy studies showed RBCs in tubules and occlusive RBCs casts predominantly in distal nephron segments [4, 5]. Several pathogenic mechanisms were proposed. The combination of even mild glomerular disease and warfarin-induced coagulopathy seems to be the key point [4]. This leads to glomerular hematuria and to a significant accumulation of RBCs within nephrons that form occlusive casts, especially when urinary flow is diminished [4, 6]. Although glomerular hematuria is essential, it seems that interstitial hemorrhage may also have an important role [3]. So the dominant mechanism of AKI in WRN is probably tubular obstruction by RBC casts, which, associated with interstitial hemorrhage, leads to increased oxidative stress in the kidney [7, 8].\n\nThere are many underlying risk factors for WRN, such as age, CKD, due to higher risk of supratherapeutic INR, diabetes and diabetic nephropathy, hypertension, and heart failure [5].\n\nDabigatran is an anticoagulant used for stroke prevention in atrial fibrillation [9]. Recent evidence suggests that dabigatran has many hemorrhagic complications. However, in what concerns kidney involvement, information is scarce [10]. Dabigatran has 80% renal elimination and is not recommended for patients with creatinine clearance less than 15 mL/min or on dialysis, needing a dose adjustment in patients with creatinine clearance between 15 and 30 mL/min, in order to reduce hemorrhagic complications [11].\n\nEvidence from animal studies revealed that dabigatran may cause AKI by two major pathogenic mechanisms: first, tubular obstruction by RBCs and, second, a mechanism possibly involving protease-activated receptor 1 (PAR-1) [1]. PAR-1 is a G protein-coupled receptor that participates in the regulation of the endothelial functions, vascular permeability, leukocyte migration, and adhesion and is the major effector of thrombin signaling [3]. Either vitamin K antagonists or direct thrombin inhibitors decrease thrombin activity. By acting on thrombomodulin, thrombin activates protein C and modulates the anticoagulation cascade. The same happens with PAR-1. In the aforementioned study the authors proposed that thrombin plays an important role in the glomerular filtration barrier function, and its decreased activity (secondary to anticoagulation) results in glomerular filtration barrier abnormalities. Indeed, treatment with selective PAR-1 inhibitor results in increased creatinine, hematuria, and tubular RBC casts, findings similar to those in animals with WRN or treated with dabigatran. These effects are similar to WRN. However in contrast to WRN, where kidney injury was seen only in animals with CKD, the effects of dabigatran were prominent in control rats as well. These findings suggest that the kidney risk with dabigatran may be greater than that of warfarin [3].\n\nTo the best of our knowledge, only two cases of dabigatran-induced AKI have been reported [12, 13]. In both cases patients presented with hematuria and had histologic evidence of hemorrhage into renal tubules. In the Moeckel et al. clinical report the patient had previously mild undiagnosed IgA nephropathy [13], as presented in our case. This raises the question if IgA nephropathy is a risk factor or a predisposing condition in anticoagulated patients with dabigatran as was described in WRN. The main clinical feature of IgA nephropathy is hematuria, which can be micro- or macroscopic, both unnoticed by our patient, and it is plausible to think that an entity, which, by nature, already predisposes hematuria, may be related or may be a risk factor to ARN. Fundamental WRN pathological lesions as described above were also observed in our patient, which suggests that the physiopathological mechanisms that induce AKI may have a common way, particularly with regard to tubular obstruction and interstitial hemorrhage. In our patient's case we propose that the combination of IgA nephropathy which associated with the age, CKD, and the medical history of hypertension possibly leads to the perfect background.\n\nConcerning treatment, restoring the aPTT into a therapeutic range while doing supportive renal treatment is primordial [1]. In what concerns dabigatran-related AKI hemodialysis seems to be effective [9, 13, 14]. About the prognosis, there seem to be discrepancies between WRN and dabigatran-related AKI. The clinical outcome in a WRN study was unfavorable: 66% of patients did not recover baseline function [4]. With regard to the two reported cases of dabigatran-induced AKI, in both renal function improved [12, 13]. In our case, there seems to be a recovery of renal function and we think that the absence of histological markers of poor prognosis of IgA nephropathy, such as the lack of interstitial fibrosis, tubular atrophy, glomerular sclerosis, or endocapillary hypercellularity, may possibly have contributed to this good outcome. The short period of administration and the lower dose of dabigatran may also have had influence. However, since there are so few published cases of dabigatran-related nephropathy, it is impossible to compare outcomes of these two entities.\n\nThis raises the note of caution about oral anticoagulation in patients with kidney disease. They are at a higher risk of overanticoagulation, gross hematuria, and AKI [15]. So physicians involved in the clinical management of anticoagulated patients should be aware of the ARN, either by warfarin or other anticoagulants like dabigatran. A correct coagulation and kidney function monitoring is required and, if needed, anticoagulants should be stopped or decreased [15].\n\nConsent\nThe patient described in the case report had given informed consent for the case report to be published.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Prominent interstitial hemorrhage and intratubular casts (haematoxylin/eosin staining, magnification 100x).\n\nFigure 2 Interstitial hemorrhage (Masson's trichrome, magnification 100x).\n\nFigure 3 Direct immunofluorescence showing granular mesangial staining for IgA in the expanded mesangium of the biopsy, magnification 400x.\n==== Refs\n1 Ryan M. Ware K. Qamri Z. Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats Nephrology Dialysis Transplantation 2014 29 12 2228 2234 \n2 Rizk D. V. Warnock D. G. Warfarin-related nephropathy: another newly recognized complication of an old drug Kidney International 2011 80 2 131 133 10.1038/ki.2011.85 2-s2.0-79959803366 21720303 \n3 Cleary C. M. Moreno J. A. Fernández B. Glomerular haematuria, renal interstitial haemorrhage and acute kidney injury Nephrology Dialysis Transplantation 2010 25 12 4103 4106 10.1093/ndt/gfq493 2-s2.0-78649507722 \n4 Brodsky S. V. Satoskar A. Chen J. Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases The American Journal of Kidney Diseases 2009 54 6 1121 1126 10.1053/j.ajkd.2009.04.024 2-s2.0-70449658993 19577348 \n5 Brodsky S. V. Nadasdy T. Rovin B. H. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate Kidney International 2011 80 2 181 189 10.1038/ki.2011.44 2-s2.0-79959774679 21389969 \n6 Wheeler D. Rangaswami J. Anticoagulation-Related Nephropathy: The Clot Thickens 2014 http://www.acc.org/ \n7 Ware K. Qamri Z. Ozcan A. N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy The American Journal of Physiology—Renal Physiology 2013 304 12 F1421 F1427 10.1152/ajprenal.00689.2012 2-s2.0-84879169619 23576637 \n8 Tracz M. J. Alam J. Nath K. A. Physiology and pathophysiology of heme: implications for kidney disease Journal of the American Society of Nephrology 2007 18 2 414 420 10.1681/asn.2006080894 2-s2.0-33846664696 17229906 \n9 Majeed A. Hwang H.-G. Connolly S. J. Management and outcomes of major bleeding during treatment with dabigatran or warfarin Circulation 2013 128 21 2325 2332 10.1161/circulationaha.113.002332 2-s2.0-84888197736 24081972 \n10 Hankey G. J. Eikelboom J. W. Dabigatran etexilate: a new oral thrombin inhibitor Circulation 2011 123 13 1436 1450 10.1161/circulationaha.110.004424 2-s2.0-79954456496 21464059 \n11 Hijazi Z. Hohnloser S. H. Oldgren J. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (randomized evaluation of long-term anticoagulation therapy) trial analysis Circulation 2014 129 9 961 970 10.1161/circulationaha.113.003628 2-s2.0-84895546812 24323795 \n12 Kadiyala D. Brewster U. C. Moeckel G. W. Dabigatran induced acute kidney injury Proceedings of the American Society of Nephrology Annual Meeting 2012 \n13 Moeckel G. W. Luciano R. L. Brewster U. C. Warfarin-related nephropathy in a patient with mild IgA nephropathy on dabigatran and aspirin Clinical Kidney Journal 2013 6 5 507 509 10.1093/ckj/sft076 2-s2.0-84885039749 26120444 \n14 Knauf F. Chaknos C. M. Berns J. S. Perazella M. A. Dabigatran and kidney disease: a bad combination Clinical Journal of the American Society of Nephrology 2013 8 9 1591 1597 10.2215/cjn.01260213 2-s2.0-84883737026 23868901 \n15 Santos C. Gomes A. M. Ventura A. Almeida C. Seabra J. An unusual cause of glomerular hematuria and acute kidney injury in a chronic kidney disease patient during warfarin therapy Nefrologia 2013 33 3 400 403 10.3265/nefrologia.pre2012.oct.11617 2-s2.0-84878027819 23712226\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-665X",
"issue": "2015()",
"journal": "Case reports in nephrology",
"keywords": null,
"medline_ta": "Case Rep Nephrol",
"mesh_terms": null,
"nlm_unique_id": "101598418",
"other_id": null,
"pages": "298261",
"pmc": null,
"pmid": "26347498",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "21464059;24081972;21389969;19577348;26120444;24009280;17229906;23712226;21720303;23868901;23576637;20709744;24323795",
"title": "Dabigatran-Related Nephropathy in a Patient with Undiagnosed IgA Nephropathy.",
"title_normalized": "dabigatran related nephropathy in a patient with undiagnosed iga nephropathy"
} | [
{
"companynumb": "PT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-50207BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Long-term evolution of HIV because of noncompliance and nonadherence to antiretroviral therapy favors the occurrence of difficult to treat HIV-related malignancies. We present the case of a female patient in “the pediatric cohort” registered at the Iaşi Regional HIV/AIDS Center since year 2000, now with stage C3 AIDS. In 2014, a Burkitt lymphoma was pathologically confirmed, and chemotherapy was initiated as recommended by the hematologist. The clinical course was characterized by multiple complications: hematologic and hepatic toxicities, opportunistic infections and depressive episodes. Highly active antiretroviral therapy associated with sustained psychological support resulted in stabilization of the patient's clinical course (lower HIV viral load and higher CD4 lymphocyte cell counts), anticancer therapy being better tolerated. Currently, patient’s clinical-biological status is quasi-normal. The depressive episodes in this HIV-positive cancer patient undergoing chemotherapy contributed to her non-adherence and non-compliance to treatment, with serious consequences both on clinical and viroimmunological status. Therapeutic strategy in this patient with AIDS and Burkitt lymphoma raised management difficulties as both the drug interactions and cumulative adverse effects had to be considered. Multidisciplinary collaboration and especially psychological intervention are essential for creating a functional team, effective communication being key to achieving long-term adherence to treatment and diagnosis acceptance.",
"affiliations": null,
"authors": "Manciuc|Carmen|C|;Adavidoaiei|Anca Maria|AM|;Afrăsânie|V A|VA|;Largu|Alexandra Maria|AM|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0048-7848",
"issue": "120(4)",
"journal": "Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi",
"keywords": null,
"medline_ta": "Rev Med Chir Soc Med Nat Iasi",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D023241:Antiretroviral Therapy, Highly Active; D018450:Disease Progression; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D010349:Patient Compliance; D011613:Psychotherapy; D016896:Treatment Outcome",
"nlm_unique_id": "0413735",
"other_id": null,
"pages": "915-9",
"pmc": null,
"pmid": "30141875",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Importance of Psychological Intervention in the Management of a Patient With Non-Hodgkin Lymphoma and Stage C3 AIDS Disease.",
"title_normalized": "importance of psychological intervention in the management of a patient with non hodgkin lymphoma and stage c3 aids disease"
} | [
{
"companynumb": "RO-JNJFOC-20181039317",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Pneumocystis jiroveci associated pneumonia (PCP) is one of the most important opportunistic conditions affecting immunocompromised patients, especially those with rheumatic diseases, often associated with lymphopenia and high serum LDH levels. The risk of PCP correlates with immunomodulators' dosage given to control patient's underlying disease. We present a case of a PCP involving a non-lymphopenic patient with psoriatic arthritis treated with low dose of methotrexate.",
"affiliations": "Internal Medicine Department, Coimbra University Hospital, Portugal.;Rheumatology Department, Hospital Universitario 12 de Octubre Madrid, Spain.",
"authors": "Lourenço|Jorge|J|;Carreira|Patricia|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101289",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30503-7\n10.1016/j.rmcr.2020.101289\n101289\nCase Report\nNon-lymphopenic pneumocystis pneumonia in low-dose methotrexate therapy: An exception to every rule\nLourenço Jorge MDjorge.v.lourenco@gmail.coma∗ Carreira Patricia MD PhDb a Internal Medicine Department, Coimbra University Hospital, Portugal\nb Rheumatology Department, Hospital Universitario 12 de Octubre Madrid, Spain\n∗ Corresponding author. jorge.v.lourenco@gmail.com\n11 11 2020 \n2020 \n11 11 2020 \n31 1012897 9 2020 4 11 2020 4 11 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pneumocystis jiroveci associated pneumonia (PCP) is one of the most important opportunistic conditions affecting immunocompromised patients, especially those with rheumatic diseases, often associated with lymphopenia and high serum LDH levels. The risk of PCP correlates with immunomodulators' dosage given to control patient's underlying disease.\n\nWe present a case of a PCP involving a non-lymphopenic patient with psoriatic arthritis treated with low dose of methotrexate.\n\nKeywords\nPneumocystisPneumoniaPsoriatic arthritisLymphopenia\n==== Body\n1 Introduction\nPneumocystis jirovecii, formally P. carinii, is an opportunistic fungus associated with severe acute and subacute infections, mostly pneumonia (PCP) affecting immunocompromised and, in rare cases, immunocompetent patients [1,2]. It can also be detected in the respiratory tract of healthy individuals, considered transiently natural reservoirs [3].\n\nThe nonspecific clinical features of PCP are challenging for early diagnosis, which could partly explain its high mortality rate [3]. Up to 15% of patients could have significant respiratory symptoms with a normal thoracic x-ray [4]. Since P.jirovecii cannot be cultured, PCP is definitely diagnosed through detection of cysts and/or trophozoites by colorimetric or immunofluorescent stains or even polymerase chain reaction (PCR) assays [3]. The serum levels of (1–3)- β-D-Glucan (BG) - a common cell wall constituent of most pathogenic fungi - is often used to confirm invasive fungal diseases (IFDs) and can differentiate pneumocystis colonization from PCP, when there are suitable clinical and radiological findings as well as positive staining or PCR [5].\n\nIn immunocompromised patients the incubation time has not been clearly defined. When it comes to rheumatic diseases, some authors estimate that previously colonized patients could develop PCP at least 4 weeks after the beginning of immunosuppressive therapy [6].\n\nIt is thought that pathogenic role of Pneumocystis stems from strains’ reactivation (old exposure) or rapid proliferation (recent exposure) [6].\n\n2 Case report\nA 55-year old woman, previous smoker, with a 3-year history of remitted ACPA positive psoriatic arthritis (dactylitis of left foot's fifth finger and oligoarthritis of carpeal and metacarpophalangeal joints). Disease remission was achieved with methotrexate (MTX), whose dose was progressively reduced to 15mg/week. About 4 months later she went to see her rheumatologist for a routine consultation when she described a 2-week history of exertional dyspnoea, non-productive cough and high-grade fever (mainly 39 °C). At that time, she had normal blood tests run by her general practitioner. She denied rhinorrea, headache or odynophagia. There was no prior history of recent corticosteroids use, recurrent respiratory infections, sexual risk behaviour, recent travel or interaction with farm animals or pets. During consultation she was normotensive, febrile (37.8 °C) with shortness of breath easily noticed and persistent cough without intercostal retraction or abnormal auscultatory findings. Hypoxaemia was confirmed with arterial blood gas. No lymphadenopathies nor abnormal cutaneous signs were found. The patient was admitted for diagnostic investigation.\n\nDuring admission, the patient presented a normal thoracic x-ray (Fig. 1A) and underwent a thoracic CT (Fig. 1B) which showed discrete upper lobe centrilobular ground-glass pattern with no pulmonary consolidation. Her blood analysis showed both normal serum leukocyte and lymphocyte counts (6500/μL and 1200/μL, respectively), high serum CRP levels (7.15mg/dl) as well as LDH levels of 360U/L.Fig. 1 (A) Patient's thoracic x-ray and CT scan (B) showing upper lobe centrilobular ground-glass pattern (arrows).\n\nFig. 1\n\nA serologic test for HIV infection was performed which came negative. Her blood cultures and direct microscopic examination of sputum came sterile, as well as negative serologic tests for Haemophilus influenzae, Chlamydia pneumoniae and Mycoplasma pneumoniae; the nasopharyngeal swab was negative for virus. Finally, a bronchoalveolar lavage (BAL) was performed and Grocott's methenamine silver (GMS) staining revealed a small amount of the cystic form of P. jiroveci along with positive PCR and elevated serum levels of BG (249 U/mL), which supported the diagnosis of PCP. The patient began standard dose of sulfamethoxazole-trimetoprim and later on discharged. About 2 weeks later she showed significant clinical improvements with normal blood tests, including low serum BG levels.\n\n3 Discussion\nMethotrexate (MTX) is a conventional disease modifying antirheumatic drug (DMARD) which represents one of the earliest therapeutic cornerstones in rheumatic diseases. Its anti-inflammatory and immunosuppressive actions include inhibition of immune cells’ activation and proliferation (particularly T-cell lymphocytes) as well as decreased production of inflammatory cytokines (mainly IL-1 and IL-6) and cell adhesion molecules [7].\n\nMost cases MTX-induced PCP have been associated with lymphopenia. Kane et al. were one of the first to propose low CD4+ lymphocyte counts in patients receiving MTX therapy as another risk factor for PCP in HIV-negative patients. They also suggested that if cumulative MTX dosage were superior to 400mg it could predict the risk of infection [8], which was eventually seen in some published reports [9,10]. More recently, Akiyama et al. compared incidence of PCP in patients with rheumatoid arthritis treated with conventional DMARDs versus those treated with biologic therapy and found no consistent correlation between peripheral serum lymphocyte count and serum BG levels [11]. Our patient reports something similar. In fact, although she had a cumulative dosage of MTX that exceeded 400mg, she didn't have lymphopenia at the time of admission and still presented high serum BG levels during diagnostic workup, which reassured the diagnosis of PCP. We could speculate that she eventually had some transient lymphopenia in the 2-month period between her last blood test and the onset of her respiratory symptoms, but we can't also neglect the other immunomodulatory properties of MTX therapy, which aren't fully clarified.\n\nOn the other hand, there is recent intriguing data related to P. jirovecii genotype sequencing which leaves some important questions unanswered, for instance which strains are prone to colonize and which ones would most certain promote infection [12]. This is to our knowledge the first report of a non-lymphopenic PCP in a patient treated with low dose of methotrexate.\n\nDisclosure of potential conflicts of interest\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Thomas C.F. Jr. Limper A.H. Pneumocystis pneumonia N. Engl. J. Med. 350 2004 2487 2498 15190141 \n2 Koshy G. Koshy J.M. John M. Deodhar D. Pneumocystis jirovecii pneumonia in an immunocompetent host Ann. Trop. Med. Publ. Health 8 4 2015 122 \n3 Alanio A. Bretagne S. Pneumocystis jirovecii detection in asymptomatic patients: what does its natural history tell us? F100Res 6 2017 739 \n4 Opravil M. Marincek B. Fuchs W.A. Shortcomings of chest radiography in detecting Pneumocystis carinii pneumonia J. Acquir. Immune Defic. Syndr. 7 1 1994 39 45 8263751 \n5 Kovacs J.A. Masur H. Evolving health effects of Pneumocystis: one hundred years of progress in diagnosis and treatment J. Am. Med. Assoc. 301 2009 2578 2857 \n6 Mori S. Cho I. Sugimoto M. A follow-up study of asymptomatic carriers of Pneumocystis jiroveci during immunosuppressive therapy for rheumatoid arthritis J. Rheumatol. 36 8 2009 1600 1605 10.3899/jrheum.081270 19531759 \n7 Cutolo M. Sulli A. Pizzorni C. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis Ann. Rheum. Dis. 60 2001 729 735 11454634 \n8 Kane G.C. Pneumocystis carinii pneumonia associated with weekly methotrexate: cumulative dose of methotrexate and low CD4 cell count may predict this complication Respir. Med. 87 1993 153 155 8497686 \n9 Tokuda H. Sakai F. Yamada H. Clinical and radiological features of Pneumocystis pneumonia in patients with rheumatoid arthritis, in comparison with methotrexate pneumonitis and Pneumocystis pneumonia in acquired immunodeficiency syndrome: a multicentre study Intern Med 47 2008 915 923 18480575 \n10 Mori S. Cho I. Ichiyasu H. Asymptomatic carriage of Pneumocystis jiroveci in elderly patients with rheumatoid arthritis in Japan: a possible association between colonization and development of Pneumocystis jiroveci pneumonia during low-dose MTX therapy Mod. Rheumatol. 18 2008 240 246 18306977 \n11 Akiyama M. Kaneko Y. Takeuchi T. Comparison of the clinical characteristics of pneumocystis pneumonia between patients with rheumatoid arthritis being treated with biologics and those being treated without biologics BioMed Res. Int. 2017 2017 3710652 28785579 \n12 Depypere M. Saegeman V. Lagrou K. Typing of Pneumocystis jirovecii by multilocus sequencing: evidence of outbreak? Eur. J. Clin. Microbiol. Infect. Dis. 35 6 2016 911 916 10.1007/s10096-016-2615 27038443\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "31()",
"journal": "Respiratory medicine case reports",
"keywords": "Lymphopenia; Pneumocystis; Pneumonia; Psoriatic arthritis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101289",
"pmc": null,
"pmid": "33251106",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "18480575;27038443;8263751;28785579;11454634;28649366;19531759;8497686;19549975;15190141;18306977",
"title": "Non-lymphopenic pneumocystis pneumonia in low-dose methotrexate therapy: An exception to every rule.",
"title_normalized": "non lymphopenic pneumocystis pneumonia in low dose methotrexate therapy an exception to every rule"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-271573",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "To assess long-term efficacy and tolerability of lacosamide (LCM) as adjunctive treatment through a retrospective study in children and adolescents with refractory epilepsies.\n\n\n\nAll patients consecutively treated with LCM as add-on for refractory focal and generalized epilepsy and followed at the Neuroscience Center of Excellence of the Meyer Children's Hospital of Florence between January 2011 and September 2015 were included in the study. Responder rate, relapse-free survival, and retention rate were calculated. Tolerability was assessed by reporting adverse events.\n\n\n\nA total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add-on LCM treatment for refractory epilepsy. Thirty-four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure-free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow-up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add-on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11).\n\n\n\nThis study documents a real-world progressive and significant loss of LCM efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of LCM efficacy over time.",
"affiliations": "Neuroscience Center of Excellence, Meyer Children's Hospital, University of Florence, Florence, Italy.;Neuroscience Center of Excellence, Meyer Children's Hospital, University of Florence, Florence, Italy.;Neuroscience Center of Excellence, Meyer Children's Hospital, University of Florence, Florence, Italy.;Neuroscience Center of Excellence, Meyer Children's Hospital, University of Florence, Florence, Italy.;Pediatric Ethics Committee, Meyer Children's Hospital, Florence, Italy.;Clinical Trial Office, Meyer Children's Hospital, Florence, Italy.;Clinical Trial Office, Meyer Children's Hospital, Florence, Italy.;Neuroscience Center of Excellence, Meyer Children's Hospital, University of Florence, Florence, Italy.",
"authors": "Rosati|Anna|A|0000-0002-8754-7214;Ilvento|Lucrezia|L|;Rizzi|Riccardo|R|;Doccini|Viola|V|;Leo|Maria Carmela|MC|;Pugi|Alessandra|A|;De Masi|Salvatore|S|;Guerrini|Renzo|R|",
"chemical_list": "D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.14071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "59(5)",
"journal": "Epilepsia",
"keywords": "children; efficacy; lacosamide; refractory epilepsy",
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D000078334:Lacosamide; D008297:Male; D000077982:Progression-Free Survival; D012189:Retrospective Studies",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1004-1010",
"pmc": null,
"pmid": "29663335",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Long-term efficacy of add-on lacosamide treatment in children and adolescents with refractory epilepsies: A single-center observational study.",
"title_normalized": "long term efficacy of add on lacosamide treatment in children and adolescents with refractory epilepsies a single center observational study"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1031837",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTreatment of tacrolimus toxicity includes holding tacrolimus and supportive care. The objective is to describe considerations for pharmacologic induction of tacrolimus metabolism.\n\n\nMETHODS\nA 52-year-old male with a failed renal transplant on chronic haemodialysis developed tacrolimus toxicity due to a drug-drug interaction with darunavir/ritonavir. Tacrolimus concentrations were >60 ng/mL for 10 days despite holding tacrolimus and darunavir/ritonavir. Development of encephalopathy prompted initiation of phenytoin to induce tacrolimus metabolism. Tacrolimus concentration was <2 ng/mL within 4 days and mental status normalized.\n\n\nCONCLUSIONS\nPhenytoin metabolic induction is a therapeutic option for prolonged tacrolimus toxicity.",
"affiliations": "Erie County Medical Center, Buffalo, New York.;University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York.;University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York.;Erie County Medical Center, Buffalo, New York.;Erie County Medical Center, Buffalo, New York.",
"authors": "Meaney|Calvin J|CJ|https://orcid.org/0000-0003-2213-693X;O'Connor|Megan|M|;McGowan|Melissa|M|;Hamid|Mohammed|M|;Su|Winnie|W|",
"chemical_list": "D007166:Immunosuppressive Agents; D010672:Phenytoin; D019438:Ritonavir; D016559:Tacrolimus; D000069454:Darunavir",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12829",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "44(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "haemodialysis; phenytoin; tacrolimus; toxicity",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000069454:Darunavir; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D010672:Phenytoin; D006435:Renal Dialysis; D019438:Ritonavir; D016559:Tacrolimus",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "640-643",
"pmc": null,
"pmid": "30830975",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient.",
"title_normalized": "treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient"
} | [
{
"companynumb": "US-TEVA-2019-US-1090571",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL"
},
"drugad... |
{
"abstract": "A 60-year-old female was diagnosed with progressive systemic sclerosis and interstitial lung disease of two months' duration. The patient was treated for Raynaud phenomenon with aspirin, nifedipine, colchicine, and naproxen. Two weeks after treatment, she developed widespread erythematous patches with blistering eruptions on the face, torso, and extremities, and also had erosion on the oral mucosa. Skin biopsy for histopathology and direct immunofluorescent studies were suggestive of lupus erythematosus. To the best of our knowledge, this is the first case of toxic epidermal necrolysis-like acute cutaneous lupus erythematosus in a patient with progressive systemic sclerosis.",
"affiliations": "1 Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.;1 Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.;2 Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.;3 Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.",
"authors": "Aiempanakit|K|K|https://orcid.org/0000-0001-5256-827X;Chiratikarnwong|K|K|;Juthong|S|S|;Auepemkiate|S|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0961203318789766",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "27(11)",
"journal": "Lupus",
"keywords": "Cutaneous lupus erythematosus; overlap syndrome; systemic lupus erythematosus; systemic sclerosis; toxic epidermal necrolysis",
"medline_ta": "Lupus",
"mesh_terms": "D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous; D008875:Middle Aged; D011928:Raynaud Disease; D012595:Scleroderma, Systemic; D012867:Skin; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1860-1863",
"pmc": null,
"pmid": "30028256",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus in a patient with progressive systemic sclerosis.",
"title_normalized": "toxic epidermal necrolysis like acute cutaneous lupus erythematosus in a patient with progressive systemic sclerosis"
} | [
{
"companynumb": "TH-ALVOGEN-2018-ALVOGEN-096951",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nPerampanel, an anticonvulsant, might induce psychological reactions.\n\n\nMETHODS\nA 70-year-old woman, who had been taking 2500 mg/day levetiracetam, complained of right-hand minor-convulsion. Perampanel of 2 mg/day was additionally prescribed, and the dosage was increased to 4 mg/day. Two weeks after taking 4 mg/day perampanel, she changed her personality and kept insulting her husband; however, the patient herself was aware of her strange behaviour. She regained her normal personality after quitting the perampanel medication.\n\n\nCONCLUSIONS\nThis self-awareness is crucial to distinguish the perampanel-induced reaction from psychosis.",
"affiliations": "Department of Neurosurgery, Teikyo University Mizonokuchi Hospital, Kanagawa, Japan.;Department of Neurosurgery, Teikyo University Mizonokuchi Hospital, Kanagawa, Japan.;Department of Neurosurgery, Teikyo University Mizonokuchi Hospital, Kanagawa, Japan.",
"authors": "Yamada|Shoko M|SM|https://orcid.org/0000-0003-0525-8927;Tomita|Yusuke|Y|;Takaya|Yoshinori|Y|",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13141",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "45(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "aggression; gait disturbance; hostility; perampanel; psychological reactions",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D005260:Female; D006801:Humans; D009570:Nitriles; D011605:Psychoses, Substance-Induced; D011728:Pyridones",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "822-824",
"pmc": null,
"pmid": "32406128",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Features of psychological reactions induced by perampanel: A case report.",
"title_normalized": "features of psychological reactions induced by perampanel a case report"
} | [
{
"companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2020-074867",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PERAMPANEL"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nUremic calciphylaxis, also called calcific uraemic arteriolopathy (CUA), is a rare disease with a poor prognosis (mortality between 45% and 80%). Treatment is currently not standardized, and is based mainly on risk factor control, often with administration of sodium thiosulfate. We report the use of rheopheresis, a double filtration apheresis technique, specifically designed to improve blood rheology and tissue perfusion, as adjunctive therapy in eight patients with severe CUA.\n\n\nMETHODS\nWe retrospectively analysed eight cases of severe CUA treated by rheopheresis after failure of conventional measures, including administration of sodium thiosulfate and discontinuation of vitamin K antagonists.\n\n\nRESULTS\nOf the patients, there were 5 (63%) women, the median age was 69 (63.9-73) years. Four (50%) patients had biopsy-proven CUA. At diagnosis, the median dialysis vintage was 35 (3.9-42) months; five (63%) patients were anuric. Weekly median dialysis duration and dose were 12 (12-12.75) hours and 1.19 (1.13-1.48) Kt/V per dialysis session, respectively. Median time from CUA onset to first rheopheresis therapy was 26 (3.2-68) days. Patients started with 2-3 weekly sessions, coupled with haemodialysis. Complete remission was obtained in five patients (66%) after 25 (19-39) sessions over a duration of 119 (114-196) days. Three patients died, two of which resulted from an infectious complication related to CUA.\n\n\nCONCLUSIONS\nRheopheresis is a promising approach, with a good safety profile, for the treatment of CUA. A prospective study with a larger population, would clarify its place in the therapeutic armamentarium.",
"affiliations": "Centre de Néphrologie et Transplantation Rénale, Assistance Publique des Hôpitaux de Marseille, Marseille, France.;Hopital Huriez Service de Néphrologie-dialyse et Transplantation, CHU Lille, Lille, France.;Institut Phocéen de Néphrologie, Marseille, France.;Néphrologie-Dialyse, Association ECHO, Le Mans, France.",
"authors": "Robert|Thomas|T|;Lionet|Arnaud|A|;Bataille|Stanislas|S|;Seret|Guillaume|G|https://orcid.org/0000-0002-9962-7537",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/nep.13666",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5358",
"issue": "25(4)",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": "calciphylaxis; haemodialysis; rheopheresis; survival; wound",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001781:Blood Component Removal; D002115:Calciphylaxis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9615568",
"other_id": null,
"pages": "298-304",
"pmc": null,
"pmid": "31576630",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Rheopheresis: A new therapeutic approach in severe calciphylaxis.",
"title_normalized": "rheopheresis a new therapeutic approach in severe calciphylaxis"
} | [
{
"companynumb": "FR-AMGEN-FRASP2020008813",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM THIOSULFATE"
},
"drugadditional": null... |
{
"abstract": "Triptans are a class of drugs with proven efficacy in the acute treatment of migraine headache. The first component of these drugs was sumatriptan, with various derivatives subsequently emerging. Until now, there has only been one reported case of liver toxicity with zolmitriptan. We now present a case of hepatotoxicity related to another drug in this group: rizatriptan.",
"affiliations": "Servicio de Digestivo, Corporación Sanitaria Parc Taulí, Universidad Autónoma de Barcelona, España. afernandeza@tauli.cat",
"authors": "Fernandez-Atutxa|Alberto|A|;Vergara|Mercedes|M|;Gil|Montserrat|M|;Dalmau|Blai|B|;Miquel|Mireia|M|;Sanchez-Delgado|Jordi|J|;Casas|Meritxell|M|",
"chemical_list": "D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; C093622:rizatriptan",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-5705",
"issue": "36(4)",
"journal": "Gastroenterologia y hepatologia",
"keywords": null,
"medline_ta": "Gastroenterol Hepatol",
"mesh_terms": "D000293:Adolescent; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007105:Immune Complex Diseases; D041781:Jaundice, Obstructive; D008881:Migraine Disorders; D017366:Serotonin Receptor Agonists; D013997:Time Factors; D014230:Triazoles; D014363:Tryptamines",
"nlm_unique_id": "8406671",
"other_id": null,
"pages": "261-3",
"pmc": null,
"pmid": "23084593",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rizatriptan-induced liver toxicity. Report of a case.",
"title_normalized": "rizatriptan induced liver toxicity report of a case"
} | [
{
"companynumb": "PHHY2013ES051058",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIZATRIPTAN BENZOATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPulmonary alveolar proteinosis is a rare lung disorder, which was first reported as idiopathic condition in 1958. The prevalence of acquired pulmonary alveolar proteinosis has been estimated to be 0.37 per 100,000 population. The cause of this condition is not entirely clear. We present alveolar proteinosis in a case recently treated for pulmonary Pneumocystis carinii infection.\n\n\nMETHODS\nA 25-year-old Caucasian female presented with shortness of breath during management of acute pancreatitis. She had a heart-transplant six years ago, a distal pancreatectomy secondary to pancreatitis two years ago, chronic renal failure secondary to Prograft taken for six years to suppress transplant rejection, and a more recent history of Pneumocystis carinii infection treated in the preceding 21 days with augmented doses of Bactrim (Trimethoprim, Sulfamethoxazole). She had bilateral pleural effusions with radiological and clinical features suspicious for interstitial lung disease. Cytopathologic evaluation of broncho-alveolar lavage (BAL) showed hyaline alveolar casts admixed with amorphous debris and scant chronic inflammatory cells, consistent with alveolar proteinosis. GMS and PAS stains were negative for P. carinii. Direct Fluorescent Antibody (DFA) test for P. carinii performed on the BAL specimen in our Microbiology Lab had been repeatedly negative.\n\n\nCONCLUSIONS\nCytopathological findings in bronchoalveolar lavage, with clinical differential diagnosis of interstitial lung disease, were diagnostic. Pulmonary alveolar proteinosis after recent treatment for P. carinii infection suggests a relationship of pulmonary alveolar proteinosis with P. carinii infection in the immunocompromised patient.",
"affiliations": "Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. pkotov@mcw.edu",
"authors": "Kotov|Petio V|PV|;Shidham|Vinod B|VB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1186/1742-6413-3-22",
"fulltext": "\n==== Front\nCytojournalCytoJournal1742-6413BioMed Central London 1742-6413-3-221703464610.1186/1742-6413-3-22Case ReportAlveolar proteinosis in a patient recovering from Pneumocystis carinii infection: a case report with a review of literature Kotov Petio V 1pkotov@mcw.eduShidham Vinod B 1vshidham@mcw.edu1 Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA2006 12 10 2006 3 22 22 21 4 2006 12 10 2006 Copyright © 2006 Kotov and Shidham; licensee BioMed Central Ltd.2006Kotov and Shidham; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground\nPulmonary alveolar proteinosis is a rare lung disorder, which was first reported as idiopathic condition in 1958. The prevalence of acquired pulmonary alveolar proteinosis has been estimated to be 0.37 per 100,000 population. The cause of this condition is not entirely clear. We present alveolar proteinosis in a case recently treated for pulmonary Pneumocystis carinii infection.\n\nCase presentation\nA 25-year-old Caucasian female presented with shortness of breath during management of acute pancreatitis. She had a heart-transplant six years ago, a distal pancreatectomy secondary to pancreatitis two years ago, chronic renal failure secondary to Prograft taken for six years to suppress transplant rejection, and a more recent history of Pneumocystis carinii infection treated in the preceding 21 days with augmented doses of Bactrim (Trimethoprim, Sulfamethoxazole). She had bilateral pleural effusions with radiological and clinical features suspicious for interstitial lung disease. Cytopathologic evaluation of broncho-alveolar lavage (BAL) showed hyaline alveolar casts admixed with amorphous debris and scant chronic inflammatory cells, consistent with alveolar proteinosis. GMS and PAS stains were negative for P. carinii. Direct Fluorescent Antibody (DFA) test for P. carinii performed on the BAL specimen in our Microbiology Lab had been repeatedly negative.\n\nConclusion\nCytopathological findings in bronchoalveolar lavage, with clinical differential diagnosis of interstitial lung disease, were diagnostic. Pulmonary alveolar proteinosis after recent treatment for P. carinii infection suggests a relationship of pulmonary alveolar proteinosis with P. carinii infection in the immunocompromised patient.\n==== Body\nBackground\nPulmonary alveolar proteinosis is an accumulation of abundant extra cellular periodic acid-Schiff (PAS) positive proteinaceous material in alveolar spaces. It was first described as an idiopathic condition in 1958 [1]. This material represents surfactant distending the alveolar space. Papanicolaou-stained smears of bronchoalveolar lavage (BAL) fluid show characteristic hyaline globular alveolar casts which are green, or orange, or centrally orange with a green rim [2]. The globules may show scant cells \"hugging\" the periphery, which appear to be imprints of the pulmonary alveoli with occasional carry-over of pneumocytes lining the alveoli. Electron microscopy demonstrates whorled myelin figures characteristic of surfactant [3].\n\nCase presentation\nA 25-year-old Caucasian female with a history of heart transplant, presented with shortness of breath. Twenty one days prior to her presentation, she had P. carinii pneumonia for which she was treated with augmented doses of Bactrim (Trimethoprim, Sulfamethoxazole). She also noticed a progressive lower extremity edema, pleuritic chest pain, dry cough, and chills. She was diagnosed as chronic renal failure and was started on hemodialysis as an outpatient. During hemodialysis, she experienced abdominal pain radiating to the back. She presented to the emergency room with acute respiratory distress syndrome and acute pancreatitis secondary to a stone in the pancreatic duct. She was admitted and shortly after, she required intubation because of decreased oxygen saturation. A chest X-ray showed increased interstitial markings, suggestive of interstitial lung disease. Bilateral pleural effusions were also noted and attributed to the chronic renal failure with fluid overload. Recurrence of P. carinii infection was also considered a possibility. BAL was performed as part of a diagnostic-treatment protocol and 15 cc of cloudy pinkish fluid was sent for cytopathologic evaluation. Two Papanicolaou (PAP) stained SurePath™ preparations were prepared.\n\nThe PAP stained SurePath preparations showed characteristic globular alveolar casts of amorphous material which stained green, orange, and centrally orange with a green rim (Figure 1). This material was PAS positive and was resistant to diastase (Figure 2). GMS stain (Figure 3) did not show the characteristic crushed ping-pong ball like structures with central to eccentric dots (Figure 3a,b) observed in the frothy casts associated with P. carinii pneumonia (Figure 3c,d).\n\nFigure 1 Characteristic globular alveolar casts of amorphous cyanophilic to acidophilic debris (a) are admixed with relatively scant cells (b). Some hyaline globules demonstrate two tone staining (c). The globules of variable sizes range in shapes and dimensions corresponding with alveolar spaces. Occasional pneumocytes may be seen \"hugging\" the periphery of globules (arrow in d). This is different from the frothy appearance of casts associated with P. carinii pneumonia which show individual vacuoles with central to eccentric dots. (Bronchoalveolar lavage; Papanicolaou stained SurePath Prep™).\n\nFigure 2 The extra-cellular globular hyaline material is homogeneously PAS positive after diastase (a, b) without any organisms, as compared to the presence of organisms in P. carinii associated frothy alveolar casts (see figure 3). (Bronchoalveolar lavage; Periodic-Acid Schiff (PAS) stained SurePath Prep™)\n\nFigure 3 The hyaline globules in the amorphous material do not show any organisms with GMS stain (a, b). Compare this with appearance of PCP in positive control (c, d), which shows frothy casts with the characteristic crushed ping-pong ball like organisms (c) with small central to eccentric dots (arrow in d). (Bronchoalveolar lavage; Gomori-Silver Methanamine (GMS) stained SurePath Prep™).\n\nOxygen saturation improved after BAL procedure. Three days later she was extubated, and was discharged within a week. Apart from a hysterectomy for severe cervical dysplasia six months after this event, she has had an uneventful healthy course. Currently she is alive and well.\n\nDiscussion\nAlthough pulmonary alveolar proteinosis is usually difficult to differentiate clinically and radiologically from interstitial lung disease, it can be recognized in BAL. BAL fluid in alveolar proteinosis is usually opaque on gross appearance. Proper interpretation of BAL in these cases spares the patient an open lung biopsy. This is especially important for debilitated or transplant patients, because pulmonary alveolar proteinosis may be amenable to treatment by a simple procedure such as BAL alone.\n\nThe globular alveolar casts of pulmonary alveolar proteinosis should be distinguished from foamy alveolar casts of P. carinii in BAL specimens. In alveolar proteinosis the globular structures are hyaline as compared to foamy in P. carinii. The globular extra cellular hyaline material is PAS (diastase resistant) positive (Figure 2). The morphological details should be scrutinized under higher magnification, especially at the periphery of these casts. The foamy casts in P. carinii show distinct dark dots in individual vacuoles even in PAP stained preparations. If the details cannot be appreciated in PAP stained preparations, special stain such as GMS are helpful (Figure 3). P. carinii organisms demonstrate characteristic crushed \"ping-pong\" ball-like GMS stained dark P. carinii cysts-structures in the frothy casts (Figure 3c,d). They are not present in the hyaline casts of alveolar proteinosis (Figure 3a,b). For further comparison of P. carinii and PAP, see Table-1.\n\nTable 1 Characteristic Features\tPulmonary Alveolar Proteinosis\tPneumocystis Carinii\t\nAppearance of the alveolar cast-like structures\tHyaline\tFoamy\t\nCrushed \"ping-pong\" ball-like cyst-structures\tAbsent\tPresent\t\nDark central dots in the cyst-like structures by fungal stains (GMS, PAS)\tAbsent\tPresent\t\nBack-ground debris\tCould be present\tAbsent\t\nAs demonstrated in humans and mouse models, ultrastructurally the alveolar spaces in pulmonary alveolar proteinosis show numerous lamellar bodies with a structural resemblance to myelin. These lamellar bodies are similar to the surfactant present in type II pneumocytes. It is hypothesized that hyperplasic and hypertrophic type II pneumocytes produce increased amounts of lamellar bodies and develop into mononucleated giant balloon cells [4]. When they rupture, these mononucleated giant cells liberate numerous myelinoid structures, lipid droplets, and many electron dense amorphous acicular crystals which are closely associated with the extracellular membranous material.\n\nPulmonary alveolar proteinosis occurs in three clinically distinct forms: idiopathic, congenital, and secondary [5].\n\nIdiopathic pulmonary alveolar proteinosis has been an enigmatic acquired disorder since its initial description [1]. The exact etiology of this variant is not entirely clear but appears to be multifactorial, comprising the combined effect of infectious, environmental and hereditary factors.\n\nThe congenital form comprises of a heterogeneous group of disorders [6] caused by mutations in the genes encoding surfactant protein B or C or the βC chain of the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) [7-11].\n\nMost of the studies report the congenital form of alveolar proteinosis. One possible explanation for this form revolves around surfactant. Normally, surfactant is inactivated by mechanical and biologic processes and converted into small, surface-inactive aggregates. Approximately 70 to 80 percent of the small aggregates are taken up by alveolar type II pneumocytes, transported to phagolysosomes, and reused or catabolized. Alveolar macrophages internalize and catabolize the remaining surfactant pool, a process critically dependent on GM-CSF. Some patients with alveolar proteinosis have shown to have genetic defects rendering the GM-CSF receptor ineffective. The interruption of GM-CSF signaling in the alveolar macrophage, for example, by targeted ablation of the gene encoding GM-CSF or its receptor in mice or, presumably, by neutralizing anti-GM-CSF auto antibodies in humans, causes accumulations of eosinophilic lipoproteinaceous material and large, foamy macrophages in the alveoli [12].\n\nThe secondary pulmonary alveolar proteinosis develops in association with conditions involving functional impairment or reduced numbers of alveolar macrophages. Such conditions include some hematologic malignancies, pharmacologic immune suppression, inhalation of inorganic dust (e.g., silica) or toxic fumes, and certain infections [13].\n\nThe relationship of pulmonary alveolar proteinosis with recently treated P. carinii infection has not been specifically stressed previously. However, one case from a series describing spectrum of morphological changes in alveolar spaces, associates co-trimoxazole (Trimethoprim, Sulfamethoxazole) treated P. carinii pneumonia with alveolar proteinosis. Ultra structural examination of alveoli in case number 5 of this study showed lamellar-body-like structures resembling those of alveolar proteinosis [14]. Our case was also recently treated for P. carinii infection with Bactrim (Trimethoprim, Sulfamethoxazole, co-trimoxazole). The patient improved after BAL and was discharged.\n\nThis case suggests a link between treated P. carinii infection and pulmonary alveolar proteinosis in this immunocompromised heart transplant patient. The treated P. carinii organisms may lead to accumulation of lamellar-body-like structures in alveolar spaces with resultant alveolar proteinosis, which if diagnosed correctly could be treated with appropriate therapy including relatively simple procedure such as BAL. Similar reports have linked pulmonary alveolar proteinosis with Mycobacterium avium-intracellulare [15] and also with active P. carinii infection as well as other opportunistic infections [16]. The later report also stresses the connection between immunosuppressed patients and pulmonary alveolar proteinosis.\n\nIn summary, this case highlights the importance of differentiating P. carinii infection from alveolar proteinosis with emphasis on correct differentiation of the frothy globular casts in P. carinii infection from the hyaline globular casts in alveolar proteinosis. Correct interpretation of BAL would facilitate proper management and clinical recovery. A relationship between Bactrim treated PCP and Pulmonary Alveolar Proteinosis should be considered during the management of such cases.\n\nAbbreviations\nPAP, Papanicolaou stain; BAL, Broncho Alveolar Lavage; GMS, Grocott Methanamine Silver; GM-CSF, granulocyte-macrophage colony-stimulating factor; PAS, periodic acid-Schiff; PCP, Pneumocystis carinii pneumonia.\n\nCompeting interests\nThe author(s) declare that they have no competing interests.\n\nAuthors' contributions\nPK, Cytopathology fellow, collected all the data, participated in cytological evaluation, and drafting of manuscript.\n\nVS, Conceptual organization, cytological-histological evaluation, and manuscript review.\n\nAcknowledgements\n1. We would like to thank Dr. Basil Varkey for reviewing the manuscript and his input on the subject.\n\n2. Due to the archival nature of the case and only one patient involved as well as the absence of any potentially identifying patient information, the Institutional Review Board at the Medical College of Wisconsin, Milwaukee, did not require patient authorization for this case report.\n==== Refs\nRosen SH Castleman B Liebow AA Pulmonary alveolar proteinosis N Engl J Med 1958 258 1123 1142 13552931 \nShidham VB Atkinson BF Respiratory Cytology Atkinson Atlas of Diagnostic Cytopathology 2004 Chapter 7 Second Philadelphia, PA: W. B. Saunders Company 273 356 \nStanley E Lieschke GJ Grail D Metcalf D Hodgson G Gall JA Maher DW Cebon J Sinickas V Dunn AR Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology Proc Natl Acad Sci USA 91 5592 6 1994 Jun 7 8202532 10.1073/pnas.91.12.5592 \nMurata Y Emi Y Denda A Konishi Y Ultrastructural analysis of pulmonary alveolar proteinosis induced by methylnaphthalene in mice Exp Toxicol Pathol 1992 44 47 54 1392517 \nBruce TrapnellC Jeffrey WhitsettA Koh Nakata Pulmonary alveolar proteinosis N Engl J Med 2003 349 2527 2539 14695413 10.1056/NEJMra023226 \nNogee LM deMello DE Dehner LP Colten HR Deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis N Engl J Med 1993 328 406 410 8421459 10.1056/NEJM199302113280606 \nNogee LM Dunbar AE IIIWert SE Askin F Hamvas A Whitsett JA A mutation in the surfactant protein C gene associated with familial interstitial lung disease N Engl J Med 2001 344 573 579 11207353 10.1056/NEJM200102223440805 \nNogee LM Garnier G Dietz HC Singer L Murphy AM deMello DE Colten HR A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds J Clin Invest 1994 93 1860 3 8163685 \nDirksen U Nishinakamura R Groneck P Hattenhorst U Nogee L Murray R Burdach S Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression J Clin Invest 100 2211 7 1997 Nov 1 9410898 \ndeMello DE Lin Z Pulmonary alveolar proteinosis: a review Pediatr Pathol Mol Med 2001 20 413 432 11552740 10.1080/152279501750399384 \nDranoff G Crawford AD Sadelain M Ream B Rashid A Bronson RT Dickersin GR Bachurski CJ Mark EL Whitsett JA Involvement of granulocyte-macrophage colony-stimulating factor in pulmonaryhomeostasis Science 264 713 6 1994 Apr 29 8171324 \nStanley E Lieschke GJ Grail D Metcalf D Hodgson G Gall JA Maher DW Cebon J Sinickas V Dunn AR Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology Proc Natl Acad Sci USA 91 5592 6 1994 Jun 7 8202532 10.1073/pnas.91.12.5592 \nMaygarden SJ Iacocca MV Funkhouser WK Novotny DB Pulmonary alveolar proteinosis: a spectrum of cytologic, histochemical, and ultrastructural findings in bronchoalveolar lavage fluid Diagn Cytopathol 2001 24 389 95 11391819 10.1002/dc.1086 \nHibiya I Morphological changes in Pneumocystis carinii in the alveolar space due to treatment with co-trimoxazole – comparison of clinical cases and experimental rats Kansenshogaku Zasshi 1990 64 455 466 2401809 \nBakhos R Gattuso P Arcot C Reddy VB Pulmonary alveolar proteinosis: an unusual association with Mycobacterium avium-intracellulare infection and lymphocytic interstitial pneumonia South Med J 1996 89 801 2 8701380 \nBedrossian C Luna M Conklin R Miller W Alveolar proteinosis as a consequence of immunosuppression Human Pathology 1980 11 527 535 7429503\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1742-6413",
"issue": "3()",
"journal": "CytoJournal",
"keywords": null,
"medline_ta": "Cytojournal",
"mesh_terms": null,
"nlm_unique_id": "101231642",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "17034646",
"pubdate": "2006-10-12",
"publication_types": "D016428:Journal Article",
"references": "11391819;11552740;13552931;1392517;14695413;2401809;7429503;8163685;8171324;8202532;8421459;8701380;9410898;11207353",
"title": "Alveolar proteinosis in a patient recovering from Pneumocystis carinii infection: a case report with a review of literature.",
"title_normalized": "alveolar proteinosis in a patient recovering from pneumocystis carinii infection a case report with a review of literature"
} | [
{
"companynumb": "US-ASTELLAS-2021US029742",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "A 39-year-old Japanese man presented with chest oppression in February 2017. Electrocardiogram showed ST-elevation myocardial infarction (MI), and cardiac catheterisation revealed thrombotic occlusion of the right coronary artery (RCA), which was treated with thrombectomy, and he received warfarin. Three days after discharge, he complained of chest oppression again, and re-cardiac catheterisation showed thrombi occlusion of the circumflex artery (LCX) and 90% stenosis with thrombosis in the proximal site of the anterior descending artery (LAD) and RCA. Drug eluting stent was implanted in the LAD and RCA; aspirin and prasugrel hydrochloride were added to warfarin. Before discharge, coronary computed tomography angiography (CTA) found new thrombi in the RCA, LAD, and LCX, and he was referred to our hospital on suspicion of Behçet's disease (BD). Past medical history was notable for recurrent aphthous stomatitis, a pudendal ulcer, and Crohn's disease, for which he had been taking infliximab (5 mg/kg) every 8 weeks until December 2016. Notably, his C-reactive protein (CRP) level increased before and after each MI, suggesting that the thrombi were caused by inflammation. Consequently, we concluded that his abnormalities were manifestations of vasculo-BD. After 3 days of hospitalisation, treatment with prednisolone and colchicine was started. His CRP and D-dimer levels decreased, and coronary CTA after 8 days showed disappearance of the thrombi. We tapered the prednisolone dose, and cardiovascular events have not been observed for 7 months after the treatment initiation. In summary, we report a rare case of MI associated with vasculo-BD and review the relevant literature.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Shinko Hospital, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Shinko Hospital, Kobe, Japan.;Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Department of Rheumatology, Shinko Hospital, Kobe, Japan.;Department of Rheumatology, Shinko Hospital, Kobe, Japan.;Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.",
"authors": "Tsuboi|Kazuyuki|K|0000-0002-5198-1019;Tamura|Masao|M|;Sone|Naohiko|N|;Kaihotsu|Kenji|K|;Tomita|Toshihiko|T|;Azuma|Naoto|N|;Kitano|Masayasu|M|;Abe|Kyosuke|K|;Tsuji|Goh|G|;Miwa|Hiroto|H|;Sano|Hajime|H|;Matsui|Kiyoshi|K|",
"chemical_list": "D015415:Biomarkers",
"country": "England",
"delete": false,
"doi": "10.1080/24725625.2019.1685149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2472-5625",
"issue": "4(2)",
"journal": "Modern rheumatology case reports",
"keywords": "C-reactive protein; Crohn’s disease; Myocardial infarction; infliximab; vasculo-Behçet’s disease",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D000328:Adult; D001528:Behcet Syndrome; D015415:Biomarkers; D019468:Disease Management; D004198:Disease Susceptibility; D006801:Humans; D008297:Male; D009203:Myocardial Infarction; D012008:Recurrence; D013927:Thrombosis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101761026",
"other_id": null,
"pages": "296-301",
"pmc": null,
"pmid": "33087010",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent myocardial infarction associated with vasculo-Behçet's disease: a case report.",
"title_normalized": "recurrent myocardial infarction associated with vasculo beh et s disease a case report"
} | [
{
"companynumb": "JP-PBT-000412",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
"drugadmini... |
{
"abstract": "BACKGROUND\nSuppression of neoangiogenesis and pegylated liposomal doxorubicin (PLD) each contribute to the management of platinum-resistant/refractory ovarian cancer. The aim of this study is to test the combination of bevacizumab and PLD in women with resistant or refractory ovarian cancer.\n\n\nMETHODS\nEligibility criteria were no more than two prior treatments with platinum-containing regimens and one additional regimen, without anthracyclines. Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m(2)). The primary end point was progression-free survival (PFS) at 6 months; the secondary end points included side-effects, overall response rates (ORR) and survival (OS).\n\n\nRESULTS\nForty-six patients were enrolled. The average number of courses administered was 7. The median PFS was 6.6 months (range 1-24.6 months) according to Gynecologic Cancer Intergroup Committee (GCIC) criteria and 7.8 months (range 2-13.3 months) according to Response Evaluation Criteria in Solid Tumors (RECIST). The median OS was 33.2 months (range 3-37.5+ months). The ORR was 30.2% [95% confidence interval (CI) 17.2-46.1] and the clinical benefit rate (CBR) was 86.1% (95% CI 72.1-94.7). Adverse events included mucosal and dermal erosions (30% grade 3) and asymptomatic cardiac dysfunction. Additional toxic effects included hypertension, headache, renal dysfunction and proteinuria, wound healing delay, and one episode each of central nervous system (CNS) ischemia and hemolytic uremic syndrome.\n\n\nCONCLUSIONS\nPLD with bevacizumab has improved activity in recurrent ovarian cancer with increased toxicity.",
"affiliations": "Department of Hematology/Oncology, University of Vermont Cancer Center, Burlington. Electronic address: claire.verschraegen@vtmednet.org.;Departments of Obstetrics and Gynecology, New York University Cancer Institute, New York.;Departments of Gynecologic Oncology, USA.;Departments of Obstetrics and Gynecology, New York University Cancer Institute, New York.;Departments of Mathematics, USA.;Departments of Gynecologic Oncology, USA.;Departments of Obstetrics and Gynecology, New York University Cancer Institute, New York.;Departments of Obstetrics and Gynecology, New York University Cancer Institute, New York.;Radiology, University of New Mexico Cancer Center, Albuquerque, USA.;Departments of Medicine, New York University Cancer Institute, New York.",
"authors": "Verschraegen|C F|CF|;Czok|S|S|;Muller|C Y|CY|;Boyd|L|L|;Lee|S J|SJ|;Rutledge|T|T|;Blank|S|S|;Pothuri|B|B|;Eberhardt|S|S|;Muggia|F|F|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D061067:Antibodies, Monoclonal, Humanized; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D000068258:Bevacizumab; D010984:Platinum; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mds172",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "23(12)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001952:Bridged-Ring Compounds; D000077216:Carcinoma, Ovarian Epithelial; D018572:Disease-Free Survival; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D010984:Platinum; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "3104-3110",
"pmc": null,
"pmid": "22851407",
"pubdate": "2012-12",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase II study of bevacizumab with liposomal doxorubicin for patients with platinum- and taxane-resistant ovarian cancer.",
"title_normalized": "phase ii study of bevacizumab with liposomal doxorubicin for patients with platinum and taxane resistant ovarian cancer"
} | [
{
"companynumb": "US-JNJFOC-20121200137",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMedication reconciliation errors, also known as unintentional discrepancies, are frequent during admission, especially in chronic patients, and have an impact on safety. Educational interventions can be a reduction strategy.\n\n\nMETHODS\nQuasi-experimental study, before-after design. Participants were chronic patients admitted into hospitalization services. Medication reconciliation was conducted at admission. The intervention consisted of a training to each prescribing physician with study contents and printed educational material. To study the association between intervention and change of frequency of unintentional discrepancies was made a logistic regression model, adjusting for selected variables.\n\n\nRESULTS\nA sample of 54 patients was studied in each stage. In the first stage it was observed that 42.6% of patients had at least one unintentional discrepancy. After intervention the proportion of patients with at least one unintentional discrepancy decreased to 24.1% (p = 0.041). In both stages, omission was the main category of unintentional discrepancy. The significant reduction after the intervention is maintained by controlling for variables such as emergency admission and pre-admission service.\n\n\nCONCLUSIONS\nIncidence of unintentional discrepancies in admission is high in chronic hospitalized patients and can be reduced through an educative strategy.",
"affiliations": "Hospital de niños Dr. Exequiel González Cortés, San Miguel, Santiago, Chile; Depto. Salud Pública y Epidemiología, Universidad de los Andes, Santiago, Chile. Electronic address: claudio.gonzalezm@redsalud.gov.cl.;Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile.;Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile.;Unidad de Desarrollo, Análisis e Investigación, Departamento de Evaluación, Medición y Registro Educacional, Universidad de Chile, Santiago, Chile.;Depto. Salud Pública y Epidemiología, Universidad de los Andes, Santiago, Chile.;Hospital de niños Dr. Exequiel González Cortés, San Miguel, Santiago, Chile.",
"authors": "González|Claudio|C|;González|Gabriela|G|;Plaza-Plaza|José Cristian|JC|;Godoy|María Inés|MI|;Cárcamo|Marcela|M|;Rojas|Cecilia|C|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anpedi.2020.07.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2341-2879",
"issue": "94(4)",
"journal": "Anales de pediatria",
"keywords": "Admisión paciente; Conciliación de la medicación; Errores de medicación; Medication Errors; Medication Reconciliation; Patient Admission; Patient Safety; Seguridad del paciente",
"medline_ta": "An Pediatr (Engl Ed)",
"mesh_terms": "D002648:Child; D004522:Educational Status; D006760:Hospitalization; D006801:Humans; D008508:Medication Errors; D059065:Medication Reconciliation; D010372:Pediatrics; D011446:Prospective Studies",
"nlm_unique_id": "101765626",
"other_id": null,
"pages": "238-244",
"pmc": null,
"pmid": "32917544",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reduction of reconciliation errors in chronic pediatric patients through an educational strategy.",
"title_normalized": "reduction of reconciliation errors in chronic pediatric patients through an educational strategy"
} | [
{
"companynumb": "CL-JNJFOC-20201001899",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugadditional": "3... |
{
"abstract": "The case of an elderly male with bilateral shoulder pain is presented. The pain had been successfully treated years earlier with surgery, but a repeat rotator cuff procedure when the pain recurred was not effective. The patient's physician asked about impact of systemic analgesics on the elderly patient and interactions with his blood pressure medications. Cardiovascular and renal risks of NSAOIDs are discussed as are potential toxicities of tramadol and too rapid withdrawal from it. Drug interactions of medications used are described.",
"affiliations": "Harald Breivik, MD, DMSc, FRCA, is Emeritus Professor of Anesthesiology, University of Oslo , Oslo , Norway.",
"authors": "Breivik|Harald|H|",
"chemical_list": "D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D014147:Tramadol",
"country": "England",
"delete": false,
"doi": "10.3109/15360288.2014.1003681",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "29(1)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "ACE-inhibitor; NSAIDs; hypertension; interactions; monitoring; serotonergic effects; tramadol",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D004347:Drug Interactions; D006801:Humans; D008297:Male; D020069:Shoulder Pain; D014147:Tramadol",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "70-1",
"pmc": null,
"pmid": "25643226",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treat the whole patient and be aware of drug interactions.",
"title_normalized": "treat the whole patient and be aware of drug interactions"
} | [
{
"companynumb": "NO-PFIZER INC-2015146889",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "BACKGROUND\nValproic acid (VPA) is an effective treatment in juvenile myoclonic epilepsy (JME), but concerns on its use during pregnancy are remarkable. Levetiracetam (LEV) is approved as second-line therapy, and used as monotherapy in clinical practice. Our objective was to analyze the outcome of LEV and VPA in JME.\n\n\nMETHODS\nWe analyzed patients with JME attending our epilepsy unit between 2010 and 2014, including all patients treated with LEV and/or VPA at some point of the disease course. The primary end point was drug retention rate in monotherapy after the final analysis.\n\n\nRESULTS\nWe identified 58 patients (62% women). All had myoclonic seizures, 86% had generalized tonic-clonic seizures (GTCS) before the diagnosis, and 9% also had absences. All had generalized spike and wave on the interictal electroencephalogram, and 86% of them also had generalized polyspike and wave discharges. In total, LEV monotherapy was maintained in 15 (65%) of 23 patients, and VPA was maintained in 37 (74%) of 50 patients (P = 0.062). In women younger than 35 years, LEV had a similar retention rate with VPA (P = 0.939). More VPA patients achieved seizure freedom during follow-up (P < 0.01), whereas LEV patients showed a trend toward higher myoclonic freedom (0.085).\n\n\nCONCLUSIONS\nLevetiracetam showed lower retention rate than VPA, primarily due to poorer seizure control during long-term follow-up. More LEV patients achieved myoclonic seizure freedom than VPA patients. In women younger than 35 years, LEV and VPA had comparable retention rate; therefore, LEV could be a good option for women with JME with prominent myoclonic seizures.",
"affiliations": "*Epilepsy Unit, †Neuropediatric Unit, and ‡Neurophysiology Unit, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.",
"authors": "Sala-Padró|Jacint|J|;Toledo|Manuel|M|;Santamarina|Estevo|E|;González-Cuevas|Montserrat|M|;Raspall-Chaure|Miquel|M|;Sueiras-Gil|Maria|M|;Quintana|Manolo|M|;Salas-Puig|Xavier|X|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D014635:Valproic Acid; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "39(6)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D004569:Electroencephalography; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D020190:Myoclonic Epilepsy, Juvenile; D010889:Piracetam; D012189:Retrospective Studies; D016896:Treatment Outcome; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "299-301",
"pmc": null,
"pmid": "27438183",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Levetiracetam and Valproate Retention Rate in Juvenile Myoclonic Epilepsy.",
"title_normalized": "levetiracetam and valproate retention rate in juvenile myoclonic epilepsy"
} | [
{
"companynumb": "ES-UNICHEM LABORATORIES LIMITED-UCM201701-000012",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIVALPROEX SODIUM"
},
... |
{
"abstract": "Background A novel strategy to combine conventional transcatheter arterial chemoembolization (TACE) and TACE during portal vein occlusion (TACE-PVO) in the presence of high-flow arterioportal shunt (APS) has been developed to treat hepatocellular carcinoma (HCC) with portal invasion. Purpose To evaluate the efficacy of this strategy. Material and Methods Twenty-five cases of HCC with portal invasion, treated between April 2006 and December 2015, were evaluated. Balloon occlusion of the portal venous outlet was performed in eight cases of high-flow APS when performing TACE. Conventional TACE was performed in the other 17 cases. The primary endpoint was overall survival. Adverse events and deterioration of liver function were also evaluated. Results The median survival time (MST) was 12 months. One-, two-, and three-year survival rates were 48.0%, 39.3%, and 26.2%, respectively. Subgroup analysis and multivariate analysis revealed the CLIP score as prognostic factor. MST was 2.5 months in the subgroup with CLIP score ≥4 and 26.0 months in the subgroup with CLIP score ≤3 (hazard ratio = 7.7, 95% confidence interval = 2.3-25.8). Transient elevations of the levels of transaminase and bilirubin were observed; however, deterioration of liver function was infrequent; upgrading of Child-Pugh class in 9.1% of cases. Conclusion A novel strategy, combining conventional TACE and TACE-PVO, is effective for HCC with portal invasion. The CLIP score may be useful for considering treatment indication.",
"affiliations": "Nippon Medical School, Tokyo, Japan.;Nippon Medical School, Tokyo, Japan.;Nippon Medical School, Tokyo, Japan.;Nippon Medical School, Tokyo, Japan.;Nippon Medical School, Tokyo, Japan.;Nippon Medical School, Tokyo, Japan.;Nippon Medical School, Tokyo, Japan.",
"authors": "Yasui|Daisuke|D|;Murata|Satoru|S|;Ueda|Tatsuo|T|;Sugihara|Fumie|F|;Onozawa|Shiro|S|;Kawamoto|Chiaki|C|;Kumita|Shinichiro|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0284185117717762",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0284-1851",
"issue": "59(3)",
"journal": "Acta radiologica (Stockholm, Sweden : 1987)",
"keywords": "Liver; angiography; balloon insertions; chemoembolization",
"medline_ta": "Acta Radiol",
"mesh_terms": "D001166:Arteriovenous Shunt, Surgical; D021721:Balloon Occlusion; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D011169:Portal Vein; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "8706123",
"other_id": null,
"pages": "266-274",
"pmc": null,
"pmid": "28651444",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Novel treatment strategy for advanced hepatocellular carcinoma: combination of conventional transcatheter arterial chemoembolization and modified method with portal vein occlusion for cases with arterioportal shunt: a preliminary study.",
"title_normalized": "novel treatment strategy for advanced hepatocellular carcinoma combination of conventional transcatheter arterial chemoembolization and modified method with portal vein occlusion for cases with arterioportal shunt a preliminary study"
} | [
{
"companynumb": "JP-GUERBET-JP-20180054",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GELATIN"
},
"drugadditional": null,
"... |
{
"abstract": "Olmesartan is an angiotensin II type 1 receptor blocker commonly used in the treatment of hypertension. Several cases of sprue-like enteropathy associated with the use of this drug have been described which, even with important signs and limitations for the patient, present a full recovery after discontinuing the use of olmesartan. The case of a 64 year-old patient is presented, diagnosed with hypertension, under treatment with olmesartan-amlodipine, with chronic diarrhoea and villous atrophy on intestinal biopsies without diagnostic criteria for celiac disease and with complete remission after suspending discontinuing the use of olmesartan. Based on the clinical features presented by the case reported, the clinical and anatomopathological findings are described as well as the evolution of drug-induced enteropathy.",
"affiliations": "Servicio de Medicina Interna, Complejo Hospitalario de Navarra. jmodestosantos@gmail.com.",
"authors": "Modesto Dos Santos|J L|JL|;González Recio|P|P|;Terry López|O A|OA|;Leturia Frade|I|I|;Aguiar Losada|B|B|;Elejalde Guerra|J I|JI|",
"chemical_list": "D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "Spain",
"delete": false,
"doi": "10.23938/ASSN.0021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1137-6627",
"issue": "40(2)",
"journal": "Anales del sistema sanitario de Navarra",
"keywords": null,
"medline_ta": "An Sist Sanit Navar",
"mesh_terms": "D000959:Antihypertensive Agents; D003967:Diarrhea; D006801:Humans; D007049:Iatrogenic Disease; D007093:Imidazoles; D007410:Intestinal Diseases; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles",
"nlm_unique_id": "9710381",
"other_id": null,
"pages": "291-294",
"pmc": null,
"pmid": "28676728",
"pubdate": "2017-08-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Olmesartan-associated enteropathy: attention to an emerging iatrogenic phenomenon.",
"title_normalized": "olmesartan associated enteropathy attention to an emerging iatrogenic phenomenon"
} | [
{
"companynumb": "ES-GLENMARK PHARMACEUTICALS-2017GMK029024",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE\\OLMESARTAN MEDOXOMIL"
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study is to identify patterns of medication-related harm from a national perspective, and to use this information to inform decisions on where to focus medication safety efforts. This study updates a 2013 study using the same methodology.\n\n\nMETHODS\nDistrict health boards (DHBs) still actively using either the Adverse Drug Event (ADE) Trigger Tool (TT) or the Global Trigger Tool (GTT), submitted two years of anonymised ADE data (1 July 2013-30 June 2015) to the Health Quality & Safety Commission (the Commission) using a standard template. Analyses were conducted using aggregated data only.\n\n\nRESULTS\nOf eight DHBs who submitted data, six datasets were included, representing a total of 2,659 chart reviews. From these reviews, 923 harms were identified in 751 patients, with 28% of patients experiencing one or more harms. Harms occurred at a rate of 34.7 per 100 admissions, 42.5 per 1,000 bed days and 28% of patients experienced one or more medication-related harms. Those harmed were more likely to be older, female and have an increased length of stay. Most harms (65%) occurred during an inpatient stay, however, a substantial number (29%) originated in the community and precipitated an admission. Across all levels of severity, the most common types of medication harm were constipation, hypotension and bleeding. In the more serious harm categories, bleeding, hypotension and delirium/confusion/over-sedation were most common. Six groups of medicines caused the greatest amount of harm: opioids (including tramadol), anticoagulants/antiplatelet agents, antibiotics, antianginals (beta-blockers, nitrates, calcium channel blockers and others), diuretics and other cardiovascular medicines (angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARBs), centrally acting agents and statins). Opioids and anticoagulants/antiplatelet agents not only accounted for 40% of all harm, they were implicated in the most severe harm.\n\n\nCONCLUSIONS\nThis paper confirms earlier work that medication-related harms are common, occur both in hospitals and in the community, and are a substantial burden for patients and our healthcare system. Work is underway at local and national levels to decrease this harm, with a focus on the high-risk medicines most commonly implicated.",
"affiliations": "Senior Advisor, Health Quality & Safety Commission, Wellington, Professional Teaching Fellow, University of Auckland.;Medication Safety Specialist, Health Quality & Safety Commission, Wellington.;Teaching Associate, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.;Director, Health Quality Intelligence, Health Quality & Safety Commission, Wellington.;Executive Director of Medical Services, West Moreton Hospital and Health Services, Queensland, Australia.",
"authors": "Robb|Gillian|G|;Loe|Elizabeth|E|;Maharaj|Ashika|A|;Hamblin|Richard|R|;Seddon|Mary E|ME|",
"chemical_list": "D000701:Analgesics, Opioid; D000925:Anticoagulants",
"country": "New Zealand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-8446",
"issue": "130(1460)",
"journal": "The New Zealand medical journal",
"keywords": null,
"medline_ta": "N Z Med J",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000701:Analgesics, Opioid; D000925:Anticoagulants; D003248:Constipation; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006470:Hemorrhage; D006761:Hospitals; D006801:Humans; D007022:Hypotension; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D064406:Patient Harm; D012111:Residence Characteristics; D012720:Severity of Illness Index",
"nlm_unique_id": "0401067",
"other_id": null,
"pages": "21-32",
"pmc": null,
"pmid": "28796769",
"pubdate": "2017-08-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Medication-related patient harm in New Zealand hospitals.",
"title_normalized": "medication related patient harm in new zealand hospitals"
} | [
{
"companynumb": "NZ-JNJFOC-20170910679",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Brugada syndrome is an example of a channelopathy caused by an alteration in the transmembrane ion currents that together constitute the cardiac action potential. Approximately 20% of the cases of Brugada syndrome have been shown to be associated with mutations in the gene coding for the sodium ion channel in the cell membranes of the muscle cells of the heart. Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest or sudden cardiac death. Many clinical situations have been reported to unmask or exacerbate the electrocardiography (ECG) pattern of Brugada syndrome. Genetic testing for Brugada syndrome is clinically available. Here we report two cases of Brugada syndrome followed by a comprehensive review of the literature.",
"affiliations": "Royal Glamorgan Hospital, Ynysmaerdy, Llantrisant, Pontyclun, UK drazeemsheikh@hotmail.com.;Newham University Hospital NHS Trust, London, UK.",
"authors": "Sheikh|Azeem S|AS|;Ranjan|Kula|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.7861/clinmedicine.14-5-482",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2118",
"issue": "14(5)",
"journal": "Clinical medicine (London, England)",
"keywords": "Brugada syndrome; atrial fibrillation; channelopathy; sudden cardiac death; syncope",
"medline_ta": "Clin Med (Lond)",
"mesh_terms": "D000328:Adult; D053840:Brugada Syndrome; D016757:Death, Sudden, Cardiac; D004569:Electroencephalography; D006801:Humans; D008297:Male; D008875:Middle Aged; D013575:Syncope",
"nlm_unique_id": "101092853",
"other_id": null,
"pages": "482-9",
"pmc": null,
"pmid": "25301907",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "9521325;24011539;12417552;19165230;19122847;16943940;22920782;23059185;11076825;1309182;19007594;20129283;12448445;8806350;16344400;18464934;20031595;9490240;11901046;22715240;17196462;15655131;18355654;15627121;15140537;10662748;17224476;16009809;16172272;21727093;9935001;21144977;15381640;22192666;11527630;17967977;11156883;19716089;9950665",
"title": "Brugada syndrome: a review of the literature.",
"title_normalized": "brugada syndrome a review of the literature"
} | [
{
"companynumb": "PHHY2014GB142724",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose-lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end-stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co-morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population.",
"affiliations": "Providence Medical Research Center, Providence Health Care, Spokane, Washington.;Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States.",
"authors": "Tuttle|Katherine R|KR|0000-0002-2235-0103;McGill|Janet B|JB|",
"chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins",
"country": "England",
"delete": false,
"doi": "10.1111/dom.13986",
"fulltext": "\n==== Front\nDiabetes Obes Metab\nDiabetes Obes Metab\n10.1111/(ISSN)1463-1326\nDOM\nDiabetes, Obesity & Metabolism\n1462-8902 1463-1326 Blackwell Publishing Ltd Oxford, UK \n\n10.1111/dom.13986\nDOM13986\nReview Article\nReview Articles\nEvidence‐based treatment of hyperglycaemia with incretin therapies in patients with type 2 diabetes and advanced chronic kidney disease\nTuttle and McGillTuttle Katherine R. MDhttps://orcid.org/0000-0002-2235-0103\n1\n\n2\nkatherine.tuttle@providence.org McGill Janet B. MD\n3\n \n1 \nProvidence Medical Research Center\nProvidence Health Care\nSpokane\nWashington\n\n\n2 \nDivision of Nephrology, Kidney Research Institute, and Institute of Translational Health Sciences\nUniversity of Washington\nSeattle\nWashington\n\n\n3 \nDivision of Endocrinology, Metabolism and Lipid Research\nWashington University School of Medicine\nSt. Louis\nMissouri\nUnited States\n\n* Correspondence\n\nKatherine R. Tuttle, MD, 105 W. 8th Avenue, Suite 6050 W, Spokane, WA 99204.\n\nEmail: katherine.tuttle@providence.org\n\n20 2 2020 \n7 2020 \n22 7 10.1111/dom.v22.71014 1023\n14 12 2019 20 1 2020 30 1 2020 © 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nType 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose‐lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end‐stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co‐morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population.\n\ncardiovascular diseasedipeptidyl peptidase‐4 inhibitorsglucagon‐like peptide‐1 receptor agonistsglycaemic controlhyperglycaemiaSupport for this article was provided by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) 10.13039/100001003 source-schema-version-number2.0cover-dateJuly 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:26.06.2020\n\n\nTuttle \nKR \n, \nMcGill \nJB \n. Evidence‐based treatment of hyperglycaemia with incretin therapies in patients with type 2 diabetes and advanced chronic kidney disease\n. Diabetes Obes Metab . 2020 ;22 :1014 –1023\n. 10.1111/dom.13986 \n32009296 \n\n\n\nPeer Review The peer review history for this article is available at https://publons.com/publon/10.1111/dom.13986.\n\n\nFunding information Support for this article was provided by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI)\n==== Body\n1 INTRODUCTION\n1.1 What is the extent of the problem of chronic kidney disease in type 2 diabetes?\nDiabetes is the leading cause of chronic kidney disease (CKD) worldwide, defined as a glomerular filtration rate (GFR) <60 mL/min/1.73m2 or urine albumin‐to‐creatinine ratio (UACR) >30 mg/g for at least 3 months.1 CKD secondary to either type 1 diabetes or type 2 diabetes (T2D), diabetic kidney disease (DKD), occurs in 30% to 40% of patients with diabetes.2, 3 For those patients with T2D, data from 2007–2012 show the overall age‐adjusted CKD prevalence to be 38.3%.4 With T2D and impaired kidney function, mortality rates approach nearly 20% per year, a rate comparable with many serious malignancies.5 The major impact of CKD on clinical outcomes is further informed by the observation that most of the excess cardiovascular disease (CVD) and all‐cause mortality risk in patients with diabetes occurs in those with either impaired kidney function or albuminuria.6\n\n\nThe occurrence of CKD, including end‐stage kidney disease (ESKD), is expected to increase as the global prevalence of diabetes continues to rise, and hence effective patient‐management strategies are of growing importance.7, 8 However, the optimal approach to glycaemic control in patients with T2D and advanced CKD remains uncertain, as most clinical trials of glucose‐lowering therapies excluded those patients.9 This review will consider the available evidence for diabetes management in this growing population of patients with T2D and advanced CKD, defined as categories 4 and 5. The Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) define category 4 CKD as eGFR 15–29 mL/min/1.73m2, and category 5 (kidney failure) as eGFR <15 mL/min/1.73m2.10\n\n\n1.2 What is the importance of glycaemic control in patients with advanced CKD and T2D?\nThe presence of CKD in patients with T2D is associated with a markedly elevated risk of CVD, and treatment strategies for patients with these two conditions must include the reduction of both CKD and cardiovascular disease (CVD) risks, as these patients are at a higher risk of all‐cause and CVD death than ESKD.2 Management of hyperglycaemia is foundational for good diabetes care. Intensive glycaemic control is associated with a reduced risk of DKD onset, and diabetic patients with established CKD may also benefit. A Canadian population‐based cohort study found strong and independent associations between higher levels of HbA1c and adverse clinical outcomes, including mortality, CVD events, hospitalization and progression to ESKD, in patients with moderate‐to‐severe CKD (categories 3 and 4).11 In observational studies, lower levels of glycaemia were also associated with reduced morbidity and mortality in diabetic patients with ESKD undergoing dialysis.12, 13 Similarly, a 6‐year cohort study showed that poor glycaemic control was associated with increased all‐cause and CVD mortality among patients with diabetes and ESKD treated by haemodialysis.14 More recently, a large study of patients with advanced CKD transitioning to dialysis showed that poor glycaemic control was associated with increased mortality.9\n\n\nThe assessment of glycaemia is particularly challenging in patients with diabetes with advanced CKD, as HbA1c may not be an accurate reflection of glycaemic control because of factors such as anaemia, enhanced red blood cell turnover and malnutrition, which bias assays toward lower results, and protein modifications such as glycation and carbamylation, which bias assays toward higher results.15 Moreover, alternative measures such as glycated albumin or fructosamine also do not correlate well with fasting plasma glucose levels in this population.16 Self‐monitoring of capillary blood glucose remains the mainstay of daily assessment of glycaemia, but glucose levels are checked intermittently and not always at times of problematic hyper‐ or hypoglycaemia. Continuous glucose monitoring (CGM) is recommended for patients treated with intensified insulin regimens consisting of more than three injections of insulin daily, but has not been widely adopted in patients on less intensive regimens. Guidelines from the American Diabetes Association17 and the American Association of Clinical Endocrinologists18 endorse the use of CGM for people at risk of hypoglycaemia, regardless of diabetes type. Thus, high‐risk patients with T2D and CKD will probably benefit from CGM technology.\n\nIn addition to the difficulties of evaluating HbA1c levels in CKD, specific glycaemic targets for diabetic patients with CKD have not been established. HbA1c levels of ~ 7%, consistent with NKF‐KDOQI guidelines,19 are recommended if they can be achieved without compromising safety, and most importantly, without increasing the number and severity of episodes of hypoglycaemia. Target HbA1c levels are also uncertain for patients with diabetes on chronic dialysis or with a kidney transplant, and will depend on age, co‐morbidities and the risk of hypoglycaemia.19, 20 Therefore, the approach to glycaemic management in patients with T2D and advanced CKD should be individualized, taking account of the needs and preferences of each patient, including the presence of co‐morbidities and concomitant therapies.19\n\n\n1.3 What are the challenges associated with treating T2D in patients with advanced CKD?\nKidney disease increases the complexity and risks associated with management of T2D.19 In particular, advanced CKD is an important risk factor for hypoglycaemia, as gluconeogenesis by the kidney is impaired.21 In addition, hepatic glycogenolysis and gluconeogenesis are reduced in advanced CKD.22, 23 The risk of hypoglycaemia in patients with CKD is further increased because the drugs commonly used to treat diabetes in these patients, insulin and sulfonylureas (SUs), are themselves associated with a risk of hypoglycaemia.17 Many glucose‐lowering drugs, including insulin, undergo clearance by the kidney, and therefore require dose adjustments or are contraindicated in patients with advanced CKD.19 Thus, choices of glucose‐lowering therapies have been limited for patients with T2D with advanced CKD.24\n\n\n1.4 What are the treatment options for patients with T2D and advanced CKD?\nOnly a few studies have evaluated the efficacy and safety of glucose‐lowering drugs in patients with advanced CKD. The number of patients studied with eGFR <30 mL/min/1.73m2 is low because these patients are often excluded from clinical trials of glucose‐lowering agents (Table 1).24 Because cardiovascular outcomes trials (CVOTs) follow the approved indications for these agents, this patient population has been under‐represented in the CVOTs (Table 2).25 There remains a need for effective glucose‐lowering therapies that have shown safety, especially for hypoglycaemia, in patients with T2D and advanced CKD.\n\nTable 1 Clinical trials including patients with type 2 diabetes and advanced chronic kidney disease (CKD)\n\nStudy\tIntervention and study size\tAdvanced CKD by baseline eGFR2 (mL/min/1.73m2)a\n\tPatients with advanced CKDb, n (%)\tDuration of follow‐up\tMean HbA1c change versus baseline (%)\tKidney outcomes\tOccurrence of 3P‐MACEc\n,\nd\n\t\nRosenstock et al51\n\t\nLinagliptin or placebo\n\n\nN = 6991\n\n\n\t<30\t1062 15\n\t2.2 years\t\n−0.51\n\n\n(−0.55, −0.46)\n\n\n\t\nComposite kidney outcome:c\n,\ne 1.04 (0.89, 1.22); P = 0.62\n\n\nProgression of albuminuria:c\n,\nf 0.86 (0.78, 0.95); P = 0.003\n\n\n\t\n1.02 (0.89, 1.17)\n\n\n\nP < 0.001 for non‐inferiority\n\n\n\t\nMcGill et al52\n\t\nLinagliptin or placebo\n\n\nN = 133\n\n\n\t\n15–30\n\n\n<15\n\n\n\t\n100 (75)\n\n\n14 (11)\n\n\n\t1 year\t\n−0.72 (−1.03, −0.41)\n\n\n\nP = 0.0001\n\n\n\tMedian difference in eGFRa from baseline to last value on treatment: linagliptin, 20.8 mL/min/1.73m2 versus placebo, 22.2 mL/min/1.73m2\n\t–\t\nLeiter et al72\n\t\nWeekly albiglutide or daily sitagliptin\n\n\nN = 771\n\n\n\t≥15 to ≤29\t36 (7.3)\t1 year\t\n−0.32 (−0.49, −0.15)\n\n\n\nP = 0.0003\n\n\n\t–\t–\t\nArjona Ferreira et al30\n\t\nSitagliptin or glipizide\n\n\nN = 426\n\n\n\t<30\t73 (25.4–27.4)g\n\t1 year\t−0.11 (−0.29, 0.06)h\n\tNumber of patients with moderate CKD at baseline who transitioned to severe CKD status: sitagliptin group, 28 (18.8%); glipizide group, 17 (11.0%)\t–\t\nArjona Ferreira et al29\n\t\nSitagliptin or glipizide\n\n\nN = 129\n\n\n\tESKD on dialysis\t129 (100)\t54 weeks\t−0.15 (−0.18, −0.49)\t–\t–\t\nLukashevich et al54\n\t\nVildagliptin or placebo\n\n\nN = 515\n\n\n\t<30\t221 (42.9)\t24 weeks\t\nModerate CKD:−0.5 ± 0.1; P < 0.0001\n\n\nSevere CKD: −0.6 ± 0.1%; P < 0.0001\n\n\n\t\t–\t\nKothny et al55\n\t\nVildagliptin or placebo\n\n\nN = 369\n\n\n\t<30\t158 (42.8)\t1 year\t\nModerate CKD: −0.4 ± 0.1%; P = 0.005\n\n\nSevere CKD: −0.7 ± 0.2%; P < 0.0001\n\n\n\t\nModerate CKD: mean change from baseline eGFRa, −1.62 and − 1.80 for vildagliptin and placebo, respectively\n\n\nSevere CKD: mean change from baseline eGFR, −1.98 and − 2.44, respectively\n\n\n\t–\t\nSatirapoj et al41\n\t\nStandard‐ versus low‐dose pioglitazone\n\n\nN = 75\n\n\n\t≥15 to ≤29\t19 (25.3)\t24 weeks\t\nStandard dose: decreased from 9.2 ± 1.8 to 7.9 ± 1.4; P < 0.05\n\n\nLow‐dose: decreased from 8.9 ± 1.4 to 7.6 ± 0.9; P < 0.05\n\n\n\t–\t–\t\nAbbreviations: 3P‐MACE, three‐point major adverse cardiovascular events; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESKD, end‐stage kidney disease.\n\na eGFR measured in mL/min/1.73m2.\n\nb Advanced CKD as defined in each study and shown in preceding column; termed ‘moderate’ or ‘severe’ in some studies.\n\nc Results expressed as hazard ratios (95% confidence intervals) for whole study population, active treatment versus placebo or comparator.\n\nd 3P‐MACE, composite of CVD death, non‐fatal myocardial infarction, and non‐fatal stroke.\n\ne Composite kidney outcome, adjudicated death because of kidney failure, ESKD, or sustained 40% or higher decrease in eGFR from baseline.\n\nf Progression of albuminuria = change from normoalbuminuria to microalbuminuria/macroalbuminuria or change from microalbuminuria to macroalbuminuria.\n\ng For this analysis, n = 277 (patients who completed the study with available data).\n\nh Met criterion for non‐inferiority.\n\nTable 2 Cardiovascular outcomes trials (CVOTs) and a glycaemic control clinical trial including patients with type 2 diabetes and advanced chronic kidney disease (CKD)\n\nStudy\tIntervention and study size\tBaseline eGFRa (mL/min/1.73m2)\tPatients with advanced CKDb, n (%)\tDuration of follow‐up (years)\tGlycaemic outcomes\tKidney outcomesc\n\tEffect on progression of kidney diseasec\n\tCV outcomesc\n\t\nUdell et al53\n\t\nSaxagliptin versus placebo\n\n\nN = 16 492\n\n\n\t<30\t336 (2.04)\t2.0\t\nAdvanced CKD group:\n\n\nHbA1c 7.1% saxagliptin versus 7.7% placebo at 1 year\n\n\n\tKidney composite outcomed in patients with eGFRa ≤50: 1.06 (0.78–1.44; P (interaction) = 0.90\tAdvanced CKD group: no overall change in risk of progressive microalbuminuria with saxagliptin (53.4%) versus placebo (46.6%); P = 0.61d\n\t\nAdvanced CKD group:\n\n\n3P‐MACEe\n\n\n\nadjusted HR 0.83\n\n\n(0.49–1.39);\n\n\n\nP = 0.48\n\n\nHHF: 0.94 (0.52–1.71); P = 0.84\n\n\n\t\nLEADER61\n\t\nLiraglutide or placebo\n\n\nN = 9340\n\n\n\t<30\t224 (2.4)\t3.8\t–\tKidney composite outcomef in patients with eGFRa <60 and microalbuminuria or macroalbuminuria (n = 1130): 0.81 (0.64–1.03) P = 0.09\tNew onset persistent macroalbuminuria: 161, liraglutide group versus 215 in placebo group, HR, 0.74 (0.60 to 0.91; P = 0.004)\t–\t\nAWARD‐764\n\t\nOnce‐weekly dulaglutide or daily insulin glargine, all + insulin lispro\n\n\nN = 577\n\n\n\t\n≥15–30\n\n\n<15\n\n\n\t\n171 (29.6)\n\n\n2 (0.003)\n\n\n\t1.0\tHbA1c change LSM –1.1% (SE 0.1), dulaglutide 1.5 mg; −1.1% (0.1), dulaglutide 0.75 mg; −1.0% (0.1), insulin glargine\t\neGFRa: dulaglutide 1.5 mg LSM 34.0 (SD 0.7); P = 0.005 versus insulin glargine; dulaglutide 0.75 mg, 33.8 (0.7); P = 0.009 versus insulin glargine, 31.3 (0.7).\n\n\nUACR: dulaglutide 1·5 mg, −22∙5% (−35∙1 to −7∙5); dulaglutide 0·75 mg, −20∙1% (−33∙1 to −4∙6); insulin glargine, −13∙0% (−27∙1 to 3∙9)\n\n\n\t–\t–\t\nREWIND65\n\t\nDulaglutide or placebo\n\n\nN = 9901\n\n\n\t<30\t105 (1)\t5.4\t–\tKidney composite outcomeg: dulaglutide versus placebo: 0.85 (0.77–0.93); P = 0.0004\t–\t–\t\nAbbreviations: 3P‐MACE, three‐point major adverse cardiovascular events; AWARD‐7, Assessment of Weekly Administration of Dulaglutide in Diabetes clinical trial program‐7; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HHF, hospitalization for heart failure; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; LSM, least squares mean; REWIND, Researching Cardiovascular Events with a Weekly Incretin in Diabetes; SE, standard error; UACR, urine albumin‐to‐creatinine ratio.\n\na eGFR, measured in mL/min/1.73m2.\n\nb Advanced CKD as defined in each study and shown in preceding column.\n\nc Results expressed as hazard ratios (95% confidence intervals) for whole study population, active treatment versus placebo.\n\nd Progressive diabetic kidney disease defined by albumin‐to‐creatinine ratio.\n\ne 3P‐MACE, composite of CVD death, non‐fatal myocardial infarction, and non‐fatal stroke.\n\nf Composite outcome of new onset of persistent macroalbuminuria, doubling of serum creatinine and eGFR <45 mL/min/1.73m2, need for continuous kidney replacement therapy (end‐stage kidney disease) or death because of kidney disease.\n\ng Composite of first occurrence of new macroalbuminuria (UACR >33.9 mg/mmol), sustained decline in eGFR of 30% or more from baseline, or chronic kidney replacement therapy.\n\n\nNote: Composite of a doubling of serum creatinine level, initiation of long‐term dialysis, kidney transplantation, or serum creatinine level of 0.6 mg/dL.\n\n2 NON‐INCRETIN THERAPIES\n2.1 Insulin\nMany oral glucose‐lowering agents must be discontinued or administered at a reduced dose because of the risk of adverse effects in diabetic patients with advanced CKD, including those with ESKD treated by dialysis. Thus, insulin is frequently used to control hyperglycaemia. However, a low GFR also results in a prolonged pharmacokinetic profile of insulin, so the dose and the schedule must be modified.26 Glycaemic control with insulin can be difficult to achieve in patients with advanced CKD because of impaired insulin clearance by the kidney as well as reduced insulin sensitivity.12, 27 Some studies of newer insulin analogues suggest less impact on pharmacokinetics than with the older insulins. Therefore, these agents may be more suitable for insulin‐requiring patients with advanced CKD.12, 28\n\n\n2.2 SUs\nAs kidney function declines, clearance of most SUs and their active metabolites falls progressively, necessitating a decrease in drug dose to avoid hypoglycaemia.19 First‐generation SUs (eg, chlorpropamide, tolazamide and tolbutamide) should not be used in CKD because these agents rely on elimination by the kidney of both the parent drug and active metabolites, resulting in a higher risk of hypoglycaemia.19 Of the second‐generation SUs (eg, glipizide, glyburide and glimepiride), glipizide is preferred as it is cleared by the liver without active metabolites and does not require dose adjustment in advanced CKD.19 However, glipizide therapy is associated with higher rates of hypoglycaemia and weight gain compared with incretin therapies such as dipeptidyl peptidase‐4 (DPP‐4) inhibitors.29, 30\n\n\n2.3 Metformin\nMetformin is eliminated by the kidneys and has historically been considered unsuitable for use in patients with advanced CKD because of concerns about development of lactic acidosis attributed to metformin accumulation.31, 32 These concerns were largely based on case reports, and observational studies have not shown the predicted increase in the risk of metformin‐associated lactic acidosis.33 Consequently, changes to recommendations for metformin use occurred in 2016 when the US Food and Drug Administration (FDA) relaxed its restrictions for metformin use in CKD following a review of the safety of this agent in patients with impairment of kidney function.34 For patients with CKD, the guidance states that starting metformin in patients with an estimated glomerular filtration rate (eGFR) of 30–45 mL/min/1.73m2 is not recommended. For patients taking metformin whose eGFR falls below 45 mL/min/1.73m2, the benefits and risks of continuing treatment should be evaluated, and metformin should be discontinued in patients whose eGFR falls below 30 mL/min/1.73m2.34\n\n\nRecent evidence suggests that low‐dose metformin (500 mg once‐daily) may be used in patients with an eGFR of 15–30 mL/min/1.73m2, provided the dosage is adjusted on an individual patient basis and that the drug is stopped during acute illness.35, 36 However, the FDA has not approved metformin use in patients with an eGFR below 30 mL/min/1.73m2.37\n\n\n2.4 Thiazolidinediones\nPioglitazone undergoes hepatic metabolism and is effective in patients with T2D and CKD without increasing the risk of hypoglycaemia.38 The pharmacokinetics of pioglitazone are not altered in patients with impaired kidney function, and dose adjustment is not required for patients with T2D and CKD.39 The main concern with thiazolidinedione (TZD) therapy is that it is associated with fluid retention and oedema, which are frequent causes of therapy discontinuation. These agents should be used with caution in patients at risk of heart failure and are not recommended for patients with symptomatic heart failure.40 However, a recent meta‐analysis of the use of TZDs in patients with T2D and kidney impairment, which included 19 randomized controlled trials and three cohort studies (a total of 21 803 patients), found that although TZDs significantly increased the risk of weight gain and oedema, the risk of heart failure, angina, myocardial infarction, CVD mortality and all‐cause mortality were not increased.38\n\n\nThe risk of fluid retention in patients with CKD can be reduced by the use of low‐dose pioglitazone. A 24‐week study of standard‐ versus low‐dose pioglitazone (15 or 7.5 mg once‐daily) in 75 patients with T2D and CKD (25.3% of whom had category 4 CKD) showed that the lower dose produced a similar degree of glycaemic control as the standard dose without adverse effects on weight gain and fluid retention (Table 1).41 In an earlier study, the effect of adding pioglitazone (30 mg) versus placebo to existing insulin therapy was evaluated in a randomized phase 2 study of 36 patients with T2D who were undergoing haemodialysis.42 The addition of pioglitazone to insulin in this patient population with ESKD was well tolerated and led to improved glycaemic control with a reduced requirement for insulin. TZDs have been associated with an increased risk of fracture,43 which is concerning in patients who may have higher fracture risk because of bone and mineral metabolism disorders that occur in advanced CKD.\n\n2.5 Sodium‐glucose co‐transporter‐2 inhibitors\nSodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors exert their glucose‐lowering effects by increasing glucose excretion through the kidneys. Because the glucose‐lowering efficacy of these agents attenuates in patients with low eGFR, SGLT‐2 inhibitors are not recommended for glycaemic control in patients with T2D and an eGFR below 45 mL/min/1.73m2.44 However, canagliflozin has recently received FDA approval for patients with T2D and diabetic kidney disease with macroalbuminuria (>300 mg/day) and eGFR of 30‐90 mL/min/1.73m2 to reduce the risk of doubling of serum creatinine, ESKD, CVD death and hospitalization for heart failure,45 based upon the landmark Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial.46\n\n\n3 INCRETIN THERAPIES\n3.1 DPP‐4 inhibitors\nThe DPP‐4 inhibitors slow the breakdown of incretin hormones, glucagon‐like peptide‐1 (GLP‐1) in particular, and improve both fasting and postprandial glucose levels. Alogliptin, sitagliptin and saxagliptin are primarily eliminated via the kidneys and, consequently, they require dose adjustment in patients with any category of CKD. By contrast, linagliptin is excreted via the bile and gut and does not require dose adjustment in patients with CKD.19, 47, 48, 49, 50 Linagliptin has been evaluated in a large population of patients with T2D and CKD in the Cardiovascular and Renal Microvascular Outcome study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA) trial (62% of the trial population with an eGFR <60 mL/min/1.73m2, and 15% with an eGFR <30 mL/min/1.73m2) (Table 1).51 The CARMELINA trial was a randomized, placebo‐controlled, multicentre, non‐inferiority trial that evaluated lingaliptin versus placebo on top of standard‐of‐care for prespecified CVD and CKD endpoints in patients with T2D and elevated CVD and CKD risks. After a median of 2.2 years of follow‐up for 6979 participants, those allocated to linagliptin showed no increase in the risk of three‐point major adverse CVD events (3P‐MACE) versus placebo: hazard ratio (HR) 1.02 (95% confidence interval [CI] 0.89–1.17); P < 0.001 for non‐inferiority. There was also no increase in the risk of hospitalization for heart failure for linagliptin versus placebo (HR 0.90 [0.74–1.08]). There was no significant difference in the rates of the secondary composite CKD endpoint (≥40% sustained reduction in eGFR, ESKD or death from kidney failure with linagliptin; Table 1). For exploratory CKD endpoints, there was no increased risk of progression to ESKD or death because of kidney disease (HR 0.87 [0.69–1.10]), but progression of albuminuria was less frequent in patients who received linagliptin versus placebo (HR 0.86 [0.78–0.95]). The results of CARMELINA extend the findings of an earlier study in 133 patients with severely impaired kidney function, in which linagliptin was shown to provide clinically relevant improvements in glycaemic control with a low risk of hypoglycaemia, stable body weight, and no occurrence of drug‐related kidney failure.52\n\n\nSitagliptin has also been evaluated in patients with CKD. In a study of 426 patients with T2D and moderate‐to‐severe CKD, sitagliptin showed similar glucose‐lowering efficacy to glipizide (Table 1).30 At week 54, similar reductions from baseline HbA1c (mean: 7.8% in both groups) were observed in both treatment groups. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia and weight loss versus weight gain, relative to glipizide. Sitagliptin has also been evaluated in comparison with glipizide in 129 patients with T2D and ESKD who were on chronic dialysis with HbA1c levels of 7.0%–9.0%.29 After 54 weeks, reductions in HbA1c were similar between groups and symptomatic hypoglycaemia was reported less frequently in the sitagliptin group versus the glipizide group (Table 1). More recently, a prespecified secondary analysis of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR‐TIMI 53) trial evaluated the efficacy and safety of saxagliptin compared with placebo according to baseline kidney function in patients with T2D (Table 2).53 Saxagliptin was shown to have a neutral impact on the risk of ischaemic CVD events while increasing the risk of hospitalization for heart failure. Although only a minority of patients had severe CKD, saxagliptin reduced progressive albuminuria, irrespective of baseline kidney function.\n\nThe safety and efficacy of adding vildagliptin or placebo to standard therapy was evaluated in 515 patients with T2D and moderate‐to‐severe CKD (Table 1).54 After 24 weeks, vildagliptin was shown to produce clinically and statistically significant reductions in HbA1c with a safety profile similar to placebo. A 1‐year study of vildagliptin versus placebo in 369 patients with T2D and moderate‐to‐severe CKD found similar results, which were maintained in the long term.55 In a subsequent clinical trial, the safety and efficacy of vildagliptin therapy was evaluated over 2 years in 32 patients with T2D and ESKD treated by chronic dialysis.56 Vildagliptin improved glycaemic control in patients with T2D and ESKD, and was well tolerated, notably without an increased risk of hypoglycaemia or weight gain.\n\nA retrospective analysis of 200 patients with ESKD who were receiving DPP‐4 inhibitor therapy (sitagliptin, vildagliptin, linagliptin) also showed that these agents are effective, with no significant difference among the individual agents in terms of glucose‐lowering efficacy after 12 weeks of treatment, in addition to beneficial effects on serum lipid profiles.57 Subsequently, a meta‐analysis of randomized controlled trials of DPP‐4 inhibitors in patients with CKD (eGFR <60 mL/min/1.73m2) identified 12 studies of 24–84 weeks’ duration that included 4403 patients with CKD and 239 patients on chronic dialysis. This systematic review showed that DPP‐4 inhibitors reduced HbA1c by ~ 0.5%, without a higher rate of adverse events compared with placebo.58\n\n\n3.2 GLP‐1 receptor agonists\nGlucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have an incretin‐like action and control blood glucose levels through several pathways, including pancreatic stimulation of insulin secretion and inhibition of glucagon release along with delay in gastric emptying.59 Although clinical trials with primary outcomes of kidney disease endpoints have not yet been performed in patients with CKD, post hoc and secondary analyses of CVOTs have shown that treatment with GLP‐1 RAs is associated with reductions in albuminuria and stabilization of eGFR (liraglutide and semaglutide).60, 61, 62 A recent meta‐analysis of seven CVOTs that compared GLP‐1 RAs with placebo in 56 004 patients showed that these agents reduce the risk of macroalbuminuria.63 The broad composite kidney outcome was reduced by 17%, mainly driven by a reduction in macroalbuminuria. Furthermore, some GLP‐1 RAs (liraglutide, semaglutide, abiglutide, dulaglutide) have been associated with a reduction in the occurrence of MACE, particularly among patients with pre‐existing CVD, in addition to a reduced risk of all‐cause mortality.63\n\n\nSeveral recent CVOTs that evaluated GLP‐1 RAs included patients with CKD (Table 2). A prespecified secondary analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial evaluated kidney outcomes in 9340 patients with T2D and high CVD risk, including subgroups with CKD.61 The results showed that the addition of liraglutide to usual care resulted in a reduction in development and progression of CKD in patients with T2D and high CVD risk, compared with placebo. Subsequently, the AWARD‐7 trial (part of the Assessment of Weekly Administration of Dulaglutide in Diabetes clinical trial programme) evaluated glycaemic control and kidney disease outcomes in patients with T2D and moderate‐to‐severe CKD (categories 3 and 4). The results showed a favourable efficacy profile of dulaglutide compared with insulin glargine for glycaemic control in addition to other benefits, including lower rates of hypoglycaemia, weight loss, reduced decline in eGFR, and greater reduction in albuminuria.64 To date, AWARD‐7 is the only study that has been conducted in patients with T2D selected for moderate‐to‐severe CKD (mean baseline eGFR: 38 mL/min/1.73m2). Over 1 year of treatment, dulaglutide produced no significant eGFR decline (mean − 0.7 mL/min/1.73m2) compared with insulin glargine (mean − 3.3 mL/min/1.73m2 overall and mean − 5.5 mL/min/1.73m2 in the macroalbuminuric subgroup). An exploratory analysis of the AWARD‐7 data also showed the risk of a ≥ 40% eGFR decline and ESKD to be reduced by more than half with dulaglutide.64 In addition, a secondary analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial evaluated kidney outcomes in a population of patients with T2D and high CVD risk who received dulaglutide versus placebo, added to usual care.65 This secondary analysis showed a reduction in the progression of kidney disease associated with dulaglutide therapy, in particular a reduction in albuminuria and a greater than 50% reduced risk of an eGFR decline ≥40%. The role of these agents to reduce kidney disease outcomes in patients with T2D and CKD is being further evaluated in an ongoing clinical trial (A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153), with an estimated enrolment of 3160 patients (including participants with eGFR as low as 25 mL/min/1.73m2). The results of FLOW are expected in 2024.\n\nDulaglutide, liraglutide, semaglutide and lixisenatide can be used in patients with T2D and concomitant CKD without dose adjustment.66, 67, 68, 69 However, lixisenatide should not be used if eGFR <15 mL/min/1.73m2, and there are limited data for the use of liraglutide in patients with advanced CKD. Kidney function should be monitored if patients have severe adverse gastrointestinal reactions to treatment. For exenatide, caution is advised when treatment is initiated or the dose is escalated in those patients with moderate impairment of kidney function (creatinine clearance 30–50 mL/min).70, 71 Of note, twice‐daily and once‐weekly exenatide, as well as lixisenatide, should not be used in patients with ESKD or severe impairment of kidney function. In summary, GLP‐1 RAs can be used safely and effectively for glycaemic control in patients with T2D and advanced CKD. Lower doses may be considered to mitigate gastrointestinal side effects.\n\n4 HOW TO MANAGE PATIENTS WITH T2D AND ADVANCED CKD\nThe following case studies provide a clinical context and practical guidance for the use of incretin therapies as glucose‐lowering agents in patients with T2D and advanced CKD.\n\n4.1 4.1.1 Case 1: Advanced CKD\nA 66‐year‐old man with T2D was referred for assessment of glucose‐lowering therapy following worsening glycaemic control, symptomatic hypoglycaemia 2–3 times per week, and progression to severe CKD. The patient reported an increasingly sedentary lifestyle because of reduced physical activity following retirement, and worsening back and joint pain. He had a 15‐year history of T2D, in addition to hypertension, osteoarthritis and chronic obstructive pulmonary disease. His current medication regimen was glipizide extended‐release 10 mg once‐daily; ramipril 5 mg twice‐daily; and over‐the‐counter ibuprofen 200 mg taken three times daily. Key clinical data: blood pressure (BP) 139/77 mmHg, body mass index (BMI) 31.1 kg/m2, HbA1c 7.8%, fasting plasma glucose 151 mg/dL, eGFR 29 mL/min/1.73m2, UACR 220 mg/g, blood urea nitrogen 50 mg/mL, serum creatinine 2.3 mg/dL. The patient's glucose‐lowering therapy was changed to dulaglutide 1.5 mg weekly instead of glipizide, with the instruction to discontinue ibuprofen because of potential nephrotoxicity; the ramipril dose was unchanged. The patient was also advised to increase physical activity. After 6 months, HbA1c had fallen to 7.2%, eGFR was stable at 30 mL/min/1.73m2, UACR decreased to 50 mg/g, BP had fallen to 134/74 mmHg, and BMI was reduced to 29.3 kg/m2. He reported no symptoms of hypoglycaemia.\n\n4.1.2 Take home message\nIn patients with T2D and advanced CKD, hyperglycaemia can be safely and effectively managed by a GLP‐1 RA with stabilization of kidney function and reduction of albuminuria, along with improvements in CVD risk factors such as hypertension and obesity.\n\n4.1.3 Case 2: ESKD\nA 58‐year‐old woman with T2D and ESKD was referred from her dialysis centre after a hypoglycaemic event that caused her to fall and suffer a head injury with subdural haematoma. She was treated for T2D with Humulin 70/30 (human insulin isophane suspension and human insulin injection), 30 units in the morning and 20 units in the evening. HbA1c upon admission was 9.1%. For this patient, the treatment goals were to improve glycaemic control and avoid hypoglycaemia. Her medication regimen was changed to linagliptin 5 mg daily with insulin glargine 22 units on non‐dialysis days and 16 units administered after dialysis on those days. After 6 months, HbA1c was 7.2% and mild hypoglycaemia occurred rarely.\n\n4.1.4 Take home message\nFor patients with T2D on haemodialysis, a DPP‐4 inhibitor combined with lower doses of a longer‐acting insulin preparation can improve glycaemic control and reduce hypoglycaemic risk.\n\n5 CONCLUSIONS\nFor patients with T2D and advanced CKD, there is a need to better understand how to appropriately manage hyperglycaemia. The goal of treatment should be glycaemic control to targets based upon individual risk profiling as well as patient preferences and values. Treatment approaches should take into account the need to avoid hypoglycaemia, and to protect kidney function while reducing CVD risk. To date, there is a relative lack of data from clinical trials to inform choices of glucose‐lowering agents for this population. Although data are available for the use of incretin therapies, DPP‐4 inhibitors and GLP‐1 RAs, in patients with T2D and advanced CKD, additional studies are needed to establish optimal strategies for glycaemic control. Until such data are available, treatment regimens with currently available glucose‐lowering agents can be individually tailored to meet the needs of these patients.\n\nCONFLICT OF INTEREST\nKRT is a consultant for Eli Lilly and Company, Boehringer Ingelheim, Gilead Sciences, Goldfinch Bio, Bayer, Novo Nordisk and AstraZeneca. JBM reports non‐financial support from Boehringer Ingelheim; personal fees from Aegerion, Bayer, Boehringer Ingelheim, Gilead, Janssen and Novo Nordisk; grants and personal fees from Dexcom and Sanofi; grants from AstraZeneca, Medtronic and Novartis; and personal fees and non‐financial support from Mannkind.\n\nAUTHOR CONTRIBUTIONS\nThe authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors, and were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version that reflects the authors’ interpretations and conclusions.\n\nACKNOWLEDGMENTS\nSupport for this article was provided by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The authors received no direct compensation related to the development of the manuscript. Writing support was provided by Jennifer Garrett, MBBS, of Elevate Scientific Solutions, which was contracted and compensated by BIPI for this service.\n==== Refs\nREFERENCES\n1 \nUnited States Renal Data System \n. USRDS annual data report. Chapter 1. CKD in the general population. 2018 \nhttps://www.usrds.org/adr.aspx. Accessed November 5, 2019.\n2 \nKDOQI \n. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease\n. Am J Kidney Dis . 2007 ;49 :S12 ‐S154\n.17276798 \n3 \n\nDuru \nOK \n, \nMiddleton \nT \n, \nTewari \nMK \n, \nNorris \nK \n. The landscape of diabetic kidney disease in the United States\n. Curr Diab Rep . 2018 ;18 :14 .29457196 \n4 \n\nWu \nB \n, \nBell \nK \n, \nStanford \nA \n, et al. Understanding CKD among patients with T2DM: prevalence, temporal trends, and treatment patterns‐NHANES 2007‐2012\n. BMJ Open Diabetes Res Care . 2016 ;4 :e000154.\n5 \n\nAdler \nAI \n, \nStevens \nRJ \n, \nManley \nSE \n, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64)\n. Kidney Int . 2003 ;63 :225 ‐232\n.12472787 \n6 \n\nAfkarian \nM \n, \nSachs \nMC \n, \nKestenbaum \nB \n, et al. Kidney disease and increased mortality risk in type 2 diabetes\n. J Am Soc Nephrol . 2013 ;24 :302 ‐308\n.23362314 \n7 \nWorld Health Organisation \n. Global Report on Diabetes. 2016 \nhttps://www.who.int/diabetes/global-report/en/. Accessed 10 October, 2019.\n8 \n\nCorriere \nM \n, \nRooparinesingh \nN \n, \nKalyani \nRR \n. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden\n. Curr Diab Rep . 2013 ;13 :805 ‐813\n.24018732 \n9 \n\nRhee \nCM \n, \nKovesdy \nCP \n, \nRavel \nVA \n, et al. Association of glycemic status during progression of chronic kidney disease with early dialysis mortality in patients with diabetes\n. Diabetes Care . 2017 ;40 :1050 ‐1057\n.28592525 \n10 \n\nLevey \nAS \n, \nde Jong \nPE \n, \nCoresh \nJ \n, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report\n. Kidney Int . 2011 ;80 :17 ‐28\n.21150873 \n11 \n\nShurraw \nS \n, \nHemmelgarn \nB \n, \nLin \nM \n, et al. Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population‐based cohort study\n. Arch Intern Med . 2011 ;171 :1920 ‐1927\n.22123800 \n12 \n\nIglesias \nP \n, \nDiez \nJJ \n. Insulin therapy in renal disease\n. Diabetes Obes Metab . 2008 ;10 :811 ‐823\n.18248491 \n13 \n\nMorioka \nT \n, \nEmoto \nM \n, \nTabata \nT \n, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis\n. Diabetes Care . 2001 ;24 :909 ‐913\n.11347753 \n14 \n\nRicks \nJ \n, \nMolnar \nMZ \n, \nKovesdy \nCP \n, et al. Glycemic control and cardiovascular mortality in hemodialysis patients with diabetes: a 6‐year cohort study\n. Diabetes . 2012 ;61 :708 ‐715\n.22315308 \n15 \n\nBloomgarden \nZ \n, \nHandelsman \nY \n. How does CKD affect HbA1c?\n\nJ Diabetes . 2018 ;10 :270 .29124865 \n16 \n\nJung \nM \n, \nWarren \nB \n, \nGrams \nM \n, et al. Performance of non‐traditional hyperglycemia biomarkers by chronic kidney disease status in older adults with diabetes: Results from the Atherosclerosis Risk in Communities Study\n. J Diabetes . 2018 ;10 :276 ‐285\n.29055090 \n17 \nAmerican Diabetes Association \n. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes‐2019\n. Diabetes Care . 2019 ;42 :S90 ‐S102\n.30559235 \n18 \n\nGarber \nAJ \n, \nAbrahamson \nMJ \n, \nBarzilay \nJI \n, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm ‐ 2019 Executive Summary\n. Endocr Pract . 2019 ;25 :69 ‐100\n.30742570 \n19 \nKDOQI \nClinical Practice Guidelines for Diabetes and CKD: 2012 Update. 2012 \nhttps://www.kidney.org/sites/default/files/docs/diabetes-ckd-update-2012.pdf. Accessed 3 October, 2019.\n20 \n\nShivaswamy \nV \n, \nBoerner \nB \n, \nLarsen \nJ \n. Post‐transplant diabetes mellitus: causes, treatment, and impact on outcomes\n. Endocr Rev . 2016 ;37 :37 ‐61\n.26650437 \n21 \n\nMoen \nMF \n, \nZhan \nM \n, \nHsu \nVD \n, et al. Frequency of hypoglycemia and its significance in chronic kidney disease\n. Clin J Am Soc Nephrol . 2009 ;4 :1121 ‐1127\n.19423569 \n22 \n\nCersosimo \nE \n, \nGarlick \nP \n, \nFerretti \nJ \n. Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans\n. Diabetes . 2000 ;49 :1186 ‐1193\n.10909977 \n23 \n\nHaviv \nYS \n, \nSharkia \nM \n, \nSafadi \nR \n. Hypoglycemia in patients with renal failure\n. Ren Fail . 2000 ;22 :219 ‐223\n.10803766 \n24 \n\nLo \nC \n, \nToyama \nT \n, \nWang \nY \n, et al. Insulin and glucose‐lowering agents for treating people with diabetes and chronic kidney disease\n. Cochrane Database Syst Rev . 2018 ;9 :CD011798.30246878 \n25 \n\nRosenstock \nJ \n, \nPerkovic \nV \n, \nAlexander \nJH \n, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA([R])): a randomized, double‐blind, placebo‐controlled clinical trial in patients with type 2 diabetes and high cardio‐renal risk\n. Cardiovasc Diabetol . 2018 ;17 :39 .29540217 \n26 \n\nWeinrauch \nLA \n, \nD'Elia \nJA \n, \nFinn \nP \n, et al. Strategies for glucose control in a study population with diabetes, renal disease and anemia (Treat study)\n. Diabetes Res Clin Pract . 2016 ;113 :143 ‐151\n.26830074 \n27 \n\nSechi \nLA \n, \nCatena \nC \n, \nZingaro \nL \n, \nMelis \nA \n, \nDe Marchi \nS \n. Abnormalities of glucose metabolism in patients with early renal failure\n. Diabetes . 2002 ;51 :1226 ‐1232\n.11916949 \n28 \n\nBetonico \nCC \n, \nTitan \nSMO \n, \nLira \nA \n, et al. Insulin glargine U100 improved glycemic control and reduced nocturnal hypoglycemia in patients with type 2 diabetes mellitus and chronic kidney disease stages 3 and 4\n. Clin Ther . 2019 ;41 :2008 ‐2020\n.31383366 \n29 \n\nArjona Ferreira \nJC \n, \nCorry \nD \n, \nMogensen \nCE \n, et al. Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54‐week randomized trial\n. Am J Kidney Dis . 2013 ;61 :579 ‐587\n.23352379 \n30 \n\nArjona Ferreira \nJC \n, \nMarre \nM \n, \nBarzilai \nN \n, et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate‐to‐severe chronic renal insufficiency\n. Diabetes Care . 2013 ;36 :1067 ‐1073\n.23248197 \n31 \n\nGraham \nGG \n, \nPunt \nJ \n, \nArora \nM \n, et al. Clinical pharmacokinetics of metformin\n. Clin Pharmacokinet . 2011 ;50 :81 ‐98\n.21241070 \n32 \n\nKajbaf \nF \n, \nArnouts \nP \n, \nde Broe \nM \n, \nLalau \nJD \n. Metformin therapy and kidney disease: a review of guidelines and proposals for metformin withdrawal around the world\n. Pharmacoepidemiol Drug Saf . 2013 ;22 :1027 ‐1035\n.23960029 \n33 \n\nSalpeter \nSR \n, \nGreyber \nE \n, \nPasternak \nGA \n, \nSalpeter \nEE \n. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus\n. Cochrane Database Syst Rev . 2010 ;14 :CD002967.\n34 \nFDA Drug Safety Communication \n: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. 2016 \nhttps://www.fda.gov/drugs/drug‐safety‐and‐availability/fda‐drug‐safety‐communication‐fda‐revises‐warnings‐regarding‐use‐diabetes‐medicine‐metformin‐certain. Accessed 16 October, 2019 .\n35 \n\nCharytan \nDM \n, \nSolomon \nSD \n, \nIvanovich \nP \n, et al. Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease\n. Diabetes Obes Metab . 2019 ;21 :1199 ‐1208\n.30672083 \n36 \n\nMcCallum \nL \n, \nSenior \nPA \n. Safe use of metformin in adults with type 2 diabetes and chronic kidney disease: lower doses and sick‐day education are essential\n. Can J Diabetes . 2019 ;43 :76 ‐80\n.30061044 \n37 \nBristol‐Myers Squibb \n. Glucophage (metformin). Highlights of prescribing information. 2018 ; https://packageinserts.bms.com/pi/pi_glucophage.pdf. Accessed 16 October, 2019 .\n38 \n\nWang \nW \n, \nZhou \nX \n, \nKwong \nJSW \n, \nLi \nL \n, \nLi \nY \n, \nSun \nX \n. Efficacy and safety of thiazolidinediones in diabetes patients with renal impairment: a systematic review and meta‐analysis\n. Sci Rep . 2017 ;7 :1717 .28496176 \n39 \n\nBudde \nK \n, \nNeumayer \nHH \n, \nFritsche \nL \n, \nSulowicz \nW \n, \nStompor \nT \n, \nEckland \nD \n. The pharmacokinetics of pioglitazone in patients with impaired renal function\n. Br J Clin Pharmacol . 2003 ;55 :368 ‐374\n.12680885 \n40 \nAccord Healthcare Inc \n. Pioglitazone. Highlights of prescribing information. 2017 ; https://www.accordhealthcare.us/uploads/Pioglitazone_PIL.pdf. Accessed 16 October, 2019.\n41 \n\nSatirapoj \nB \n, \nWatanakijthavonkul \nK \n, \nSupasyndh \nO \n. Safety and efficacy of low dose pioglitazone compared with standard dose pioglitazone in type 2 diabetes with chronic kidney disease: A randomized controlled trial\n. PLoS One . 2018 ;13 :e0206722.30379936 \n42 \n\nGalle \nJ \n, \nKleophas \nW \n, \nDellanna \nF \n, et al. Comparison of the Effects of Pioglitazone versus Placebo when Given in Addition to Standard Insulin Treatment in Patients with Type 2 Diabetes Mellitus Requiring Hemodialysis: Results from the PIOren Study\n. Nephron Extra . 2012 ;2 :104 ‐114\n.22739963 \n43 \n\nKahn \nSE \n, \nZinman \nB \n, \nLachin \nJM \n, et al. Rosiglitazone‐associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT)\n. Diabetes Care . 2008 ;31 :845 ‐851\n.18223031 \n44 \n\nScheen \nAJ \n. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease\n. Clin Pharmacokinet . 2015 ;54 :691 ‐708\n.25805666 \n45 \nJanssen Pharmaceutical Companies \n. Invokana (canagliflozin). Highlights of prescribing information. 2019 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204042s032lbl.pdf. Accessed 18 November, 2019.\n46 \n\nPerkovic \nV \n, \nJardine \nMJ \n, \nNeal \nB \n, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy\n. N Engl J Med . 2019 ;380 :2295 ‐2306\n.30990260 \n47 \nTakeda Pharmaceuticals \n. Nesina (aloglitin). Highlights of prescribing information. 2019 \nhttps://general.takedapharm.com/NESINAPI. Accessed 3 October, 2019.\n48 \n\nMerck \nSharp \n & \nDohme \nCorp \n. Januvia (sitagliptin). Highlights of prescribing information. 2019 \nhttps://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed 3 October, 2019.\n49 \nAstraZeneca Pharmaceuticals \n. Onglyza (saxagliptin). Highlights of prescribing information. 2019 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022350s023lbl.pdf. Accessed 3 October, 2019.\n50 \nBoehringer Ingelheim Pharmaceuticals I \n. Tradjenta (linagliptin). Highlights of prescribing information. 2019 \nhttps://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Tradjenta/Tradjenta.pdf. Accessed 3 October, 2019.\n51 \n\nRosenstock \nJ \n, \nPerkovic \nV \n, \nJohansen \nOE \n, et al. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial\n. JAMA . 2019 ;321 :69 ‐79\n.30418475 \n52 \n\nMcGill \nJB \n, \nSloan \nL \n, \nNewman \nJ \n, et al. Long‐term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1‐year, randomized, double‐blind, placebo‐controlled study\n. Diabetes Care . 2013 ;36 :237 ‐244\n.23033241 \n53 \n\nUdell \nJA \n, \nBhatt \nDL \n, \nBraunwald \nE \n, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR‐TIMI 53 Trial\n. Diabetes Care . 2015 ;38 :696 ‐705\n.25552421 \n54 \n\nLukashevich \nV \n, \nSchweizer \nA \n, \nShao \nQ \n, \nGroop \nPH \n, \nKothny \nW \n. Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24‐week randomized placebo‐controlled trial\n. Diabetes Obes Metab . 2011 ;13 :947 ‐954\n.21733061 \n55 \n\nKothny \nW \n, \nShao \nQ \n, \nGroop \nPH \n, \nLukashevich \nV \n. One‐year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment\n. Diabetes Obes Metab . 2012 ;14 :1032 ‐1039\n.22690943 \n56 \n\nMera \nJ \n, \nOkada \nE \n, \nOkuda \nM \n, \nOta \nT \n, \nSibata \nS \n, \nUchida \nS \n. Long‐term efficacy of vildagliptin in patients with type 2 diabetes undergoing hemodialysis\n. J Diabetes Metab Disord . 2015 ;14 :83 .26550558 \n57 \n\nPark \nSH \n, \nNam \nJY \n, \nHan \nE \n, et al. Efficacy of different dipeptidyl peptidase‐4 (DPP‐4) inhibitors on metabolic parameters in patients with type 2 diabetes undergoing dialysis\n. Medicine . 2016 ;95 :e4543.27512877 \n58 \n\nWalker \nSR \n, \nKomenda \nP \n, \nKhojah \nS \n, et al. Dipeptidyl peptidase‐4 inhibitors in chronic kidney disease: a systematic review of randomized clinical trials\n. Nephron . 2017 ;136 :85 ‐94\n.28178698 \n59 \n\nvan Baar \nMJB \n, \nvan der Aart \nAB \n, \nHoogenberg \nK \n, \nJoles \nJA \n, \nHeerspink \nHJL \n, \nvan Raalte \nDH \n. The incretin pathway as a therapeutic target in diabetic kidney disease: a clinical focus on GLP‐1 receptor agonists\n. Ther Adv Endocrinol Metab . 2019 ;10 :2042018819865398.31384419 \n60 \n\nVerma \nS \n, \nBain \nSC \n, \nMonk Fries \nT \n, et al. Duration of diabetes and cardiorenal efficacy of liraglutide and semaglutide: A post hoc analysis of the LEADER and SUSTAIN 6 clinical trials\n. Diabetes Obes Metab . 2019 ;21 :1745 ‐1751\n.30851070 \n61 \n\nMann \nJFE \n, \nOrsted \nDD \n, \nBrown‐Frandsen \nK \n, et al. Liraglutide and renal outcomes in type 2 diabetes\n. N Engl J Med . 2017 ;377 :839 ‐848\n.28854085 \n62 \n\nMarso \nSP \n, \nBain \nSC \n, \nConsoli \nA \n, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes\n. N Engl J Med . 2016 ;375 :1834 ‐1844\n.27633186 \n63 \n\nGiugliano \nD \n, \nMaiorino \nMI \n, \nBellastella \nG \n, \nLongo \nM \n, \nChiodini \nP \n, \nEsposito \nK \n. GLP‐1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: An updated meta‐analysis including the REWIND and PIONEER 6 trials\n. Diabetes Obes Metab . 2019 ;21 :2576 ‐2580\n.31373167 \n64 \n\nTuttle \nKR \n, \nLakshmanan \nMC \n, \nRayner \nB \n, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate‐to‐severe chronic kidney disease (AWARD‐7): a multicentre, open‐label, randomised trial\n. Lancet Diabetes Endocrinol . 2018 ;6 :605 ‐617\n.29910024 \n65 \n\nGerstein \nHC \n, \nColhoun \nHM \n, \nDagenais \nGR \n, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo‐controlled trial\n. Lancet . 2019 ;394 :131 ‐138\n.31189509 \n66 \nEli Lilly and Company \n. Trulicity (dulaglutide). Highlights of prescribing information. 2019 \nhttp://pi.lilly.com/us/trulicity-uspi.pdf. Accessed 1 October, 2019.\n67 \nNovo Nordisk \n. Victoza (liraglutide). Highlights of prescribing information. 2019 \nhttps://www.novo-pi.com/victoza.pdf. Accessed 1 October, 2019.\n68 \nSanofi‐Aventis \n. Adlyxyn (lixisenatide). Highlights of prescribing information. 2019. http://products.sanofi.us/Adlyxin/Adlyxin.pdf. Accessed 1 October, 2019 .\n69 \nNovo Nordisk \n. Ozempic (semaglutide). Highlights of prescribing information. 2019 \nhttps://www.novo-pi.com/ozempic.pdf. Accessed 27 November, 2019.\n70 \nFDA \n. Byetta (exenatide). Highlights of prescribing information. 2009 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf. Accessed 1 October, 2019.\n71 \nFDA \n. Bydureon. Highlights of prescribing information. 2012 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022200s000lbl.pdf. Accessed 1 October, 2019.\n72 \n\nLeiter \nLA \n, \nCarr \nMC \n, \nStewart \nM \n, et al. Efficacy and safety of the once‐weekly GLP‐1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study\n. Diabetes Care . 2014 ;37 :2723 ‐2730\n.25048383\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1462-8902",
"issue": "22(7)",
"journal": "Diabetes, obesity & metabolism",
"keywords": "cardiovascular disease; dipeptidyl peptidase-4 inhibitors; glucagon-like peptide-1 receptor agonists; glycaemic control; hyperglycaemia",
"medline_ta": "Diabetes Obes Metab",
"mesh_terms": "D003924:Diabetes Mellitus, Type 2; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D006943:Hyperglycemia; D007004:Hypoglycemic Agents; D054795:Incretins; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "100883645",
"other_id": null,
"pages": "1014-1023",
"pmc": null,
"pmid": "32009296",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "28592525;18248491;31384419;30379936;23362314;12680885;22123800;22739963;21150873;30246878;30559235;23352379;30061044;22315308;24018732;10909977;22690943;28178698;28496176;26830074;21241070;19423569;21733061;26550558;27512877;27633186;30672083;29540217;11916949;12472787;31383366;23960029;30990260;25552421;25048383;30742570;10803766;30851070;20393934;29457196;28854085;30418475;18223031;23033241;29910024;31189509;26650437;17276798;31373167;29055090;32009296;11347753;23248197;27110365;25805666;29124865",
"title": "Evidence-based treatment of hyperglycaemia with incretin therapies in patients with type 2 diabetes and advanced chronic kidney disease.",
"title_normalized": "evidence based treatment of hyperglycaemia with incretin therapies in patients with type 2 diabetes and advanced chronic kidney disease"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP008639",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RAMIPRIL"
},
"drugadditional":... |
{
"abstract": "Tyrosine kinase inhibitors (TKIs) have changed the landscape of treatment for patients with chronic myeloid leukemia (CML) leading to a life expectancy comparable to the general population. Side effects commonly encountered during TKI treatment are pleural effusion due to use of dasatinib and vascular side effects due to nilotinib and ponatinib. Coronary artery spasm (CAS), although encountered during treatment with other chemotherapeutic drugs, have to our knowledge never been reported during TKI treatment. Here, we describe two cases of coronary artery spasms which are likely due to TKIs.",
"affiliations": "Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.",
"authors": "Fiets|R B|RB|;Staal|A H J|AHJ|;Cramer|G E|GE|;Blijlevens|N M A|NMA|",
"chemical_list": "D000970:Antineoplastic Agents; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "76(7)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000970:Antineoplastic Agents; D003329:Coronary Vasospasm; D000069439:Dasatinib; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "330-335",
"pmc": null,
"pmid": "30220658",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coronary artery spasms due to tyrosine kinase inhibitors used in chronic myeloid leukemia.",
"title_normalized": "coronary artery spasms due to tyrosine kinase inhibitors used in chronic myeloid leukemia"
} | [
{
"companynumb": "NL-PFIZER INC-2018422423",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DASATINIB"
},
"drugadditional": "1",
... |
{
"abstract": "Intra-arterial injection of sclerosants is a significant but uncommon complication of sclerotherapy that may result in extensive tissue necrosis and in rare cases digit or limb amputation. We have managed three cases in the past 10 years. One patient was referred for immediate treatment following intra-arterial injection of liquid polidocanol. The other two had undergone foam sclerotherapy with polidocanol and sodium tetradecyl sulphate, respectively. All patients were treated with a combination of oral steroids (prednisone 0.5-1 mg/kg) and systemic anticoagulants (enoxaparin 1.5 mg/kg daily subcutaneous injection). One case progressed to skin ulceration where prednisone was started five days after the adverse event and prematurely stopped after four weeks. The other cases did not progress to necrosis or other long-term sequelae. In these patients, prednisone was commenced immediately and slowly reduced over the following 12 weeks. The inflammation that follows ischemia plays a significant role in tissue necrosis and the immediate management of this adverse event may benefit from anti-inflammatory measures and in particular systemic steroid therapy unless contraindicated.",
"affiliations": "Dermatology, Phlebology and Fluid Mechanics Research Laboratory, St Vincent's Centre for Applied Medical Research (AMR), St. Vincent's Hospital, Sydney, Australia Department of Dermatology, St. Vincent's Hospital, Sydney, Australia University of New South Wales, Sydney, Australia kparsi@stvincents.com.au.;Dermatology, Phlebology and Fluid Mechanics Research Laboratory, St Vincent's Centre for Applied Medical Research (AMR), St. Vincent's Hospital, Sydney, Australia University of New South Wales, Sydney, Australia.",
"authors": "Parsi|Kurosh|K|;Hannaford|Patricia|P|",
"chemical_list": "D017984:Enoxaparin; D012597:Sclerosing Solutions; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1177/0268355515578988",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3555",
"issue": "31(4)",
"journal": "Phlebology",
"keywords": "Sclerosants; foam; intra-arterial injections; sclerotherapy; steroids",
"medline_ta": "Phlebology",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D017984:Enoxaparin; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D008875:Middle Aged; D011239:Prednisolone; D012597:Sclerosing Solutions; D014648:Varicose Veins",
"nlm_unique_id": "9012921",
"other_id": null,
"pages": "241-50",
"pmc": null,
"pmid": "25837790",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intra-arterial injection of sclerosants: Report of three cases treated with systemic steroids.",
"title_normalized": "intra arterial injection of sclerosants report of three cases treated with systemic steroids"
} | [
{
"companynumb": "AU-MERZ NORTH AMERICA, INC.-15MRZ-00159",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "POLIDOCANOL"
},
"drugadditiona... |
{
"abstract": "Intravascular lymphoma is a rare disease that progresses to multiple organ dysfunction caused primarily by tumor cell proliferation in small blood vessels. Few studies have investigated critical care management of intravascular lymphoma. We describe a rare case of multiple organ failure due to intravascular lymphoma with severe lactic acidosis in a patient who survived. A 64-year-old man with impaired consciousness was diagnosed as having intravascular large B-cell lymphoma by means of a random skin biopsy. The patient arrived at our hospital's intensive care unit (ICU) with impaired consciousness, respiratory failure that required mechanical ventilation, and lactic acidosis that required renal replacement therapy. Mechanical ventilation and renal replacement therapy were continued in the ICU, and his respiratory status and circulatory dynamics eventually stabilized. However, his impaired consciousness and hyperlactatemia did not improve until after the start of chemotherapy with doxorubicin, cyclophosphamide, vincristine, prednisolone, and rituximab. Although he developed tumor lysis syndrome immediately after chemotherapy, his systemic condition was gradually stabilized by continued critical care management primarily comprising renal replacement therapy. He was weaned from ventilator support after a tracheotomy and moved to the general ward. Hematopoietic malignancy with hyperlactatemia has a very poor prognosis; however, hyperlactatemia and impaired consciousness were dramatically improved in this patient by critical care management and chemotherapy.",
"affiliations": "Department of Anesthesiology, Nippon Medical School.;Department of Anesthesiology, Nippon Medical School.;Department of Anesthesiology, Nippon Medical School.;Department of Anesthesiology, Nippon Medical School.;Department of Surgical Intensive Care, Nippon Medical School.;Department of Anesthesiology, Nippon Medical School.",
"authors": "Mase|Hiroshi|H|;Ogawa|Yutaro|Y|;Takeuchi|Jumpei|J|;Genda|Yuki|Y|;Ichiba|Shingo|S|;Sakamoto|Atsuhiro|A|",
"chemical_list": "D019344:Lactic Acid; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.1272/jnms.JNMS.2019_86-606",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1345-4676",
"issue": "87(1)",
"journal": "Journal of Nippon Medical School = Nippon Ika Daigaku zasshi",
"keywords": "chemotherapy; critical care; lactic acidosis; lymphoma; renal replacement therapy",
"medline_ta": "J Nippon Med Sch",
"mesh_terms": "D000138:Acidosis; D000971:Antineoplastic Combined Chemotherapy Protocols; D003422:Critical Care; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D019344:Lactic Acid; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D011239:Prednisolone; D017582:Renal Replacement Therapy; D000069283:Rituximab; D012720:Severity of Illness Index; D015275:Tumor Lysis Syndrome; D019043:Vascular Neoplasms; D014750:Vincristine",
"nlm_unique_id": "100935589",
"other_id": null,
"pages": "32-36",
"pmc": null,
"pmid": "31308316",
"pubdate": "2020-03-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Intensive Care Treatment of Severe Lactic Acidosis and Tumor Lysis Syndrome Related to Intravascular Lymphoma.",
"title_normalized": "successful intensive care treatment of severe lactic acidosis and tumor lysis syndrome related to intravascular lymphoma"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-242578",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"dru... |
{
"abstract": "To describe a case of zonisamide-induced bilateral choroidal effusion.\n\n\n\nA 72-year-old woman presented with a 4-day history of bilateral blurred vision 9 days after initiating oral zonisamide for essential tremor. Clinical examination revealed an asymmetric choroidal detachment with open anterior chamber angle and intraocular pressure within the normal range. Posterior segment ultrasonography and ultrasound biomicroscopy both confirmed the presence of bilateral ciliochoroidal effusion. Zonisamide treatment was discontinued. One month after treatment discontinuation, the ophthalmological examination was normal and no further treatment was needed.\n\n\n\nZonisamide can cause an idiosyncratic reaction leading to choroidal effusion with or without acute angle closure. Early withdrawal of the causative agent is the key to reversing this condition. These findings indicate that zonisamide and other sulfa-derived drugs must be ruled out in the differential diagnosis of choroidal effusion of unknown cause.",
"affiliations": "Bellvitge University Hospital, Barcelona, Spain.",
"authors": "Baradad Jurjo|Maria C|MC|;Sanz Moreno|Sílvia|S|;Moix Gil|Eugènia|E|;Lillo Sopena|Juan|J|;Caminal Mitjana|Josep M|JM|",
"chemical_list": "D000927:Anticonvulsants; D000078305:Zonisamide",
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000001596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "29(9)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D000080324:Choroidal Effusions; D005260:Female; D006801:Humans; D007429:Intraocular Pressure; D033401:Microscopy, Acoustic; D014786:Vision Disorders; D000078305:Zonisamide",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "e100-e102",
"pmc": null,
"pmid": "32649452",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Zonisamide-induced Choroidal Effusion: A Case Report.",
"title_normalized": "zonisamide induced choroidal effusion a case report"
} | [
{
"companynumb": "ES-BION-008870",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZONISAMIDE"
},
"drugadditional": "1",
"drugadm... |
{
"abstract": "Ultra-deep sequencing (UDS) allows detection of minority resistant variants (MRVs) with a threshold of 1% and could be useful to identify variants harbouring single or multiple drug-resistance mutations (DRMs).\n\n\n\nWe analysed the integrase gene region longitudinally using UDS in an HIV-1-infected child rapidly failing a raltegravir-based regimen.\n\n\n\nLongitudinal plasma samples at baseline and weeks 4, 8, 13, 17 and 39 were obtained, as well as the mother's baseline plasma sample. Sanger sequencing and UDS were performed on the integrase gene using Roche 454 GS-Junior. A bioinformatic workflow was developed to identify the major DRMs, accessory mutations and the linkage between mutations.\n\n\n\nIn Sanger sequencing and UDS, no MRV in the integrase gene was detected at baseline in either the mother or the child. The major DRM N155H conferring resistance to raltegravir and elvitegravir was detected in 4% of the sequences by week 4 using UDS, whereas it was not detected by Sanger sequencing. The double mutant E92Q + N155H, conferring resistance to the entire integrase inhibitor class, including dolutegravir, emerged at week 8 (16%) and became rapidly dominant (57% by week 13). At the last timepoint under raltegravir (week 17), Y143R emerged, leading to different resistance mutation patterns: single mutants N155H (47%) and Y143R (24%) and double mutants E92Q + N155H (13%), Y143R + N155H (2%) and E92Q + Y143R (2%). The polymorphic substitution M50I was preferentially selected on resistant variants, especially on E92Q + N155H variants.\n\n\n\nThis case study illustrates the usefulness of UDS in detecting early MRVs and determining the dynamics of selected HIV-1 variants in longitudinal analysis.",
"affiliations": "Inserm U966, Université François Rabelais, Tours, France.;Inserm U941, Université Paris Diderot, Paris, France.;Inserm U941, Université Paris Diderot, Paris, France.;Inserm U941, Université Paris Diderot, Paris, France.;CHU Bretonneau, Médecine Interne et Maladies Infectieuses, Tours, France.;Inserm U941, Université Paris Diderot, Paris, France.;CHU Bretonneau, Médecine Interne et Maladies Infectieuses, Tours, France.;Inserm U941, Université Paris Diderot, Paris, France.;Inserm U966, Université François Rabelais, Tours, France.;Inserm U941, Université Paris Diderot, Paris, France.",
"authors": "Stefic|Karl|K|;Salmona|Maud|M|;Capitao|Marisa|M|;Splittgerber|Marion|M|;Maakaroun-Vermesse|Zoha|Z|;Néré|Marie-Laure|ML|;Bernard|Louis|L|;Chaix|Marie-Laure|ML|;Barin|Francis|F|;Delaugerre|Constance|C|",
"chemical_list": "D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D015363:Quinolones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; C509700:elvitegravir; C562325:dolutegravir; D019427:HIV Integrase",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkw507",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "72(3)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D002648:Child; D024882:Drug Resistance, Viral; D015658:HIV Infections; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D015363:Quinolones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D012641:Selection, Genetic",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "850-854",
"pmc": null,
"pmid": "27999055",
"pubdate": "2017-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unravelling the dynamics of selection of multiresistant variants to integrase inhibitors in an HIV-1-infected child using ultra-deep sequencing.",
"title_normalized": "unravelling the dynamics of selection of multiresistant variants to integrase inhibitors in an hiv 1 infected child using ultra deep sequencing"
} | [
{
"companynumb": "FR-VIIV HEALTHCARE LIMITED-FR2017GSK163155",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARUNAVIR\\RITONAVIR"
},
"dr... |
{
"abstract": "IntroductionLamotrigine is a commonly used drug in the treatment of bipolar disorder. Although there are reports of its effectiveness in the management of bipolar disorder and comorbid obsessive-compulsive disorder (OCD), lamotrigine has also been associated with obsessionality in patients with bipolar disorder.\n\n\n\nCharts of 8 patients with bipolar disorder who had de novo onset of obsessions and compulsions after the use of lamotrigine were reviewed. The Naranjo scale was used to assess the likelihood of patients developing OCD due to lamotrigine use.\n\n\n\nTwo to 8 months after the initiation of lamotrigine, patients with no such prior history developed obsessions and compulsions meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for medication-induced OCD. In all except 1 patient, the symptoms resolved within a month of lamotrigine discontinuation.\n\n\n\nSome patients with bipolar disorder may develop OCD after initiation of lamotrigine. Due to the inherent limitations of a case series, the findings should be interpreted with caution.",
"affiliations": "Department of Psychiatry and Obstetrics & Gynecology,University of Western Ontario,London,Ontario,Canada.;Parkwood Mental Health Building,St. Joseph's Health Care,London,Ontario,Canada.",
"authors": "Sharma|Verinder|V|;Doobay|Minakshi|M|",
"chemical_list": "D014150:Antipsychotic Agents; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1017/S1092852918001049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-8529",
"issue": "24(4)",
"journal": "CNS spectrums",
"keywords": "Antipsychotic; bipolar disorder; comorbidity; lamotrigine; obsessive compulsive disorder",
"medline_ta": "CNS Spectr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder",
"nlm_unique_id": "9702877",
"other_id": null,
"pages": "390-394",
"pmc": null,
"pmid": "30086812",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lamotrigine-induced obsessive-compulsive disorder in patients with bipolar disorder.",
"title_normalized": "lamotrigine induced obsessive compulsive disorder in patients with bipolar disorder"
} | [
{
"companynumb": "CA-TEVA-2019-CA-1105352",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOPICLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Hepatitis B virus reactivation (HBV-R), which can lead to HBV-related morbidity and mortality, is a common and well-known complication that occurs during the treatment of non-Hodgkin lymphoma (NHL) patients with current or past exposure to HBV infection. HBV-R is thought to be closely associated with chemotherapeutic or immunosuppressive therapies. However, immunosuppressive agents such as anti-CD20 antibodies (e.g., rituximab and ofatumumab), glucocorticoids, and hematopoietic stem cell transplantation (HSCT) administered to NHL patients during treatment can cause deep immunodepression and place them at high risk of HBV-R. In this review, we explore the current evidence, the guidelines of several national and international organizations, and the recommendations of expert panels relating to the definition, risk factors, screening and monitoring strategies, whether to use prophylaxis or pre-emptive therapy, and the optimal antiviral agent and duration of antiviral therapy for HBV-R.",
"affiliations": "Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Respiratory and Critical Care Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"authors": "Cao|Xing|X|;Wang|Yafei|Y|;Li|Panyun|P|;Huang|Wei|W|;Lu|Xiaojuan|X|;Lu|Hongda|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.685706",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.685706\nOncology\nReview\nHBV Reactivation During the Treatment of Non-Hodgkin Lymphoma and Management Strategies\nCao Xing 1 †\n\nWang Yafei 2 †\nLi Panyun 1\nHuang Wei 1\nLu Xiaojuan 1\nLu Hongda 1 *\n1 Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China\n2 Department of Respiratory and Critical Care Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China\nEdited by: Luca Arcaini, University of Pavia, Italy\n\nReviewed by: Guido Gini, Azienda Ospedaliero Universitaria Ospedali Riuniti, Italy\n\n*Correspondence: Hongda Lu, phlonda@163.com\n†These authors have contributed equally to this work and share first authorship\n\nThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n01 7 2021\n2021\n11 68570625 3 2021\n16 6 2021\nCopyright © 2021 Cao, Wang, Li, Huang, Lu and Lu\n2021\nCao, Wang, Li, Huang, Lu and Lu\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nHepatitis B virus reactivation (HBV-R), which can lead to HBV-related morbidity and mortality, is a common and well-known complication that occurs during the treatment of non-Hodgkin lymphoma (NHL) patients with current or past exposure to HBV infection. HBV-R is thought to be closely associated with chemotherapeutic or immunosuppressive therapies. However, immunosuppressive agents such as anti-CD20 antibodies (e.g., rituximab and ofatumumab), glucocorticoids, and hematopoietic stem cell transplantation (HSCT) administered to NHL patients during treatment can cause deep immunodepression and place them at high risk of HBV-R. In this review, we explore the current evidence, the guidelines of several national and international organizations, and the recommendations of expert panels relating to the definition, risk factors, screening and monitoring strategies, whether to use prophylaxis or pre-emptive therapy, and the optimal antiviral agent and duration of antiviral therapy for HBV-R.\n\nhepatitis B virus reactivation (HBV-R)\nrisk factors\nantiviral prophylaxis\nnon-Hodgkin lymphoma (NHL)\nrituximab\nimmunosuppressive therapy\n==== Body\nIntroduction\n\nHepatitis B virus (HBV) is a double-stranded DNA virus belonging to the family Hepadnaviridae (1). HBV infection has reached epidemic proportions globally. It is estimated that over one-third of the world’s population has been infected with HBV, with approximately 248 million of them suffering from chronic infection (2, 3). Compared with uninfected individuals, those infected with HBV have a 2–3-fold greater risk of developing non-Hodgkin’s lymphoma (NHL), particularly diffuse large B-cell lymphoma (DLBCL), which represents the major NHL subtype (4–9). Although the mechanism underlying this phenomenon remains unclear, it is likely to be due to the hepatotropic and lymphotropic nature of HBV, which can assure HBV replication in lymphoid tissue (10–12). Interestingly, it has been reported that HBV infection is uncorrelated with Hodgkin’s lymphoma (HL) (13, 14). HBV reactivation (HBV-R) is defined as resolved/occult HBV that becomes active again, leading to adverse consequences. Occult HBV infection is characterized by the presence of replication-competent HBV DNA (i.e., covalently closed circular DNA [cccDNA] comprising the episomal HBV genome) in the liver and/or blood of hepatitis B surface antigen (HBsAg)-negative individuals as determined by currently available assays (15). Over recent years, a close link has been established between HBV-R and cytotoxic chemotherapeutic drugs, such as anthracyclines, cyclophosphamide, vincristine, and prednisone, as well as anti-CD20 monoclonal antibody therapy (e.g., rituximab) (16–21). Nevertheless, an R-CHOP regimen comprising rituximab, anthracyclines, cyclophosphamide, vincristine, and prednisone is now widely used as the first-line treatment for NHL, highlighting the need to be vigilant for HBV-R in concerned patients. The rate of HBV-R in HBsAg(+) patients who undergo rituximab-containing therapy is reported to range from 33 to 65% and between 6 and 24% in those negative for HBsAg and positive for anti-hepatitis B core antibody (HBcAb), respectively (22). The clinical manifestations of HBV-R can vary from asymptomatic hepatitis to lethal liver failure (23). Additionally, patients with HBV-R may postpone scheduled chemotherapy or present with abnormal liver function, leading to adverse effects on treatment outcome for the primary disease (24, 25). There are no standard screening, monitoring, or management strategies for HBV-R, and recommendations for the clinical management of HBV-R for patients treated with R-CHOP differ among institutions. Here, we review the recent literature relating to HBV-R, as the appropriate and timely identification of HBV-R, as well as suitable strategies for its management, remain crucial for improving the quality of life of NHL patients.\n\nDefinition of HBV-R\n\nNo uniform criteria for the definition of HBV-R currently exist and different guidelines have heterogeneous definitions for HBV-R diagnosis and management. The American Association for the Study of Liver Diseases (AASLD), the Asian Pacific Association for the Study of the Liver (APASL), and the American Gastroenterological Association (AGA) give clear definitions of HBV-R (26–28), whereas the European Association for the Study of the Liver (EASL) does not (29). Table 1 summarizes the definitions of HBV-R based on the different guidelines. Additionally, the AASLD also provides explicit concepts for HBV-associated hepatitis, namely, acute serum alanine aminotransferase (ALT) levels ≥3-fold higher than that at baseline and an absolute value >100 U/L (26). Interestingly, it has been reported that monitoring ALT levels can lead to the earlier detection of HBV-R because ALT levels increase 2–3 weeks before a rise in HBV DNA levels is detected (31).\n\nTable 1 Definition of HBV-R according to different guidelines.\n\nGuidelines\tReactivation of chronic infection\tReactivation of resolved infection\t\nAmerican Association for the Study of Liver Diseases. (AASLD, 2018) (26)\tOne of the following: 1) a ≥100-fold elevation in the HBV DNA load compared with the baseline level; 2) ≥1,000 IU/ml of HBV DNA with an undetectable baseline level; 3) ≥10,000 IU/ml HBV DNA if the baseline level is not available.\tOne of the following:\n1) HBV DNA is detectable;\n2) reappearance of HBsAg\t\nThe Asian Pacific Association for the Study of the Liver. (APASL, 2016) (27)\tOne of the following: 1) a ≥100-fold increase in the HBV DNA load from baseline levels; 2) the reappearance of HBV DNA to a level of 100 IU/ml if the baseline level is undetectable; 3) ≥20,000 IU/ml HBV DNA if the baseline level is not available.\tOne of the following:\n1) reverse HBsAg seroconversion (reappearance of HBsAg);\n2) the appearance of HBV DNA in serum if HBsAg is negative\t\nAmerican Gastroenterological\nAssociation. (AGA, 2015) (30)\tOne of the following:\n1) de novo detectable HBV DNA if baseline level is undetectable; 2) a ≥10-fold increase in HBV DNA levels if the baseline DNA level is detectable.\tA change in HBsAg status (negative to positive).\t\nEuropean Association for the\nStudy of the Liver (EASL, 2017) (29)\tNot defined\tNot defined\t\nHBsAg, hepatitis B surface antigen; HBcAb, anti-hepatitis B core antibody.\n\nChronic infection: HBsAg(+) and HBcAb(+) patients.\n\nResolved infection: HBsAg(−) and HBcAb(+) patients.\n\nCollectively, HBV-R can be identified in a timely manner by combining ALT levels with HBV DNA and HBsAg. In HBsAg(+) patients, a dramatic rise in HBV DNA concentrations (usually 100-fold or more) are indicative of HBV-R, while in patients with resolved HBV infection (HBsAg[−] and HBcAb[+]), HBV-R usually means the reappearance of HBsAg or an increase in serum HBV DNA concentrations with or without HBsAg seroconversion and ALT exacerbation.\n\nRisk Factors and Possible Mechanism of HBV-R During NHL Treatment\n\nNotably, HBV-R can be induced by coinfection with HBV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (32–34). Other coinfections, such as that with HCV or HDV, can also increase the likelihood of HBV-R (35). The crucial risk factors for HBV-R can be classified into three types, namely, host-related, virus-related, and medication-related (35). Medication-related factors are usually associated with underlying disease that requires immunosuppressive therapy, such as chemotherapy, solid organ or bone marrow transplantation, rheumatological conditions, dermatological conditions, or inflammatory bowel disease) (36). As mentioned above, the drugs that are currently used to treat NHL (anthracyclines, cyclophosphamide, vincristine, prednisone, and anti-CD20 monoclonal antibody) are usually immunosuppressive, and constitute the focus of this review.\n\nHost-Related Risk Factors\n\nMales are more prone to undergoing HBV-R than females. Yeo et al. reported that in 600 HBsAg(+) cancer patients exposed to chemotherapy, the HBV-R ratio was almost three-fold higher in men than women (37, 38). Additionally, people that are more than 50 years old, HBeAg(+), and with underlying disease that requires immunosuppressive therapy (e.g. lymphomas) are at greater risk of developing HBV-R (37).\n\nVirus-Related Risk Factors\n\nThe virus-related, high-risk factors for HBV-R identified to date include detectable HBV DNA, HBsAg and HBcAb positivity, mutations in HBsAg, and HBV genotype (23, 39). Among these, detectable HBV DNA was reported to be the most important predictive factor for HBV-R. In one study, 37.8% of patients (31/82) with detectable viral load developed HBV-R (P = 0.0003, odds ratio [OR] 8.4, 95% CI 2.6–27.2) (39). Salpini et al. further identified mutations in HBsAg as being risk factors for HBV-R. The authors analyzed HBsAg-associated genetic features and found that 75.9% of patients (22/29) with HBV-R carried HBsAg mutations compared with 3.1% for control patients (2/64; P < 0.001). Among the HBsAg mutations identified, 61.5% were found to reside in a major hydrophilic region, while some were known immune escape-associated mutations, such as the sD144E mutation that disrupts humoral response-mediated HBsAg recognition. The remaining mutations were found to reside in class-I/II-restricted T-cell epitopes, suggesting that they were important for HBV escape from T-cell-mediated responses (40). HBsAg(+) patients have an eight-fold higher likelihood of HBV-R when compared with patients with resolved infection (HBsAg[−] and HBcAb[+]) (41). Notably, HBV genotype A is rarely involved in HBV-R, while other genotypes are reported (35, 42). Coinfection with other viruses, such as HCV, HDV, HIV, or SARS-CoV-2, also puts patients at higher risk of HBV-R, as mentioned before (26, 35).\n\nMedication-Related Risk Factors\n\nNumerous studies have indicated that immunosuppressive and chemotherapeutic medications represent the major risk for HBV-R (43–45). The greatest and most reported risk for HBV-R is associated with B-cell-depleting therapy, such as that with the anti-CD20 antibody, rituximab (35). The AGA and the AASLD have stratified the HBV-R-related risk of individual medications or therapies (26, 30). Additionally, the risk of HBV-R has been graded through different immunosuppressive treatments and HBV infection status, as follows ( Table 2 ): (1) Very high risk, greater than 20% chance of reactivation, and is associated with anti-CD20 antibody therapy (rituximab or ofatumumab) and hematopoietic stem cell transplantation (HSCT); (2) high risk, between 10 and 20% chance of reactivation, and is mainly related to high-dose glucocorticoid and anthracycline treatment; (3) moderate risk, between 1 and 10% chance of reactivation; (4) low risk, less than 1% chance of reactivation (30, 35, 45–47). Importantly, the immunosuppressive therapies included in the very-high- and high-risk groups are those usually administered to NHL patients, rendering them prone to HBV-R and incidental adverse events.\n\nTable 2 HBV-R risk groups based on patient infection status and associated immunosuppressive treatment.\n\nRisk group\tHBV-R rate (%)\tHepatitis status\tAssociated medications\t\nVery high risk\t>20%\tChronic infection\tAnti-CD20 monoclonal antibodies (rituximab, ofatumumab), HSCT\t\nHigh risk\t10–20%\tChronic infection\tAnthracycline derivatives: daunorubicin, doxorubicin, epirubicin\nHigh-dose glucocorticoids (>20 mg/day for 4 weeks and longer)\nAnti-CD52 antibody: alemtuzumab\t\nModerate risk\t1–10%\tChronic infection\tCytotoxic therapy without glucocorticoids:\ncyclophosphamide, vincristine;\nTNF-α inhibitors: infliximab, etanercept, golimumab, adalimumab;\nCytokine and integrin inhibitors (mogamulizumab);\nTyrosine kinase inhibitors (TKIs): imatinib, dasatinib, nilotinib;\nProteasome inhibitors: carfilzomib\t\nLow risk\t<1%\tChronic infection\tGlucocorticoids (methotrexate or azathioprine) lasting less than a week or a low-dose (<10 mg prednisone) within 4 weeks\t\nResolved infection\tHigh-dose glucocorticoid or the anti-CD52 antibody alemtuzumab\t\nHBsAg, hepatitis B surface antigen; HBcAb, anti-hepatitis B core antibody; HSCT, hematopoietic stem cell transplantation; TNF, tumor necrosis factor.\n\nChronic infection: HBsAg(+) and HBcAb(+) patients.\n\nResolved infection: HBsAg(−) and HBcAb(+) patients.\n\nAnti-CD20 Antibodies—Rituximab and Ofatumumab\n\nRituximab, approved in 1997, is used for the treatment of NHL and chronic lymphocytic leukemia. Numerous cases of HBsAg(+) lymphoma patients treated with rituximab-containing therapy developing HBV-R have been documented since 1999 (48, 49). Rituximab and ofatumumab are humanized anti-CD20 monoclonal antibodies targeting CD20, a cell-surface marker on B lymphocytes, resulting in B-cell depletion and the subsequent impairment of B-cell antigen-presenting function, with the consequent reduction of specific anti-HBV CD4-positive T-cell activation and proliferation (50). Rituximab affects cell signaling by directly inducing the apoptosis of malignant B cells and activating complement-dependent cytotoxicity. These effects result in the rapid death of rituximab-targeted cells and the activation of natural killer (NK) cells, which then produce interferon-gamma (IFNγ), and thereby induce antibody-dependent cellular cytotoxicity when they interact with rituximab-coated target cells (51).\n\nOfatumumab functions through a similar mechanism. These types of drugs are commonly associated with serious HBV-R-related events and can increase the risk of hepatocyte dysfunction and mortality if HBV-R is not quickly identified and cleared (35, 52). Few retrospective data are available for the incidence of HBV-R in HBsAg(+) patients treated with rituximab-containing therapy without any antiviral prophylaxis. The HBV-R rate in NHL patients has been reported to vary between 18.2 and 80%. HBV-R occurs from after a few weeks to up to 55 months after rituximab administration, indicating that rituximab represents a very high-risk factor for HBV-R (48, 53–57). Between 1997 and 2009, the US Food and Drug Administration (FDA) MedWatch Database reported 118 cases of HBV-R. Among these patients, those administered rituximab-containing therapy had a prominently increased risk of HBV-R compared with those given non-rituximab-containing therapy (OR 5.73, 95% CI 2.01–16.33, P = 0.0009) without heterogeneity (19). Consequently, the FDA alerted healthcare professionals that rituximab and ofatumumab were associated with a high risk of HBV-R and added “boxed warnings” (the strongest warnings) to the product labels in September 2013 (58). In the Emerging Trends Conference sponsored by the AASLD held in 2015, entitled “Reactivation of Hepatitis B,” HBV-R was reported to be a possible underestimated clinical challenge related to ofatumumab or rituximab treatment. Furthermore, it was suggested that all patients undergoing ofatumumab- or rituximab-containing therapies should be screened for HBV-R, and that HBsAg(+) or HBcAb(+) patients should start prophylactic antiviral therapy to prevent HBV-R (59).\n\nCollectively, these data indicate that rituximab and other B-cell-depleting therapies pose the greatest risk for HBV-R (35, 46, 60), which warrants vigilance by the medical community.\n\nCorticosteroids\n\nCorticosteroids were first reported to be associated with HBV-R by Sagnelli et al. in 1980, which was subsequently widely confirmed (38, 61). The risk for HBV-R with corticosteroid use is deemed to be dose- and time-dependent, with studies having indicated that a high dose (>20 mg/day) of chronic prednisone therapy for longer than 4 weeks is associated with a high risk of HBV-R (28, 62). Cheng et al. conducted a randomized study on 50 HBsAg(+) lymphoma patients and compared the HBV-R rate in patients undergoing an identical chemotherapeutic regimen receiving or not corticosteroid treatment. The authors reported that the cumulative incidence of HBV-R at 9 months was significantly higher in the corticosteroid treatment group (38 vs. 73%, P = 0.03) (63). In a recent 6-year prospective cohort study, HBV-R was reported to occur a median of 10 months (range, 4–32) after steroid administration (53).\n\nCorticosteroids enhance HBV replication mainly through two mechanisms. First, they suppress cell-mediated immunity via the inhibition of interleukins, which then prevents T and B cell proliferation (43). Second, corticosteroids stimulate the glucocorticoid-responsive element present in the HBV genome, thereby exerting a direct suppressive effect on T-cell-mediated immunity (23, 64). Corticosteroids were also reported to be able to increase HBsAg secretion via inducing autophagy, i.e., inhibiting autophagy using 3-MA, an autophagy inhibitor, decreased HBV replication and HBsAg secretion (65); however, this possibility requires further investigation. These observations suggest that the reported HBV-R in patients coinfected with SARS-CoV-2 and HBV might be associated with corticosteroid use during the treatment of COVID-19. The R-CHOP regimen, which contains prednisone, is still conventionally administered to patients with NHL as first-line standard therapy. Hence, the risk for HBV-R should be taken into consideration when treating NHL patients with a corticosteroid-containing regimen.\n\nAnthracyclines\n\nAnthracyclines, such as doxorubicin and epirubicin, have also been linked to a high risk of HBV-R (35, 66). This class of chemotherapeutic drugs is applied to treat a variety of solid and hematological cancers, including lymphoma, bladder cancer, soft-tissue sarcoma, leukemia, breast cancer, and multiple myeloma. Doxorubicin exerts its HBV-R-related effects by increasing the expression of the cell cycle regulator p21 (Waf1/Cip1), which upregulates the expression level of enhancer-binding protein α (C/EBPα) and, consequently, promotes the binding of C/EBPα to the HBV promoter; this, in turn, enhances HBV transcription, and thus also viral replication (67). Nevertheless, it is difficult to evaluate the anthracycline-associated risks for HBV-R as these drugs are often used in combination with other immunosuppressive or chemotherapeutic agents, such as rituximab.\n\nImmune Checkpoint Inhibitors\n\nImmune checkpoint inhibitors (ICPIs), such as antibodies targeting programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD- L1) (anti-PD-1: pembrolizumab and nivolumab; anti-PD-L1: atezolizumab, durvalumab, and avelumab) and cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4: ipilimumab and tremelimumab), have been used as immunotherapy in the treatment of various types of cancer. Pembrolizumab is an FDA-approved agent used to treat relapsed or refractory primary mediastinal large B-cell lymphoma after ≥2 prior lines of therapy. It has been suggested that this class of drugs may give rise to HBV-R. Given that their mechanism of action involves activating the immune system, it seems unlikely that ICPIs induce HBV-R (35); however, sporadic incidents of HBV-R after ICPI administration have been described in case reports and a retrospective cohort study (68–72). In the latter, of 114 HBsAg(+) patients given anti-PD-1/PD-L1 antibody therapy, six (5.3%) developed HBV-R in a median time of 18 weeks after treatment initiation (72). Therefore, given the concern that ICPI treatment may lead to HBV-R, prophylactic antiviral therapy should be an appropriate option for HBV-infected or resolved patients undergoing ICPI therapy.\n\nOther biological agents, such as TNF-α inhibitors (infliximab, etanercept, golimumab, and adalimumab), tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, and nilotinib), the Janus kinase (JAK) 1/2 inhibitor ruxolitinib, and the proteasome inhibitor bortezomib, are also thought to be related to HBV-R; however, they are not currently applied to lymphomas (38, 44).\n\nScreening Before Treatment\n\nThe prevention of HBV-R begins with patient screening. Numerous approaches have been adopted by different organizations and institutions to address the issue of screening for HBV infection before the initiation of immunosuppressive therapy. There is a consensus among various cancer governing bodies that all patients at high risk of HBV-R or those receiving B-cell-depleting therapies should be screened before the initiation of therapy (26, 30, 35). The AGA, AASLD, EASL, and the American Society of Clinical Oncology (ASCO) screening guidelines are presented in Table 3 (26, 28, 29, 73). The National Comprehensive Cancer Network (NCCN) Guidelines for B-cell lymphomas suggest that both HBsAg and HBcAb should be tested among NHL patients before the beginning of immunosuppressive treatment, especially that involving anti-CD20 antibody-containing regimens. The baseline HBV DNA burden should be obtained if patients are positive for HBsAg or HBcAb to quickly detect HBV-R and take the appropriate measures (74).\n\nTable 3 Guidelines for the screening, management, and monitoring of HBV-R during immunosuppressive therapy.\n\nGuidelines\tScreen object\tManagement strategies for HBV-R\tDuration of antiviral therapy\tMonitoring during prophylaxis\tMonitoring after prophylaxis\t\nAmerican Association for the\nStudy of Liver Diseases (AASLD, 2018) (26)\tAll patients\tChronic infection: prophylaxis\nResolved infection: either prophylaxis or pre-emptive therapy, but prophylaxis is needed when patients are receiving anti-CD20 antibody therapy\tAt least 6 months (12 months for patients receiving anti-CD20 antibody therapy) after the completion of immunosuppressive therapy\tNot mentioned\tHBV DNA levels should\nbe tested every 1–3 months\t\nThe Asian Pacific Association for\nthe Study of the Liver (APASL, 2016) (27)\tAll patients\tHBsAg(+) cancer patients: prophylaxis;\nResolved HBV with\ndetectable HBV DNA: prophylaxis;\nResolved HBV with\nundetectable HBV DNA: pre-emptive therapy, except with anti-CD20 antibody therapy or stem cell transplantation\tAt least 12 months after the cessation of therapy\tResolved HBV with\nundetectable HBV DNA:\nALT and HBV DNA every\n1–3 months\tNot mentioned\t\nAmerican Gastroenterological\nAssociation (AGA, 2015) (30)\tPatients at moderate or high risk of HBV-R\tHigh and moderate risk: prophylaxis;\nLow risk: routine prophylaxis not recommended\tThe same as for AASLD\tNo recommendation\tNo recommendation\t\nEuropean Association for the Study of the Liver (EASL, 2017) (29)\tAll patients\tHBsAg(+) patients: prophylaxis;\nResolved HBV, high risk: prophylaxis;\nResolved HBV, moderate and low risk: pre-emptive therapy (monitor HBsAg and HBV DNA every 1–3 months)\tAt least 12 months after the cessation of immunosuppressive treatment and at least 18 months for rituximab-based regimens\tNot mentioned\tLiver function tests and HBV DNA should be tested every 3–6 months\t\nAmerican Society of Clinical Oncology (ASCO, 2020) (73)\tAll cancer patients\tHBsAg(+) patients: prophylaxis;\nResolved HBV, high risk: prophylaxis;\nResolved HBV, moderate\nand low risk: pre-emptive therapy (monitor HBsAg and HBV DNA every 3 months)\tFor a minimum of 12 months\nfollowing anticancer therapy\tALT and HBV DNA levels should be tested every 6 months during antiviral therapy\tHBsAg(+) and resolved HBV with high risk: at least monthly for the first 3 months after the cessation of antiviral therapy and every 3 months\nthereafter\t\nHBsAg, hepatitis B surface antigen; ALT, alanine aminotransferase.\n\nOwing to the immunosuppressive agents used in the treatment of NHL that place patients at a very high, high, or moderate risk of HBV-R, all NHL patients should be tested for HBV infection (at least for HBsAg and HBcAb) before the initiation of therapy to minimize the risk of HBV-R and related complications, including mortality.\n\nManagement Strategies for HBV-R in Clinical Practice\n\nAfter screening, the next challenge is the management of HBV-R in individuals receiving immunosuppressive agents. There are two strategies targeting HBV-R, namely, antiviral prophylaxis and pre-emptive therapy. Antiviral prophylaxis means treating patients (usually at least 1 week before immunosuppressive therapy) with HBsAg(+) or HBcAb(+) regardless of viral load or whether or not there are clinical symptoms of HBV-R. Pre-emptive therapy refers to the close surveillance of HBV DNA, in which antiviral therapy begins at the first sign of an increase in the HBV DNA load (26, 74, 75). The guidelines for management strategies are also presented in Table 3 .\n\nIn oncological practice, it is usually too late to take measures to deal with HBV-R and schedule treatments are interrupted when HBV-R begins to take shape causing poor outcomes for NHL patients. Consequently, we think that it is appropriate to initiate antiviral prophylaxis before immunosuppressive therapies are given to NHL patients.\n\nAgents for Antiviral Prophylaxis\n\nTo date, no antiviral medication has been approved for the prevention of HBV-R. Two types of treatment are available for patients with chronic HBV infection, including nucleoside analogs (NAs) and interferon-alpha. However, interferons are no longer conventionally used to treat lymphoma patients owing to the associated intolerance, adverse effects, and selective effectiveness (46). Hence, several NAs, such as entecavir (ETV), lamivudine (LMV), adefovir, and tenofovir, are the only effective options available for the treatment of HBV-R among NHL patients.\n\nLamivudine\n\nLMV is a cost-effective alternative for HBV treatment and was the first NA approved for this purpose. Consequently, it has been widely used for antiviral prophylaxis among NHL patients (76). In the first study, none of 30 HBsAg(+) patients with lymphoma undergoing intensive chemotherapy experienced HBV-R in the LMV prophylaxis group, whereas 8 out of 15 patients (53%) in the no-prophylaxis arm had HBV-R (P = 0.002). Survival free from HBV-R-related hepatitis in the group receiving LMV prophylaxis was significantly longer than that of the control group (P = 0.002 on the log-rank test) (77). In the second randomized trial, among 51 patients undergoing CHOP chemotherapy, HBV-R was detected in 30.8% (95% CI, 14.3–51.8%) of those undergoing LMV prophylaxis vs. 60% (95% CI, 38.7–78.9%) for those not receiving LMV treatment (P = 0.05) (78). A meta-analysis involving 16 studies reported that the HBV-R rate was significantly lower in patients receiving LMV prophylaxis than in those of the control group (8.6% [11/127] vs. 50.6% [136/269], respectively), suggesting that LMV can reduce the incidence of HBV-R (relative risk [RR] 0.21, 95% CI 0.13–0.35), as well as HBV-related mortality (RR 0.68, 95% CI 0.19–2.49) (79). A recent retrospective study (80) on consecutively enrolled HBsAg(−) and HBcAb(+) NHL patients who received rituximab-based chemotherapy found that none of the patients who were given LMV prophylaxis experienced HBV-R or treatment-related side effects (81). However, the long-term use of LMV is liable to generate a high rate of drug resistance, especially when used beyond 1 year. The incidence of resistance to LMV has been reported to be as high as 20% in patients treated for more than 1 year with non-immunosuppressive-containing medication (30); this incidence escalated dramatically to 30% after 2 years, and then increased exponentially with continued use (76). The most commonly identified mutation conferring resistance to LMV occurs in the tyrosine–methionine–aspartate–aspartate (YMDD) motif of the HBV-DNA polymerase gene (82). Hence, owing to the low threshold for the generation of resistance to LMV (83), this drug was replaced by next-generation NAs such as ETV or tenofovir that possess a high barrier to resistance, as demonstrated by multiple studies and meta-analyses (28, 80, 84, 85).\n\nEntecavir and Tenofovir\n\nETV and tenofovir disoproxil fumarate are new-generation NAs that have a high barrier to drug resistance and superior viral suppressive capability (23, 86–88). A retrospective analysis of HBsAg(+) NHL patients (stage III–IV) who received antiviral prophylaxis with ETV (n = 34) or LMV (n = 89) during chemotherapy suggested that ETV-treated patients had lower rates of hepatitis (5.9 vs. 27.0%, P = 0.007) and HBV-R (0 vs. 12.4%, P = 0.024), as well as fewer interruptions of chemotherapy (5.9 vs. 20.2%, P = 0.042) (89) compared with those treated with LMV. A prospective, randomized, multicenter clinical trial conducted in China that included 121 patients compared the efficacy of ETV (n = 61) and LMV (n = 60) in preventing HBV-R among HBsAg(+) patients undergoing R-CHOP treatment for DLBCL. The results indicated that patients in the ETV group had a markedly lower incidence of HBV-related hepatitis (0 vs. 13.3%, P = 0.003) and HBV-R (6.6 vs. 30%, P = 0.001), as well as fewer interruptions of chemotherapy (1.6 vs. 18.3%, P = 0.002), with respect to those in the LMV group. No difference in terms of incidence of adverse events was identified between these two agents (90). Another meta-analysis that included 770 lymphoma patients also confirmed that patients with HBsAg(+) receiving LMV prophylaxis during chemotherapy had a significantly higher chance of HBV-R compared with those receiving ETV (OR 5.0, P < 0.001) (80). In a study conducted to evaluate the effectiveness of tenofovir for the treatment of HBV-R in patients undergoing immunosuppressive treatment, 25 of 38 patients were given tenofovir as prophylaxis, and 13 were administered the drug as pre-emptive therapy. None of the patients receiving tenofovir as prophylaxis developed HBV-R during immunosuppression. In addition, the remaining 13 patients received tenofovir at the first sign of HBV-R and all had a complete biochemical and virological response within 9 months (91).\n\nBased on the above observations, ETV or tenofovir (especially ETV) is recommended as the standard agent for the prevention and treatment of HBV-R by NCCN, AASLD, and others as they possess superior viral suppressive ability and a high barrier to resistance (26, 35, 74, 92).\n\nDuration of Therapy and Monitoring\n\nThe optimal duration of prophylactic antiviral therapy remains controversial. Data derived from multiple sources indicate that antiviral prophylaxis should last for at least 6 months after the cessation of immunosuppressive therapy, and should be lengthened to 12 months for patients receiving regimens with B-cell-depleting therapies or antiviral prophylaxis (46, 86). The reason for extending the duration of antiviral prophylaxis use is that immune recovery may take longer, while the immunosuppressive effects of rituximab have been reported to persist for longer than 1 year after the last delivery (35, 93). HBV-R has also been reported to occur more than 2 years after the completion of rituximab-containing chemotherapy (54, 94). The AGA, AASLD, EASL, and ASCO guidelines regarding the duration of therapy and monitoring are presented in Table 3 . Additionally, the NCCN guidelines for B-cell lymphomas recommend that monitoring and antiviral prophylaxis should be continued for at least 12 months after the completion of anticancer treatment, and that HBV DNA levels should be tested monthly during treatment, and then every 3 months after completion of antiviral prophylaxis (74).\n\nIn the clinic, prophylactic antiviral therapy tends to be delivered before or at the onset of anticancer therapy to patients with prior HBV infection, regardless of baseline HBV DNA levels, because HBV-R has been reported to occur even after 1 year of infection. Consequently, close monitoring and longer use of antiviral prophylaxis should be considered, particularly in patients receiving anti-CD20-antibody-containing therapy (84, 95–97).\n\nDiscussion\n\nHBV-R in NHL patients undergoing immunosuppressive therapies, especially rituximab-containing treatment, is now a well-recognized and preventable complication in clinical practice. Nevertheless, there is a large knowledge gap in our understanding of this disease process, making HBV-R a vexing and persistent problem. Among NHL patients with chronic HBV infection, HBV-R has gained extensive attention because of the associated significant morbidity and mortality. The immunosuppressive therapies used during the entire NHL treatment period, such as anti-CD20 antibody therapy, glucocorticoid treatment, and HSCT, usually amplify the odds of HBV-R, as mentioned before. Whether to screen patients at risk, stratify patients for risk based on HBV serological status and type of immunosuppression, whether to use prophylaxis or pre-emptive therapy, and the identification of the optimal antiviral agent and treatment duration remain unresolved issues.\n\nSeveral screening strategies have been proposed by different organizations, namely, risk factor-based, risk-adaptive, and universal screening. HBV testing rates in cancer patients before therapy based on risk factors have been estimated to be low (19–55%) (98–100); however, the morbidity associated with HBV risk factors among patients with cancer may be high (101). Universal screening is the preferred option for the AGA and the AASLD given the limitations of risk factor-based and risk-adaptive screening. These two organizations recommend universal HBV screening as a reasonable and cost-effective strategy before anticancer therapies are administered to reduce the risk of HBV-R (26, 30). Accordingly, it is appropriate to test HBsAg, HBcAb, and HBsAb (if available) among all NHL patients to identify and cure HBV-R earlier and provide better clinical outcomes.\n\nThe current guidelines agree that HBsAg(+) patients or those receiving anti-CD20 antibody therapy or HSCT are at high risk of HBV-R and should be given prophylaxis until after the cessation of anticancer therapy. Among moderate or low-risk HBV-R patients, pre-emptive antiviral therapy initiating at the first sign of HBV-R may also be a decent option. Recent studies and multiple meta-analysis have demonstrated the greater efficacy and lesser drug resistance of ETV and tenofovir as first-line agents for the prevention of HBV-R. The optimal duration of prophylaxis for HBV-R remains unclear. Indeed, Tasuku et al. reported a rare case of a 54-year-old woman diagnosed with DLBCL and HBsAg(−) and HBcAb(+) in whom HBV-R occurred 55 months after the completion of chemotherapy (54). Owing to the deep immunodepression exerted by rituximab or HSCT, lifelong antiviral treatment may be the better option (23, 102).\n\nIn the era of immunotherapy, numerous novel agents have emerged targeting the treatment of NHL and other solid cancers; however, prospective data showing how they interact with the immune system and their relation to HBV-R are limited. Additional, well-designed, prospective studies are needed to allow the stratification of patients at risk of HBV-R as well as a better understanding of the appropriate antiviral therapy and the optimal duration of prophylaxis. With accumulating evidence and experience, it is expected that HBV-R can be avoided, identified, controlled, and, perhaps cured.\n\nAuthor Contributions\n\nHL conceived and designed the study and reviewed the manuscript. XC and YW collected the data and wrote the manuscript. PL, WH, and XL revised the manuscript. XC designed and wrote the table. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1 Suhail M Abdel-Hafiz H Ali A Fatima K Damanhouri GA Azhar E . Potential Mechanisms of Hepatitis B Virus Induced Liver Injury. World J Gastroenterol (2014) 20 (35 ):12462–72. 10.3748/wjg.v20.i35.12462\n2 Lee WM . Hepatitis B Virus Infection. N Engl J Med (1997) 337 (24 ):1733–45. 10.1056/NEJM199712113372406\n3 Schweitzer A Horn J Mikolajczyk RT Krause G Ott JJ . Estimations of Worldwide Prevalence of Chronic Hepatitis B Virus Infection: A Systematic Review of Data Published Between 1965 and 2013. Lancet (2015) 386 (10003 ):1546–55. 10.1016/S0140-6736(15)61412-X\n4 Kang X Bai L Han C Qi X . . 10.2147/cmar.s244381\n5 Qi Z Wang H Gao G . Association of Risk of non-Hodgkin’s Lymphoma With Hepatitis B Virus Infection: A Meta-Analysis. Int J Clin Exp Med (2015) 8 (12 ):22167–74.\n6 Su TH Liu CJ Tseng TC Chou SW Liu CH Yang HC . Chronic Hepatitis B is Associated With an Increased Risk of B-cell non-Hodgkin’s Lymphoma and Multiple Myeloma. Aliment Pharmacol Ther (2019) 49 (5 ):589–98. 10.1111/apt.15132\n7 Zhou X Wuchter P Egerer G Kriegsmann M Mataityte A Koelsche C . Role of Virological Serum Markers in Patients With Both Hepatitis B Virus Infection and Diffuse Large B-cell Lymphoma. Eur J Haematol (2019) 103 (4 ):410–6. 10.1111/ejh.13300\n8 Zhou X Pan H Yang P Ye P Cao H Zhou H . Both Chronic HBV Infection and Naturally Acquired HBV Immunity Confer Increased Risks of B-cell non-Hodgkin Lymphoma. BMC Cancer (2019) 19 (1 ):477. 10.1186/s12885-019-5718-x 31113483\n9 Taborelli M Polesel J Montella M Libra M Tedeschi R Battiston M . Hepatitis B and C Viruses and Risk of Non-Hodgkin Lymphoma: A Case-Control Study in Italy. Infect Agent Cancer (2016) 11 :27. 10.1186/s13027-016-0073-x 27340429\n10 Chen J Wang J Yang J Zhang W Song X Chen L . Concurrent Infection of Hepatitis B Virus Negatively Affects the Clinical Outcome and Prognosis of Patients With non-Hodgkin’s Lymphoma After Chemotherapy. PLoS One (2013) 8 (7 ):e69400. 10.1371/journal.pone.0069400 23861969\n11 Coluccio C Begini P Marzano A Pellicelli A Imperatrice B Anania G . Hepatitis B in Patients With Hematological Diseases: An Update. World J Hepatol (2017) 9 (25 ):1043–53. 10.4254/wjh.v9.i25.1043\n12 Kwok RM Tran TT . Hepatitis B and Risk of Non-Hepatocellular Carcinoma Malignancy. Clin Liver Dis (2016) 20 (4 ):693–702. 10.1016/j.cld.2016.06.005 27742008\n13 Marcucci F Mele A . Hepatitis Viruses and non-Hodgkin Lymphoma: Epidemiology, Mechanisms of Tumorigenesis, and Therapeutic Opportunities. Blood (2011) 117 (6 ):1792–8. 10.1182/blood-2010-06-275818\n14 Marcucci F Spada E Mele A Caserta CA Pulsoni A . The Association of Hepatitis B Virus Infection With B-Cell Non-Hodgkin Lymphoma - a Review. Am J Blood Res (2012) 2 (1 ):18–28.22432084\n15 Raimondo G Locarnini S Pollicino T Levrero M Zoulim F Lok AS . Update of the Statements on Biology and Clinical Impact of Occult Hepatitis B Virus Infection. J Hepatol (2019) 71 (2 ):397–408. 10.1016/j.jhep.2019.03.034 31004683\n16 Kim HY Kim W . Chemotherapy-Related Reactivation of Hepatitis B Infection: Updates in 2013. World J Gastroenterol (2014) 20 (40 ):14581–8. 10.3748/wjg.v20.i40.14581\n17 Kusumoto S Arcaini L Hong X Jin J Kim WS Kwong YL . Risk of HBV Reactivation in Patients With B-Cell Lymphomas Receiving Obinutuzumab or Rituximab Immunochemotherapy. Blood (2019) 133 (2 ):137–46. 10.1182/blood-2018-04-848044\n18 Hwang JP Barbo AG Perrillo RP . Hepatitis B Reactivation During Cancer Chemotherapy: An International Survey of the Membership of the American Association for the Study of Liver Diseases. J Viral Hepat (2015) 22 (3 ):346–52. 10.1111/jvh.12305\n19 Evens AM Jovanovic BD Su YC Raisch DW Ganger D Belknap SM . Rituximab-Associated Hepatitis B Virus (HBV) Reactivation in Lymphoproliferative Diseases: Meta-Analysis and Examination of FDA Safety Reports. Ann Oncol (2011) 22 (5 ):1170–80. 10.1093/annonc/mdq583\n20 Yeo W Chan TC Leung NW Lam WY Mo FK Chu MT . Hepatitis B Virus Reactivation in Lymphoma Patients With Prior Resolved Hepatitis B Undergoing Anticancer Therapy With or Without Rituximab. J Clin Oncol (2009) 27 (4 ):605–11. 10.1200/JCO.2008.18.0182\n21 Castelli R Ferraris L Pantaleo G Lambertenghi Deliliers G Cicardi M . High Rate of Hepatitis B Viral Breakthrough in Elderly Non-Hodgkin Lymphomas Patients Treated With Rituximab Based Chemotherapy. Dig Liver Dis (2016) 48 (11 ):1394–7. 10.1016/j.dld.2016.08.113\n22 Hwang JP Ferrajoli A Lok AS . Hepatitis B Reactivation After Chemoimmunotherapy: Screen Before Treatment. Lancet (2021) 397 (10273 ):510. 10.1016/S0140-6736(21)00210-5 33549195\n23 Pattullo V . Prevention of Hepatitis B Reactivation in the Setting of Immunosuppression. Clin Mol Hepatol (2016) 22 (2 ):219–37. 10.3350/cmh.2016.0024\n24 Su WP Wen CC Hsiung CA Su IJ Cheng AL Chang MC . Long-Term Hepatic Consequences of Chemotherapy-Related HBV Reactivation in Lymphoma Patients. World J Gastroenterol (2005) 11 (34 ):5283–8. 10.3748/wjg.v11.i34.5283\n25 Arora A Anand AC Kumar A Singh SP Aggarwal R Dhiman RK . Inasl Guidelines on Management of Hepatitis B Virus Infection in Patients Receiving Chemotherapy, Biologicals, Immunosupressants, or Corticosteroids. J Clin Exp Hepatol (2018) 8 (4 ):403–31. 10.1016/j.jceh.2018.06.010\n26 Terrault NA Lok ASF McMahon BJ Chang KM Hwang JP Jonas MM . Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: Aasld 2018 Hepatitis B Guidance. Clin Liver Dis (Hoboken) (2018) 12 (1 ):33–4. 10.1002/cld.728\n27 Sarin SK Kumar M Lau GK Abbas Z Chan HL Chen CJ . Asian-Pacific Clinical Practice Guidelines on the Management of Hepatitis B: A 2015 Update. Hepatol Int (2016) 10 (1 ):1–98. 10.1007/s12072-015-9675-4\n28 Perrillo RP Gish R Falck-Ytter YT . American Gastroenterological Association Institute Technical Review on Prevention and Treatment of Hepatitis B Virus Reactivation During Immunosuppressive Drug Therapy. Gastroenterology (2015) 148 (1 ):221–44.e3. 10.1053/j.gastro.2014.10.038 25447852\n29 European Association for the Study of the Liver. Electronic Address Eee, European Association for the Study of the L. Easl 2017 Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection. J Hepatol (2017) 67 (2 ):370–98. 10.1016/j.jhep.2017.03.021\n30 Reddy KR Beavers KL Hammond SP Lim JK Falck-Ytter YT . American Gastroenterological Association I. American Gastroenterological Association Institute Guideline on the Prevention and Treatment of Hepatitis B Virus Reactivation During Immunosuppressive Drug Therapy. Gastroenterology (2015) 148 (1 ):215–9. 10.1053/j.gastro.2014.10.039\n31 Yeo W Johnson PJ . Diagnosis, Prevention and Management of Hepatitis B Virus Reactivation During Anticancer Therapy. Hepatology (2006) 43 (2 ):209–20. 10.1002/hep.21051\n32 Aldhaleei WA Alnuaimi A Bhagavathula AS . Covid-19 Induced Hepatitis B Virus Reactivation: A Novel Case From the United Arab Emirates. Cureus (2020) 12 (6 ):e8645. 10.7759/cureus.8645 32550096\n33 Pley CM McNaughton AL Matthews PC Lourenco J . The Global Impact of the COVID-19 Pandemic on the Prevention, Diagnosis and Treatment of Hepatitis B Virus (HBV) Infection. BMJ Glob Health (2021) 6 (1 ):e004275. 10.1136/bmjgh-2020-004275\n34 Reddy KR . Sars-CoV-2 and the Liver: Considerations in Hepatitis B and Hepatitis C Infections. Clin Liver Dis (Hoboken) (2020) 15 (5 ):191–4. 10.1002/cld.970\n35 Loomba R Liang TJ . Hepatitis B Reactivation Associated With Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions. Gastroenterology (2017) 152 (6 ):1297–309. 10.1053/j.gastro.2017.02.009\n36 Doo EC Hoofnagle JH Rodgers GP . NIH Consensus Development Conference: Management of Hepatitis B. Introduction. Hepatology (2009) 49 (5 Suppl ):S1–3. 10.1002/hep.22993\n37 Yeo W Chan PK Zhong S Ho WM Steinberg JL Tam JS . Frequency of Hepatitis B Virus Reactivation in Cancer Patients Undergoing Cytotoxic Chemotherapy: A Prospective Study of 626 Patients With Identification of Risk Factors. J Med Virol (2000) 62 (3 ):299–307. 10.1002/1096-9071(200011)62:3<299::aid-jmv1>3.0.co;2-0 11055239\n38 Sagnelli C Pisaturo M Calo F Martini S Sagnelli E Coppola N . Reactivation of Hepatitis B Virus Infection in Patients With Hemo-Lymphoproliferative Diseases, and its Prevention. World J Gastroenterol (2019) 25 (26 ):3299–312. 10.3748/wjg.v25.i26.3299\n39 Yeo W Zee B Zhong S Chan PK Wong WL Ho WM . Comprehensive Analysis of Risk Factors Associating With Hepatitis B Virus (HBV) Reactivation in Cancer Patients Undergoing Cytotoxic Chemotherapy. Br J Cancer (2004) 90 (7 ):1306–11. 10.1038/sj.bjc.6601699\n40 Salpini R Colagrossi L Bellocchi MC Surdo M Becker C Alteri C . Hepatitis B Surface Antigen Genetic Elements Critical for Immune Escape Correlate With Hepatitis B Virus Reactivation Upon Immunosuppression. Hepatology (2015) 61 (3 ):823–33. 10.1002/hep.27604\n41 Shouval D Shibolet O . Immunosuppression and HBV Reactivation. Semin Liver Dis (2013) 33 (2 ):167–77. 10.1055/s-0033-1345722\n42 Borentain P Colson P Coso D Bories E Charbonnier A Stoppa AM . Clinical and Virological Factors Associated With Hepatitis B Virus Reactivation in HBsAg-negative and Anti-HBc Antibodies-Positive Patients Undergoing Chemotherapy and/or Autologous Stem Cell Transplantation for Cancer. J Viral Hepat (2010) 17 (11 ):807–15. 10.1111/j.1365-2893.2009.01239.x\n43 Kelling M Sokol L Dalia S . Hepatitis B Reactivation in the Treatment of Non-Hodgkin Lymphoma. Cancer Control (2018) 25 (1 ):1073274818767879. 10.1177/1073274818767879 29606020\n44 Smalls DJ Kiger RE Norris LB Bennett CL Love BL . Hepatitis B Virus Reactivation: Risk Factors and Current Management Strategies. Pharmacotherapy (2019) 39 (12 ):1190–203. 10.1002/phar.2340\n45 Ziogas DC Kostantinou F Cholongitas E Anastasopoulou A Diamantopoulos P Haanen J . Reconsidering the Management of Patients With Cancer With Viral Hepatitis in the Era of Immunotherapy. J Immunother Cancer (2020) 8 (2 ):e000943. 10.1136/jitc-2020-000943 33067316\n46 Ozoya OO Chavez J Sokol L Dalia S . Optimizing Antiviral Agents for Hepatitis B Management in Malignant Lymphomas. Ann Transl Med (2017) 5 (3 ):39. 10.21037/atm.2016.12.25 28251118\n47 Iannitto E Minardi V Calvaruso G Mule A Ammatuna E Di Trapani R . Hepatitis B Virus Reactivation and Alemtuzumab Therapy. Eur J Haematol (2005) 74 (3 ):254–8. 10.1111/j.1600-0609.2004.00375.x\n48 Merli M Rattotti S Gotti M Arcaini L . Antiviral Therapies for Managing Viral Hepatitis in Lymphoma Patients. Expert Opin Pharmacother (2017) 18 (4 ):363–76. 10.1080/14656566.2017.1288718\n49 Oh MJ Lee HJ . A Study of Hepatitis B Virus Reactivation Associated With Rituximab Therapy in Real-World Clinical Practice: A Single-Center Experience. Clin Mol Hepatol (2013) 19 (1 ):51–9. 10.3350/cmh.2013.19.1.51\n50 Xu X Shang Q Chen X Nie W Zou Z Huang A . Reversal of B-cell Hyperactivation and Functional Impairment Is Associated With HBsAg Seroconversion in Chronic Hepatitis B Patients. Cell Mol Immunol (2015) 12 (3 ):309–16. 10.1038/cmi.2015.25\n51 Weiner GJ . Rituximab: Mechanism of Action. Semin Hematol (2010) 47 (2 ):115–23. 10.1053/j.seminhematol.2010.01.011\n52 Mozessohn L Chan KK Feld JJ Hicks LK . Hepatitis B Reactivation in HBsAg-negative/HBcAb-positive Patients Receiving Rituximab for Lymphoma: A Meta-Analysis. J Viral Hepat (2015) 22 (10 ):842–9. 10.1111/jvh.12402\n53 Notsumata K Nomura Y Tanaka A Nomura Y Ueda T Sanada T . Efficient Prophylactic Management of HBV Reactivation by an Information Technology Encoding System: Results of a 6-Year Prospective Cohort Study. Intern Med (2020) 59 (20 ):2457–64. 10.2169/internalmedicine.4445-20\n54 Hara T Oka K Iwai N Inada Y Tsuji T Okuda T . Hepatitis B Virus Reactivation 55 Months Following Chemotherapy Including Rituximab and Autologous Peripheral Blood Stem Cell Transplantation for Malignant Lymphoma. Intern Med (2021) 60 (3 ):417–21. 10.2169/internalmedicine.5678-20\n55 Pei SN Chen CH Lee CM Wang MC Ma MC Hu TH . Reactivation of Hepatitis B Virus Following Rituximab-Based Regimens: A Serious Complication in Both HBsAg-positive and HBsAg-negative Patients. Ann Hematol (2010) 89 (3 ):255–62. 10.1007/s00277-009-0806-7\n56 Mendez-Navarro J Corey KE Zheng H Barlow LL Jang JY Lin W . Hepatitis B Screening, Prophylaxis and Re-Activation in the Era of Rituximab-Based Chemotherapy. Liver Int (2011) 31 (3 ):330–9. 10.1111/j.1478-3231.2010.02332.x\n57 Chen XQ Peng JW Lin GN Li M Xia ZJ . The Effect of Prophylactic Lamivudine on Hepatitis B Virus Reactivation in HBsAg-Positive Patients With Diffuse Large B-cell Lymphoma Undergoing Prolonged Rituximab Therapy. Med Oncol (2012) 29 (2 ):1237–41. 10.1007/s12032-011-9974-0\n58 Mitka M . Fda: Increased HBV Reactivation Risk With Ofatumumab or Rituximab. JAMA (2013) 310 (16 ):1664. 10.1001/jama.2013.281115 24150447\n59 Di Bisceglie AM Lok AS Martin P Terrault N Perrillo RP Hoofnagle JH . Recent US Food and Drug Administration Warnings on Hepatitis B Reactivation With Immune-Suppressing and Anticancer Drugs: Just the Tip of the Iceberg? Hepatology (2015) 61 (2 ):703–11. 10.1002/hep.27609\n60 Wang B Mufti G Agarwal K . Reactivation of Hepatitis B Virus Infection in Patients With Hematologic Disorders. Haematologica (2019) 104 (3 ):435–43. 10.3324/haematol.2018.210252\n61 Sagnelli E Manzillo G Maio G Pasquale G Felaco FM Filippini P . Serum Levels of Hepatitis B Surface and Core Antigens During Immunosuppressive Treatment of HBsAg-positive Chronic Active Hepatitis. Lancet (1980) 2 (8191 ):395–7. 10.1016/s0140-6736(80)90442-0\n62 Bessone F Dirchwolf M . Management of Hepatitis B Reactivation in Immunosuppressed Patients: An Update on Current Recommendations. World J Hepatol (2016) 8 (8 ):385–94. 10.4254/wjh.v8.i8.385\n63 Cheng AL Hsiung CA Su IJ Chen PJ Chang MC Tsao CJ . Steroid-Free Chemotherapy Decreases Risk of Hepatitis B Virus (HBV) Reactivation in HBV-carriers With Lymphoma. Hepatology (2003) 37 (6 ):1320–8. 10.1053/jhep.2003.50220\n64 Tur-Kaspa R Burk RD Shaul Y Shafritz DA . Hepatitis B Virus DNA Contains a Glucocorticoid-Responsive Element. Proc Natl Acad Sci USA (1986) 83 (6 ):1627–31. 10.1073/pnas.83.6.1627\n65 He Q Song X Huang Y Huang W Ye B Luo H . Dexamethasone Stimulates Hepatitis B Virus (Hbv) Replication Through Autophagy. Med Sci Monit (2018) 24 :4617–24. 10.12659/MSM.906250\n66 Paul S Saxena A Terrin N Viveiros K Balk EM Wong JB . Hepatitis B Virus Reactivation and Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-Analysis. Ann Intern Med (2016) 164 (1 ):30–40. 10.7326/M15-1121 26595058\n67 Chen YF Chong CL Wu YC Wang YL Tsai KN Kuo TM . Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPalpha Expression. PloS One (2015) 10 (6 ):e0131743. 10.1371/journal.pone.0131743 26121644\n68 Lake AC . Hepatitis B Reactivation in a Long-Term Nonprogressor Due to Nivolumab Therapy. AIDS (2017) 31 (15 ):2115–8. 10.1097/QAD.0000000000001599\n69 Pandey A Ezemenari S Liaukovich M Richard I Boris A . A Rare Case of Pembrolizumab-Induced Reactivation of Hepatitis B. Case Rep Oncol Med (2018) 2018 :5985131. 10.1155/2018/5985131 30416833\n70 Kundumadam S Mohamad B Muthusamy A Kathi PR Ehrinpreis MN . Pembrolizumab-Induced Immune-Mediated Hepatitis and Concurrent Hepatitis B Reactivation in a Patient With Non-Small Cell Lung Cancer. Cureus (2020) 12 (11 ):e11522. 10.7759/cureus.11522 33354466\n71 Koksal AS Toka B Eminler AT Hacibekiroglu I Uslan MI Parlak E . HBV-Related Acute Hepatitis Due to Immune Checkpoint Inhibitors in a Patient With Malignant Melanoma. Ann Oncol (2017) 28 (12 ):3103–4. 10.1093/annonc/mdx502\n72 Zhang X Zhou Y Chen C Fang W Cai X Zhang X . Hepatitis B Virus Reactivation in Cancer Patients With Positive Hepatitis B Surface Antigen Undergoing PD-1 Inhibition. J Immunother Cancer (2019) 7 (1 ):322. 10.1186/s40425-019-0808-5 31753012\n73 Hwang JP Feld JJ Hammond SP Wang SH Alston-Johnson DE Cryer DR . Hepatitis B Virus Screening and Management for Patients With Cancer Prior to Therapy: Asco Provisional Clinical Opinion Update. J Clin Oncol (2020) 38 (31 ):3698–715. 10.1200/JCO.20.01757\n74 2020 NCCNB-cl. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf (Accessed January 3, 2021).\n75 Liang R . How I Treat and Monitor Viral Hepatitis B Infection in Patients Receiving Intensive Immunosuppressive Therapies or Undergoing Hematopoietic Stem Cell Transplantation. Blood (2009) 113 (14 ):3147–53. 10.1182/blood-2008-10-163493\n76 Lok AS McMahon BJ . Chronic Hepatitis B: Update 2009. Hepatology (2009) 50 (3 ):661–2. 10.1002/hep.23190\n77 Lau GK Yiu HH Fong DY Cheng HC Au WY Lai LS . Early is Superior to Deferred Preemptive Lamivudine Therapy for Hepatitis B Patients Undergoing Chemotherapy. Gastroenterology (2003) 125 (6 ):1742–9. 10.1053/j.gastro.2003.09.026\n78 Hsu C Hsiung CA Su IJ Hwang WS Wang MC Lin SF . A Revisit of Prophylactic Lamivudine for Chemotherapy-Associated Hepatitis B Reactivation in non-Hodgkin’s Lymphoma: A Randomized Trial. Hepatology (2008) 47 (3 ):844–53. 10.1002/hep.22106\n79 Ziakas PD Karsaliakos P Mylonakis E . Effect of Prophylactic Lamivudine for Chemotherapy-Associated Hepatitis B Reactivation in Lymphoma: A Meta-Analysis of Published Clinical Trials and a Decision Tree Addressing Prolonged Prophylaxis and Maintenance. Haematologica (2009) 94 (7 ):998–1005. 10.3324/haematol.2009.005819 19454492\n80 Yu S Luo H Pan M Luis AP Xiong Z Shuai P . Comparison of Entecavir and Lamivudine in Preventing HBV Reactivation in Lymphoma Patients Undergoing Chemotherapy: A Meta-Analysis. Int J Clin Pharm (2016) 38 (5 ):1035–43. 10.1007/s11096-016-0358-6\n81 Loglio A Vigano M Grossi G Labanca S Goldaniga M Pompa A . Lamivudine Prophylaxis Prevents Hepatitis B Virus Reactivation in anti-HBc Positive Patients Under Rituximab for Non-Hodgkin Lymphoma. Dig Liver Dis (2019) 51 (3 ):419–24. 10.1016/j.dld.2018.08.024\n82 Law JK Ali JA Harrigan PR Sherlock CH Savage KJ Yoshida EM . Fatal Postlymphoma Chemotherapy Hepatitis B Reactivation Secondary to the Emergence of a YMDD Mutant Strain With Lamivudine Resistance in a Noncirrhotic Patient. Am J Hematol (2006) 81 (12 ):969–72. 10.1002/ajh.20737\n83 Loomba R Rowley A Wesley R Liang TJ Hoofnagle JH Pucino F . Systematic Review: The Effect of Preventive Lamivudine on Hepatitis B Reactivation During Chemotherapy. Ann Intern Med (2008) 148 (7 ):519–28. 10.7326/0003-4819-148-7-200804010-00008\n84 Zhang MY Zhu GQ Shi KQ Zheng JN Cheng Z Zou ZL . Systematic Review With Network Meta-Analysis: Comparative Efficacy of Oral Nucleos(T)Ide Analogues for the Prevention of Chemotherapy-Induced Hepatitis B Virus Reactivation. Oncotarget (2016) 7 (21 ):30642–58. 10.18632/oncotarget.8907\n85 Yang C Qin B Yuan Z Chen L Zhou HY . Meta-Analysis of Prophylactic Entecavir or Lamivudine Against Hepatitis B Virus Reactivation. Ann Hepatol (2016) 15 (4 ):501–11. 10.5604/16652681.1202910\n86 Hwang JP Artz AS Somerfield MR . Hepatitis B Virus Screening for Patients With Cancer Before Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update. J Oncol Pract (2015) 11 (4 ):e487–9. 10.1200/JOP.2015.004846\n87 Tseng CM Chen TB Hsu YC Chang CY Lin JT Mo LR . Comparative Effectiveness of Nucleos(T)Ide Analogues in Chronic Hepatitis B Patients Undergoing Cytotoxic Chemotherapy. Asia Pac J Clin Oncol (2016) 12 (4 ):421–9. 10.1111/ajco.12520\n88 Wani MA Sodhi JS Yatoo GN Shah A Geelani S Zargar SA . Clinical Profile and Efficacy of Antivirals in Hepatitis B Virus Reactivation, in Patients With Cancer Receiving Chemotherapy. J Clin Exp Hepatol (2020) 10 (6 ):590–8. 10.1016/j.jceh.2020.06.008\n89 Li HR Huang JJ Guo HQ Zhang X Xie Y Zhu HL . Comparison of Entecavir and Lamivudine in Preventing Hepatitis B Reactivation in Lymphoma Patients During Chemotherapy. J Viral Hepat (2011) 18 (12 ):877–83. 10.1111/j.1365-2893.2010.01386.x\n90 Huang H Li X Zhu J Ye S Zhang H Wang W . Entecavir vs Lamivudine for Prevention of Hepatitis B Virus Reactivation Among Patients With Untreated Diffuse Large B-cell Lymphoma Receiving R-CHOP Chemotherapy: A Randomized Clinical Trial. JAMA (2014) 312 (23 ):2521–30. 10.1001/jama.2014.15704\n91 Koskinas JS Deutsch M Adamidi S Skondra M Tampaki M Alexopoulou A . The Role of Tenofovir in Preventing and Treating Hepatitis B Virus (HBV) Reactivation in Immunosuppressed Patients. A Real Life Experience From a Tertiary Center. Eur J Intern Med (2014) 25 (8 ):768–71. 10.1016/j.ejim.2014.06.028\n92 Zheng JN Zou TT Zou H Zhu GQ Ruan LY Cheng Z . Comparative Efficacy of Oral Nucleotide Analogues for the Prophylaxis of Hepatitis B Virus Recurrence After Liver Transplantation: A Network Meta-Analysis. Expert Rev Anti Infect Ther (2016) 14 (10 ):979–87. 10.1080/14787210.2016.1220831\n93 Ceccarelli L Salpini R Sarmati L Svicher V Bertoli A Sordillo P . Late Hepatitis B Virus Reactivation After Lamivudine Prophylaxis Interruption in an anti-HBs-positive and anti-HBc-negative Patient Treated With Rituximab-Containing Therapy. J Infect (2012) 65 (2 ):180–3. 10.1016/j.jinf.2011.11.021\n94 Muraishi J Shibata M Honma Y Hiura M Abe S Harada M . Reactivation of Occult Hepatitis B Virus Infection 27 Months After the End of Chemotherapy Including Rituximab for Malignant Lymphoma. Intern Med (2017) 56 (15 ):1967–71. 10.2169/internalmedicine.56.8233\n95 Cerva C Colagrossi L Maffongelli G Salpini R Di Carlo D Malagnino V . Persistent Risk of HBV Reactivation Despite Extensive Lamivudine Prophylaxis in Haematopoietic Stem Cell Transplant Recipients Who Are anti-HBc-positive or HBV-negative Recipients With an anti-HBc-positive Donor. Clin Microbiol Infect (2016) 22 (11 ):946.e1–e8. 10.1016/j.cmi.2016.07.021\n96 Liu WP Wang XP Zheng W Ping LY Zhang C Wang GQ . Hepatitis B Virus Reactivation After Withdrawal of Prophylactic Antiviral Therapy in Patients With Diffuse Large B Cell Lymphoma. Leuk Lymphoma (2016) 57 (6 ):1355–62. 10.3109/10428194.2015.1116121\n97 Nakaya A Fujita S Satake A Nakanishi T Azuma Y Tsubokura Y . Delayed HBV Reactivation in Rituximab-Containing Chemotherapy: How Long Should We Continue Anti-Virus Prophylaxis or Monitoring HBV-DNA? Leuk Res (2016) 50 :46–9. 10.1016/j.leukres.2016.09.014\n98 Hwang JP Fisch MJ Zhang H Kallen MA Routbort MJ Lal LS . Low Rates of Hepatitis B Virus Screening at the Onset of Chemotherapy. J Oncol Pract (2012) 8 (4 ):e32–9. 10.1200/JOP.2011.000450\n99 Hwang JP Fisch MJ Lok AS Zhang H Vierling JM Suarez-Almazor ME . Trends in Hepatitis B Virus Screening at the Onset of Chemotherapy in a Large US Cancer Center. BMC Cancer (2013) 13 :534. 10.1186/1471-2407-13-534 24209764\n100 Visram A Chan KK McGee P Boro J Hicks LK Feld JJ . Poor Recognition of Risk Factors for Hepatitis B by Physicians Prescribing Immunosuppressive Therapy: A Call for Universal Rather Than Risk-Based Screening. PLoS One (2015) 10 (4 ):e0120749. 10.1371/journal.pone.0120749 25875198\n101 Hwang JP Lok AS Fisch MJ Cantor SB Barbo A Lin HY . Models to Predict Hepatitis B Virus Infection Among Patients With Cancer Undergoing Systemic Anticancer Therapy: A Prospective Cohort Study. J Clin Oncol (2018) 36 (10 ):959–67. 10.1200/JCO.2017.75.6387\n102 Hashino S Nozawa A Izumiyama K Yonezumi M Chiba K Kondo T . Lamivudine Treatment for Reverse Seroconversion of Hepatitis B 4 Years After Allogeneic Bone Marrow Transplantation. Bone Marrow Transplant (2002) 29 (4 ):361–3. 10.1038/sj.bmt.1703387\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "antiviral prophylaxis; hepatitis B virus reactivation (HBV-R); immunosuppressive therapy; non-Hodgkin lymphoma (NHL); risk factors; rituximab",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "685706",
"pmc": null,
"pmid": "34277431",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "23861969;20350658;9392700;26121644;16440366;26727044;26563120;19075267;26231459;30316785;22432084;16937392;11896435;16149133;19714720;33055468;20002298;24209764;25220947;31753012;30733266;15693796;19697028;28945827;18302293;27665181;31113483;27435683;21556931;19399814;28768965;27004086;3006059;28951776;25447850;30568345;27590841;27340429;25447852;27475741;15054446;23180996;27450506;33402334;27491868;21115603;32716741;24150447;23593610;25412906;20959600;26595058;26885191;30416833;25253946;30341058;18378948;25849120;29972684;12774010;32425598;27291888;30988907;19454492;32963163;33549195;25765930;25875198;21054683;32489654;27121321;6105519;28140702;14724827;11055239;28906278;25356022;33311896;31338887;32550096;31004683;19144986;27236149;22138369;31596963;33067316;25418031;28219691;29447061;29606020;25991637;28251118;25037900;31341357;23749673;28427875;30681172;33354466;20738779;25514302;27742008",
"title": "HBV Reactivation During the Treatment of Non-Hodgkin Lymphoma and Management Strategies.",
"title_normalized": "hbv reactivation during the treatment of non hodgkin lymphoma and management strategies"
} | [
{
"companynumb": "CN-JNJFOC-20210813906",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": "3",
"... |
{
"abstract": "New-onset diabetes mellitus after solid-organ transplant makes for complicated tacrolimus immunosuppression. However, tacrolimus-associated diabetic ketoacidosis has not been reported in bone marrow transplant. We report 24-year-old women, hospitalized with diabetic ketoacidosis, 70 days after undergoing a bone marrow transplant with tacrolimus immunosuppression. Clinicians should be wary about tacrolimus levels and the risk of hyperglycemic states after bone marrow transplant as with other solid-organ transplants.",
"affiliations": "Department of Hematology, Başkent University, Adana, Turkey.",
"authors": "Solmaz|Soner|S|;Gökgöz|Zafer|Z|;Gereklioğlu|Çiğdem|Ç|;Yeral|Mahmut|M|;Boğa|Can|C|;Özdoğu|Hakan|H|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2015.0047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "15(6)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D016026:Bone Marrow Transplantation; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D016883:Diabetic Ketoacidosis; D016903:Drug Monitoring; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015470:Leukemia, Myeloid, Acute; D016559:Tacrolimus; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "702-703",
"pmc": null,
"pmid": "26643544",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tacrolimus-Induced Diabetic Ketoacidosis After Allogeneic Bone Marrow Transplant.",
"title_normalized": "tacrolimus induced diabetic ketoacidosis after allogeneic bone marrow transplant"
} | [
{
"companynumb": "TR-ASTELLAS-2015US046823",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSarcomatoid urothelial carcinoma (SUC) is a rare malignant neoplasm of the urinary bladder comprising 0.2-0.6 % of all histological bladder tumor subtypes. It presents as a high-stage malignancy and exhibits aggressive biological behavior, regardless of the treatment employed. It is defined as histologically indistinguishable from sarcoma and as a high-grade biphasic neoplasm with malignant epithelial and mesenchymal components. The mean age of patients presenting with SUC is 66 years, and the male-to-female ratio is 3:1. In addition, gross hematuria is usually present. The prognosis of SUC is poorer than that of typical urothelial carcinoma because of uncertainty concerning the optimal treatment regimen.\n\n\nMETHODS\nWe report the case of a 77-year-old woman with SUC containing a chondrosarcoma component who, 12 years previously, had undergone a nephroureterectomy for pT3N0M0 ureter cancer of the contralateral upper urinary tract. From the 4th year of follow-up after nephroureterectomy, multiple recurrent bladder tumors staged as Ta transitional cell carcinoma developed, and six transurethral resections of the bladder (TURB) with multiple intravesical instillations were performed without any evidence of metastases and upper tract recurrences. In 2015, a right partial distal ureterectomy and an additional TURB were performed due to a papillary mass at the right contralateral ureterovesical junction of the bladder, which was confirmed as a high-grade pT1 transitional cell carcinoma. After a further 2 years of follow-up, total pelvic exenteration with an ileal conduit diversion was performed to remove the mass, which was a pT4N0M0 tumor composed of carcinomatous and sarcomatous elements compatible with a sarcomatoid carcinoma including grade 3 transitional cell carcinoma and chondrosarcoma. Immunohistochemical examination showed that tumor cells were positive for vimentin and p63 and negative for NSE and Cd56 markers. In the first postoperative month, a metastatic lung nodule was detected on chest CT. The patient was scheduled for adjuvant gemcitabine-cisplatin chemotherapy.\n\n\nCONCLUSIONS\nThe present case was interesting because we cannot be sure if the SUC chondrosarcoma originated from the 12-year-ago proximal ureter tumor, the 2-year-ago contralateral distal ureter tumor, or a new primary bladder tumor. Genetic profiling might have been useful to determine the origin of the SUC chondrosarcoma.",
"affiliations": "Department of Urology, Seoul National University Hospital, Seoul, South Korea.;Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, South Korea.;Department of Pathology, Center for Prostate Cancer, National Cancer Center, Goyang, South Korea.;Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, South Korea.;Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, South Korea.;Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, South Korea.;Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, South Korea. uroonco@ncc.re.kr.",
"authors": "Cho|Min Hyun|MH|;Kim|Sung Han|SH|;Park|Weon Seo|WS|;Joung|Jae Young|JY|;Seo|Ho Kyung|HK|;Chung|Jinsoo|J|;Lee|Kang Hyun|KH|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1186/s12957-016-1021-3",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 102110.1186/s12957-016-1021-3Case ReportBladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract: a case report and literature review Cho Min Hyun 62198@ncc.re.kr 1Kim Sung Han 12112@ncc.re.kr 2Park Weon Seo thymus@ncc.re.kr 3Joung Jae Young urojoy@ncc.re.kr 2Seo Ho Kyung seohk@ncc.re.kr 2Chung Jinsoo cjs5225@ncc.re.kr 2Lee Kang Hyun 82-31-920-2799uroonco@ncc.re.kr 21 Department of Urology, Seoul National University Hospital, Seoul, South Korea 2 Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769 South Korea 3 Department of Pathology, Center for Prostate Cancer, National Cancer Center, Goyang, South Korea 20 10 2016 20 10 2016 2016 14 2702 7 2016 7 10 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSarcomatoid urothelial carcinoma (SUC) is a rare malignant neoplasm of the urinary bladder comprising 0.2–0.6 % of all histological bladder tumor subtypes. It presents as a high-stage malignancy and exhibits aggressive biological behavior, regardless of the treatment employed. It is defined as histologically indistinguishable from sarcoma and as a high-grade biphasic neoplasm with malignant epithelial and mesenchymal components. The mean age of patients presenting with SUC is 66 years, and the male-to-female ratio is 3:1. In addition, gross hematuria is usually present. The prognosis of SUC is poorer than that of typical urothelial carcinoma because of uncertainty concerning the optimal treatment regimen.\n\nCase presentation\nWe report the case of a 77-year-old woman with SUC containing a chondrosarcoma component who, 12 years previously, had undergone a nephroureterectomy for pT3N0M0 ureter cancer of the contralateral upper urinary tract. From the 4th year of follow-up after nephroureterectomy, multiple recurrent bladder tumors staged as Ta transitional cell carcinoma developed, and six transurethral resections of the bladder (TURB) with multiple intravesical instillations were performed without any evidence of metastases and upper tract recurrences. In 2015, a right partial distal ureterectomy and an additional TURB were performed due to a papillary mass at the right contralateral ureterovesical junction of the bladder, which was confirmed as a high-grade pT1 transitional cell carcinoma. After a further 2 years of follow-up, total pelvic exenteration with an ileal conduit diversion was performed to remove the mass, which was a pT4N0M0 tumor composed of carcinomatous and sarcomatous elements compatible with a sarcomatoid carcinoma including grade 3 transitional cell carcinoma and chondrosarcoma. Immunohistochemical examination showed that tumor cells were positive for vimentin and p63 and negative for NSE and Cd56 markers. In the first postoperative month, a metastatic lung nodule was detected on chest CT. The patient was scheduled for adjuvant gemcitabine-cisplatin chemotherapy.\n\nConclusions\nThe present case was interesting because we cannot be sure if the SUC chondrosarcoma originated from the 12-year-ago proximal ureter tumor, the 2-year-ago contralateral distal ureter tumor, or a new primary bladder tumor. Genetic profiling might have been useful to determine the origin of the SUC chondrosarcoma.\n\nKeywords\nUrothelial carcinomaChondrosarcomaBladderUreterRecurrencenonenoneissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSarcomatoid urothelial carcinoma (SUC) is a rare malignant neoplasm of the urinary bladder comprising 0.2–0.6 % of all histological bladder tumor subtypes [1, 2]. It presents as a high-stage malignancy and exhibits aggressive biological behavior, regardless of the treatment employed. It is defined as histologically indistinguishable from sarcoma and as a high-grade biphasic neoplasm with malignant epithelial and mesenchymal components. In the past, when SUC showed specific mesenchymal differentiation such as that in chondrosarcoma, some pathologists have preferred to use the term “carcinosarcoma” [3]. The mean age of patients presenting with SUC is 66 years, and the male-to-female ratio is 3:1. In addition, gross hematuria is usually present. The prognosis of SUC is poorer than that of typical urothelial carcinoma because of uncertainty concerning the optimal treatment regimen.\n\nHere, we report the case of a 77-year-old woman with SUC containing a chondrosarcoma component who, 12 years previously, had undergone a nephroureterectomy for pT3N0M0 transitional cell carcinoma of ureter cancer of the contralateral upper urinary tract.\n\nCase presentation\nA 77-year-old woman visited our hospital for multiple recurred bladder tumors. She had a history of well-controlled hypertension. Twelve years previously, at a different hospital, she underwent a left nephroureterectomy with adjuvant chemotherapy (6 cycles of monthly Gemzar-cisplatin combination chemotherapy and 3 cycles of monthly Gemzar-carboplatin chemotherapy) for pT3N0M0 poorly differentiated UC of the ureter. No further recurrence was detected during the routine follow-ups. On the 4th year of follow-up after nephroureterectomy, she developed gross hematuria and left lower quadrant discomfort that had persisted for 2 months. She was referred to our institution after cystoscopy revealed multiple recurred papillary bladder tumors. Transurethral resection of the bladder tumors (TURB) was performed followed by 6 cycles of intravesical instillation therapy. Histologically, the tumor was a high-grade pTa transitional cell carcinoma (TCC). During the next 6 years, a further five TURB operations were performed for recurred bladder tumors, and three different courses of postoperative intravesical instillations using mitomycin-C, epirubicin, or BCG agents were performed after each TURB. Pathologically, the tumors were low- to high-grade pTa TCC with or without carcinoma in situ. In 2015, a gross hematuria developed, and routine cystoscopy follow-up revealed a papillary mass appearing at the right contralateral ureterovesical junction of the bladder. Computed tomography (CT) did not reveal any metastases or lymph node enlargements. She underwent a right, 1.5-cm length, partial, distal ureterectomy and an end-to-end ureteroureterostomy with an additional TURB at the right ureteral orifice. Frozen section analysis and final pathology confirmed that the distal and proximal ureteral margins and the resected bladder sections were negative for tumor cells. The mass was confirmed as a high-grade pT1 TCC. After a further 2 years of follow-up, CT revealed a 4-cm, submucosal, invasive, non-pedunculated, elevated bladder mass with an intact mucosa involving the bladder neck, urethra, and upper vagina (Fig. 1). Total pelvic exenteration with an ileal conduit diversion was performed to remove the mass, which was a pT4N0M0 tumor composed of carcinomatous and sarcomatous elements compatible with a sarcomatoid carcinoma including grade 3 TCC and chondrosarcoma (Fig. 2). Immunohistochemical examination showed that tumor cells were positive for vimentin and p63 and negative for NSE and Cd56 markers. In the first postoperative month, a metastatic lung nodule was detected on chest CT. The patient underwent two more cycles of adjuvant Gemzar-cisplatin chemotherapy, but further chemotherapy was not performed because of her poor general condition and neutropenic side effects.Fig. 1 Preoperative gynecologic MRI and abdominal CT images. a A 4-cm recurred tumor involving the bladder neck, urethra, and upper vagina (horizontal view, abdominal pelvis CT). b An increased recurred tumor involving the bladder neck, urethra, and upper vagina (4.6 cm). There were no newly appearing lesions in the pelvic cavity indicating a lack of metastasis (sagittal view, MRI gynecology). c. A 4-cm recurred tumor involving the bladder neck, urethra, and upper vagina. There were no other newly appearing lesions in abdominopelvic cavity indicating a lack of metastasis (horizontal view, MRI gynecology)\n\n\nFig. 2 Representative photomicrographs of the urothelial carcinoma in the bladder. a Sectional gross photograph of the specimen. The upper part shows the bladder and the lower part shows the vagina. There is a well-demarcated round mass under the bladder mucosa. b Photomicrograph of the TURB (×40). A poorly differentiated urothelial carcinoma is noted on the mucosa and in the subepithelial connective tissue. c A poorly differentiated urothelial carcinoma surrounded by a sarcomatoid component (center, chondrosarcoma; ×40). d High-powered view of the chondrosarcoma component (hematoxylin and eosin staining; ×100)\n\n\n\n\nDiscussion\nSUC is an unusual malignancy containing both carcinomatous and sarcomatous components. It is a rare, but aggressive, bladder cancer, comprising <1 % of all bladder cancers [2]. In most reported SUC cases, the epithelial component was UC, although squamous cell and small-cell carcinoma components have been reported. The mesenchymal component varies from homogeneous sarcoma to heterotopic elements, such as malignant bone, cartilage, and other mesenchymal tissues. Radiation and intravesical cyclophosphamide instillation therapy are typical risk factors. In addition, a recent multicenter study showed that 50–79 % of patients with SUC were current smokers [2]. Nodal and visceral metastases are often present at diagnosis (>20 % of patients). However, the present case did not present with any of these risk factors.\n\nA multimodal approach that includes definitive surgery, local radiation therapy, and chemotherapy is often used for locally advanced disease. For patients with sarcomatoid carcinoma of the bladder, previous studies and reviews have indicated that a GC-based regimen is well tolerated and effective, given its ability to induce complete remission [2–5]. Chemotherapy, therefore, has been the mainstay treatment for metastatic disease; however, the response rates have been varied. The 5-year cancer-specific survival after cystectomy is 20 %, and the median overall survival is 14 months. SUC tends to present at an advanced stage and is associated with a poor prognosis.\n\nAccording to the WHO classification [4], macroscopically, sarcomatoid carcinomas are large and polypoid with infiltrative margins, a fleshy appearance, and the presence of hemorrhage, necrosis, and cavitation. Microscopically, conventional urothelial, squamous, glandular, or small-cell components may be mixed with sarcomatous components that usually predominate. The sarcomatoid component consists of high-grade spindle-shaped or pleomorphic cells. Heterologous components can include osteocarcinoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, and angiosarcoma [4]. Previous studies have suggested that patients whose tumors harbor heterologous elements may have a worse prognosis compared to those without them. In 80 % of cases, epithelial cells are vimentin positive, which is congruent with the findings in the present case. Conversely, the sarcomatoid component can retain focal expression of high molecular weight cytokeratins, p63, and GATA3.\n\nThe histogenesis of SUC is unclear, and Armstrong et al. [5] examined TP53 mutation status and p53 protein expression in both the sarcomatoid and epithelial components of SUC. They suggested a common clonal origin of the phenotypically different tumor components, and that TP53 mutations probably occurred early in the common tumorigenesis of these morphologically distinct tumor components. Subsequently, these lesions were likely exposed to additional stimuli, giving rise to the biphasic phenotype [5].\n\nThe present case was interesting because the patient had a history of both high-stage pT3 ureter cancer and contralateral distal ureter tumor. After several endoscopic resections for superficial low-grade recurrent bladder tumors and intravesical instillation therapies with multiple agents, SUC chondrosarcoma occurred in the bladder after cystectomy. We cannot be sure if the SUC chondrosarcoma originated from the proximal ureter tumor that occurred 12 years earlier, the contralateral distal ureter tumor that occurred 2 years earlier, or a new primary bladder tumor. Genetic profiling might have been useful to determine the origin of the SUC chondrosarcoma. However, the patient was diagnosed with metastatic lung cancer during the follow-up and was scheduled to undergo chemotherapy.\n\nConclusions\nWe reported the case of a 77-year-old woman with SUC containing a chondrosarcoma component. Further accumulated cases studies with genetic profiling would improve the understanding of SUC and enable optimal treatment planning.\n\nAbbreviations\nCTComputed tomography\n\nSUCSarcomatoid urothelial carcinoma\n\nTCCTransitional cell carcinoma\n\nTURBTransurethral resection of bladder\n\nAcknowledgements\nNone.\n\nAvailability of data and materials\nThe data and material are freely available upon requests.\n\nFurther information may be obtained by contacting Dr. Kang Hyun Lee (uroonco@ncc.re.kr), who is responsible for the dataset.\n\nAuthors’ contributions\nSHK, JYJ, and KHL contributed to the manuscript conception and preparation. MHC, SHK, and WSP contributed to the data collection and analysis. WSP, JYJ, HKS, KHL, and JC did the internal review of the draft. All authors were responsible for the manuscript approval.\n\nCompeting interest\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWe have obtained consent to publish from the patient and her caregiver to report individual patient data.\n\nEthics approval and consent to participate\nInformed written was obtained from the patient and her caregiver to participate in and to approve the case report with the exemption of the IRB approval (The IRB of National Cancer Center, Goyang, Korea).\n\nFinancial disclosure\nNone of the authors have financial disclosures.\n==== Refs\nReferences\n1. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur Urol 2016; [Epub ahead of print] doi: 10.1016/j.eururo.2016.02.028\n2. Malla M, Wang JF, Trepeta R, Feng A, Wang J. Sarcomatoid carcinoma of the urinary bladder. Clin Genitourin Cancer 2016; [Epub ahead of print] doi: 10.1016/j.clgc.2016.03.004\n3. Sung MT Wang M MacLennan GT Eble JN Tan PH Lopez-Beltran A Montironi R Harris JJ Kuhar M Cheng L Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation J Pathol 2007 211 420 3 10.1002/path.2129 17236170 \n4. Moch H Humphrey PA Ulbright TM Reuter VE The 2016 WHO Classification of tumours of the urinary system and male genital organs 2016 4 Lyon IARC 91 2 \n5. Armstrong AB Wang M Eble JN MacLennan GT Montironi R Tan PH Lopez-Beltran A Zhang S Baldridge LA Spartz H Cheng L TP53 mutational analysis supports monoclonal origin of biphasic sarcomatoid urothelial carcinoma (carcinosarcoma) of the urinary bladder Mod Pathol 2009 22 113 8 10.1038/modpathol.2008.176 18997737\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-7819",
"issue": "14(1)",
"journal": "World journal of surgical oncology",
"keywords": "Bladder; Chondrosarcoma; Recurrence; Ureter; Urothelial carcinoma",
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002295:Carcinoma, Transitional Cell; D017024:Chemotherapy, Adjuvant; D002813:Chondrosarcoma; D002945:Cisplatin; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D007668:Kidney; D007680:Kidney Neoplasms; D008175:Lung Neoplasms; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D014057:Tomography, X-Ray Computed; D014516:Ureteral Neoplasms; D001749:Urinary Bladder Neoplasms; D013520:Urologic Surgical Procedures",
"nlm_unique_id": "101170544",
"other_id": null,
"pages": "270",
"pmc": null,
"pmid": "27765044",
"pubdate": "2016-10-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26996659;17236170;18997737;27050715;26935559",
"title": "Bladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract: a case report and literature review.",
"title_normalized": "bladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract a case report and literature review"
} | [
{
"companynumb": "KR-ACCORD-045416",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Red blood cell (RBC) Thomsen-Friedenreich antigen exposure (T activation) in infants with necrotizing enterocolitis (NEC) has occasionally been associated with posttransfusional intravascular hemolysis thought to be due to anti-T antibodies in the donor plasma.\n\n\n\nWe describe an infant with NEC and Clostridium perfringens infection complicated by severe hemolysis after plasma transfusion. After this case, infants with confirmed NEC were prospectively evaluated for T activation. We checked for hemolysis in patients with T activation receiving plasma-containing blood products.\n\n\n\nThe infant had received 80 mL of fresh-frozen plasma (FFP). His RBCs displayed strong T activation, and agglutination was observed with four of six ABO-compatible FFP units. A direct antiglobulin test was negative. IgM-class anti-T antibodies were present in small amounts (titer of 8) in the transfused FFP. Anti-T antibodies from the blood donor were not hemolytic in vitro. In the prospective study, T activation was observed in three of 28 infants with NEC (11%). One infant presented moderate T activation and two infants presented very strong T activation but only moderate decreases in sialic acid expression on the RBC membrane. These three infants presented no signs of hemolysis after transfusion with unwashed blood products or FFP.\n\n\n\nAnti-T antibodies are unlikely to be the etiologic factor for the hemolytic reactions observed in infants with NEC and T activation. Massive RBC desialylation and the direct action of bacterial toxins are more probable causes. Strict avoidance of plasma-containing blood products does not seem justified in these infants.",
"affiliations": "Etablissement Français du Sang (EFS) Ile-de-France, Paris.;Etablissement Français du Sang (EFS) Ile-de-France, Paris.;Réanimation Chirurgicale Pédiatrique, Hôpital Necker-Enfants Malades, Paris.;Etablissement Français du Sang (EFS) Ile-de-France, Paris.;Réanimation Pédiatrique et Néonatale, Le Kremlin Bicêtre, France.;Réanimation Pédiatrique et Néonatale, Le Kremlin Bicêtre, France.;Etablissement Français du Sang (EFS) Ile-de-France, Paris.;Unité d'Hémovigilance, Hôpital Bicêtre, Le Kremlin Bicêtre, France.;Réanimation Pédiatrique et Néonatale, Le Kremlin Bicêtre, France.;Etablissement Français du Sang (EFS) Ile-de-France, Paris.;Etablissement Français du Sang (EFS) Ile-de-France, Paris.;Etablissement Français du Sang (EFS) Ile-de-France, Paris.;Etablissement Français du Sang (EFS) Ile-de-France, Paris.",
"authors": "Moh-Klaren|Julia|J|;Bodivit|Gwellaouen|G|;Jugie|Myriam|M|;Chadebech|Philippe|P|;Chevret|Laurent|L|;Mokhtari|Mostafa|M|;Chamillard|Xavier|X|;Gallon|Philippe|P|;Tissières|Pierre|P|;Bierling|Philippe|P|;Djoudi|Rachid|R|;Pirenne|France|F|;Burin-des-Roziers|Nicolas|N|",
"chemical_list": "D000906:Antibodies; D015295:Antigens, Tumor-Associated, Carbohydrate; D001426:Bacterial Proteins; C016467:Thomsen-Friedenreich antigen; C025991:Thomsen-Friedenreich antibodies; D002439:Cefotaxime",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.14196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "57(11)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000328:Adult; D000906:Antibodies; D015295:Antigens, Tumor-Associated, Carbohydrate; D001426:Bacterial Proteins; D001782:Blood Donors; D002439:Cefotaxime; D003015:Clostridium Infections; D003016:Clostridium perfringens; D020345:Enterocolitis, Necrotizing; D004912:Erythrocytes; D005260:Female; D006461:Hemolysis; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D011446:Prospective Studies",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "2571-2577",
"pmc": null,
"pmid": "28643465",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Severe hemolysis after plasma transfusion in a neonate with necrotizing enterocolitis, Clostridium perfringens infection, and red blood cell T-polyagglutination.",
"title_normalized": "severe hemolysis after plasma transfusion in a neonate with necrotizing enterocolitis clostridium perfringens infection and red blood cell t polyagglutination"
} | [
{
"companynumb": "FR-VALIDUS PHARMACEUTICALS LLC-FR-2017VAL001612",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"... |
{
"abstract": "Anaphylaxis against gadolinium based contrast agents (GBCAs) has been reported in all severity grades but is less frequent than hypersensitivity/allergy against iodinated contrast materials. Once a patient acquires such an adverse reaction a life-long premedication is usually the consequence in concert with GBCA-enhanced MR-imaging procedures. The usefulness of this prophylaxis has been questioned, and discussed controversially during the past. The herein presented case may shed some light into the dynamic of contrast-medium-induced hypersensitivity reactions.",
"affiliations": "Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Experimental Radiology, Department of BioMedical Research, University of Bern, Switzerland. Electronic address: Ingrid.boehm@insel.ch.;Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Experimental Radiology, Department of BioMedical Research, University of Bern, Switzerland.;Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Experimental Radiology, Department of BioMedical Research, University of Bern, Switzerland.",
"authors": "Boehm|Ingrid|I|;Hungerbühler|Martin|M|;Heverhagen|Johannes T|JT|",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mri.2017.12.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-725X",
"issue": "49()",
"journal": "Magnetic resonance imaging",
"keywords": "Breakthrough reaction; Contrast medium allergy; Dynamic of GBCA-allergy; Gadolinium-based contrast agent (GBCA); Hypersensitivity",
"medline_ta": "Magn Reson Imaging",
"mesh_terms": "D000328:Adult; D003287:Contrast Media; D004342:Drug Hypersensitivity; D005682:Gadolinium; D006801:Humans; D012075:Remission, Spontaneous",
"nlm_unique_id": "8214883",
"other_id": null,
"pages": "1-3",
"pmc": null,
"pmid": "29247752",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Insight into the dynamic of gadolinium based contrast agent (GBCA) hypersensitivity: Acquisition, persistence and disappearance.",
"title_normalized": "insight into the dynamic of gadolinium based contrast agent gbca hypersensitivity acquisition persistence and disappearance"
} | [
{
"companynumb": "CH-BAYER-2018-022000",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GADOPENTETATE DIMEGLUMINE"
},
"drugadditional": nu... |
{
"abstract": "Introduction A patient who had no symptoms suggestive of bilateral loss of vestibular function presented no responses in rotational and caloric tests. Objectives To demonstrate the importance of the video head impulse test in neuro-otologic diagnosis. Resumed Report This patient had a neuro-otologic evaluation and presented no responses in torsion swing tests, caloric tests, and rotational tests in a Bárány chair. The video head impulse test elicited responses in four of the six semicircular canals. Conclusion Absent responses in caloric and rotatory tests alone are not sufficient to diagnose bilateral loss of vestibular function.",
"affiliations": "Department of Otolaryngology, Hospital Albert Einstein, São Paulo, SP, Brazil.;Department of Audiology and Speech Pathology, Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil.",
"authors": "Albernaz|Pedro L Mangabeira|PL|;Cusin|Flavia Salvaterra|FS|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.1055/s-0034-1395999",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1809-4864",
"issue": "20(1)",
"journal": "International archives of otorhinolaryngology",
"keywords": "head impulse test; vestibular diseases; vestibular function tests",
"medline_ta": "Int Arch Otorhinolaryngol",
"mesh_terms": null,
"nlm_unique_id": "101637652",
"other_id": null,
"pages": "84-6",
"pmc": null,
"pmid": "26722351",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports",
"references": "11710461;22460150;9577395;8985896;10436470;3390028;8985897;12410118",
"title": "The Video Head Impulse Test in a Case of Suspected Bilateral Loss of Vestibular Function.",
"title_normalized": "the video head impulse test in a case of suspected bilateral loss of vestibular function"
} | [
{
"companynumb": "BR-BAXTER-2017BAX006813",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MANNITOL"
},
"drugadditional": null,
... |
{
"abstract": "Symptomatic cerebrospinal fluid (CSF) viral escape (sCVE) is reported in people with HIV, who are on ritonavir-boosted protease inhibitor (PI/r) containing antiretroviral therapy (ART). Management of sCVE includes performing genotypic HIV-1 resistance testing (GRT) on CSF and plasma HIV and changing ART accordingly. Neither GRT nor newer drugs (Dolutegravir and Darunavir/ritonavir) are routinely available in India. As a result, management of sCVE includes 2 modalities: a) ART intensification by adding drugs that reach therapeutic concentrations in CSF, like Zidovudine, to existing ART or b) Changing to a regimen containing newer boosted PI/r and integrase strand transfer inhibitor (INSTI) as per GRT or expert opinion. In this retrospective study, we report the outcomes of above 2 modalities in treatment of sCVE in Pune, India.Fifty-seven episodes of sCVE in 54 people with HIV taking PI/r-containing ART were identified. Clinical, demographic, laboratory and ART data were recorded. Forty-seven cases had follow-up data available after ART change including measurement of plasma and CSF viral load (VL).Of the 47 cases, 23 received zidovudine intensification (Group A, median VL: plasma- 290, CSF- 5200 copies/mL) and 24 received PI/INSTI intensification (Group B, median VL: plasma- 265, CSF-4750 copies/mL). CSF GRT was performed in 16 participants: 8 had triple class resistance. After ART change, complete resolution of neurologic symptoms occurred in most participants (Group A: 18, Group B: 17). In Group A, follow-up plasma and CSF VL were available for 21 participants, most of whom achieved virologic suppression (VL < 20 copies/mL) in plasma (17) and CSF (15). Four participants were shifted to the PI/INSTI intensification group due to virologic failure (plasma or CSF VL > 200 copies/mL). In Group B, follow-up plasma and CSF VL were available for 23 participants, most of whom also achieved virologic suppression in plasma (21) and CSF (18). Four deaths were noted, 2 of which were in individuals who interrupted ART.This is a unique sCVE cohort that was managed with 1 of 2 approaches based on treatment history and the availability of GRT. At least 75% of participants responded to either approach with virologic suppression and improvement in symptoms.",
"affiliations": "Department of Medicine, Ruby Hall Clinic.;Department of Medicine, Poona hospital and research centre.;Department of Medicine, Poona hospital and research centre.;Department of Medicine, Poona hospital and research centre.;Department of Medicine, Poona hospital and research centre.;Department of Medicine, Poona hospital and research centre.;Department of Medicine, Ruby Hall Clinic.;VMK Diagnostics private limited, Pune.;VMK Diagnostics private limited, Pune.;Department of Dermatology, Ashwini Sahakari Rugnalaya, Solapur.;Department of Medicine, Apex hospital, Kolhapur.;GeneOmbio Technologies Private limited, Pune, Maharashtra, India.;University of California, San Diego, San Diego, California, USA.;Department of Medicine, Ruby Hall Clinic.;Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.",
"authors": "Dravid|Ameet N|AN|0000-0002-1909-7530;Gawali|Raviraj|R|;Betha|Tarun P|TP|;Sharma|Avadesh K|AK|;Medisetty|Mahenderkumar|M|;Natrajan|Kartik|K|;Kulkarni|Milind M|MM|;Saraf|Chinmay K|CK|;Mahajan|Uma S|US|;Kore|Sachin D|SD|;Rathod|Niranjan M|NM|;Mahajan|Umakant S|US|;Letendre|Scott L|SL|;Wadia|Rustom S|RS|;Calcagno|Andrea|A|",
"chemical_list": "D019380:Anti-HIV Agents; D015215:Zidovudine",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000020516",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32541474\nMD-D-20-00060\n10.1097/MD.0000000000020516\n20516\n4850\nResearch Article\nObservational Study\nTwo treatment strategies for management of Neurosymptomatic cerebrospinal fluid HIV escape in Pune, India\nDravid Ameet N. MDabc∗ Gawali Raviraj MBBSb Betha Tarun P. MBBSb Sharma Avadesh K. MBBSb Medisetty Mahenderkumar MDb Natrajan Kartik MDb Kulkarni Milind M. MBBSa Saraf Chinmay K. MDd Mahajan Uma S. M.Scd Kore Sachin D. MDe Rathod Niranjan M. MDf Mahajan Umakant S. BM. Techg Letendre Scott L. MDh Wadia Rustom S. MDa Calcagno Andrea MDi Bakir. Mehmet a Department of Medicine, Ruby Hall Clinic\nb Department of Medicine, Poona hospital and research centre\nc Department of Medicine, Noble hospital\nd VMK Diagnostics private limited, Pune\ne Department of Dermatology, Ashwini Sahakari Rugnalaya, Solapur\nf Department of Medicine, Apex hospital, Kolhapur\ng GeneOmbio Technologies Private limited, Pune, Maharashtra, India.\nh University of California, San Diego, San Diego, California, USA\ni Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.\n∗ Correspondence: Ameet N. Dravid, Ruby Hall Clinic, 40, Sassoon road, Pune, State- Maharashtra, India. Pin code 411004 (e-mail: ameet.dravid@gmail.com).\n12 6 2020 \n12 6 2020 \n99 24 e2051602 1 2020 09 4 2020 25 4 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This 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\nSymptomatic cerebrospinal fluid (CSF) viral escape (sCVE) is reported in people with HIV, who are on ritonavir-boosted protease inhibitor (PI/r) containing antiretroviral therapy (ART). Management of sCVE includes performing genotypic HIV-1 resistance testing (GRT) on CSF and plasma HIV and changing ART accordingly. Neither GRT nor newer drugs (Dolutegravir and Darunavir/ritonavir) are routinely available in India. As a result, management of sCVE includes 2 modalities: a) ART intensification by adding drugs that reach therapeutic concentrations in CSF, like Zidovudine, to existing ART or b) Changing to a regimen containing newer boosted PI/r and integrase strand transfer inhibitor (INSTI) as per GRT or expert opinion. In this retrospective study, we report the outcomes of above 2 modalities in treatment of sCVE in Pune, India.\n\nFifty-seven episodes of sCVE in 54 people with HIV taking PI/r-containing ART were identified. Clinical, demographic, laboratory and ART data were recorded. Forty-seven cases had follow-up data available after ART change including measurement of plasma and CSF viral load (VL).\n\nOf the 47 cases, 23 received zidovudine intensification (Group A, median VL: plasma- 290, CSF- 5200 copies/mL) and 24 received PI/INSTI intensification (Group B, median VL: plasma- 265, CSF-4750 copies/mL). CSF GRT was performed in 16 participants: 8 had triple class resistance. After ART change, complete resolution of neurologic symptoms occurred in most participants (Group A: 18, Group B: 17). In Group A, follow-up plasma and CSF VL were available for 21 participants, most of whom achieved virologic suppression (VL < 20 copies/mL) in plasma (17) and CSF (15). Four participants were shifted to the PI/INSTI intensification group due to virologic failure (plasma or CSF VL > 200 copies/mL). In Group B, follow-up plasma and CSF VL were available for 23 participants, most of whom also achieved virologic suppression in plasma (21) and CSF (18). Four deaths were noted, 2 of which were in individuals who interrupted ART.\n\nThis is a unique sCVE cohort that was managed with 1 of 2 approaches based on treatment history and the availability of GRT. At least 75% of participants responded to either approach with virologic suppression and improvement in symptoms.\n\nKeywords\ncerebral penetration effectiveness scoreCSF HIV escapegenotypic HIV-1 resistance testingprotease inhibitorszidovudineOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nSymptomatic cerebrospinal fluid (CSF) viral escape (sCVE) is defined as discordance in HIV ribonucleic acid (RNA) in plasma and CSF which is associated with new neurologic symptoms. This phenomenon was first described by Canestri et al in 2010.[1] It has been reported from higher income countries[2–15] and low and middle income countries (LMIC).[16–20] Several risk factors associated with sCVE have been described such as low nadir CD4 count (associated with HIV entry into the central nervous system (CNS) and productive infection of perivascular macrophages and other cells),[21,22] suboptimal adherence to antiretroviral therapy (ART, leading to low level plasma viremia and continual seeding of the CNS by infected cells that traffic into the brain),[23] treatment with drugs with limited CNS penetration (associated with low level replication of CNS HIV),[23–25] selection of drug resistant HIV strains[23–25] and chronic sustained immune activation.[25,26] In India, ritonavir boosted protease inhibitors (PI/r) are used as components of second or third line ART regimens [27]. Use of PI/r also increases the risk of sCVE.[28]\n\nManagement of sCVE appears to require ART regimen change to address these 2 elements (ie, drug resistance in CSF and subtherapeutic drug concentrations).[23] Based on genotypic HIV-1 resistance testing (GRT) and ART history, the new regimen should include at least 2 drugs to which HIV derived from CSF is sensitive. The ART drugs in the new regimen should also reach therapeutic concentrations in CSF.[23] However, neither GRT nor newer drugs like darunavir (DRV/r)[29] or dolutegravir (DTG)[30] are routinely available in LMIC like India. For this reason, our clinic in Pune, India has managed sCVE by 2 treatment strategies:\n\n(1) ART intensification, ie, adding to the existing regimen, drugs that reach high concentrations in CSF,[31] typically zidovudine (AZT) or\n\n(2) ART change, ie, changing to a new ART regimen that includes active drugs based on GRT or expert physician opinion. In this study, we report the outcomes of above 2 modalities used in treatment of sCVE developing in individuals on PI/r containing ART in Pune, India.\n\n2 Methods\n2.1 Study design\nThis cohort study was conducted between March 2009 and March 2019 at 3 private, tertiary level hospitals and research centers in Pune, Maharashtra (Ruby Hall Clinic, Poona Hospital and Noble Hospital). These 3 private hospitals provide clinical care, diagnostic and treatment services to people with HIV (PWH). All data, including demographic, clinical, laboratory and treatment are entered into a secure electronic database (Livehealth software solutions, Pune, India).\n\n2.2 Diagnoses of CSF HIV escape (sCVE) and data collection\nWe retrospectively compiled data of all PWH who were taking PI/r-containing ART and were diagnosed with sCVE in our cohort. All participants consented to use of their data for research purposes and analyses were approved by the Institutional Review Board of all 3 hospitals. sCVE was defined as either a) CSF HIV RNA >20 copies/mL when plasma HIV RNA ≤20 copies/mL or b) when plasma HIV RNA was >20 copies/mL, CSF HIV RNA was ≥0.5 log10 higher than plasma HIV RNA. A subset of these cases has been previously described.[19] Neurologic symptoms included headache, imbalance, tremor, slurred speech, memory loss, seizures, limb weakness or paralysis, bowel or bladder incontinence, delirium, and coma. Demographic, laboratory, and imaging data were collected, including pre ART CD4+ T-cell count, nadir CD4+ T-cell count, CD4+ T-cell count at sCVE, paired plasma and CSF HIV RNA ((NucliSENS EasyQ, BioMérieux, France, lower limit of quantification 20 copies/ml), Magnetic resonance imaging reports (MRI, 1.5 Tesla), and CSF HIV GRT (ABI 3130, PE Applied Biosystems, minimum HIV RNA for successful sequencing: 1000 copies/mL). All CSF specimens had negative diagnostic tests for Treponema pallidum, Cryptococcus, Toxoplasma gondii, Mycobacterium tuberculosis, Herpes simplex virus, Varicella zoster virus and John Cunningham (JC) virus. Genotyping was interpreted according to the International Antiviral Society-USA guidelines.[32] CNS penetration effectiveness (CPE)[33] value of ART regimens was calculated. Genotypic susceptibility score (GSS) of each ART regimen was calculated in participants undergoing GRT by assigning a score of 0 (resistant), 0.5 (intermediate resistance), or 1 (susceptible) to each drug. GSS-adjusted CPE values were calculated by multiplying the CPE value by the GSS for each ART drug and summing scores.[28]\n\n2.3 Management strategies used for CSF HIV escape\nAfter diagnosis of sCVE, 1 of the 2 methods were followed as standard of care in our cohort (Fig. 1). A) AZT intensification- Criteria for inclusion were:\n\n(1) Use of 2 nucleoside reverse transcriptase inhibitors (NRTI) plus PI/r at the time of sCVE,\n\n(2) not currently using AZT,\n\n(3) no prior history of AZT toxicity, and\n\n(4) CSF GRT not performed or no drug resistance mutations (DRMs) to AZT or current ART.\n\nFigure 1 Flow chart illustrating the diagnostic criteria used for identifying CSF HIV escape and criteria used for changing ART regimen in patients. AZT = zidovudine, CSF = cerebrospinal fluid, DRM = drug resistance mutations, GRT = genotypic HIV-1 resistance testing, INSTI = integrase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI/r = boosted protease inhibitor.\n\nIn this group, AZT was added to the current regimen. B) ART change or PI/INSTI intensification.\n\nCriteria for inclusion were:\n\n(1) Individual on 2 NRTIs plus PI/r or PI/r plus Integrase inhibitor (INSTI) regimen at the time of sCVE,\n\n(2) history of prior AZT toxicity or current use of AZT,\n\n(3) DRMs to current ART drugs on CSF GRT.\n\nThis group was changed to a new ART regimen that included a new boosted PI/r, an INSTI, or both. Other drugs in the new regimen were guided by GRT or expert opinion.\n\n2.4 Follow up of cases of CSF HIV escape\nPatients with sCVE were followed up clinically at 2, 4, 12, and 24 weeks post ART change to look for resolution of neurologic symptoms. Plasma and CSF viral load (VL) analysis was done at 24 weeks post ART change and yearly thereafter. Follow up plasma and CSF HIV-1 VL was noted for both modalities. Total duration of follow up (in months) and CPE score of new ART regimen was recorded. Overall outcomes of these cases of sCVE (alive and well/ partial resolution of symptoms/ lost to follow up/ death) were noted. Patients in whom follow up plasma/CSF VL and outcome data was unavailable were excluded from analysis.\n\n2.5 Statistical methods\nBaseline characteristics for continuous variables were summarized using median and interquartile range (IQR), and for categorical variables using frequency and percentages. Continuous variables were compared using a median test. Categorical variables were compared using Chi-square test and Fisher exact test. All analyses were performed using STATA version 12.1.\n\n3 Results\nOf 513 PWH on PI/r containing ART (2 NRTI + 1 PI/r or 1 PI/r + 1 INSTI) in our cohort, 57 episodes of sCVE in 54 individuals (10.5%) were identified. Of these, 47/57 (82.5%) had follow-up data available and were included in our study (Fig. 1). Twenty-three cases underwent AZT intensification (Group A) and 24 underwent ART change (PI/INSTI intensification, Group B). Demographic data and neurologic symptoms are summarized in Table 1 and Figure 2. Median age was 42 years in Group A (IQR: 40–47) and 40 years in Group B (IQR: 34–45). Nadir CD4+ T-cell count was 65 cells/μL in Group A (IQR: 33–92) and 103 cells/μL in Group B (IQR: 75–122). At the time of sCVE, Group A had been on a stable PI/r containing ART regimen for a median of 33 months (IQR: 21–46) and Group B for 21 months (IQR: 15–36). Imbalance during walking, tremors of hands and memory loss were the most common neurologic symptoms (Fig. 2). Most symptoms had subacute onset (≥ 2 weeks) but 6 participants in each group had acute onset (< 2 weeks) of severe neurologic symptoms like seizures, delirium, or coma. Tenofovir disoproxil fumarate (TDF) plus lamivudine or emtricitabine (3TC, FTC) plus Atazanavir/ritonavir (ATV/r) was the most common ART regimen at the time of sCVE (32 of 47 episodes (68.1%), 21 in group A and 11 in Group B). Three individuals had 2 episodes of sCVE each (A9 and B22, A15 and B19, B9 and B15, Tables 2 and 3).\n\nTable 1 Baseline demographic, clinical and laboratory characteristics of patients with Neurosymptomatic CSF HIV escape.\n\nFigure 2 Major neurologic symptoms seen in patients with CSF HIV escape in Pune Cohort and their relative frequency. CSF = cerebrospinal fluid.\n\nTable 2 Follow-up plasma and CSF HIV-1 viral load values in AZT intensification arm (Group A).\n\nTable 3 Follow up plasma and CSF HIV-1 VL values in PI/INSTI intensification arm (Group B).\n\nCD4+ T-cell count at sCVE was 378/μL in Group A (IQR: 209–475) and 387/μL (IQR: 312–456) in Group B. Twenty of 23 cases in Group A and all 24 cases in Group B had elevated CSF protein levels (median, 90 mg/dL; IQR: 53–113 mg/dL versus median, 98 mg/dL; IQR: 83–118 mg/dL). CSF pleocytosis (CSF leukocytes > 5 cells/μL) was observed in 19/23 (82.6%) cases in Group A (median 16; IQR: 11–29) and 19/24 (79.2%) cases in Group B (median 14; IQR: 10–26). Median plasma HIV RNA at the time of developing sCVE was 290 copies/mL in Group A (IQR: 105–1045) and 265 copies/mL in Group B (IQR: 50–623). Median CSF HIV RNA was 5,200 copies/mL in Group A (IQR: 2000–19500) and 4,750 copies/mL in Group B (IQR: 3100–16450). CSF GRT was performed in 3 participants in Group A (13.0%) and 13 participants in Group B (54.2%). Triple class resistance (NRTI, non-NRTI [NNRTI] and PI DRMs) was seen in no participants in Group A and 8 (33.3%) in Group B. Median CPE at the time of sCVE was 5 in Group A (IQR: 5–6) and 6 in Group B (IQR: 6–7). GSS-adjusted CPE values was <5 in all 16 individuals in whom CSF GRT was performed.\n\n3.1 AZT intensification group (Group A)\nFollow up data of Group A is summarized in Table 2. At the time of sCVE, none of the 23 PWH were on thymidine analogues. TDF plus 3TC or FTC plus ATV/r was the ART regimen used by 21 (91.3%) participants. Duration of follow up after AZT intensification was 14 months (IQR: 9–19). Median CPE value after AZT intensification was 9 (IQR: 9–9). After AZT intensification, 18/23 (78.3%) cases had complete resolution of symptoms. All 6 individuals with severe neurologic symptoms like seizures and altered sensorium had neurologic recovery and could resume all activities of daily living. Follow up plasma HIV-1 RNA was available for 21/23 (91.3%, Table 2) patients, of whom 17 had viral suppression (VL < 20 copies/mL), 1 had VL between 20 and 200 copies/ml, and 3 had VL > 200 copies/ml. Follow up CSF HIV-1 RNA was also available for 21/23 (91.3%) patients, of whom 15 had VL < 20 copies/ml, 2 had VL between 20 and 200 copies/ml while 4 had VL > 200 copies/ml. In 16/21 (76.2%) cases, discordance between CSF and plasma HIV RNA replication completely resolved at follow-up. In 3 cases, discordance persisted but at a lower level (A8, A9 and A18, Table 2). In 2 cases, discordance worsened (A15 and A17). Virologic failure of CNS active ART (VL > 200 copies/ml in either of the compartments) was seen in 4 cases (A9, A15, A17 and A18, Table 2). CSF GRT was performed in 2 cases (A9 and A15) both of whom had triple class resistance. All 4 were subjected to ART change with PI/INSTI intensification (Group B). Incomplete efficacy of CNS active ART (either plasma or CSF HIV RNA or both > 20 copies/ml) was seen in 6/21 (28.6%, Fig. 3) cases.\n\nFigure 3 Flow chart depicting follow up of patients with CSF HIV escape after change of ART in Pune, India. Majority of patients had neurologic improvement at follow-up due to plasma and CSF HIV-1 RNA suppression (HIV RNA < 20 copies/ml). Incomplete efficacy was defined as either plasma or CSF HIV RNA > 20 copies/ml despite change of ART regimen. There were 4 deaths during follow-up in entire cohort. ART = antiretroviral therapy, AZT = zidovudine, CSF = cerebrospinal fluid, INSTI = integrase inhibitors, PI = protease inhibitors, RNA = ribonucleic acid, T1 = follow up plasma and CSF viral loads.\n\nOne death occurred in Group A (A5) and 1 participant was lost to follow up (A14). Both had complete resolution of neurologic symptoms after AZT addition. A5 developed severe anemia (Hemoglobin < 6 g/dL) after 12 weeks and discontinued AZT. After AZT withdrawal, neurologic symptoms recurred followed by status epilepticus and rapid clinical deterioration, culminating in coma and death. After availability of generic DTG in India in August 2018, 11 of the 23 participants in Group A substituted AZT with DTG and have not had a relapse of neurologic symptoms till date.\n\n3.2 ART change or PI/INSTI intensification group (Group B)\nFollow up data of participants managed in Group B are summarized in Table 3. In this group, median duration of exposure to thymidine analogues during first line ART was 47 months (IQR: 15–66). At the time of development of sCVE, 5 patients were already taking AZT and 9 had a history of AZT toxicity. Twenty of 24 (87.5%) were taking 2 NRTIs and a PI/r at the time of sCVE. Four were taking a PI/r and an INSTI. CSF GRT was performed in 13 (Table 4) and all had M184 V present, which confers high level resistance to 3TC and emtricitabine. Ten patients also had intermediate to high level resistance to AZT with T215Y/V/F being the most common thymidine analog mutation (TAM). M46I and V82A were the most common protease mutations seen in 3 participants each. Integrase mutations were identified in CSF GRT in 2 patients (B7 and B13)\n\nTable 4 CSF HIV-1 Genotypic resistance testing performed in patients with neurosymptomatic CSF HIV escape.\n\nThe 2 most common ART changes occurring in Group B were a) Replacing current PI/r (mostly Atazanavir) with a better CNS penetrating PI/r like lopinavir/ritonavir or DRV/r plus addition of an INSTI (9 cases, B1–B7, B11 and B17, Table 5) or b) Replacing current PI/r with a better CNS penetrating PI/r plus addition of AZT/3TC plus continuation of TDF (4 cases, B10, B14, B15 and B24). Median CPE score of ART regimens after PI/INSTI intensification was 8 (IQR: 6–10). After modification of ART regimen, median GSS improved from 1 (IQR: 1–1) to 2 (IQR: 2–2). Total duration of follow up in Group B was 32 (IQR: 14–45) months. After PI/INSTI intensification, 17/24 (70.83%) patients had complete resolution of symptoms while 6 had partial resolution. Five out of 6 individuals developing acute onset, severe neurologic symptoms like seizures and altered sensorium had neurologic recovery with resumption of activities of daily living. Follow up plasma VL were available for 23/24 (95.8%) patients, out of which 21 (91.3%) had VL suppression (VL < 20 copies/mL), 1 had VL between 20 and 200 copies/ml while 1 had VL > 200 copies/mL. Follow up CSF VL were available for 23/24 (95.8%) patients, out of which 18 had VL < 20 copies/ml, 4 had VL between 20 and 200 copies/ml while 1 had VL > 200 copies/ml. In 18/23 (78.3%) cases, discordance between CSF and plasma HIV-1 replication completely resolved at follow-up. In 5 cases, discordance persisted but at a lower level (B2, B14–16, B24 Table 3). Discordance did not worsen at follow up in any patient. Virologic failure on CNS active ART (VL > 200 copies/ml in either compartment) was seen in 1 individual (B24, Table 3). B24 had CSF VL > 1000 copies/mL despite controlled plasma VL at follow up. CSF GRT was attempted but DRM could not be amplified in CNS HIV. B24 was then shifted to a new regimen of DRV/r plus DTG. Incomplete efficacy of CNS active ART (either plasma or CSF VL or both > 20 copies/mL) after PI/INSTI intensification was seen in 6/23 (26. 1%, Fig. 3) patients.\n\nTable 5 New antiretroviral treatment strategy prescribed to patients in PI/INSTI intensification arm (Group B).\n\nThere were 3 deaths in the cohort (B9, B13 and B14). B9 and B14 had attained plasma and CSF HIV suppression (VL< 20 copies/mL) on follow up. B9 stopped CNS active ART after 16 months of follow up resulting in reappearance of neurologic symptoms over a period of 1 month for which he refused medical care and died at home. B14 had partial recovery of neurologic symptoms with persistence of imbalance during walking and aggressive anti-social behavior. He died in a road traffic accident. B13 had developed sCVE on a regimen consisting of Lopinavir/r and RTG (raltegravir). We changed her ART to a new regimen containing AZT/3TC plus DRV/r plus DTG. But there was no improvement in neurologic symptoms. B13 continued to remain comatose and died of aspiration pneumonia. After availability of low cost generic DTG in India in August 2018, 5 out of the 24 cases in Group B substituted RTG with DTG, keeping rest of the regimen intact.\n\n4 Discussion\nIn India, first-line ART comprises of a NRTI backbone, preferably Non-Thymidine (Tenofovir plus 3TC (TDF/3TC) or AZT plus 3TC (AZT/3TC)) and 1 NNRTI, preferably efavirenz.[34] Virologic failure under the national ART programme (National AIDS control organization) is defined as a Plasma VL of 1,000 or more copies/mL after 6 months of ART, with individual being treatment adherent by >95%. A low-level viremia (LLV, VL< 1000 copies/mL), does not require switch in therapy.[34] Second-line ART is based on use of a Ritonavir boosted PI (ATV/r (preferred) or Lopinavir/ritonavir) supported by at least 1 new and unused NRTI (AZT or Tenofovir) or in an inevitable situation an integrase inhibitor (RTG, Alternate second line ART).[27,34] In cases of virologic failure on second line ART, individual is shifted to third line ART which consists of INSTI (RTG) and a new PI/r (Darunavir/ritonavir).[27,34] Implementation of World health organization[35] and National AIDS control organization ART[34] guidelines may result in ideal conditions for compartmental replication of HIV.[16] Use of first-line ART with low genetic barrier to resistance,[16,19,34] delayed switch to second or third line ART due to infrequent VL monitoring,[19,36] higher cut off (1000 copies/mL) for ART switch which encourages low level viremia and accumulation of DRM,[16,19] recycling of NRTI for second line ART favoring functional PI monotherapy[16,19] and Use of ATV/r which does not consistently achieve in vitro 50% inhibitory concentrations (IC50) for wild-type HIV-1 in CSF[37,38] are factors which contribute to higher prevalence of sCVE in LMIC like India.[39,40] In addition, drugs required to combat multidrug resistant CNS HIV like second generation PI/r (DRV/r), newer integrase inhibitors (DTG), entry inhibitors (Maraviroc) and second generation NNRTI (Etravirine) are scarcely available in India. In such circumstances, we describe 47 cases of Neurosymptomatic CSF HIV escape (sCVE) identified during a 10 year period at our cohort in Pune, India and their follow up virologic and outcome data. Two treatment modalities, AZT intensification (to improve CNS penetrability of ART) and ART change with PI/INSTI intensification (to tackle CNS HIV drug resistance) were used in our cohort for management of sCVE. Both treatment modalities were effective in resolution of neurologic symptoms. Almost 75% cases in Group A and B had plasma and CSF VL <20 copies/mL after change to CNS active ART. To the best of our knowledge, our study is 1 of the first reports of follow up plasma and CSF VL and outcome data of a large number of sCVE cases from a LMIC. We also believe that recent World health organization guidelines recommending initiating ART irrespective of baseline CD4 count (test and treat strategy) and use of DTG plus 2NRTI as preferred ART regimen will go a long way in reducing incidence of HIV associated neurocognitive disease in LMIC like India.[35]\n\nIn AZT intensification group (group A), 20/23 (87%) cases had a past history of virologic failure on Thymidine analogue (AZT or Stavudine (d4T) as NRTI backbone) containing first line ART. The median exposure to Thymidine analogs was 4 years. These drugs carry well-recognized risks of side-effects like Anemia (AZT), Dyslipidemia and Lipodystrophy syndrome (AZT, Stavudine). Twenty 1 patients in Group A were on TDF plus 3TC/FTC plus ATV/r while 2 used TDF plus 3TC/FTC plus lopinavir/ritonavir at the time of sCVE. Due to inability to access newer potent drugs, we were forced to reuse AZT due to its excellent CNS penetration in spite of knowledge about its toxicity and compromised antiviral activity. Despite all the drawbacks, addition of AZT to current PI/r containing ART led to complete resolution of symptoms in more than 70% cases in cohort. Plasma viral suppression (VL < 20 copies/ml) improved from 17.9% at sCVE to 81% at follow up (Fig. 4). CSF viral suppression (VL < 20 copies/mL) improved from 0% at sCVE to 71.4% at follow up. This suggests that adding AZT increased the antiviral potency of PI/r containing ART in plasma and CNS compartments leading to resolution of sCVE in majority of cases.\n\nFigure 4 Significant increase in plasma and CSF HIV-1 viral load suppression (VL < 20 copies/mL) after change of ART in both groups of patients with CSF HIV escape. ART = antiretroviral therapy, AZT = zidovudine, BL = baseline, CSF = cerebrospinal fluid, PI/INSTI = boosted protease inhibitor and/or integrase inhibitor, T1 = follow up visit, VL = viral load.\n\nOne explanation could be that there was low level or no resistance to Thymidine analogs after virologic failure of first line ART because of which AZT was effective in VL suppression when used again. This might be the case for A6, A7 and A8 in whom CSF GRT showed resistance only to 3TC (Table 4). However, in all these 3 cases, Thymidine analogs were not a part of ART at the time of sampling of CSF for GRT. As a result, TAM's could have been archived in the past but not seen on current CSF HIV-1 GRT. Second explanation could be that TAM's were generated due to long duration of exposure to Thymidine analogs. However the power of TAM's to compromise efficacy of NRTI component of PI/r containing ART in vivo was overestimated. As a result, AZT and TDF along with PI/r were successful in VL suppression in both compartments in majority of cases. Unfortunately, this could not be confirmed as GRT was not done for rest of the 20 individuals in Group A. Virologic efficacy of NRTI component in a 2NRTI plus PI/r containing ART regimen was well elucidated in EARNEST trial[41] which was done in LMIC with late diagnosis of first-line ART failure and no resistance testing to inform decisions about drug choice. In this trial, PI/r plus RTG offered no advantage over PI/r plus 2 NRTI in virologic efficacy or safety in individuals failing 1st line NNRTI containing ART. The trial confirmed the contribution that NRTIs make to the virologic efficacy of a PI/r containing regimen, even when their activity is predicted to be substantially, or even completely, compromised by cross-resistance. Contribution of NRTI's to a PI/r containing regimen can also be judged from the fact that in patients who have developed sCVE on PI/r monotherapy, CSF HIV-1 RNA returned to undetectable levels along with complete resolution of neurologic symptoms after reintroduction of baseline NRTI's.[42,43] Some patients in Group A may have had functional PI monotherapy which was reversed by AZT intensification. A third explanation could be that Epstein Barr Virus (EBV) de-oxyribonucleic acid (DNA) is frequently detected in CSF of PWH on ART. CSF EBV DNA is associated with higher CSF HIV RNA, higher CSF pleocytosis, higher levels of biomarkers of neuronal damage/inflammation and could be responsible for HIV-associated CNS disorders like sCVE.[44] AZT effectively inhibits Epstein-Barr virus (EBV) DNA replication along with HIV RNA suppression.[45] This could be another reason for symptomatic improvement in PWH with sCVE. However, EBV DNA PCR was not performed on any of the CSF samples in our cohort. AZT is freely available in LMIC like India and it can help clinicians to successfully manage majority of cases of sCVE developing on a regimen containing TDF and PI/r. It will serve as a bridge till individuals with sCVE get access to newer drugs like DRV/r and DTG.\n\nThe Mind Exchange Consensus Report[46] suggests that for patients with persistent or worsening cognitive impairment and detectable HIV RNA in CSF, doctors should consider patient adherence to ART, co-morbidities, plasma and CSF resistance profiles and possibly the CPE score of ART regimen prior to modification of therapy. European AIDS clinical society (EACS) guidelines for the treatment of cognitive impairment in HIV-seropositive individuals have made similar recommendations.[47] Management of patients in PI/INSTI intensification group (group B) followed these guidelines. We could tackle both the aspects causing sCVE i.e. CSF HIV drug resistance and CNS ART penetration as majority of patients could perform a CSF HIV-1 GRT and also had access to DRV/r and DTG. In group B, 20/24 (87.5%) cases had a past history of virologic failure on Thymidine analogue containing first line ART with a median exposure of 4 years. 58.3% cases either had AZT as a part of current PI/r containing ART regimen or had past history of AZT toxicity. In addition, out of the 13 CSF GRT reports, TAM's were seen in 10 while triple class resistance was seen in 8 patients. Despite the lack of GRT in Group A, it is safe to conclude that individuals in Group B had a much more drug resistant CSF HIV as compared to Group A. PI/INSTI intensification led to complete resolution of symptoms in more than 75% cases in cohort. Plasma viral suppression (VL < 20 copies/mL) improved from 17.4% at sCVE to 91.3% at follow up while CSF viral suppression (VL < 20 copies/mL) improved from 0% at sCVE to 78.3% at follow up (Fig. 4).\n\nOut of the 4 deaths in entire cohort, 2 occurred in individuals who interrupted CNS active ART leading to rapid viral rebound in plasma and CNS compartment (A5 and B9). This led to incident neurologic symptoms which were much more severe than the first instance. sCVE relapse on ART simplification has also been described by Zan et al in their CSF HIV escape case series from Italy.[48] This reinforces the fact that strict adherence to neuroactive ART maintains plasma and CSF HIV suppression, prevents relapse of sCVE and prevents death.\n\n4.1 Limitations\nOur study has several limitations. First, as for all retrospective studies, some episodes of sCVE may be unreported leading to measurement bias and underestimation of prevalence. Second, milder neurologic symptoms such as headache may not have triggered lumbar puncture and measurement of CSF HIV-1 RNA, leading to unaccounted cases of mildly symptomatic CSF escape. Third, neuropsychological testing for cognitive impairment was not performed at baseline or follow-up in our cohort and hence milder forms of HIV-associated neurocognitive disease[49] could not be identified and sCVE in these patients could not be studied. Screening for functional impairment and mood disorders[50] was also not performed. Fourth, GRT of CNS virus was not routinely performed in Group A leading to potential selection bias. Fifth, different follow up duration in both treatment modalities (32 months in Group B versus 14 months in Group A) may have influenced our results. Virologic suppression in protected compartments like CNS may require extra time. Sixth, our follow-up data is limited in some cases because further studies were not pursued as individuals had declined repeated CSF examination after the first follow up lumbar puncture and once symptoms resolved. Seventh, EBV DNA was not studied in CSF samples in our cohort and hence contribution of EBV to sCVE could not be identified. Despite these limitations, this is a unique cohort of individuals with CSF HIV escape with homogeneous treatment interventions leading to successful resolution in a majority of cases.\n\n5 Conclusions\nPhysicians in resource limited settings like India should perform CSF HIV-1 VL analysis in patients who develop neurologic symptoms while on PI/r containing ART with well controlled plasma HIV. After noting GRT of CSF HIV and history of prior treatments, the new regimen should include at least 2 drugs that penetrate the CNS well and to whom the CSF HIV is sensitive. In majority of cases it involves using better CNS penetrating PI/r like Lopinavir or Darunavir (DRV/r) and Integrase inhibitor like DTG. In absence of GRT and newer drugs like DRV/r and DTG, AZT intensification of PI/r containing regimen serves as a practical, effective and easily implementable therapeutic modality in a subset of cases. Both modalities, PI/INSTI intensification and AZT intensification were successful in resolving neurologic symptoms and suppressing plasma/CSF HIV in majority of cases in our cohort. These cases add to the growing literature on Neurosymptomatic CSF HIV escape that underscores the need for further investigation into the mechanism of establishment of CNS HIV reservoir and long term consequences of HIV replication and persistence in the CNS.\n\nAuthor contributions\nAmeet Dravid – Writing Manuscript, Study concept and design, acquisition of data.\n\nKartik Natrajan – Study concept and design, acquisition of data.\n\nMahenderkumar Medisetty- Study concept and design, acquisition of data.\n\nAvadesh K Sharma- Study concept and design, acquisition of data.\n\nTarun Betha- Study concept and design, acquisition of data.\n\nRaviraj Gawali- Study concept and design, acquisition of data.\n\nMilind Kulkarni – Study concept and design, acquisition of data.\n\nChinmay Saraf – Study concept and design, acquisition of data.\n\nUma Mahajan – Analysis and Interpretation of Data.\n\nSachin Kore – Study concept and design, acquisition of data.\n\nNiranjan Rathod – Study concept and design, acquisition of data.\n\nRustom Wadia – Critical review of manuscript for intellectual content.\n\nAndrea Calcagno – Writing Manuscript, Study concept and design\n\nScott Letendre – Writing Manuscript, Study concept and design\n\nConceptualization: Ameet N Dravid, Milind M Kulkarni, Chinmay K Saraf, Uma S Mahajan, Sachin D Kore, Niranjan M Rathod, Andrea Calcagno.\n\nData curation: Ameet N Dravid, Raviraj Gawali, Tarun P Betha, Avadesh K Sharma, Mahenderkumar Medisetty, Kartik Natrajan, Milind M Kulkarni, Uma S Mahajan, Sachin D Kore, Niranjan M Rathod.\n\nFormal analysis: Ameet N Dravid, Uma S Mahajan.\n\nInvestigation: Ameet N Dravid, Chinmay K Saraf, Umakant S Mahajan.\n\nMethodology: Milind M Kulkarni, Uma S Mahajan, Sachin D Kore.\n\nProject administration: Ameet N Dravid, Kartik Natrajan, Milind M Kulkarni, Chinmay K Saraf, Uma S Mahajan, Sachin D Kore, Niranjan M Rathod.\n\nResources: Uma S Mahajan.\n\nSupervision: Niranjan M Rathod.\n\nValidation: Uma S Mahajan, Niranjan M Rathod.\n\nVisualization: Niranjan M Rathod.\n\nWriting – original draft: Ameet N Dravid.\n\nWriting – review & editing: Ameet N Dravid, Milind M Kulkarni, Scott L Letendre, Rustom S Wadia, Andrea Calcagno.\n\nManisha Ghate MD, PhD (National AIDS research institute (NARI), Pune, India) - edited the manuscript for non-intellectual content.\n\nGaurav Arun Joshi, MBA (Director, AArete LLC) – helped in data analysis, and preparing figures and tables\n\nAbbreviations: 3TC = lamivudine, ART = antiretroviral therapy, ATV/r = atazanavir/ritonavir, AZT = zidovudine, CNS = central nervous system, CPE = central nervous system penetration effectiveness score, CSF = cerebrospinal fluid, DNA = de-oxyribonucleic acid, DRM = drug resistance mutations, DRV/r = darunavir/ritonavir, DTG = dolutegravir, EBV = Epstein barr virus, FTC = emtricitabine, GRT = genotypic HIV-1 resistance testing, GSS = genotypic susceptibility score, INSTI = integrase strand transfer inhibitor, IQR = interquartile range, LMIC = low and middle income countries, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI/r = protease inhibitor, PWH = people with HIV, RNA = ribonucleic acid, RTG = raltegravir, sCVE = symptomatic CSF HIV escape, TAM = thymidine analog mutation, TDF = tenofovir disoproxyl fumarate, VL = viral load.\n\nHow to cite this article: Dravid AN, Gawali R, Betha TP, Sharma AK, Medisetty M, Natrajan K, Kulkarni MM, Saraf CK, Mahajan US, Kore SD, Rathod NM, Mahajan US, Letendre SL, Wadia RS, Calcagno A. Two treatment strategies for management of Neurosymptomatic CSF HIV escape in Pune, India. Medicine. 2020;99:24(e20516).\n\nThe current study did not receive any funding from any agency.\n\nThe authors have no funding and no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n[1] Canestri A Lescure FX Jaureguiberry S \nDiscordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy\n. Clin Infect Dis \n2010 ;50 :773 –8\n.20100092 \n[2] Peluso MJ Ferretti F Peterson J \nCerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load\n. AIDS \n2012 ;26 :1765 –74\n.22614889 \n[3] Rawson T Muir D Mackie NE \nFactors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting\n. J Infect \n2012 ;65 :239 –45\n.22522289 \n[4] Nightingale S Geretti AM Beloukas A \nDiscordant CSF/plasma HIV-1 RNA in patients with unexplained low-level viremia\n. J Neurovirol \n2016 ;22 :852 –60\n.27194435 \n[5] Mukerji S Misra V Lorenz D \nTemporal patterns and drug resistance in CSF viral escape among ART-experienced HIV-1 infected adults\n. J Acquir Immune Defic Syndr \n2017 ;75 :246 –55\n.28328546 \n[6] Pérez-Valero I Ellis R Heaton R \nCerebrospinal fluid viral escape in aviremic HIV-infected patients receiving antiretroviral therapy: prevalence, risk factors and neurocognitive effects\n. AIDS \n2019 ;33 :475 –81\n.30702516 \n[7] Wendell KA McArthur JC \nAcute meningoencephalitis in chronic human immunodeficiency virus (HIV) infection: putative central nervous system escape of HIV replication\n. Clin Infect Dis \n2003 ;37 :1107 –11\n.14523776 \n[8] Garvey LJ Everitt A Winston A \nDetectable cerebrospinal fluid HIV RNA with associated neurological deficits, despite suppression of HIV replication in the plasma compartment\n. AIDS \n2009 ;23 :1443 –4\n.19564723 \n[9] Bingham R Ahmed N Rangi P \nHIV encephalitis despite suppressed viremia: a case of compartmentalized viral escape\n. Int J STD AIDS \n2011 ;22 :608 –9\n.21998185 \n[10] Bogoch II Davis BT Venna N \nReversible dementia in a patient with central nervous system escape of human immunodeficiency virus\n. J Infect \n2011 ;63 :236 –9\n.21658774 \n[11] Khoury MN Tan CS Peaslee M \nCSF viral escape in a patient with HIV-associated neurocognitive disorder\n. J Neurovirol \n2013 ;19 :402 –3\n.23737348 \n[12] Tamarit Mdel P Quereda C Gonzalez-Rozas M \nHIV type 1 viral encephalitis after development of viral resistance to plasma suppressive antiretroviral therapy\n. AIDS Res Hum Retrovir \n2012 ;28 :83 –6\n.21504362 \n[13] Imaz A Cayuela N Niubo J \nShort communication: focal encephalitis related to viral escape and resistance emergence in cerebrospinal fluid in a patient on lopinavir/ritonavir monotherapy with plasma HIV-1 RNA suppression\n. AIDS Res Hum Retrovir \n2014 ;30 :984 –7\n.25096495 \n[14] Bierhoff M Boucher CA Fibriani A \nOngoing HIV replication in cerebrospinal fluid under successful monotherapy\n. Antivir Ther \n2013 ;18 :641 –3\n.23344463 \n[15] Mangioni D Muscatello A Sabbatini F \nA case of cerebrospinal fluid viral escape on a dual antiretroviral regimen: worth the risk?\n\nClin Infect Dis Off Publ Infect Dis Soc Am \n2014 ;59 :1655 –6\n.\n[16] Ssebambulidde K Segawa I Laker E \nSymptomatic cerebrospinal fluid HIV- 1 escape in two patients on second - line antiretroviral therapy in Uganda\n. Oxf Med Case Reports \n2019 ;2019 :omy132 .30800328 \n[17] Patel AK Patel KK Gohel S \nIncidence of symptomatic CSF viral escape in HIV infected patients receiving atazanavir/ritonavir (ATV/r)-containing ART: a tertiary care cohort in western India\n. J Neurovirol \n2018 ;4 :498 –505\n.\n[18] Kulkarni V Kulkarni R Parchure R \nNeurosymptomatic cerebrospinal fluid escape in HIV-2: a case report\n. Int J STD AIDS \n2018 ;29 :726 –8\n.29251118 \n[19] Dravid AN Natrajan K Kulkarni MM \nDiscordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India\n. Medicine \n2018 ;97 :e9969 .29465595 \n[20] Manesh A Barnabas R Mani S \nSymptomatic HIV CNS viral escape among patients on effective cART\n. Int J Infect Dis \n2019 ;84 :39 –43\n.30951880 \n[21] Ellis RJ Badiee J Vaida F \nCD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy\n. AIDS \n2011 ;25 :1747 –51\n.21750419 \n[22] McArthur JC Steiner J Sacktor N \nHuman immunodeficiency virus-associated neurocognitive disorders: mind the gap\n. Ann Neurol \n2010 ;67 :699 –714\n.20517932 \n[23] Ferretti F Gisslen M Cinque P \nFluid HIV escape from antiretroviral therapy\n. Curr HIV/AIDS Rep \n2015 ;12 :280 –8\n.25860317 \n[24] Letendre S MD \nCentral nervous system complications in HIV Disease: HIV-associated neurocognitive disorder\n. Top Antivir Med \n2011 ;19 :137 –42\n.22156215 \n[25] Nightingale S Winston A Letendre S \nControversies in HIV-associated neurocognitive disorders Lancet Neurology NIH Public Access\n. XXX \n2014 ;13 :1139 –51\n.\n[26] Edén A Marcotte TD Heaton RK \nIncreased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment\n. PLoS One \n2016 ;11 :e0157160 .27295036 \n[27] National AIDS control organization (NACO). National Technical guidelines on Antiretroviral therapy_ October 2018. Available at: http://naco.gov.in/sites/default/files/NACO%20-%20National%20Technical%20Guidelines%20on%20ART_October%202018%20%281%29.pdf .\n[28] Mukerji SS Misra V Lorenz DR \nImpact of antiretroviral regimens on CSF viral escape in a prospective multicohort study of ART experienced HIV-1 infected adults in the United States\n. Clin Infect Dis \n2018 ;67 :1182 –90\n.29617912 \n[29] Deeks ED \nDarunavir: a review of its use in the management of HIV-1 infection\n. Drugs \n2014 ;74 :99 –125\n.24338166 \n[30] McCormack PL \nDolutegravir: a review of its use in the management of HIV-1 infection in adolescents and adults\n. Drugs \n2014 ;74 :1241 –52\n.25005775 \n[31] Letendre S Marquie-Beck J Capparelli E \nValidation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system\n. Arch Neurol \n2008 ;65 :65 –70\n.18195140 \n[32] Thompson MA Aberg JA Cahn P \nAntiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel\n. JAMA \n2010 ;304 :321 –33\n.20639566 \n[33] Letendre S, Ellis RJ, Deutsch R, et al. 17th Conference on Retroviruses and Opportunistic Infections. San Fransisco, CA, USA: 2010. Correlates of time-to-loss-of-viral-response in CSF and plasma in the CHARTER cohort.; p. 430 .\n[34] National AIDS control organization (NACO): Policy and Guidelines. Available at: http://naco.gov.in/documents/policy-guidelines .\n[35] World Health Organization (WHO): Guidelines and policy briefs on HIV. Available at: http://www.who.int/hiv/pub/guidelines/en/ .\n[36] National AIDS control organization. National operational guidelines for viral load testing. March 2018. Available at: http://naco.gov.in/sites/default/files/National%20Operational%20Guidelines%20for%20Viral%20Load%20Testing%20Mar%2718.pdf .\n[37] Best BM Letendre SL Brigid E \nLow atazanavir concentrations in cerebrospinal fluid\n. AIDS \n2009 ;23 :83 –7\n.19050389 \n[38] Calcagno A Simiele M Alberione MC \nCerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV infected patients are associated with compartmental viral control\n. Clin Infect Dis \n2015 ;60 :311 –7\n.25281609 \n[39] Joseph J Cinque P Colosi D \nHighlights of the Global HIV-1 CSF escape consortium meeting, 9 June 2016, Bethesda, MD, USA\n. J virus Erad \n2016 ;2 :243 –50\n.27781109 \n[40] Lewin SR Mellors JW \nHIV persistence in the CNS: the final frontier for a cure?\n\nJ Virus Erad \n2016 ;2 :242 .27781108 \n[41] Hakim JG Thompson J Kityo C \nLopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial\n. Lancet Infect Dis \n2018 ;18 :47 –57\n.29108797 \n[42] Gutmann C Cusini A Gunthard HF \nRandomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir\n. AIDS \n2010 ;24 :2347 –54\n.20802298 \n[43] Arenas-Pinto A Stöhr W Clarke A \nEvaluation of cerebrospinal fluid virological escape in patients on long-term protease inhibitor monotherapy\n. Antivir Ther \n2017 ;22 :535 –8\n.28234235 \n[44] Lupia T Milia MG Atzori C \nPresence of EBV DNA in cerebrospinal fluid is associated with greater HIV RNA and inflammation\n. AIDS \n2019 ;34 :373 –80\n.\n[45] Lin JC Zhang ZX Smith MC \nAnti-human immunodeficiency virus agent 3′-azido-3′-deoxythymidine inhibits replication of Epstein-Barr virus\n. Antimicrob Agents Chemother \n1988 ;32 :265 –7\n.2834997 \n[46] Mind Exchange Working Group . Assessment, diagnosis, and treatment of HIV-associated neurocognitive disorder: a consensus report of the mind exchange program\n. Clinical Infectious Diseases \n2013 ;56 :1004 –17\n.23175555 \n[47] European AIDS Clinical Society. [July 3, 2014] Guidelines version 7.02. Available at: http://www.eacsociety.org/Portals/0/140601_EACEN7.02.pdf .\n[48] Zan VD, Calcagno A, Trunfio M, et al. Clinical and Laboratory Characterization of Neurosymptomatic Cerebrospinal fluid (CSF) Viral escape in a Large Multicentre survey. Presented as a poster at European AIDS Clinical society (EACS) conference 2017, Milan, Italy .\n[49] Antinori A Arendt G Becker JT \nUpdated research nosology for HIV-associated neurocognitive disorders\n. Neurology \n2007 ;69 :1789 –99\n.17914061 \n[50] Savard J Laberge B Gauthier JG \nScreening clinical depression in HIV-seropositive patients using the Hospital Anxiety and Depression Scale\n. AIDS Behav \n1999 ;3 :167 –75\n.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "99(24)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D005260:Female; D015658:HIV Infections; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015215:Zidovudine",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e20516",
"pmc": null,
"pmid": "32541474",
"pubdate": "2020-06-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Two treatment strategies for management of Neurosymptomatic cerebrospinal fluid HIV escape in Pune, India.",
"title_normalized": "two treatment strategies for management of neurosymptomatic cerebrospinal fluid hiv escape in pune india"
} | [
{
"companynumb": "IN-GLAXOSMITHKLINE-IN2020GSK108273",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": "3"... |
{
"abstract": "Data were collected on 176 consecutive cases of drug overdose evaluated in an emergency department. Quantitative serum toxic screening (TS) was performed for 164 (93%) of these patients; positive results were noted for 133 patients (81%). Six classes of drugs (ethanol, benzodiazepines, salicylates, acetaminophen, barbiturates, and tricyclic antidepressants) were responsible for nearly 70% of all drug detections and were associated with 80% of all admissions in this patient sample. Only two patients (1%) had drug-specific treatment initiated because of TS results. In 12 patients (7%), TS confirmed substances for which specific treatments had been initiated on clinical grounds. Four patients (2%) had drug-specific treatment discontinued because of TS results. Thirty-two patients (19%) were admitted to a medical service; however, only seven patients (4%) were admitted primarily because of TS results. All other patients were admitted because of clinical abnormalities that required inpatient care. It is concluded that only a few drugs are responsible for most drug overdoses. Moreover, TS results rarely change the treatment or disposition of overdose patients; these decisions are typically based on clinical parameters.",
"affiliations": "Emergency Services Department, Massachusetts General Hospital, Boston 02114.",
"authors": "Mahoney|J D|JD|;Gross|P L|PL|;Stern|T A|TA|;Browne|B J|BJ|;Pollack|M H|MH|;Reder|V|V|;Mulley|A G|AG|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D001463:Barbiturates; D012459:Salicylates; D000082:Acetaminophen; D003975:Diazepam",
"country": "United States",
"delete": false,
"doi": "10.1016/0735-6757(90)90287-a",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "8(1)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000082:Acetaminophen; D000435:Alcoholic Intoxication; D000929:Antidepressive Agents, Tricyclic; D001463:Barbiturates; D001774:Blood Chemical Analysis; D003975:Diazepam; D062787:Drug Overdose; D004630:Emergencies; D006801:Humans; D012189:Retrospective Studies; D012459:Salicylates",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "16-22",
"pmc": null,
"pmid": "2293827",
"pubdate": "1990-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Quantitative serum toxic screening in the management of suspected drug overdose.",
"title_normalized": "quantitative serum toxic screening in the management of suspected drug overdose"
} | [
{
"companynumb": "US-ROCHE-2031275",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
"d... |
{
"abstract": "Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen.\n\n\n\nEligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS).\n\n\n\nA total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0).\n\n\n\nThis trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care.\n\n\n\nClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).",
"affiliations": "Haematology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK. Electronic address: andrew.mcmillan@nuh.nhs.uk.;Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, UK; Division of Cancer Sciences, University of Manchester and The Christie Hospital NHS Trust, Manchester, UK.;Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, UK.;HMDS, St James' University Hospital, Leeds, UK.;HMDS, St James' University Hospital, Leeds, UK.;Plymouth University Medical School, Plymouth, UK.;Haematology Department, Castle Hill Hospital, Hull, UK.;Clinical Sciences, St George's University of London, London, UK.;Haematology Department, University College Hospital London, London, UK.;Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, UK.;Centre for Haemato-oncology, Barts Health NHS Trust, London, UK.;Haematology Department, Heart of England NHS Trust, Birmingham, UK.;Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, UK.;Haematology Department, University College Hospital London, London, UK; UCL Cancer Institute, University College London, UK.",
"authors": "McMillan|A K|AK|;Phillips|E H|EH|;Kirkwood|A A|AA|;Barrans|S|S|;Burton|C|C|;Rule|S|S|;Patmore|R|R|;Pettengell|R|R|;Ardeshna|K M|KM|;Lawrie|A|A|;Montoto|S|S|;Paneesha|S|S|;Clifton-Hadley|L|L|;Linch|D C|DC|",
"chemical_list": "D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D007069:Ifosfamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1016/j.annonc.2020.05.016",
"fulltext": "\n==== Front\nAnn Oncol\nAnn. Oncol\nAnnals of Oncology\n0923-7534 1569-8041 Oxford University Press \n\nS0923-7534(20)39837-9\n10.1016/j.annonc.2020.05.016\nOriginal Article\nFavourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3–5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial✰\nMcMillan A.K. andrew.mcmillan@nuh.nhs.uk1∗† Phillips E.H. 23† Kirkwood A.A. 2 Barrans S. 4 Burton C. 4 Rule S. 5 Patmore R. 6 Pettengell R. 7 Ardeshna K.M. 8 Lawrie A. 2 Montoto S. 9 Paneesha S. 10 Clifton-Hadley L. 2 Linch D.C. 811 1 Haematology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK\n2 Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, UK\n3 Division of Cancer Sciences, University of Manchester and The Christie Hospital NHS Trust, Manchester, UK\n4 HMDS, St James' University Hospital, Leeds, UK\n5 Plymouth University Medical School, Plymouth, UK\n6 Haematology Department, Castle Hill Hospital, Hull, UK\n7 Clinical Sciences, St George's University of London, London, UK\n8 Haematology Department, University College Hospital London, London, UK\n9 Centre for Haemato-oncology, Barts Health NHS Trust, London, UK\n10 Haematology Department, Heart of England NHS Trust, Birmingham, UK\n11 UCL Cancer Institute, University College London, UK\n∗ Correspondence to: Dr Andrew K. McMillan, Haematology Department, Nottingham City Hospital, Hucknall Road, Nottingham, UK NG5 1PB. Tel: +44-115-969-1169 andrew.mcmillan@nuh.nhs.uk† These authors contributed equally to this paper.\n\n\n1 9 2020 \n9 2020 \n31 9 1251 1259\n© 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Background\nOutcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen.\n\nPatients and methods\nEligible patients were aged 18–65 years with stage II–IV untreated DLBCL and an International Prognostic Index (IPI) score of 3–5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS).\n\nResults\nA total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9–74.6] and 2-year overall survival was 76.0% (90% CI 68.5–82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9–58.0).\n\nConclusions\nThis trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care.\n\nTrial Registration\nClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).\n\nHighlights\n• R-CODOX-M/R-IVAC is an effective regimen for treatment of high-risk DLBCL and high-grade B-cell lymphoma (IPI score 3–5).\n\n• Treatment was well tolerated in patients aged <50 years, or aged 50–65 with performance status 0 or 1.\n\n• The 2-year PFS was 67.9% (90% CI: 59.9–74.6) for the whole cohort.\n\n• This regimen warrants further evaluation against standard of care in high-risk DLBCL.\n\n\n\nKey words\nchemotherapydiffuse large B-cell lymphoma (DLBCL)double-hithigh-grade B-cell lymphomaR-CODOX-M\n==== Body\nIntroduction\nThe addition of rituximab to standard CHOP chemotherapy [cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)] has improved survival rates for diffuse large B-cell lymphoma (DLBCL) and other forms of high-grade B-cell lymphoma (HGBL) by 10%–15%.1, 2, 3 However, a third of DLBCL patients still progress after R-CHOP, and outcomes for these patients are extremely poor.4, 5, 6 The greatest unmet need is for patients with high-risk disease; R-CHOP failure rates for patients with an International Prognostic Index (IPI) score of 3–5 approach 50%.7, 8, 9, 10\n\nThere have been extensive, largely unsuccessful attempts to improve on standard 21-day R-CHOP chemotherapy for untreated DLBCL. Increasing the dose density of R-CHOP has not been shown to improve outcomes,11 nor has consolidation with high-dose therapy-autologous stem cell transplantation.12, 13, 14 Randomised studies have not shown clear evidence of benefit for incorporation of novel agents for most patients.15, 16, 17, 18, 19 Several attempts to incorporate additional chemotherapeutic agents have similarly failed to improve outcomes.20,21\n\nThere is some evidence, however, that treatment intensification can improve survival. The phase 3 GELA LNH03-2B trial demonstrated an overall survival (OS) advantage for treatment with R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone) plus consolidation chemotherapy over R-CHOP in patients with an age-adjusted IPI score (aaIPI) of 1, albeit with unexpectedly poor outcomes in the R-CHOP arm.22 Favourable outcomes have been achieved with the same regimen for high-risk patients (aaIPI 2–3), although it remains unclear whether there is a benefit over R-CHOP in this group.23,24 A number of population-based and non-randomised studies have suggested that combining etoposide with R-CHOP can improve outcomes for high-risk patients, although randomised studies in the rituximab era are lacking.25,26\n\nA different approach is widely used in Burkitt lymphoma (BL), using rapid cycling of dose-dense chemotherapy, combining hyperfractionated alkylating agents with multiple central nervous system (CNS)–penetrating agents.27 One such example is the Magrath regimen, consisting of alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) and IVAC chemotherapy (ifosfamide, etoposide and cytarabine),28 which, with the addition of rituximab, can achieve survival rates in BL approaching 80%, even in patients with multiple high-risk features.29,30 The LY10 study demonstrated that the same treatment regimen, without rituximab, was both feasible and effective in highly proliferative DLBCL and HGBL.28 Two-year OS was 59% with CODOX-M/IVAC in patients with a proliferation rate >95%. The aim of this UK National Cancer Research Institute (NCRI) trial was to build on these encouraging results and assess the efficacy of CODOX-M and IVAC, together with rituximab, for the treatment of high-risk DLBCL.\n\nMethods\nThis trial was designed as two parallel single-arm trials to treat both DLBCL and BL patients with the same regimen under the same protocol, with crossover between arms according to central pathology review. Outcomes for DLBCL patients are reported here; outcomes for BL patients will be reported separately.\n\nEligibility\nPatients were eligible for this phase 2 trial if aged 18–65 years with stage II–IV newly diagnosed DLBCL (or any morphological variant according to World Health Organisation (WHO) Classification of Lymphoid Neoplasms)31,32 and an IPI score of ≥3. Prior corticosteroid treatment was permitted but no other chemotherapy or radiotherapy. Performance status (PS) was permissive, but patients must have been deemed able to tolerate the intensive regimen with adequate renal, liver and cardiac function. A protocol amendment allowed inclusion of HIV-positive patients with PS ≤2 and baseline CD4 count ≥100 cells/mm3, with no history of opportunistic infection.\n\nDiagnostic tissue was centrally reviewed by the Leeds Haematological Malignancy Diagnostic Service, UK. Cell of origin was assessed post hoc according to the Hans algorithm.33 FISH studies for MYC,\nBCL2 and BCL6 translocations were not mandated but were routinely performed in patients recruited in later stages of the trial. Disease staging was with contrast-enhanced computed tomography (CT) of the neck to pelvis, bone marrow biopsy and cerebrospinal fluid examination. All patients provided informed consent prior to study entry.\n\nStudy treatment and assessments\nPatients received two cycles of CODOX-M alternating with two cycles of IVAC, plus eight doses of rituximab (375 mg/m2; Table 1). Subsequent treatment cycles were commenced as soon as neutrophils were >1 × 109/l and platelets >75 × 109/l. Tumour lysis prophylaxis with allopurinol or rasburicase was commenced prior to study treatment. All patients received supportive care with pegylated granulocyte–colony stimulating factor, aciclovir and Pneumocystis jirovecii prophylaxis.Table 1 R-CODOX-M and R-IVAC regimen\n\n\t\nR-CODOX-M regimen\tIVAC regimen\t\nRituximab\t375 mg/m2 i.v.\tDays 1 and 11\tRituximab\t375 mg/m2 i.v.\tDay 1\t\nCyclophosphamide\t800 mg/m2 i.v.\n200 mg/m2 i.v.\tDay 1\nDay 2-5\tEtoposide\t60 mg/m2\tDays 1–5\t\nVincristine\t1.5 mg/m2 i.v. (max 2 mg)\tDays 1 and 8\tIfosfamide\t1500 mg/m2\tDays 1–5\t\nDoxorubicin\t40 mg/m2 i.v.\tDay 1\tMesna\t1200 mg\tDays 1–5\t\nCytarabine\t70 mg i.t.\tDays 2 and 4\nDay 6b if CNS disease\tCytarabine\t2000 mg/m2 i.v. 12 h\tDays 1 and 2\t\nMethotrexate\t3000 mg/m2 i.v. over 24 hd\tDay 10\tMethotrexate\t12 mg i.t.\tDay 5\t\nLeucovorin\tFrom 36 h after methotrexate until clearance, starting at a dose of 15 mg/m2 i.v. 6 h\tPegfilgrastim\t6 mg s.c.\tDay 7\t\nPegfilgrastim\t6 mg s.c.\tDay 13\tCytarabine\t70 mg i.t.\tDays 7 and 9, if CNS diseaseb\t\nMethotrexate\t12 mg i.t.\tDay 15\nDay 17b if CNS disease\tRituximabc\t375 mg/m2 i.v.\tDays 21 and 42\t\nCNS, central nervous system; CODOX-M, cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate; i.t., intrathecal; i.v., intravenous; IVAC, ifosfamide, etoposide and high-dose cytarabine; R-CODOX-M, rituximab + R-CODOX-M; R-IVAC, rituximab + IVAC; s.c., subcutaneous.\n\na Estimated timeline based on median cycle length.\n\nb First cycle of R-CODOX-M and R-IVAC only, for patients with evidence of CNS disease.\n\nc After fourth cycle of chemotherapy (second IVAC cycle) only.\n\nd 300 mg administered over 1 h followed by 2700 mg over 23 h.\n\n\n\nResponse was assessed by contrast-enhanced CT according to standard criteria,34 1 month after completion of chemotherapy. Use of positron emission tomography (PET) was encouraged but was not routinely available in the UK at the time of study design. Radiotherapy consolidation was permitted at investigators' discretion to initial sites of disease bulk, intraparenchymal CNS disease and sites of residual positron emission tomography-positive disease. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events version 3.0.\n\nEnd points and statistical methods\nThe primary end point was progression-free survival (PFS) at 2 years. Secondary end points included complete response (CR) rate and toxicity. At the time of study design, PFS for DLBCL patients with IPI 3–5 after standard therapy was estimated to be 40%–50%, based on historical data and assuming a 10%–15% improvement in the rituximab era. A PFS rate of ≥65% was deemed to warrant further investigation but a rate of ≤45% would be of no interest. Using a Fleming design, it was calculated that a sample size of ∼95 patients would have 90% power to detect a 15% difference at 5% (one-sided) significance. The trial was designed to treat both BL and DLBCL patients under one protocol and was terminated once the total target sample size of 150 patients was met, irrespective of numbers of DLBCL patients recruited. PFS was calculated as the time from registration until progression or death. Patients who were alive and progression-free were censored at the date last seen. Competing risks survival analysis was used to calculate the risk of CNS relapse, with death and systemic-only relapse treated as competing events. All analyses were performed using Stata version 15.1 (StataCorp, College Station, TX).\n\nResults\nPatient characteristics\nBetween May 2008 and April 2013, 121 patients were registered with DLBCL at 32 UK centres. Three patients were deemed ineligible prior to treatment and have been excluded from all analyses (Figure 1). An additional seven patients were found not to meet eligibility criteria after starting treatment and have been included in toxicity analyses only. One eligible patient did not commence treatment because of rapid disease progression and was included in survival, but not toxicity, analyses.Figure 1 Consort diagram.\n\nDLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; MCL, mantle cell lymphoma; RT, radiotherapy; TRM, treatment-related mortality.\n\n\n\nThe primary analysis included 111 DLBCL patients. Baseline clinical and pathological characteristics are shown in Table 2. Central pathology review was performed in 86 patients (77.5%); pathology reports issued by haematopathologists were reviewed for all other patients to confirm DLBCL. FISH studies were performed equally in germinal centre (GC) B-cell and non-GC DLBCL; seven patients (12.3% of those assessed) had double-hit cytogenetics.Table 2 Baseline characteristics\n\nBaseline characteristic\tN = 111\t\nDemographics\t\t\n Age (years), median (range)\t50 (18–65)\t\n Sex, n (%)\t\t\n Female\t45 (40.5)\t\n Male\t66 (59.5)\t\nPrognostic factors, n (%)\t\t\n Age\t\t\n ≤60\t98 (88.3)\t\n >60\t13 (11.7)\t\n WHO performance status\t\t\n 0\t23 (20.7)\t\n 1\t28 (25.2)\t\n 2\t38 (34.2)\t\n 3\t22 (19.8)\t\n Stage\t\t\n III\t7 (6.3)\t\n IV\t104 (93.7)\t\n More than 1 extra nodal site\t\t\n No\t23 (20.7)\t\n Yes\t88 (79.3)\t\n LDH above upper limit of normal\t\t\n No\t5 (4.5)\t\n Yes\t106 (95.5)\t\nIPI score, n (%)\t\t\n 3\t67 (60.4)\t\n 4\t43 (38.7)\t\n 5\t1 (0.9)\t\nOther baseline demographics, n (%)\t\t\n Age-adjusted IPI score\t\t\n 1\t1 (0.9)\t\n 2\t54 (48.6)\t\n 3\t56 (50.5)\t\n B symptoms\t\t\n Absent\t34 (30.6)\t\n Present\t77 (69.4)\t\n CNS disease at registration\t\t\n Yes\t10 (9.0)\t\n No\t101 (91.0)\t\n HIV status\t\t\n Negative\t108 (99.1)\t\n Positive\t1 (0.9)\t\n Unknown\t2\t\n Disease bulk ≥10 cm\t\t\n Present\t38 (39.6)\t\n Absent\t58 (60.4)\t\n Incomplete information\t15\t\n LDH ≥3× ULN, n (%)\t\t\n No\t60 (56.1)\t\n Yes\t47 (43.9)\t\n Unknown\t4\t\nPathology classification (post hoc review), n (%)\t\t\n Cell of origin\t\t\n GCB\t54 (54.0)\t\n Non-GCB\t46 (46.0)\t\n Unknown\t11\t\n Double-hit\t\t\n No\t50 (87.7)\t\n Yes\t7 (12.3)\t\n Unknown\t54\t\nCNS, central nervous system; GCB, germinal centre B-cell; HIV, human immunodeficiency virus; IPI, International Prognostic Index; LDH, lactate dehydrogenase; ULN, upper limit of normal; WHO, World Health Organisation.\n\n\n\nStudy treatment\nEighty-five patients (77.3%) completed all four cycles of chemotherapy. The median interval between the start of consecutive treatment cycles was 27 days between cycles 1 and 2 (range 18–45), 23 days between cycles 2 and 3 (range 16–53) and 30 days between cycles 3 and 4 (range 21–83). The interval was ≥35 days for 16.5% (44/266) of treatment cycles.\n\nTwenty-five patients (22.7%) stopped treatment early, after receiving one (n = 16), two (n = 3) or three (n = 6) cycles of chemotherapy. The main reason for early discontinuation was toxicity (n = 18; Figure 1). Patients were less likely to complete chemotherapy if aged ≥50 years (62.5%, compared with 92.7% <50 years; P < 0.001), or if PS = 3 (54.6%, compared with 83.2% for PS 0–2; P = 0.004).\n\nRadiotherapy consolidation was given to 13 of 85 (15.3%) patients. Only one of 20 (5%) patients with baseline tumour bulk ≥7.5 cm was irradiated after achieving CR. Two patients received allogeneic stem cell transplant off-trial in CR, one of whom died of transplant-related complications.\n\nToxicity\nGrade 3–5 adverse events are detailed in Table 3. As expected, haematological toxicity was high with this dose-intense regimen, with 88% grade 4 neutropoenia and 61.1% grade 4 thrombocytopoenia. Grade ≥3 nonhaematological toxicity occurred in 88.9%, the most frequent of which were infections (70.9%), mucositis (31.6%) and febrile neutropoenia (17.9%). Intracranial haemorrhage occurred in six patients (5.1%), all during the first cycle and in patients without CNS disease. One patient (0.9%) developed secondary acute myeloid leukaemia. One patient who had received prior radiotherapy for spinal lymphoma (thus should have been ineligible, although it was only reported after completing study treatment) developed paraparesis secondary to radiotherapy-induced spinal necrosis, emphasising the need for caution with intensive CNS-directed therapy after CNS irradiation.Table 3 Grade 3–5 adverse events\n\nCTCAE system organ class/event\tWorst grade\t\nGrade 3–4\tGrade 5\t\nN = 117\t\nn (%)\tn (%)\t\nBlood and bone marrow\t115 (98.3)\t\t\n Anaemia\t32 (27.4)\t\t\n Leukopenia\t14 (12.0)\t\t\n Neutropaenia\t112 (95.7)\t\t\n Thrombocytopaenia\t110 (94.0)\t\t\nCardiac\t12 (10.3)\t\t\n Cardiac NOS\t10 (8.5)\t\t\n Hypotension\t2 (1.7)\t\t\nConstitutional\t26 (22.2)\t\t\n Fatigue\t7 (6.0)\t\t\n Fever\t20 (17.1)\t\t\nDermatology and skin: rash\t2 (1.7)\t\t\nGastrointestinal\t56 (47.9)\t\t\n Anorexia\t12 (10.3)\t\t\n Diarrhoea\t10 (8.5)\t\t\n Mucositis\t37 (31.6)\t\t\n Nausea\t14 (12.0)\t\t\n Perforated small bowel\t2 (1.7)\t\t\n Vomiting\t7 (6.0)\t\t\nHaemorrhage\t9 (7.7)\t2 (1.7)\t\n CNS\t5 (4.3)\t1 (0.1)\t\n Gastrointestinal\t4 (3.4)\t1 (0.1)\t\nInfection\t80 (68.4)\t3 (2.6)\t\n Febrile neutropoenia\t21 (17.9)\t\t\n Infection\t72 (61.5)\t3 (2.6)\t\n Sepsis\t3 (2.6)\t\t\nLaboratory/Metabolism\t20 (17.1)\t\t\n Hypokalaemia\t7 (6.0)\t\t\n Abnormal transaminases or bilirubin\t8 (6.8)\t\t\nNeurology\t16 (13.7)\t\t\n Mood alterations\t2 (1.7)\t\t\n Neurological NOS\t11 (9.4)\t\t\nPain\t18 (15.4)\t\t\n Gastrointestinal\t3 (2.6)\t\t\n Musculoskeletal\t5 (4.3)\t\t\n Headache\t7 (6.0)\t\t\n Pain NOS\t4 (3.4)\t\t\n Chest\t3 (2.6)\t\t\nPulmonary/Upper respiratory\t11 (9.4)\t\t\n Dyspnoea\t4 (3.4)\t\t\n Pleural effusion\t3 (2.6)\t\t\nSyndromes\t3 (2.6)\t\t\n Tumour lysis\t2 (1.7)\t\t\nVascular\t3 (2.6)\t\t\n DVT/thrombosis\t3 (2.6)\t\t\nNon-haematological\t99 (84.6)\t5 (4.3)\t\nAny CTCAE grades 3+\t112 (95.7)\t5 (4.4)\t\nData listed by organ class according to the Common Toxicity Criteria for Adverse Events version 3. Individual grade ≥3 events are only listed if occurring in ≥2 patients.\n\nCNS, central nervous system; CTCAE, Common Toxicity Criteria for Adverse Events (version 3.0); DVT, deep vein thrombosis; NOS, not otherwise specified.\n\n\n\nTreatment-related mortality (TRM) was 4.3%, with five deaths, due to neutropoenic sepsis (n = 3) and haemorrhage (n = 2; intracranial and gastrointestinal). These patients were all aged >50 years with a PS of 3 at registration.\n\nOutcomes\nFor eligible patients that commenced R-CODOX-M (N = 110), overall response rate by CT was 74.5%: 52 patients (47.3%) achieved CR/unconfirmed CR (CRu) and 30 (27.3%) achieved partial response (PR). Seven patients (8.2%) had stable or progressive disease and 20 patients (18.2%) did not undergo response assessment because of early treatment termination or death (Figure 1).\n\nWith a median follow-up of 54.6 months for the whole cohort (N = 111), 30 patients have relapsed or died of lymphoma and eight died without progression (38 PFS events). The 2- and 4-year PFS rates were 67.9% [90% confidence interval (CI) 59.9–74.6] and 66.9% (90% CI 58.9–73.7), respectively (Figure 2A). The 2- and 4-year OS rates were 76.0% (90% CI 68.5–82.0) and 72.8% (90% CI 64.9–79.2), respectively (Figure 2B). There have been 32 deaths in total, due to lymphoma (n = 22), TRM (n = 5), toxicity of further treatment (n = 3), pneumonia (n = 1) and other malignancy (T-cell lymphoma; n = 1).Figure 2 Kaplan–Meier curves for (A) progression-free survival and (B) overall survival. (C) Progression-free survival according to age and performance status (PS).\n\n\n\nA post hoc analysis assessing the effect of age and PS highlighted worse outcomes for patients with PS ≥2 who were aged >50 years (Figure 2C), which was largely driven by excess TRM in this group (supplementary Table S1, available at Annals of Oncology online). There was no clear difference in outcomes for those with IPI score 3 compared with those with IPI score 4 or 5 (supplementary Figure S1A, available at Annals of Oncology online). There was also no overt difference in outcomes for DLBCL diagnoses made by external versus central pathology review, or between patients with a GC B-cell phenotype and non-GC disease (supplementary Figure S1B and C, available at Annals of Oncology online), albeit according to the Hans algorithm, which is an imperfect predictor of cell of origin. Although numbers are small, outcomes for patients with double-hit lymphoma were not overtly different from other DLBCL patients in whom FISH excluded double-hit disease (supplementary Figure 1D, available at Annals of Oncology online).\n\nCentral nervous system-directed therapy\nFor patients with CNS involvement at registration (n = 10), 2-year PFS was 70% (32.9%–89.2%), without any patient receiving radiotherapy or high-dose therapy and stem cell transplant in CR. There was one isolated CNS progression; the other two patients had either refractory disease or concurrent systemic progression.\n\nFor patients without evidence of CNS involvement (N = 101), CNS relapse risk according to the CNS-IPI35 was evaluable for 90 (89.1%; supplementary Table S2, available at Annals of Oncology online). There were no CNS relapses in intermediate-risk patients (n = 38). There were two CNS relapses among 58 high-risk patients, both without evidence of systemic disease, giving a 2-year CNS relapse rate of 3.6% (95% CI 0.9–13.8).\n\nOutcomes for relapsed/refractory disease\nTwenty-six patients experienced disease progression after R-CODOX-M/R-IVAC, nine of whom relapsed from CR/CRu, and two patients received further treatment for inadequate response (PR and stable disease). Of these, 20 patients (71.4%) received intensive salvage chemotherapy, five (17.9%) were palliated and further treatment history is unknown in three (10.7%). Seven patients with relapsed/refractory disease (25.0%) are alive, with a minimum of 29 months' follow-up post-progression.\n\nDiscussion\nThis trial demonstrates that treatment with R-CODOX-M/R-IVAC is both feasible and effective in a high-risk group of DLBCL/HGBL patients. The primary end point was met, with a 2-year PFS rate of 67.9% (90% CI 59.9–74.6), exceeding the 65% target and comfortably excluding the lower limit of 45%.\n\nOur results appear to compare favourably with contemporary outcomes with R-CHOP in high-risk DLBCL, notwithstanding the inherent limitations of making comparisons between studies. We report a 4-year PFS rate of 66.9% (90% CI 58.9–73.7), despite inclusion of patients with CNS involvement, in whom R-CHOP is ineffective, and patients with PS >2, who are excluded from many prospective trials.11 In the UK NCRI R-CHOP 14-21 trial,11 5-year PFS for high-risk DLBCL patients (IPI 3–5), aged ≤60 years with PS 0–2 was 54.4%.10 In other large cohorts of patients treated with R-CHOP or similar regimens, PFS rates at 4–5 years for patients with IPI score 3 and 4 or 5 were 54%–59% and 41%–56%, respectively.8,9 Outcomes in this trial were similar to those reported with other intensive treatment regimens.24,25 We observed a 4-year OS rate of 72.8%, compared with 78% for high-risk patients (aaIPI 2–3) treated with the R-ACVBP regimen, noting that CNS disease was excluded in the latter and fewer patients (58%) had IPI score 3–5.24\n\nThe main limitation of this trial is the lack of a randomised comparator, particularly in light of the failure of other apparently promising regimens to translate into a survival benefit over R-CHOP in phase 3 trials.16,17,19,21 Our findings must therefore be interpreted with caution and randomised studies are clearly required if this regimen is to be brought forwards into standard care for high-risk DLBCL. However, conducting a large phase 3 trial in this relatively small subset of DLBCL patients with widespread disease and poor PS, many of whom require urgent chemotherapy, will be challenging.\n\nToxicity with R-CODOX-M/R-IVAC was greater than expected with R-CHOP, particularly with respect to haematological toxicity, infection and mucositis, but was manageable for most patients. TRM was 4.3%, which is comparable to TRM rates with other intensive treatment strategies12,22,24 but higher than the 1%–2% TRM seen in most R-CHOP trials.11,21 All treatment-related deaths occurred in patients aged >50 years with PS 3. These deaths and higher rates of early treatment discontinuation highlight the need for caution in using this regimen for older patients (>50 years) with PS ≥2. A corticosteroid prephase may improve PS and allow for better assessment of suitability for intensive treatment. Use of published dose-adjusted CODOX-M/IVAC protocols for older/less-fit patients may also improve tolerability,28,36 although alternative regimens may be warranted for such patients. The resource burden with R-CODOX-M/R-IVAC is higher than with R-CHOP, usually requiring inpatient administration, but the duration of treatment (14 weeks) is shorter than with R-CHOP-21 (18 weeks) and other intensive regimens, such as R-ACVBP (26 weeks).22\n\nOne benefit of R-CODOX-M/R-IVAC is the ability to deliver multiple CNS-directed agents, particularly to those with concurrent CNS involvement or at highest risk of CNS relapse. The favourable outcomes for those with CNS involvement in this trial demonstrate the feasibility of this approach for secondary CNS lymphoma, although patient numbers are small, and our findings require exploration in larger cohorts. It is also noteworthy that none of these patients received high-dose therapy and stem cell transplant or radiotherapy consolidation in CR. There were also fewer CNS relapses than anticipated in this trial, with observed 2-year CNS progression rates of 0% and 3.6% for patients with intermediate- and high-risk CNS IPI scores, respectively, compared with 3.4%–3.9% and 10.2%–12.0%, respectively, in R-CHOP-treated patients.35\n\nR-CODOX-M/R-IVAC has already been used to treat specific high-risk groups of HGBL, particularly those with ‘double-hit’ lymphoma, based on retrospective evidence of efficacy.37,38 Only 51.4% of patients underwent FISH studies in this trial, which was conceived prior to the widespread use of FISH to identify double-hit patients. Therefore, our findings cannot be extrapolated to recently categorised HGBL populations in the 2016 WHO Classification of Lymphoid Neoplasms.39 Where FISH studies were performed, the frequency of double-hit cytogenetics in our high-risk DLBCL cohort (12%) was not appreciably higher than the reported incidence in wider DLBCL cohorts (5%–10%). There was no clear difference in outcomes for the few patients with double-hit lymphoma in this trial. This demonstrates that adverse risk is multifactorial and double-hit lymphoma accounts for only a small proportion of ‘high-risk’ HGBL. Our findings suggest that R-CODOX-M/R-IVAC may have broader applicability across high-risk patients with both HGBL and DLBCL.\n\nOne argument against the use of intensive upfront treatment is the limited availability of treatment options in the event of relapse; R-IVAC contains several agents that are typically used in salvage regimens. However, outcomes after DLBCL progression are generally poor, with PFS rates following intensive salvage therapy of only 20%–30% across studies.4, 5, 6 Even with chimeric antigen receptor T-cell therapy, relatively short-term PFS rates for the selected patients included in pivotal trials remain below 40% on a per-protocol basis, and intention-to-treat analyses are lacking.40,41 In this trial, 25% of all patients with relapsed/refractory disease are alive and in ongoing remission, in keeping with other studies and emphasising the importance of effective front-line treatment.\n\nIn summary, this phase 2 trial demonstrates that R-CODOX-M/R-IVAC is an effective regimen for the treatment of high-risk DLBCL, with promising survival rates. Toxicity with this intensive regimen was manageable for most patients, although it was less well tolerated in patients aged >50 years with impaired PS (≥2). Our findings indicate that R-CODOX-M/R-IVAC warrants being explored further in comparative studies against standard R-CHOP chemotherapy.\n\nSupplementary data\nSupplementary Material\n \n\nAcknowledgements\nThe CRUK & UCL Cancer Trials Centre acknowledges the support of the National Institute for Health Research, through the National Cancer Research Institute. We are grateful to Paul Smith, Jo Gambell, Toyin Adedayo and Humra Shah for their expertise and assistance with trial management. KMA receives support from the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London. The study was approved by UK National Research Ethics Committee (reference 05/Q0201/81).\n\nFunding\n10.13039/501100007903Bloodwise supported the conduct of this trial through the 10.13039/501100000289Cancer Research UK and University College London Cancer Trials Centre [grant number LLR04058]. Pegylated granulocyte–colony stimulating factor (Neulasta) was supplied free of charge by Amgen Ltd.\n\nDisclosure\nAKM has received funding for travel and medical advisory board participation from F. Hoffman-La Roche and Amgen, and speakers' fees from F. Hoffman-La Roche. EHP has received research funding from F. Hoffman-La Roche. KMA has received funding for travel expenses and medical advisory board participation from F. Hoffman-La Roche. RPa has received funding for medical advisory board participation from F. Hoffman-La Roche. All other authors declare no relevant conflicts of interest.\n\n✰ Note: These data were presented orally at the European Hematology Association Annual Congress in Stockholm, Sweden in June 2018, and at the International Conference on Malignant Lymphoma in Lugano, Switzerland in June 2015.\n==== Refs\nReferences\n1 Coiffier B. Lepage E. Brière J. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med 346 4 2002 235 242 11807147 \n2 Pfreundschuh M. Kuhnt E. Trümper L. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group Lancet Oncol 12 11 2011 1013 1022 21940214 \n3 Habermann T.M. Weller E.A. Morrison V.A. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma J Clin Oncol 24 19 2006 3121 3127 16754935 \n4 Crump M. Kuruvilla J. Couban S. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12 J Clin Oncol 32 31 2014 3490 3496 25267740 \n5 Crump M. Neelapu S.S. Farooq U. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study Blood 130 16 2017 1800 1808 28774879 \n6 Imhoff GWv McMillan A. Matasar M.J. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large b-cell lymphoma: the ORCHARRD study J Clin Oncol 35 5 2017 544 551 28029326 \n7 Sehn L.H. Berry B. Chhanabhai M. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP Blood 109 5 2007 1857 1861 17105812 \n8 Ziepert M. Hasenclever D. Kuhnt E. Standard international prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era J Clin Oncol 28 14 2010 2373 2380 20385988 \n9 Zhou Z. Sehn L.H. Rademaker A.W. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era Blood 123 6 2014 837 842 24264230 \n10 Gleeson M. Counsell N. Cunningham D. A comparison of prognostic indices in diffuse large B-cell lymphoma within the UK NCRI R-CHOP 14 versus 21 phase III trial Blood 132 Suppl 1 2018 2956 \n11 Cunningham D. Hawkes E.A. Jack A. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles Lancet 381 9880 2013 1817 1826 23615461 \n12 Stiff P.J. Unger J.M. Cook J.R. Autologous transplantation as consolidation for aggressive non-hodgkin's lymphoma N Engl J Med 369 18 2013 1681 1690 24171516 \n13 Chiappella A. Martelli M. Angelucci E. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study Lancet Oncol 18 8 2017 1076 1088 28668386 \n14 Linch D.C. Yung L. Smith P. Final analysis of the UKLG LY02 trial comparing 6–8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients <65 years with poor prognosis histologically aggressive NHL Br J Haematol 149 2 2010 237 243 20201949 \n15 Vitolo U. Trněný M. Belada D. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma J Clin Oncol 35 31 2017 3529 3537 28796588 \n16 Davies A. Cummin T.E. Barrans S. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial Lancet Oncol 20 5 2019 649 662 30948276 \n17 Vitolo U. Witzig T.E. Gascoyne R.D. ROBUST: first report of phase III randomized study of lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma Hematol Oncol 37 S2 2019 36 37 \n18 Nowakowski G.S. Hong F. Scott D.W. Addition of lenalidomide to R-CHOP (R2CHOP) improves outcomes in newly diagnosed diffuse large B-cell lymphoma (DLBCL): first report of ECOG-ACRIN1412 a randomized phase 2 US intergroup study of R2CHOP vs R-CHOP Hematol Oncol 37 S2 2019 37 38 \n19 Younes A. Sehn L.H. Johnson P. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non–germinal center B-cell diffuse large B-cell lymphoma J Clin Oncol 37 15 2019 1285 1295 30901302 \n20 Fisher R.I. Gaynor E.R. Dahlberg S. Comparison of a standard regimen (CHOP) with Three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma N Engl J Med 328 14 1993 1002 1006 7680764 \n21 Bartlett N.L. Wilson W.H. Jung S.-H. Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III intergroup trial alliance/CALGB 50303 J Clin Oncol 37 21 2019 1790 1799 30939090 \n22 Récher C. Coiffier B. Haioun C. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial Lancet 378 9806 2011 1858 1867 22118442 \n23 Casasnovas R.-O. Ysebaert L. Thieblemont C. FDG-PET–driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study Blood 130 11 2017 1315 1326 28701367 \n24 Fitoussi O. Belhadj K. Mounier N. Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA Haematologica 96 8 2011 1136 1143 21546499 \n25 Schmitz N. Nickelsen M. Ziepert M. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1) Lancet Oncol 13 12 2012 1250 1259 23168367 \n26 Gang A.O. Strøm C. Pedersen M. R-CHOEP-14 improves overall survival in young high-risk patients with diffuse large B-cell lymphoma compared with R-CHOP-14. A population-based investigation from the Danish Lymphoma Group Ann Oncol 23 1 2011 147 153 21460380 \n27 Linch D.C. Burkitt lymphoma in adults Br J Haematol 156 6 2012 693 703 21923642 \n28 Mead G.M. Barrans S.L. Qian W. A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial) Blood 112 6 2008 2248 2260 18612102 \n29 Phillips E.H. Burton C. Kirkwood A.A. Favourable outcomes for high-risk Burkitt lymphoma patients (IPI 3-5) treated with rituximab plus CODOX-M/IVAC: results of a phase 2 UK NCRI trial eJHaem 2020 10.1002/jha2.3 \n30 Zhu K.Y. Song K.W. Connors J.M. Excellent real-world outcomes of adults with Burkitt lymphoma treated with CODOX-M/IVAC plus or minus rituximab Br J Haematol 181 6 2018 782 790 29741758 \n31 Jaffe E.S. Harris N.L. Stein H. Vardiman J.W. World Health Organization Classification of Tumours. Pathology & Genetics of Tumours of Haematopoietic and Lymphoid Tissues 2001 IARC Publications Lyon \n32 Swerdlow S.H. Campo E. Harris N.L. WHO classification of Tumours of Haematopoietic and Lymphoid Tissues 4th ed. 2008 IARC Lyon, France \n33 Hans C.P. Weisenburger D.D. Greiner T.C. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray Blood 103 1 2004 275 282 14504078 \n34 Cheson B.D. Horning S.J. Coiffier B. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas J Clin Oncol 17 4 1999 1244 10561185 \n35 Schmitz N. Zeynalova S. Nickelsen M. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP J Clin Oncol 34 26 2016 3150 3156 27382100 \n36 Maruyama D. Watanabe T. Maeshima A.M. Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL Int J Hematol 92 5 2010 732 743 21120644 \n37 Petrich A.M. Gandhi M. Jovanovic B. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis Blood 124 15 2014 2354 2361 25161267 \n38 Savage K.J. Karsan A. Slack G.W. Outcome of patients with double-hit lymphomas treated with CODOX-M/IVAC + R followed by hematopoietic stem cell transplantation in British Columbia Blood 122 21 2013 1788 \n39 Swerdlow S.H. Campo E. Pileri S.A. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 127 20 2016 2375 2390 26980727 \n40 Locke F.L. Ghobadi A. Jacobson C.A. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial Lancet Oncol 20 1 2019 31 42 30518502 \n41 Schuster S.J. Bishop M.R. Tam C.S. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma N Engl J Med 380 1 2019 45 56 30501490\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0923-7534",
"issue": "31(9)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "R-CODOX-M; chemotherapy; diffuse large B-cell lymphoma (DLBCL); double-hit; high-grade B-cell lymphoma",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D006801:Humans; D007069:Ifosfamide; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D006113:United Kingdom; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1251-1259",
"pmc": null,
"pmid": "32464282",
"pubdate": "2020-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "27382100;21546499;30518502;17105812;25267740;16754935;11807147;30948276;30939090;21120644;21460380;23168367;28668386;28774879;23615461;24264230;10561185;18612102;25161267;29741758;24171516;22118442;28701367;30501490;21940214;26980727;7680764;32464282;21923642;20201949;28029326;28796588;14504078;20385988;30901302",
"title": "Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3-5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial.",
"title_normalized": "favourable outcomes for high risk diffuse large b cell lymphoma ipi 3 5 treated with front line r codox m r ivac chemotherapy results of a phase 2 uk ncri trial"
} | [
{
"companynumb": "GB-PFIZER INC-2020377409",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nTo evaluate cyclosporine A (CSA)-related neurotoxicity after haploidentical hematopoietic stem cell transplantation (HID-HSCT) in children with hematopathy.\n\n\nMETHODS\nThis retrospective case series study included children with hematopathy who underwent HID-HSCT at Fujian Medical University Union Hospital between February 2013 and January 2017.\n\n\nRESULTS\nFifty-one children (39 males) were included in the study with a median age of 8 (range, 1.1-18) years. Seven patients (13.7%) developed CSA-related neurotoxicity after a median 38 (range, - 3 to 161) days from HID-HSCT. Hypertension (5/7, 71%) was the most common prodrome. Brain magnetic resonance imaging showed posterior reversible encephalopathy syndrome in six patients and atypical abnormalities in one patient. One patient died from grade IV graft-versus-host disease (GvHD) on day + 160, and six patients were alive at the last follow-up. Four patients (71.4%) achieved complete remission, while two patients developed secondary epilepsy and exhibited persistent MRI and electroencephalogram abnormalities at the 5-year follow-up. Hypertension after CSA was more common in patients with CSA-related neurotoxicity than in those without (71% vs. 11%, P = 0.002). Five-year overall survival did not differ significantly between patients with CSA-related neurotoxicity (85.7 ± 13.2%) and those without (65.8 ± 7.2%).\n\n\nCONCLUSIONS\nThe incidence of CSA-related neurotoxicity in children with hematopathy undergoing HID-HSCT is relatively high.",
"affiliations": "Department of Pediatric, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China.;Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China.;Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China.;Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China.;Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China.;Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China. yang.hopeting@gmail.com.;Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China. drjiandahu@163.com.",
"authors": "Wang|Yong|Y|;Zheng|Yongzhi|Y|;Wen|Jingjing|J|;Ren|Jinhua|J|;Yuan|Xiaohong|X|;Yang|Ting|T|;Hu|Jianda|J|",
"chemical_list": "D065095:Calcineurin Inhibitors; D016572:Cyclosporine",
"country": "England",
"delete": false,
"doi": "10.1186/s13052-021-01037-0",
"fulltext": "\n==== Front\nItal J Pediatr\nItal J Pediatr\nItalian Journal of Pediatrics\n1824-7288\nBioMed Central London\n\n1037\n10.1186/s13052-021-01037-0\nResearch\nCyclosporine A-related neurotoxicity after haploidentical hematopoietic stem cell transplantation in children with hematopathy\nWang Yong 1\nZheng Yongzhi 2\nWen Jingjing 2\nRen Jinhua 2\nYuan Xiaohong 2\nYang Ting yang.hopeting@gmail.com\n\n2\nHu Jianda drjiandahu@163.com\n\n2\n1 grid.411176.4 0000 0004 1758 0478 Department of Pediatric, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province China\n2 grid.411176.4 0000 0004 1758 0478 Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province China\n1 4 2021\n1 4 2021\n2021\n47 8324 11 2020\n23 3 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nTo evaluate cyclosporine A (CSA)-related neurotoxicity after haploidentical hematopoietic stem cell transplantation (HID-HSCT) in children with hematopathy.\n\nMethods\n\nThis retrospective case series study included children with hematopathy who underwent HID-HSCT at Fujian Medical University Union Hospital between February 2013 and January 2017.\n\nResults\n\nFifty-one children (39 males) were included in the study with a median age of 8 (range, 1.1–18) years. Seven patients (13.7%) developed CSA-related neurotoxicity after a median 38 (range, − 3 to 161) days from HID-HSCT. Hypertension (5/7, 71%) was the most common prodrome. Brain magnetic resonance imaging showed posterior reversible encephalopathy syndrome in six patients and atypical abnormalities in one patient. One patient died from grade IV graft-versus-host disease (GvHD) on day + 160, and six patients were alive at the last follow-up. Four patients (71.4%) achieved complete remission, while two patients developed secondary epilepsy and exhibited persistent MRI and electroencephalogram abnormalities at the 5-year follow-up. Hypertension after CSA was more common in patients with CSA-related neurotoxicity than in those without (71% vs. 11%, P = 0.002). Five-year overall survival did not differ significantly between patients with CSA-related neurotoxicity (85.7 ± 13.2%) and those without (65.8 ± 7.2%).\n\nConclusions\n\nThe incidence of CSA-related neurotoxicity in children with hematopathy undergoing HID-HSCT is relatively high.\n\nKeywords\n\nCyclosporine a\nNeurotoxicity syndrome\nHematopoietic stem cell transplantation\nChild\nHematopathy\nConstruction Project of Fujian Medical Center of HematologyMin201704 Startup Fund for scientific research, Fujian Medical University2019QH1032 issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nHematopoietic stem cell transplantation (HSCT) is the most effective curative therapy for a variety of hematological disorders [1]. Excitingly, the success of haploidentical HSCT (HID-HSCT) has ushered in a new era wherein “everyone has a donor” [2]. The number of children with hematopathy who undergo HID-HSCT has increased dramatically in China, where donor sourcing has been complex because the former one-child policy resulted in sibling donors being a relative rarity [3]. However, the success of HSCT is restricted by graft-versus-host disease (GvHD), a serious complication that affects quality of life and is the main cause of death after transplantation [4, 5]. Prophylaxis against GvHD usually involves the administration of a calcineurin inhibitor, such as cyclosporine A (CSA) or tacrolimus, together with an immunosuppressant, such as low-dose methotrexate or mycophenolate, although alternative agents are also available [6].\n\nCSA is the cornerstone of GvHD prophylaxis. However, neurotoxicity is one of the most common early complications occurring with CSA usage in clinical practice because CSA has a narrow therapeutic index and large inter-individual and intra-individual variability in its pharmacokinetics [7, 8]. Neurotoxicity occurs in 5–11% of patients receiving CSA as GvHD prophylaxis after HSCT [9–13]. The presentation of CSA-related neurotoxicity includes impaired consciousness, seizures, visual disturbance, headache, involuntary movements and paresis [9–14]. Magnetic resonance imaging (MRI) usually shows radiologic features of posterior reversible encephalopathy syndrome (PRES) such as focal regions of symmetric edema affecting the white mater of the parietal and occipital lobes [15]. CSA-related neurotoxicity usually resolves completely with dose reduction or drug withdrawal, but this can have major implications on clinical outcomes, particularly in the face of ongoing GvHD. Furthermore, some CSA-related neurological lesions are irreversible and associated with the later occurrence of epilepsy and persistent abnormalities in the electroencephalogram (EEG) [16]. However, little information is available regarding CSA-related neurotoxicity in children undergoing HID-HSCT.\n\nIn this study, we retrospectively examined the data of children who underwent HID-HSCT in order to describe the risk factors and long-term outcomes of CSA-related neurotoxicity. Our aim was to identify factors that potentially could be targeted to prevent post-transplantation CSA-related neurotoxicity or facilitate its early diagnosis and thereby improve survival outcomes and quality of life for patients following HID-HSCT.\n\nMethods\n\nStudy design and patients\n\nThis retrospective case series study included pediatric patients treated with HID-HSCT at the Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China between February 2013 and January 2017. The inclusion criteria were: 1) age ≤ 18 years; 2) received HID-HSCT from a family member who shared one HLA haplotype with the recipient (but differed to varying degrees with regard to the HLA-A, −B and -DR antigens of the unshared HLA haplotype); and 3) received CSA as prophylaxis against GvHD. Patients with neurological disorders before HID-HSCT, including cerebral hemorrhage and central nervous system leukemia, were excluded. The Ethics Committee of Fujian Medical University Union Hospital approved the study (No. 2020ky043) and waived the requirement for informed consent because the analysis was retrospective.\n\nCSA administration\n\nThe FA5-BUCY conditioning regimen and GvHD prophylaxis were administered as described previously by Yang et al. [17]. Briefly, all 51 patients underwent aplasia-inducing salvage therapy consisting of 30 mg/m2/day fludarabine and 2 g/m2/day Ara-C (cytarabine) for 5 consecutive days from day − 13 to day − 9, followed after 1 day of rest by 3.2 mg/kg/day BU from day − 7 to day − 5 and 1.8 g/m2/day CY from day − 4 to day − 3. GvHD prophylaxis consisted of rabbit anti-thymocyte globulin (Thymoglobulin [Genzyme] at 10 mg/kg, 20 patients; ATG-Fresenius® at 40 mg/kg, 23 patients) from day − 4 to day-1, CSA (plasma levels of 100–250 ng/ml; starting from day − 10 intravenously at 1.5 mg/kg every 12 h, followed by oral administration at 5–6 mg/kg/day after completion of the transplantation, and tapering from the second or third month if no signs of GvHD were present), mycophenolate mofetil (5 mg/kg bid, starting from day + 7 and tapered after engraftment), and short-term methotrexate (MTX, 15 mg/m2 at day + 1, and 10 mg/m2 at day + 3 and + 6). All patients received methylprednisolone for preventing serum sickness associated ATG at 0.8 mg/kg/day from day − 4 to granulocyte implantation. All stem cells were derived from the bone marrow or peripheral blood of the patients’ fathers.\n\nMonitoring for adverse effects\n\nMonitoring for CSA-related adverse effects consisted of physical examination, blood pressure measurements and routine blood biochemistry tests (including magnesium level), which were performed daily up to day 30 and then 3 times weekly up to day 60. Hypertension was defined according to the 2010 Chinese guidelines for the management of hypertension in children and adolescents (blood pressure above the 75th percentile for age and weight) [18] and was treated with oral calcium channel antagonists. Fluid overload was considered if hypertension or neurological symptoms developed and was treated with intravenous furosemide. Magnesium supplementation was given if plasma magnesium levels fell below 0.8 mmol/L.\n\nSince there are no definitive criteria for CSA-related neurotoxicity, this adverse effect was diagnosed clinically using similar guidelines to those described in previous reports [13, 14, 19]. The diagnosis of CSA-related neurotoxicity was based on the appearance of neurological manifestations during CSA administration (including altered consciousness, seizures, tremors and continuous headache) and the exclusion of other conceivable causes (such as infection, cerebral hemorrhage, metabolic abnormalities, central nervous system leukemia and electrolyte disturbances). If CSA-related neurotoxicity was suspected, CSA was immediately discontinued, and the patient was examined using computed tomography (CT), MRI and electroencephalography. Furthermore, the amelioration of neurological symptoms after the withdrawal of CSA was taken as further evidence in support of a diagnosis of CSA-related neurotoxicity. MRI was performed to exclude other diagnoses and to look for radiological manifestations of PRES (which would support the diagnosis of CSA-related neurotoxicity). In cases with manifestations of epilepsy, electroencephalography was repeated after 24 h and again at 1 month following control of the acute symptoms with anticonvulsants. Electroencephalography was then performed every 3 months for 1 year and annually thereafter if there was no recurrence of seizures or every 3–6 months if recurrence occurred.\n\nStatistical analysis\n\nFor the analysis, the patients were divided into two groups (neurotoxicity group and non-neurotoxicity group) based on whether CSA-related neurotoxicity occurred. Categorical variables are presented as n (%) and were compared between groups using Fisher’s exact test or the chi-squared test. Continuous variables were tested for normality, and all the datasets were found not to be normally distributed. Therefore, continuous variables are expressed as median (range) and were compared between groups using the Mann-Whitney U test. Deaths and relapses were considered as competing events, and treatment-related mortality (TRM) was determined using Kaplan-Meier analysis by the log-rank method. The null hypothesis was rejected for P-values < 0.05. Statistical analyses were performed using SPSS version 21 (IBM, Armonk, NY, USA).\n\nResults\n\nClinical characteristics of the patients included in the analysis\n\nA total of 51 pediatric patients (39 males, 76.5%) with a median age of 8 (range 1.1–18) years were included in this study. The clinical characteristics of these 51 patients are summarized in Table 1. Table 1 Clinical characteristics of the 51 children who underwent haploidentical hematopoietic stem cell transplantation\n\nCharacteristic\tValue\t\nAge at HID-HSCT (years), median (range)\t8 (1.1–18)\t\nGender, n (%)\t\n Female\t12 (23.5%)\t\n Male\t39 (76.5%)\t\nPrimary disease, n (%)\t\n Acute lymphoblastic leukemia\t14 (27.4%)\t\n Acute myeloid leukemia\t25 (49.0%)\t\n Myelodysplastic syndrome-secondary acute myeloid leukemia\t4 (7.9%)\t\n Advanced myelodysplastic syndrome\t2 (3.9%)\t\n Acquired severe aplastic anemia\t6 (11.8%)\t\naRemission status, n (%)\t\n First complete remission (CR1)\t24 (55.8%)\t\n Second complete remission (CR2)\t5 (11.6%)\t\n Not in remission\t14 (32.6%)\t\nRelationship of donor to recipient, n (%)\t\n Parent\t49 (96.1%)\t\n Sibling\t2 (3.9%)\t\nABO blood type match between donor and recipient, n (%)\t\n Matched\t30 (58.8%)\t\n Mismatched\t21 (41.2%)\t\nDonor-recipient gender, n (%)\t\n Male-male\t18 (35.3%)\t\n Male-female\t9 (17.6%)\t\n Female-female\t3 (5.9%)\t\n Female-male\t21 (41.2%)\t\nTime to engraftment (days), median (range)\t\n Neutrophils\t12 (10–22)\t\n Thrombocytes\t13 (7–35)\t\nNumber of CD34+ cells infused (× 106/kg), median (range)\t5.33 (2.3–28)\t\nFollow-up time (days), median (range)\t405 (44–1432)\t\naRemission status is for 43 children with acute leukemia. HID-HSCT, haploidentical hematopoietic stem cell transplantation\n\nClinical characteristics of the patients diagnosed with CSA-related neurotoxicity\n\nEleven of the 51 children (21.5%) who received HID-HSCT during the study period developed seizure disorders or encephalopathy, but 4 of these 11 children was excluded of CSA-related neurotoxicity due to obvious alternative causes (cerebral hemorrhage in 2 patients, CNS infection in 1 patient and metabolic encephalopathy in 1 patient). Therefore, 7 patients (13.7%) were diagnosed with CSA-related neurotoxicity (neurotoxicity group). The 7 children with CSA-related neurotoxicity included 5 boys and 2 girls with a median age of 7 (range, 4–9) years. The median time to neutrophil and thrombocyte engraftment was 11 (range, 10–19) days and 12 (range, 10–22) days, respectively. The clinical characteristics of the 7 patients with CSA-related neurotoxicity are summarized in Table 2. Table 2 Clinical characteristics of the 7 patients diagnosed with cyclosporine A-related neurotoxicity\n\nPatient number\t#1\t#2\t#3\t#4\t#5\t#6\t#7\t\nGender\tM\tF\tM\tM\tF\tM\tM\t\nAge at HID-HSCT (years)\t8\t7\t7\t9\t8\t7\t4\t\nUnderlying disease\tMDS\tALL\tAML\tMDS-SAML\tAML\tAML\tALL\t\nRemission status\tNR\tCR1\tCR1\tCR1\tCR1\tCR1\tPR\t\nHLA typing\t6/10\t5/10\t7/10\t5/10\t5/10\t5/10\t5/10\t\nDonor-recipient gender\tF-M\tF-F\tF-M\tF-M\tM-F\tM-M\tM-M\t\nABO type of donor and recipient\tMatched\tMismatched\tMismatched\tMismatched\tMatched\tMismatched\tMatched\t\nMononuclear cells (× 108/kg)\t6.14\t13.1\t17.5\t17.45\t5.6\t1.82\t16.37\t\nCD34+ cells (×106/kg)\t2.3\t2.5\t6.85\t3.17\t8.81\t10.14\t5.33\t\nNeutrophil engraftment time (days)\t11\t10\t11\t19\t12\t16\t10\t\nThrombocyte engraftment time (days)\t15\t10\t11\t22\t12\t17\t10\t\nALL Acute lymphoblastic leukemia, AML Acute myeloid leukemia, CR Complete remission, F Female, HID-HSCT Haploidentical hematopoietic stem cell transplantation, M Male, MDS-SAML Myelodysplastic syndrome-secondary acute myeloid leukemia, NR No response, PR Partial remission\n\nThe median number of days from HID-HSCT to neurotoxicity was 38 (range, − 3 to 161) days. The diagnosis of CSA-related neurotoxicity was made during the conditioning stage in 1 patient, at 0–100 days after transplantation in 4 patients, and after day 100 in 2 patients. During CSA dose adjustment, the trough plasma level of CSA ranged from 107.8 ng/mL to 584 ng/mL (the CSA dose was reduced whenever the level exceeded 250 ng/mL). All 7 patients who developed neurotoxicity presented with prodromes 1–2 days before overt neurotoxicity, and the prodromes included hypertension (n = 5), transient headache (n = 3), vomiting (n = 2), fatigue (n = 2), dysphoria (n = 2) and visual hallucinations (n = 1). At the time of overt neurotoxicity, 5 cases were complicated with GvHD, 5 cases with infection, 3 cases with hemorrhagic cystitis, and 5 cases with hypertension. CSA-related neurotoxicity manifested as generalized seizures (n = 7), persistent headache (n = 3), tremors (n = 2), visual disturbance (n = 2), psychosis (n = 1), aphasia (n = 1) and dysphagia (n = 1). Plasma levels of CSA were within the desired range in all patients (median, 82.1 ng/mL; range, 57.7–118.3 ng/mL) at the time that neurological symptoms appeared. CSF examinations were performed in 5 patients and returned normal findings in all cases.\n\nNeuroimaging and electroencephalography\n\nNeuroimaging and electroencephalography were performed in all patients with CSA-related neurotoxicity. Emergency CT scanning was carried out within 24 h of the appearance of neurological symptoms to exclude intracranial hemorrhage. In patient #4, CT demonstrated a minimal subdural hemorrhagic layer compatible with post-epileptic trauma. MRI was performed within 3 days of the appearance of neurological symptoms after the patient’s vital signs had stabilized (our hospital did not have access to emergency MRI). In 6 of the 7 patients, MRI showed asymmetric involvement of the posterior portions of the cerebral hemispheres, and hyperintense signals were evident on apparent diffusion coefficient (ADC) maps that were consistent with vasogenic edema (Fig. 1a). In the remaining case (patient #6), MRI demonstrated an atypical abnormality that manifested as hyperintense signals in the thalamus and hippocampus predominantly involving the white matter but also the cortex (Fig. 1b). Patient #4 had a complicated cerebral hemorrhage that was associated with PRES (Fig. 1 c). Follow-up MRI examinations were obtained over a period of 2–4 months after the first MRI scan in the 6 children who survived despite developing CSA-related neurotoxicity. Four of these 6 patients exhibited complete resolution of the MRI abnormalities at a median of 2 months (range, 2–8 months) after CSA withdrawal, while 2 cases (patients #2 and #3) had MRI abnormalities that persisted over 3 years (Fig. 1d and e). Fig. 1 Brain magnetic resonance imaging (MRI) and electroencephalography. a, b, c MRI of the brain of patient #1 showing asymmetrical involvement of the cortex and subcortical white matter with high-intensity signals evident on axial T2-weighted. a T2-fluid attenuation inversion recovery (T2-FLAIR). b Apparent diffusion coefficient (ADC). c Scans. Similar MRI findings were obtained in five other patients with cyclosporine A-related neurotoxicity (patients #2, #3, #4, #5 and #7). d and e. Axial FLAIR MRI of the brain of patient #6 (obtained 3 days after the onset of symptoms) showing hyperintense signals in the periventricular white matter (white arrow in d and e) as well as the thalamus (blue arrow in d) and hippocampus (blue arrow in e). f Axial T1-weighted MRI of the brain of patient #4 obtained 3 days after the onset of symptoms. This patient had cerebral hemorrhage associated with posterior reversible encephalopathy syndrome that manifested as a parenchymal hematoma and small hemorrhages < 5 mm in size. The white arrow indicates a microbleed in the occipital lobe. g, h and i. Follow-up MRI of the brain of patient #2. g Patchy shadows with high signal intensity were observed in the lateral periventricular white matter 3 days after the onset of symptoms. h Hyperintense patchy shadowing in the lateral periventricular white matter was increased at 1 month after onset, despite an improvement in clinical symptoms at this time. i Patchy shadowing was less evident at 6 months after symptom onset. j and k. Electroencephalography and MRI findings in patient #3. MRI showed local cortical atrophy in the left parietal and occipital lobes, and the electroencephalogram demonstrated a spike rhythm originating from the same region of the brain\n\nIt was possible to record an EEG at the time of neurological symptom onset in 6 of the 7 children. The main EEG abnormalities included high-voltage slow-waves (n = 5), sharp waves (n = 4), spikes (n = 3) and spike-wave complexes (n = 3). The EEG demonstrated status epilepticus in 3 of the 6 patients and focal delta activity and focal epileptiform discharges in the other 3 patients. Non-epileptiform EEG abnormalities were still detectable in 5 patients (#1, #4, #5, #6 and #7) during the 2–8-week period after the onset of symptoms. Long-term follow-up electroencephalography examinations were performed in 2 cases (patients #2 and #3) with persistent neurological symptoms; the resolution of their EEG abnormalities correlated with their clinical improvement.\n\nManagement of CSA-related neurotoxicity\n\nThe treatments administered to the 7 patients with CSA-related neurotoxicity are summarized in Table 3. CSA was withdrawn immediately following the occurrence of neurotoxicity. Tacrolimus alone (n = 2) or with mycophenolate mofetil (n = 5) was initiated 2 days after CSA washout, with monitoring of the plasma levels. Seizures were treated immediately with intravenous diazepam, and this was followed by anticonvulsive therapy with midazolam. Patients #3 and #4 also required sodium valproate injections to control status epilepticus. Anticonvulsive therapy was tapered and stopped after normalization of the EEG. However, patients #2 and #3 subsequently required anti-epileptic drugs and trihexyphenidyl due to the development of secondary epilepsy (focal epileptiform activity) and tremors. Patient #4 was given anti-psychotic drugs due to the development of psychosis. Additionally, intravenous mannitol was used in 4 patients to treat cerebral edema secondary to seizure recurrence and confusion, vomiting, headache and blurred vision related to intracranial hypertension. Furosemide and captopril were used to control blood pressure and maintain water, electrolyte and acid-base balance. Other forms of supportive care were also provided as necessary. Table 3 Clinical and treatment-related data for the 7 patients with cyclosporine A-related neurotoxicity\n\nPatient number\t#1\t#2\t#3\t#4\t#5\t#6\t#7\t\nDay of onset post-HSCT\t+ 38\t+ 161\t+ 24\t−3\t+ 1\t+ 46\t+ 137\t\nProdromes\tTransient headache, hypertension\tVomiting, transient headache, hypertension\tDysphoria, hypertension\tFatigue, hypertension, visual hallucination\tTransient headache, vomiting\tDysphoria, hypertension\tFatigue\t\nAcute symptoms\tPersistent headache, seizures\tStatus epilepticus, tremors, dysphagia, persistent headache\tStatus epilepticus, aphasia, tremors\tStatus epilepticus, visual disturbance, psychosis\tSeizures, visual disturbance, persistent headache\tStatus epilepticus\tSeizures\t\nCSA level at time of neurotoxicity (ng/mL)\t118.3\t110\t89.4\t68.3\t57.7\t67.2\t82.1\t\nMaximum trough CSA level before CSA-related neurotoxicity (ng/mL)\t307\t500\t135\t211\t107.8\t118\t584\t\nMost severe GvHD grade before CSA-related neurotoxicity\tGrade II, skin and gut\tGrade III, skin and gut\tGrade II, skin\tNo GvHD\tNo GvHD\tGrade III, gut\tGrade IV, gut\t\nImmune suppression after CSA-related neurotoxicity\tTacrolimus, MMF, CS, basiliximab\tTacrolimus, MMF, CS, basiliximab\tTacrolimus, MMF, CS, basiliximab\tTacrolimus, MMF\tTacrolimus\tTacrolimus, CS\tTacrolimus, MMF, CS, basiliximab\t\nAcute treatment for neurological symptoms\tDiazepam, midazolam,\tDiazepam, midazolam, trihexyphenidyl\tDiazepam, midazolam, sodium valproate, trihexyphenidyl\tDiazepam, midazolam, sodium valproate\tDiazepam, midazolam\tDiazepam, midazolam\tDiazepam, midazolam\t\nNeurological sequelae\tNone\tSecondary epilepsy\tSecondary epilepsy\tPsychosis\tNone\t–\tNone\t\nChronic treatment/duration\tNil\tOxcarbazepine/3 years\tOxcarbazepine/continuous\tRisperidone/2 years\tNone\t–\tNone\t\nOutcome/alast follow-up (days post-HSCT)\tAlive/+ 2023\tAlive/+ 1909\tAlive/+ 1818\tAlive /+ 1899\tAlive/+ 1798\tDead/+ 160\tAlive/+ 958\t\nCause of death/current complications\tSymptom-free\tSymptom-free\tSecondary epilepsy\tSymptom-free\tSymptom-free\tGrade IV GvHD\tSymptom-free\t\nCS Corticosteroids, CSA Cyclosporine A, GvHD Graft-versus-host disease, HSCT Hematopoietic stem cell transplantation, MMF Mycophenolate mofetil. aAs of 15 November 2018, except for patient #6 for whom the last follow-up was 29 May 2016\n\nOutcomes\n\nDeath occurred in 1 of the 7 patients with CSA-related neurotoxicity (patient #6), who developed grade IV GvHD and disseminated intravascular coagulation at 5 months post-HSCT and subsequently died from hemorrhagic shock and respiratory failure on day + 160 without neurological symptoms. The remaining 6 patients were alive at the last follow-up. Three of these 6 patients had neurological sequelae, including secondary epilepsy (patients #2 and #3) and psychosis (patient #4). The 2 patients with secondary epilepsy were administered oxcarbazepine, which was successfully withdrawn in patient #2 after 3 years. However, patient #3 required continuous treatment with the anti-epileptic agent because drug withdrawal for 3–6 months resulted in EEG abnormalities and seizure recurrence characterized by sensory disturbances. Patient #4 was given risperidone as an anti-psychotic agent and did not have symptom recurrence. Five patients were alive and symptom-free at a median follow-up of 61.9 (range, 31.9–67.4) months after HSCT (Table 3).\n\nRisk factors and prognosis\n\nUnivariate analysis revealed that the incidence of hypertension during treatment with CSA was significantly higher in the neurotoxicity group than in the non-neurotoxicity group (71% vs. 11%, P = 0.002; Table 4). However, there were no significant differences between groups with regard to age at HSCT, gender, underlying diseases, electrolyte imbalance, maximum CSA level, ABO blood type matching between donor and recipient, or gender matching between donor and recipient (Table 4). Treatment-related mortality (TRM) rates were 87.71 and 85.15% in the neurotoxicity (n = 7) and non-neurotoxicity (n = 44) groups, respectively, with no significant difference between the two groups (P = 0.93), as shown in Fig. 2. Table 4 Comparison of clinical characteristics between patients with cyclosporine A-related neurotoxicity and those without\n\nCharacteristic\tNeurotoxicity\tNon-neurotoxicity\tP\t\nNo. of patients\t7\t44\t\t\nMale gender, n (%)\t5 (72%)\t34 (78%)\t0.662\t\nAge at HID-HSCT (years), median (range)\t7 (1.6)\t8 (4.4)\t0.212\t\nUnderlying disease, n (%)\t\t\t0.221\t\n Acute leukemia\t6 (86%)\t38 (87%)\t\t\n Myelodysplastic syndrome\t1 (14%)\t1 (2%)\t\t\n Aplastic anemia\t0 (0%)\t5 (11%)\t\t\nState of underlying disease at HSCT, n (%)\t\t\t0.685\t\nComplete remission\t5 (72%)\t25 (57%)\t\t\nNot in remission\t2 (28%)\t19 (43%)\t\t\nHypertension after CSA, n (%)\t5 (71%)\t5 (11%)\t0.002\t\nElectrolyte imbalance, n (%)\t\t\t\t\n Hyponatremia\t3 (43%)\t7 (16%)\t0.095\t\n Hypokalemia\t6 (86%)\t33 (75%)\t0.223\t\n Hypocalcemia\t5 (71%)\t18 (41%)\t0.221\t\n Hypomagnesemia\t2 (29%)\t10 (23%)\t0.662\t\nMaximum trough CSA level > 250 ng/mL, n (%)\t3 (43%)\t12 (27%)\t0.406\t\nABO blood type of donor and recipient, n (%)\t\t\t0.427\t\n Matched\t3 (43%)\t27 (61%)\t\t\n Mismatched\t4 (57%)\t17 (39%)\t\t\nGender of donor and recipient, n (%)\t\t\t0.923\t\n Matched\t3 (43%)\t18 (41%)\t\t\n Mismatched\t4 (57%)\t26 (59%)\t\t\nAcute GvHD, n (%)\t\t\t0.300\t\n Yes\t5 (72%)\t38 (86%)\t\t\n No\t2 (28%)\t6 (14%)\t\t\nCSA Cyclosporine A, HID-HSCT Haploidentical hematopoietic stem cell transplantation, SD Standard deviation, GvHD Graft-versus-host disease\n\nFig. 2 Kaplan-Meier analysis of treatment-related mortality (TRM) in the neurotoxicity and non-neurotoxicity groups. TRM rates were 87.71 and 85.15% in the neurotoxicity (n = 7) and non-neurotoxicity (n = 44) groups, respectively, with no significant difference between the two groups (P = 0.93)\n\nDiscussion\n\nA notable finding of this study was that 13.7% of children who underwent HID-HSCT for hematopathy developed CSA-related neurotoxicity after a median 38 days. Furthermore, 6 of the 7 patients with CSA-related neurotoxicity had MRI features consistent with PRES, although 1 patient exhibited atypical abnormalities. Hypertension was the most common prodrome, occurring in 71% of those who developed CSA-related neurotoxicity. Importantly, hypertension during prophylaxis with CSA was more common in patients with CSA-related neurotoxicity than in those without neurotoxicity (71% vs. 11%). Our findings indicate that CSA-related neurotoxicity is not uncommon in children with hematopathy undergoing HID-HSCT. Furthermore, blood pressure should be carefully evaluated during the early post-transplantation period, since hypertension was the most common prodrome and the only factor in our analysis that differed significantly between patients with CSA-related neurotoxicity and those without.\n\nIn this case series, the incidence of CSA-related neurotoxicity was 13.7% in children with hematological malignancies or aplastic anemia treated with HID-HSCT. This incidence was higher than 4.7% reported by a previous Italian multi-center retrospective study [20]. This might be based on the following reasons. On the one hand, the patients in the Italian study mostly had nonmalignant hematological diseases, and previous studies have suggested that the incidence of CSA-related neurotoxicity after HSCT is higher in patients with malignant disorders (9–28.8%) compared with those with nonmalignant disorders (4–11%) [14, 21]. On the other hand, transplantation was mostly HLA-matched allo-HSCT and autologous HSCT in Zama et al. [20], while HLA-unmatched HSCT is considered a risk factor for PRES [22]. In addition, the incidence of CSA-related neurotoxicity may be associated with donor type. For example, Faraci et al. reported that the rate of neurological complications varied with the source of stem cells (27.1% for cells from unrelated donors, 13.9% for cells from related donors, and 2.3% for autologous cells) [11]. Similarly, Koh et al. described neurotoxicity rates of 18.0% for unrelated donors, 11.1% for mismatched related donors and 3.3% for matched related donors [10]. Moreover, Elgarten et al. reported no cases of calcineurin inhibitor-related neurotoxicity in pediatric patients with malignant and nonmalignant diseases who underwent HSCT with matched sibling donors [23]. Since Zimmer et al. also found that the frequency of CSA-related neurotoxicity increased with greater HLA disparity between donor and recipient [24], it is likely that our rate of 13.7% would be higher than that for children who receive HSCT from HLA-matched siblings.\n\nSeveral factors may be associated with a higher incidence of CSA-related neurotoxicity in pediatric patients who undergo HID-HSCT. First, patients with GvHD above grade II may be at an increased risk of neurotoxicity [25]. Second, CSA-related neurotoxicity is more likely to occur in patients undergoing HSCT from unrelated or unmatched donors [26], which in part may be due to differences in GvHD incidence and severity. Third, the use of intravenous busulfan in the preparative regimen can induce seizures, and this may play a role in the subsequent appearance of CSA-related neurotoxicity [14]. Fourth, younger children (< 6 years of age) tend to suffer more severe seizures in the acute stage than older patients and are relatively more likely to develop epilepsy and neurotoxicity disorders in the future [19]. The vertebrobasilar circulation in children has reduced adrenergic innervation [27], and is less tolerant to changes in arterial blood pressure [28]. Therefore, young children may be particularly susceptible to CSA-related neurotoxicity. Fifth, there is evidence that hypertension may be associated with CSA-related neurotoxicity. For example, hypertension has been reported as a prodrome to CSA-related neurotoxicity in 83% [14] and 46% [29] of patients, which is broadly comparable to our finding that 71% of patients exhibited hypertension as a prodrome. Furthermore, hypertension after CSA treatment was the only factor in our analysis associated with an increased risk of CSA-related neurotoxicity.\n\nNeuroimaging now plays a central role in the diagnosis and long-term follow-up of CSA-related neurotoxicity. CT is typically the first tool used to investigate patients with acute neurological disorders, but this imaging technique identifies lesions in only about 50% of PRES cases [30]. Since children receiving transplants can present with a wide spectrum of acute neurologic complications, MRI-based evaluation is essential for the accurate diagnosis of PRES. DWI and ADC maps can help to distinguish vasogenic edema from cytotoxic edema [31]. Vasogenic edema typically presents as hyperintensity on ADC and isointensity or hypointensity on DWI, while cytotoxic edema usually manifests as hypointensity on ADC and hyperintensity on DWI [32]. Although CSA-related neurotoxic events are typically thought to be confined to fluid extravasation, more severe endothelial damage has been reported, including erythrocyte extravasation with parenchymal hemorrhage [33]. Cerebral hemorrhage is associated with PRES in 5–19% of cases [34], which might explain the focal hemorrhages observed in the MRI scans of patient #4 in our study.\n\nThe clinical and imaging manifestations of PRES are reversible in the majority of patients (70%) provided CSA is promptly reduced in dosage or withdrawn, but a delay in the diagnosis and treatment of PRES can result in irreversible neurological damage [33]. Karia et al. reported a strong association between MRI severity and clinical outcome [35]. Furthermore, children with persistent EEG or imaging abnormalities have been reported to be at higher risk of seizure recurrence following CSA-related neurotoxicity [36]. Cerebral hyperperfusion due to hypertension and aggravation of vascular endothelial injury may be important mechanisms by which CSA increases the permeability of the blood-brain barrier [37]. Irrespective of the underlying pathology, MRI and electroencephalography can be extremely useful for the detection of lesions due to CSA-related neurotoxicity and the long-term follow-up of patients with persistent abnormalities. In the present study, three patients with persistent EEG or imaging abnormalities had neurological sequelae. However, two patients subsequently recovered, and the symptoms in the other patient were controlled after standardized treatment.\n\nIn the case of severe hypertension during the acute phase of neurotoxicity, arterial blood pressure should be reduced by ∼25% within the first hour (after the exclusion of cerebral infarction) and then more slowly [38]. CSA should be discontinued following the occurrence of neurotoxicity, and tacrolimus is the most commonly used alternative agent in the event of CSA-related neurotoxicity [13, 34, 39]. Although tacrolimus is also associated with neurotoxicity [13, 39], it did not produce neurological adverse effects in this series of patients. Anti-convulsive therapy should be administered as early as possible to control ongoing seizures. Prolonged prophylactic treatment with anti-epileptic drugs is unnecessary in patients with occasional or provoked seizures due to CSA-related neurotoxicity, but such drugs should be considered in cases with later development of secondary epilepsy [34]. In the present study, 1 of the 7 patients with CSA-related neurotoxicity (14%) required long-term anti-convulsive therapy.\n\nThe 5-year OS rate for the pediatric patients who developed CSA-related neurotoxicity after HID-HSCT was not significantly different to that for the patients who did not exhibit neurotoxicity. This is a promising finding, as it suggests that appropriate detection and intervention can ameliorate the long-term consequences of these relatively common adverse events.\n\nThis study has some limitations. First, this was a retrospective analysis, so the results are prone to information bias and selection bias. In addition, the rate of hypertension could be underestimated in control patients. Second, this was a single-center study, so the generalizability of the findings is not known. Third, the sample size was small, so the study may have been underpowered to detect some real differences between groups. Fourth, unknown confounding factors may have influenced the analysis. Fifth, CSA-related neurotoxicity was diagnosed on the basis of clinical and radiological findings, but it is possible that some mild cases may have been missed, leading to an underestimation of the incidence.\n\nConclusion\n\nThere is a relatively high incidence of CSA-related neurotoxicity in children with hematological disorders undergoing HID-HSCT. Awareness of the clinical features of CSA-related neurotoxicity (particularly hypertension) can facilitate rapid diagnosis and timely implementation of appropriate interventions. Moreover, patients with persistent EEG or imaging abnormalities can benefit from MRI and EEG examinations as part of their long-term follow-up program.\n\nAbbreviations\n\nADC Apparent diffusion coefficient\n\nCSA Cyclosporine A\n\nCT Computed tomography\n\nDWI Diffusion weighted imaging\n\nGvHD Graft-versus-host disease\n\nEEG Electroencephalogram\n\nHID-HSCT Haploidentical hematopoietic stem cell transplantation\n\nMRI Magnetic resonance imaging\n\nOS Overall survival\n\nPRES Posterior reversible encephalopathy syndrome\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nYW, TY, JH conceived and designed the experiments. YW, YZ, JR, XY, TY performed the experiments. YW, YZ, JW analyzed and interpreted the data. YW wrote the manuscript. JH critically revised manuscript. All authors read and approved the manuscript.\n\nFunding\n\nThis study was supported by Construction Project of Fujian Medical Center of Hematology (grant number Min201704) and Startup Fund for scientific research, Fujian Medical University (grant number 2019QH1032).\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was approved by the Ethics Committee of Fujian Medical University Union Hospital (No. 2020ky043) and waived the requirement for informed consent because the analysis was retrospective.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nYong Wang and Yongzhi Zheng contributed equally to this work.\n==== Refs\nReferences\n\n1. Xu L Chen H Chen J Han M Huang H Lai Y The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology J Hematol Oncol 2018 11 1 33 10.1186/s13045-018-0564-x 29495966\n2. Lv M Chang Y Huang X Everyone has a donor: contribution of the Chinese experience to global practice of haploidentical hematopoietic stem cell transplantation Front Med 2019 13 1 45 56 10.1007/s11684-017-0595-7 29675688\n3. Sun YQ Chang YJ Huang XJ Update on current research into haploidentical hematopoietic stem cell transplantation Expert Rev Hematol 2018 11 4 273 284 10.1080/17474086.2018.1447379 29493370\n4. Kurosawa S Oshima K Yamaguchi T Yanagisawa A Fukuda T Kanamori H Quality of life after allogeneic hematopoietic cell transplantation according to affected organ and severity of chronic graft-versus-host disease Biol Blood Marrow Transplant 2017 23 10 1749 1758 10.1016/j.bbmt.2017.06.011 28669922\n5. Huang K Li Y Huang SL Fang JP Zhou DH Chen C Prophylaxis and treatment of chronic graft versus host disease Zhonghua Er Ke Za Zhi 2005 43 174 177 15833186\n6. Hamilton BK Current approaches to prevent and treat GVHD after allogeneic stem cell transplantation Hematol Am Soc Hematol Educ Program 2018 2018 1 228 235 10.1182/asheducation-2018.1.228\n7. Dulamea AO Lupescu IG Neurological complications of hematopoietic cell transplantation in children and adults Neural Regen Res 2018 13 6 945 954 10.4103/1673-5374.233431 29926815\n8. Fu R Tajima S Suetsugu K Watanabe H Egashira N Masuda S Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation Acta Pharmacol Sin 2019 40 2 151 159 10.1038/s41401-018-0070-2 29950613\n9. Woo M Przepiorka D Ippoliti C Warkentin D Khouri I Fritsche H Toxicities of tacrolimus and cyclosporin a after allogeneic blood stem cell transplantation Bone Marrow Transplant 1997 20 12 1095 1098 10.1038/sj.bmt.1701027 9466284\n10. Koh KN Park M Kim BE Im HJ Seo JJ Early central nervous system complications after allogeneic hematopoietic stem cell transplantation in children Kor J Hematol 2010 45 3 164 170 10.5045/kjh.2010.45.3.164\n11. Faraci M Lanino E Dini G Fondelli MP Morreale G Dallorso S Severe neurologic complications after hematopoietic stem cell transplantation in children Neurology. 2002 59 12 1895 1904 10.1212/01.WNL.0000036608.42104.B9 12499480\n12. Chohan R Vij R Adkins D Blum W Brown R Tomasson M Long-term outcomes of allogeneic stem cell transplant recipients after calcineurin inhibitor-induced neurotoxicity Br J Haematol 2003 123 1 110 113 10.1046/j.1365-2141.2003.04550.x 14510951\n13. Straathof K Anoop P Allwood Z Silva J Nikolajeva O Chiesa R Long-term outcome following cyclosporine-related neurotoxicity in paediatric allogeneic haematopoietic stem cell transplantation Bone Marrow Transplant 2017 52 1 159 162 10.1038/bmt.2016.232 27643866\n14. Noè A Cappelli B Biffi A Chiesa R Frugnoli I Biral E High incidence of severe cyclosporine neurotoxicity in children affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell transplantation: early diagnosis and prompt intervention ameliorates neurological outcome Ital J Pediatr 2010 36 1 14 10.1186/1824-7288-36-14 20181110\n15. Bartynski WS Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features AJNR Am J Neuroradiol 2008 29 6 1036 1042 10.3174/ajnr.A0928 18356474\n16. Stevens CJ Heran MK The many faces of posterior reversible encephalopathy syndrome Br J Radiol 2012 85 1020 1566 1575 10.1259/bjr/25273221 23175479\n17. Yang T Lin Q Ren J Chen P Yuan X Luo X A 5-day cytoreductive chemotherapy followed by haplo-identical hsct (FA5-BUCY) as a tumor-ablative regimen improved the survival of patients with advanced hematological malignancies Oncotarget. 2016 7 48 78773 78786 10.18632/oncotarget.12383 27705929\n18. Liu LS 2010 Chinese guidelines for the management of hypertension Zhonghua Xin Xue Guan Bing Za Zhi 2011 39 579 615 22088239\n19. Chen LW Chen JS Tu YF Wang ST Wang LW Tsai YS Age-dependent vulnerability of cyclosporine-associated encephalopathy in children Eur J Paediatr Neurol 2015 19 4 464 471 10.1016/j.ejpn.2015.02.003 25769225\n20. Zama D Gasperini P Berger M Petris M De Pasquale MD Cesaro S A survey on hematology-oncology pediatric AIEOP centres: the challenge of posterior reversible encephalopathy syndrome Eur J Haematol 2018 100 1 75 82 10.1111/ejh.12984 29032616\n21. Bartynski WS Zeigler ZR Shadduck RK Lister J Variable incidence of cyclosporine and FK-506 neurotoxicity in hematopoeitic malignancies and marrow conditions after allogeneic bone marrow transplantation Neurocrit Care 2005 3 1 33 45 10.1385/NCC:3:1:033 16159093\n22. Zama D Masetti R Cordelli DM Vendemini F Giordano L Milito G Risk factor analysis of posterior reversible encephalopathy syndrome after allogeneic hematopoietic SCT in children Bone Marrow Transplant 2014 49 12 1538 1540 10.1038/bmt.2014.182 25133894\n23. Elgarten CW, Arnold DE, Bunin NJ, Seif AE. Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease. Pediatr Blood Cancer. 2018;65(1). 10.1002/pbc.26726.\n24. Zimmer WE Hourihane JM Wang HZ Schriber JR The effect of human leukocyte antigen disparity on cyclosporine neurotoxicity after allogeneic bone marrow transplantation AJNR Am J Neuroradiol 1998 19 601 608 9576643\n25. Uckan D Cetin M Yigitkanli I Tezcan I Tuncer M Karasimav D Life-threatening neurological complications after bone marrow transplantation in children Bone Marrow Transplant 2005 35 1 71 76 10.1038/sj.bmt.1704749 15531898\n26. Zhong ZD Li L Wu YH You Y Li WM Zou P Analysis of seizure risk factors after allogeneic hematopoietic stem cell transplantation: a 8 case report and literature review J Huazhong Univ Sci Technolog Med Sci 2013 33 5 656 660 10.1007/s11596-013-1176-x 24142716\n27. Edvinsson L Owman C Sjöberg NO Autonomic nerves, mast cells, and amine receptors in human brain vessels. A histochemical and pharmacological study Brain Res 1976 115 3 377 393 10.1016/0006-8993(76)90356-5 184880\n28. Gottschalk S Cummins CL Leibfritz D Christians U Benet LZ Serkova NJ Age and sex differences in the effects of the immunosuppressants cyclosporine, sirolimus and everolimus on rat brain metabolism Neurotoxicology. 2011 32 1 50 57 10.1016/j.neuro.2010.10.006 21075140\n29. Luo XD Liu QF Ning J Fan ZP Xu D Wei YQ A clinical analysis of severe cyclosporine A-related neurotoxicity after allogenic hematopoietic stem cell transplantation Zhonghua Nei Ke Za Zhi 2008 47 40 43 18346325\n30. Roth C Ferbert A Posterior reversible encephalopathy syndrome: long-term follow-up J Neurol Neurosurg Psychiatry 2010 81 7 773 777 10.1136/jnnp.2009.189647 19955114\n31. Bartynski WS Boardman JF Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome AJNR Am J Neuroradiol 2007 28 7 1320 1327 10.3174/ajnr.A0549 17698535\n32. Fischer M Schmutzhard E Posterior reversible encephalopathy syndrome J Neurol 2017 264 8 1608 1616 10.1007/s00415-016-8377-8 28054130\n33. Magnasco A Rossi A Catarsi P Gusmano R Ginevri F Perfumo F Cyclosporin and organ specific toxicity: clinical aspects, pharmacogenetics and perspectives Curr Clin Pharmacol 2008 3 3 166 173 10.2174/157488408785747674 18781903\n34. Masetti R Cordelli DM Zama D Vendemini F Biagi C Franzoni E PRES in children undergoing hematopoietic stem cell or solid organ transplantation Pediatrics. 2015 135 5 890 901 10.1542/peds.2014-2325 25917987\n35. Karia SJ Rykken JB McKinney ZJ Zhang L McKinney AM Utility and significance of gadolinium-based contrast enhancement in posterior reversible encephalopathy syndrome AJNR Am J Neuroradiol 2016 37 3 415 422 10.3174/ajnr.A4563 26564441\n36. Gleeson JG du Plessis AJ Barnes PD Riviello JJ Jr Cyclosporin a acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence J Child Neurol 1998 13 7 336 344 10.1177/088307389801300706 9701483\n37. Bartynski WS Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema AJNR Am J Neuroradiol 2008 29 6 1043 1049 10.3174/ajnr.A0929 18403560\n38. Servillo G Bifulco F De Robertis E Piazza O Striano P Tortora F Posterior reversible encephalopathy syndrome in intensive care medicine Intensive Care Med 2007 33 2 230 236 10.1007/s00134-006-0459-0 17119920\n39. Ayas M Al-Jefri A Al-Seraihi A In cyclosporine induced neurotoxicity, is tacrolimus an appropriate substitute or is it out of the frying pan and into the fire? Pediatr Blood Cancer 2008 50 2 426 10.1002/pbc.21211 17427233\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1720-8424",
"issue": "47(1)",
"journal": "Italian journal of pediatrics",
"keywords": "Child; Cyclosporine a; Hematopathy; Hematopoietic stem cell transplantation; Neurotoxicity syndrome",
"medline_ta": "Ital J Pediatr",
"mesh_terms": "D000293:Adolescent; D001927:Brain Diseases; D065095:Calcineurin Inhibitors; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine; D004827:Epilepsy; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "101510759",
"other_id": null,
"pages": "83",
"pmc": null,
"pmid": "33794964",
"pubdate": "2021-04-01",
"publication_types": "D016428:Journal Article",
"references": "184880;25917987;26564441;9701483;17698535;21075140;29493370;22088239;17427233;18356474;21120204;29926815;15833186;29950613;17119920;27705929;29495966;12499480;14510951;25769225;9576643;9466284;23175479;24142716;27643866;28054130;18346325;20181110;30504315;28669922;18403560;16159093;29675688;15531898;19955114;25133894;28748621;29032616;18781903",
"title": "Cyclosporine A-related neurotoxicity after haploidentical hematopoietic stem cell transplantation in children with hematopathy.",
"title_normalized": "cyclosporine a related neurotoxicity after haploidentical hematopoietic stem cell transplantation in children with hematopathy"
} | [
{
"companynumb": "CN-TEVA-2021-CN-1914788",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1",
... |
{
"abstract": "This is a case of recurrent intravascular leiomyomatosis in a pre-menopausal woman of African-Caribbean heritage. She presented in 2006 with multiple uterine leiomyomata, tumour invading the inferior vena cava (IVC) extending into the right atrium, and pulmonary metastases. Her initial presentation was treated surgically. On recurrence she was treated by oestrogen suppression using a combination of goserelin and letrozole, with a substantial response. She subsequently reported further regression of disease following exposure to strong sunlight enabling her to discontinue oestrogen suppression without relapse. The hypothesis is that the benefit was due to vitamin D. The role of hypovitaminosis D in the pathogenesis of uterine leiomyomata is discussed, including epidemiology data demonstrating a link between ethnicity and risk and the proven mechanisms by which vitamin D controls oestrogen and progesterone receptor expression and influences other signalling pathways involved in the pathogenesis of leiomyomas. Data indicating the intermediate malignancy nature of intravascular leiomyomatosis, are discussed. We are not aware of other reports indicating a link between intravascular leiomyomatosis and a lack of vitamin D.",
"affiliations": "The Institute of Cancer Research, Fulham Rd, London SW3 6JB, UK.;The Royal Marsden NHS Foundation Trust, Fulham Rd, London SW3 6JJ, UK.",
"authors": "Judson|Ian|I|;Messiou|Christina|C|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2020.100681",
"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 Elsevier \n\nS2352-5789(20)30147-8\n10.1016/j.gore.2020.100681\n100681\nCase Report\nVitamin D deficiency in the pathogenesis of leiomyoma and intravascular leiomyomatosis: A case report and review of the literature\nJudson Ian Ian.Judson@icr.ac.uka⁎ Messiou Christina b a The Institute of Cancer Research, Fulham Rd, London SW3 6JB, UK\nb The Royal Marsden NHS Foundation Trust, Fulham Rd, London SW3 6JJ, UK\n⁎ Corresponding author. Ian.Judson@icr.ac.uk\n13 12 2020 \n2 2021 \n13 12 2020 \n35 1006815 8 2020 1 12 2020 6 12 2020 © 2020 The Authors. Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Epidemiologic link between vitamin D deficiency and ethnicity.\n\n• Link between vitamin D deficiency and leiomyoma.\n\n• Impact of vitamin D on estrogen receptor expression.\n\n• Vitamin D supplementation by sunbed use.\n\n• Previously unreported link between vitamin D and intravascular leiomyomatosis.\n\n\n\nThis is a case of recurrent intravascular leiomyomatosis in a pre-menopausal woman of African-Caribbean heritage. She presented in 2006 with multiple uterine leiomyomata, tumour invading the inferior vena cava (IVC) extending into the right atrium, and pulmonary metastases. Her initial presentation was treated surgically. On recurrence she was treated by oestrogen suppression using a combination of goserelin and letrozole, with a substantial response. She subsequently reported further regression of disease following exposure to strong sunlight enabling her to discontinue oestrogen suppression without relapse. The hypothesis is that the benefit was due to vitamin D. The role of hypovitaminosis D in the pathogenesis of uterine leiomyomata is discussed, including epidemiology data demonstrating a link between ethnicity and risk and the proven mechanisms by which vitamin D controls oestrogen and progesterone receptor expression and influences other signalling pathways involved in the pathogenesis of leiomyomas. Data indicating the intermediate malignancy nature of intravascular leiomyomatosis, are discussed. We are not aware of other reports indicating a link between intravascular leiomyomatosis and a lack of vitamin D.\n\nAbbreviations\nER, oestrogen receptorPgR, progesterone receptorSMA, smooth muscle actin\n==== Body\n1 Case report\nHerein we report a case of strong sunlight, supplemented with oral vitamin D3, causing stabilisation of uterine leiomyomas permitting withdrawal of oestrogen suppression therapy in a patient with uterine leiomyomas and intravascular leiomyomatosis.\n\nA pre-menopausal woman of African-Caribbean heritage presented in 2006, at the age of 36, with pulmonary embolus, an intracardiac mass tumour thrombus extending from the pelvis up the inferior vena cava (IVC) to the right ventricle. She also had uterine leiomyomas. The intravascular tumour was resected on cardio-pulmonary bypass by a cardiothoracic surgeon and an abdominal surgeon with special expertise in renal surgery. The majority of the tumour was pulled out from the right ventricle as it was quite mobile. However an incision was also made in the IVC from the level of the left renal vein to remove the mass from the left renal vein and an incision was also made in the left renal vein itself. There was a small amount of tumour in the left ovarian vein and therefore the left ovarian vein was removed. The uterus, fallopian tubes and ovaries were not resected because the patient was unwilling to be rendered infertile. The histology of the mass removed from the right ventricle was reported as benign leiomyoma. Fig. 1A, Fig. 1B shows haematoxylin and eosin (H&E) a stained section of the resected specimen at two different magnifications. It was reported as follows: “Sections show an encapsulated, elongated spindle cell tumour with large areas of infarction. The tumour is composed of bland spindle cells arranged in loose fascicles, and admixed with thick-walled blood vessels, few of which show hyalinization. Myxoid change is noted focally, mitoses and nuclear pleomorphism is not seen. The tumours cells stain for ER, PgR, desmin, SMA, Bcl-2 and caldesmon and are negative for S100, CD34, CD117, calretinin, AE1/3 and HMB45.” We also note the presence of clear cells and both this and hyalinisation have been reported in intravascular leiomyomatosis together with the suggestion that the appearances of intravascular leiomyomatosis differ somewhat from benign leiomyoma (Han et al., 1998, Yaguchi et al., 2010).Fig. 1A H&E stained section of resected tumour from the right ventricle at 10X magnification showing a large thick-walled blood vessel, spindle cells loosely packed in a myxoid stroma. No mitoses are seen.\n\nFig. 1B Part of the same section is shown at 20x magnification.\n\n\n\nNo prophylaxis was offered following surgery and the patient was lost to follow-up. She re-presented in 2009 with large pelvic and abdominal masses (Fig. 2a), lung nodules (Fig. 2b) and a suspicion of recurrence in the IVC indicating a diagnosis of intravascular leiomyomatosis. The following year in 2010 a cardiac MRI scan confirmed the presence of tumour in the IVC and right atrium. Treatment with a combination of goserelin and letrozole was commenced in August 2010 resulting in a rapid reduction in the size of pelvic and abdominal leiomyomas (Fig. 3A and B), a slight reduction in the size of pulmonary metastases was also seen together with regression of disease in the IVC on cardiac MRI.Fig. 2 Axial contrast enhanced CT abdomen & pelvis performed in 2009 demonstrates large uterine leiomyomata (A) and pulmonary nodules (arrow B).\n\nFig. 3 Coronal CT reformat from a contrast enhanced CT performed in July 2010 (A), September 2010 (B) and 2012 (C) shows shrinkage of the masses.\n\n\n\nThere was a further slight reduction in the volume of intra-abdominal disease (Fig. 3C) in 2011. However, the patient was increasingly distressed by the side effects of oestrogen suppression, particularly by insomnia and reduced libido and discontinued treatment to relieve these symptoms in 2012. A CT in March 2013 showed slight progression in both the pelvic and abdominal disease and lung metastases. In June 2013 a repeat CT showed a further increase in the size of the pelvic disease and a cardiac MRI and echocardiogram showed possible recurrent disease in the IVC. Ulipristal acetate was commenced in March 2013 but has since been discontinued. Letrozole and goserelin treatment was recommenced in October 2013 and continued until 2015.\n\nAt an out-patient visit in August 2015 she reported that during a trip to the Southern USA in February 2013 to visit a relative, during which she had much more exposure to sunlight than in the UK, she experienced a significant reduction in the size of the abdominal masses and the associated abdominal bloating and discomfort. She was also taking oral vitamin D3 supplements in the form of cod liver oil and vitamin D3. Following this experience, noting that her tumours were smaller in the Summer, during the year 2015 she started regularly using a sunbed twice a week, when access to strong sunshine was not possible. She continued to take cod liver oil and vitamin D3. This combined strategy proved successful and she was able to stop the letrozole and goserelin in 2015 without suffering a relapse. Vitamin D blood levels were not examined following this new information, because we had no baseline prior to the start of self-medicated vitamin D supplementation. Fig. 4 shows a comparison between a representative tumour in 2013 and the same tumour in 2015 showing a small reduction in tumour volume. The patient remains well to this day with stable disease by RECIST, although a more recent scan may show slight progression, and has not needed to recommence treatment with letrozole and goserelin in the last 5 years.Fig. 4 Axial T2W MRI in 2013 (A) and 2015 (B) showing a large soft tissue mass centred on the uterus (*). Maximum axial dimension in 2013 was 24.2 × 13.9 cm compared with 22.4 × 12.2 cm in 2015.\n\n\n\n2 Discussion\nUterine leiomyomas (fibroids) are extremely common. It is estimated that by the age of 50, nearly 70% of white women and >80% of African-American women will have ultrasound evidence of uterine fibroids. A recent study demonstrated a link between low blood levels of 25-hydroxyvitamin D (<20 ng/ml) and an increased risk of leiomyomata (Han et al., 1998). A study in Italy reported similar findings, demonstrating that women with at least one uterine leiomyoma had a significantly lower blood level of 25-hydroxyvitamin D3. In this study 25-hydroxyvitamin D3 deficiency was defined as <10 ng/ml and this was associated with an odds ratio for leiomyoma of 2.4 (95% confidence interval 1.2–4.9, P-0.16) compared with controls (Yaguchi et al., 2010). An American nutrition survey African-American women were 10 times more likely to have low vitamin D levels than white women (Baird et al., 2013). The increased incidence of uterine leiomyomas in African–American women has been identified as a public health issue (Eltoukhi et al., 2014; Paffoni et al., 2013). It has been shown that 1–25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates the expression of oestrogen and progesterone receptors in uterine leiomyoma cells (Al-Hendy et al., 2015; Nesby-O'Dell et al., 2002). Treating these cells with 1,25(OH)2D3 reduced the expression of oestrogen receptor-α, progesterone receptor-A and B and members of the steroid receptor coactivator (SRC) family. In addition, 1,25(OH)2D3 also reduces TGFβ3- induced fibrosis-related gene expression, e.g. collagen and fibronectin genes, in uterine leiomyoma cells (Halder et al., 2011; Sharan et al., 2011). Vitamin D3 has also been shown to inhibit the proliferation of uterine leiomyoma cells via inhibition of catechol-o-methyltransferase (Al-Hendy et al., 2016) and to inhibit WNT/β-catenin and mTOR signalling pathways in uterine leiomyoma cells (Ciavattini et al., 2016). There is a strong case for considering vitamin D supplementation in women of reproductive age and hypovitaminosis D as a preventive measure and some evidence that this can prevent the progression of pre-existing uterine leiomyomas (Ordulu et al., 2016).\n\n3 Conclusions\nThe role of vitamin D in the pathogenesis of leiomyomas is still not universally recognised by gynecologists. Hypovitaminosis D is a significant problem in women of darker skin ethnicity living in Northern climates, since they require greater sun exposure to generate sufficient vitamin D in the skin, sometimes compounded by cultural factors. This case highlights the potential value of sunlight and vitamin D supplementation in controlling leiomyomas. What is particularly unusual is the fact that this woman was diagnosed with the potentially life-threatening situation of intravascular leiomyomatosis with tumour extending up the IVC into the right atrium prior to successful treatment with combined oestrogen deprivation. This is now recognised to be a disease of intermediate grade malignancy as reported by Ordulu et al. (2016), with a gene expression profile similar to that of leiomyosarcoma, rather than leiomyoma or normal myometrium and the frequent finding of a translocation der[14]t[12;14](q14.3;q24) as shown by co-localization of probes for HMGA2 (12q14.3) and 14q24 by FISH. In contrast, this study also showed no evidence in the intravenous leiomyomatosis cases of loss of 7q22, frequently deleted in uterine leiomyomata. This case is by no means proof, but it seems likely that this condition is also influenced by the same hormonal factors as common leiomyomas and hence its growth is potentially enhanced by lack of vitamin D and impeded by repletion.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nAuthorship\nBoth authors contributed to the manuscript, IJ was mainly responsible for the case report and discussion and was the physician who initially cared for the patient. CM was responsible for the choice and presentation of the images. Both authors reviewed the final manuscript.\n\nDeclaration of Competing Interest\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nFunding acknowledgements\nWe wish to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre, Clinical Research Facility in Imaging and the Cancer Research Network. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health.\n==== Refs\nReferences\nAl-Hendy A. Diamond M.P. El-Sohemy A. Halder S.K. 1,25-Dihydroxyvitamin D3 regulates expression of sex steroid receptors in human uterine fibroid cells J. Clin. Endocrinol. Metabol. 100 4 2015 E572 E582 10.1210/jc.2014-4011 \nAl-Hendy A. Diamond M.P. Boyer T.G. Halder S.K. Vitamin D3 inhibits Wnt/β-catenin and mTOR signaling pathways in human uterine fibroid cells J. Clin. Endocrinol. Metab. 101 4 2016 1542 1551 26820714 \nBaird D.D. Hill M.C. Schectman J.M. Hollis B.W. Vitamin D and the risk of uterine fibroids Epidemiology 24 3 2013 447 453 10.1097/EDE.0b013e31828acca0 23493030 \nCiavattini A. Delli Carpini G. Serri M. Vignini A. Sabbatinelli J. Tozzi A. Aggiusti A. Clemente N. Hypovitaminosis D and “small burden” uterine fibroids: Opportunity for a vitamin D supplementation Medicine 95 52 2016 e5698 10.1097/MD.0000000000005698 28033263 \nEltoukhi H.M. Modi M.N. Weston M. Armstrong A.Y. Stewart E.A. The health disparities of uterine fibroid tumors for African American women: a public health issue Am. J. Obstetr. Gynecol. 210 3 2014 194 199 10.1016/j.ajog.2013.08.008 \nHalder S.K. Goodwin J.S. Al-Hendy A. 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells J. Clin. Endocrinol. Metab. 96 4 2011 E754 E762 21289245 \nHan H.S. Park I.A. Kim S.H. Lee H.P. The clear cell variant of epithelioid intravenous leiomyomatosis of the uterus: report of a case Pathol Int. 48 11 1998 892 896 9832059 \nNesby-O’Dell S. Scanlon K.S. Cogswell M.E. Gillespie C. Hollis B.W. Looker A.C. Allen C. Doughertly C. Gunter E.W. Bowman B.A. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994 Am. J. Clin. Nutr. 76 1 2002 187 192 12081833 \nOrdulu Z. Nucci M.R. Dal Cin P. Hollowell M.L. Otis C.N. Hornick J.L. Park P.J. Kim T.-M. Quade B.J. Morton C.C. Intravenous leiomyomatosis: an unusual intermediate between benign and malignant uterine smooth muscle tumors Mod. Pathol. 29 5 2016 500 510 10.1038/modpathol.2016.36 26892441 \nPaffoni A. Somigliana E. Vigano' P. Benaglia L. Cardellicchio L. Pagliardini L. Papaleo E. Candiani M. Fedele L. Vitamin D status in women with uterine leiomyomas J. Clin. Endocrinol. Metabol. 98 8 2013 E1374 E1378 10.1210/jc.2013-1777 \nSharan C. Halder S.K. Thota C. Jaleel T. Nair S. Al-Hendy A. Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase Fertility Sterility 95 1 2011 247 253 10.1016/j.fertnstert.2010.07.1041 20736132 \nYaguchi C. Oi H. Kobayashi H. Miura K. Kanayama N. A case of intravenous leiomyomatosis with high levels of hyaluronan J. Obstet. Gynaecol. Res. 36 2 2010 454 458 20492407\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "35()",
"journal": "Gynecologic oncology reports",
"keywords": "ER, oestrogen receptor; PgR, progesterone receptor; SMA, smooth muscle actin",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "100681",
"pmc": null,
"pmid": "33364287",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "21289245;28033263;20492407;23493030;26820714;26892441;23824422;9832059;12081833;25625804;23942040;20736132",
"title": "Vitamin D deficiency in the pathogenesis of leiomyoma and intravascular leiomyomatosis: A case report and review of the literature.",
"title_normalized": "vitamin d deficiency in the pathogenesis of leiomyoma and intravascular leiomyomatosis a case report and review of the literature"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-280346",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"druga... |
{
"abstract": "Exposure to propylthiouracil in early pregnancy may be associated with an increased risk of birth defects. But the spectrum of associated congenital anomalies is not yet well defined. While preliminary reports suggest that most cases of propylthiouracil-associated birth defects are restricted to the preauricular and urinary systems, careful consideration should be given to other possible manifestations of teratogenicity. We propose that congenital bands may potentially represent a rare yet serious complication of propylthiouracil exposure in early pregnancy, possibly arising from an early mesenteric developmental anomaly. We report a case of a 17-day-old girl that presented with acute small bowel obstruction associated with intestinal malrotation arising from several anomalous congenital bands. Her mother was treated for Graves' disease during pregnancy with first trimester exposure to propylthiouracil but remained clinically and biochemically euthyroid at conception and throughout the duration of pregnancy. This case suggests that the use of propylthiouracil in early pregnancy may be associated with congenital bands and intestinal malrotation. More reports are needed to further support this association.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada T2T 5C7.;Division of Endocrinology and Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada T2T 5C7.;Division of Endocrinology and Metabolism, Department of Pediatrics, University of Calgary, Calgary, AB, Canada T3B 6A9.;Division of Pediatric Surgery, Department of Surgery, University of Calgary, Calgary, AB, Canada T3B 6A9.;Division of Endocrinology and Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada T2T 5C7.",
"authors": "Leung|Alexander A|AA|;Yamamoto|Jennifer|J|;Luca|Paola|P|;Beaudry|Paul|P|;McKeen|Julie|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/789762",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi Publishing Corporation 10.1155/2015/789762Case ReportCongenital Bands with Intestinal Malrotation after Propylthiouracil Exposure in Early Pregnancy Leung Alexander A. \n1\nYamamoto Jennifer \n1\nLuca Paola \n2\nBeaudry Paul \n3\nMcKeen Julie \n1\n\n*\n1Division of Endocrinology and Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada T2T 5C72Division of Endocrinology and Metabolism, Department of Pediatrics, University of Calgary, Calgary, AB, Canada T3B 6A93Division of Pediatric Surgery, Department of Surgery, University of Calgary, Calgary, AB, Canada T3B 6A9*Julie McKeen: julie.mckeen@albertahealthservices.caAcademic Editor: Yuji Moriwaki\n\n2015 18 11 2015 2015 78976215 9 2015 11 11 2015 Copyright © 2015 Alexander A. Leung et al.2015This 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.Exposure to propylthiouracil in early pregnancy may be associated with an increased risk of birth defects. But the spectrum of associated congenital anomalies is not yet well defined. While preliminary reports suggest that most cases of propylthiouracil-associated birth defects are restricted to the preauricular and urinary systems, careful consideration should be given to other possible manifestations of teratogenicity. We propose that congenital bands may potentially represent a rare yet serious complication of propylthiouracil exposure in early pregnancy, possibly arising from an early mesenteric developmental anomaly. We report a case of a 17-day-old girl that presented with acute small bowel obstruction associated with intestinal malrotation arising from several anomalous congenital bands. Her mother was treated for Graves' disease during pregnancy with first trimester exposure to propylthiouracil but remained clinically and biochemically euthyroid at conception and throughout the duration of pregnancy. This case suggests that the use of propylthiouracil in early pregnancy may be associated with congenital bands and intestinal malrotation. More reports are needed to further support this association.\n==== Body\n1. Introduction\nAntithyroid drugs, such as propylthiouracil (PTU) and methimazole (MMI), are widely considered to be first line therapy in the treatment of hyperthyroidism in pregnancy [1–3]. Still, treatment is not without potential risk. The use of MMI in pregnancy has been associated with an increased risk of congenital anomalies [4–6]. PTU, on the other hand, may rarely cause severe maternal hepatotoxicity [3, 7]. In order to balance these risks, a number of expert panels, such as the American Thyroid Association and the Endocrine Society, have recommended treatment of hyperthyroidism during the first trimester of pregnancy with PTU to reduce the risk of teratogenicity to the fetus but recommended switching to MMI for the remainder of pregnancy to minimize unnecessary PTU exposure for the mother [1, 2].\n\nNotably, these recommendations were initially formed in response to studies linking MMI (but not PTU) exposure to a variety of birth defects. However, emerging evidence now suggests that PTU may not be as safe to fetal development as previously believed and may actually pose an increased risk of malformations as well [4, 8–10]. Preliminary data suggest that the congenital anomalies associated with PTU appear to be rare, less severe, and of a different spectrum compared to those associated with MMI and as such may be easily overlooked. Accordingly, there has been a call for more reports of possible cases of PTU-associated birth defects to better characterize this condition [8]. Herein, we report the first case of congenital bands resulting in intestinal malrotation in a neonatal girl following PTU exposure in early pregnancy.\n\n2. Case Presentation\nA 17-day-old girl presented to hospital with irritability, decreased appetite, and repeated bilious vomiting for a day. Examination revealed a tender and distended abdomen. A subsequent computed tomography scan of the abdomen with contrast revealed the presence of a high-grade small bowel obstruction with multiple dilated, fluid-filled loops of bowel in the proximal ileum, characterized by muscosal hypoenhancement. There also appeared to be a reversal of the relationship between the superior mesenteric artery and superior mesenteric vein, suggestive of an underlying rotational abnormality.\n\nAn emergency laparotomy was then performed. Upon entering the abdomen, the cecum and ascending colon were found to be loose without any obvious lateral attachments in keeping with a rotational abnormality. Further exploration revealed a necrotic, closed loop obstruction at the distal jejunum. Using gentle traction, this twisted segment was exteriorized and several congenital bands were noted. Ligation of the bands was performed and the bowel was detorted. The segment of necrotic bowel was then resected and a primary end-to-end anastomosis was performed. The remaining bowel was examined and no other anatomical abnormalities were found. The postoperative course was uneventful.\n\nThe patient is the first child of nonconsanguineous Sri Lankan parents, born at term by elective cesarean section, and was initially discharged home two days after birth in stable condition without any perinatal complications. Incidentally, a small (3 mm) ventricular septal defect was discovered on routine newborn examination and managed expectantly. She was initially breastfed and remained well until she eventually presented with a small bowel obstruction on day 17 of life, as described. Prior to this, she had no surgeries.\n\nNotably, during pregnancy, the child's mother, who was 29 years old, was treated for hyperthyroidism. She was diagnosed with Graves' disease 5 months before pregnancy and was initially treated with PTU 100 mg p.o. t.i.d. The dosage was reduced to 50 mg p.o. t.i.d. a month before conception; she continued on this same dose at conception and for the duration of the first trimester until the 14th week of gestation. Afterwards, MMI 5 mg p.o. q.d. was prescribed. She was clinically and biochemically euthyroid at the time of conception and thyroid function tests remained normal for the entire pregnancy. Immediately after birth, the patient's thyroid function was monitored closely because of her maternal history of Graves' disease. On the newborn screen (collected on the second day of life), her thyroid stimulating hormone (TSH) level was modestly elevated at 41 mIU/L. After two weeks, her TSH level remained elevated at 27.84 mIU/L but with a normal free T4 of 19.8 pmol/L. Although she remained well (and clinically euthyroid), levothyroxine replacement was initiated as a precaution with subsequent normalization of thyroid function tests soon thereafter.\n\nThere were no other significant maternal illnesses or medication exposures during pregnancy. The child had no other past medical history. There was no family history of any significant congenital birth defects.\n\n3. Discussion\nConcerns of potential teratogenicity of antithyroid drugs were initially raised in 1972 when the first report of aplasia cutis was noted in children born to mothers treated with MMI during pregnancy [11]. Since then, numerous reports and several large studies have emerged, confirming this association, as well as noting a number of other related birth defects (i.e., choanal atresia, esophageal atresia, and omphalocele), now collectively referred to as “methimazole embryopathy” [4–6]. Up until recently though, PTU was widely believed to pose no major threat to fetal development and was therefore recommended as the preferred therapy during the first trimester of pregnancy [1, 2]. However, this notion was challenged by a large Danish cohort study, which reported a higher prevalence of congenital malformations of the face, neck, and urinary systems in children exposed to PTU in early pregnancy [4]. When compared to the birth defects associated with MMI exposure, however, those associated with PTU appeared to largely involve different organ systems, tended to be less severe, and sometimes remained undiagnosed for longer periods of time [8].\n\nIndeed, both MMI and PTU freely cross the placenta and likely pose the greatest risk to fetal development during the first trimester of pregnancy (i.e., during the critical period of organogenesis) [3]. A recent review of 91 case reports of potential birth defects associated with antithyroid drug exposure in utero found that, with the exception of only two cases, nearly all the reports claimed antithyroid drug exposure between the 6th week and 10th week of gestation [9]. While the timing of medication exposure appears to be crucial, there has been no detectable association between the dose of antithyroid drug and the subsequent risk of malformation [6, 9]. Therefore, the most important considerations in identifying potential cases of PTU-associated birth defects are exposure to PTU during early pregnancy as well as biological plausibility.\n\nWe propose that congenital bands may potentially represent a rare yet serious complication of PTU exposure in early pregnancy. While most cases of intestinal obstruction in the pediatric population are from postoperative adhesions or stenosis, other causes should be considered in those without prior history of abdominal surgery [12]. Uncommonly, intestinal obstruction may be secondary to embryological remnants of the vitelline vessels, omphalomesenteric ducts, or mesourachus; these are typically recognized by their anatomical location [13]. Rarely, obstruction may be caused by anomalous congenital bands without apparent embryogenic origin [14–17]. While their etiology is not well understood, it has been suggested that these fibrous bands of tissue arise from a mesenteric anomaly occurring around the 4th week of gestation and are later associated with malrotation, anomalous intestinal fixation, and obstruction [14, 17]. In our case, we also found evidence of several anomalous congenital bands associated with an intestinal rotational abnormality resulting in complete obstruction, therefore raising the suspicion of an early mesenteric developmental abnormality. To date, no teratogen has yet been implicated in the development of congenital bands. Although hypothyroidism may rarely result in intestinal pseudoobstruction (i.e., paralytic ileus) [18], this did not appear to be a contributing factor in our patient, as she was euthyroid at the time and had a demonstrable anatomic reason for her obstruction.\n\nOf note, our patient was also incidentally found to have a small ventricular septal defect shortly after birth. Normally, the major septa of the heart are formed by the 5th week of fetal development. Incomplete closure of the interventricular septum may result in an isolated ventricular septal defect [19]. This condition is common and is estimated to be present in up to 5% of all newborns, and the vast majority close spontaneously without intervention [20]. Accordingly, multiple large studies have reported that the prevalence of ventricular septal defects among children exposed to PTU appears similar to those never exposed to any antithyroid drugs in utero [4, 7]. As such, it is unclear whether the presence of an incidental ventricular septal defect in our patient had any causal relationship with her prior exposure to PTU in early pregnancy at all.\n\nIt should be pointed out that thyrotoxicosis itself may be teratogenic [21]. Indeed, critics have raised concern that most of the previous large-scale studies showing an association between antithyroid drugs and congenital malformations have not consistently reported on maternal thyroid function [22–24]. As such, some have proposed that poorly controlled hyperthyroidism may be the underlying reason for the increased rate of congenital malformations rather than treatment itself [25]. However, the striking differences in the spectrum of birth defects associated with MMI compared to PTU argue that these congenital anomalies are more likely mediated by antithyroid drug exposure rather than abnormal maternal thyroid hormone levels [4]. In our case, specifically, we can confirm that maternal thyroid function was checked at least once each trimester and was normal at the time of conception and throughout the duration of the pregnancy.\n\nThe potential teratogenicity of PTU remains to be elucidated. While preliminary reports have suggested that most cases are mild in nature and are restricted to preauricular and urinary system malformations [4, 8, 9], careful consideration should also be given to other manifestations of disease that may potentially be more severe and possibly involve other organ systems too. Congenital bands may potentially represent a rare yet serious complication of PTU exposure in early pregnancy. More reports are needed to further support this association. This case report serves to alert clinicians of a potential new teratogenic association of PTU, thus prompting further confirmatory reports and future definitive studies.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthors' Contribution\nAll listed authors consented to the submission of this paper and meet criteria for authorship through conception (Alexander A. Leung and Julie McKeen), acquisition of data (Paul Beaudry, Paola Luca, and Julie McKeen), drafting of initial paper (Alexander A. Leung), critical revision for important intellectual content (Alexander A. Leung, Jennifer Yamamoto, Paola Luca, Paul Beaudry, and Julie McKeen), and supervision (Julie McKeen).\n==== Refs\n1 De Groot L. Abalovich M. Alexander E. K. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline Journal of Clinical Endocrinology and Metabolism 2012 97 8 2543 2565 10.1210/jc.2011-2803 2-s2.0-84864802168 22869843 \n2 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 10.1089/thy.2011.0087 2-s2.0-80053181984 21787128 \n3 Cooper D. S. Laurberg P. Hyperthyroidism in pregnancy The Lancet Diabetes and Endocrinology 2013 1 3 238 249 10.1016/S2213-8587(13)70086-X 2-s2.0-84886929517 24622372 \n4 Andersen S. L. Olsen J. Wu C. S. Laurberg P. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study Journal of Clinical Endocrinology and Metabolism 2013 98 11 4373 4381 10.1210/jc.2013-2831 2-s2.0-84887423969 24151287 \n5 Clementi M. Di Gianantonio E. Cassina M. Treatment of hyperthyroidism in pregnancy and birth defects Journal of Clinical Endocrinology and Metabolism 2010 95 11 E337 E341 10.1210/jc.2010-0652 2-s2.0-77958585476 20668039 \n6 Yoshihara A. Noh J. Y. 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 and Metabolism 2012 97 7 2396 2403 10.1210/jc.2011-2860 2-s2.0-84863600669 22547422 \n7 Lo J. C. Rivkees S. A. Chandra M. Gonzalez J. R. Korelitz J. J. Kuzniewicz M. W. Gestational thyrotoxicosis, antithyroid drug use and neonatal outcomes within an integrated healthcare delivery system Thyroid 2015 25 6 698 705 10.1089/thy.2014.0434 25747892 \n8 Andersen S. L. Olsen J. Wu C. S. Laurberg P. Severity of birth defects after propylthiouracil exposure in early pregnancy Thyroid 2014 24 10 1533 1540 10.1089/thy.2014.0150 2-s2.0-84910110031 24963758 \n9 Laurberg P. Andersen S. L. Therapy of endocrine disease: antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk? European Journal of Endocrinology 2014 171 1 R13 R20 10.1530/eje-14-0135 2-s2.0-84903532030 24662319 \n10 Rivkees S. A. Propylthiouracil versus methimazole during pregnancy: an evolving tale of difficult choices Journal of Clinical Endocrinology and Metabolism 2013 98 11 4332 4335 10.1210/jc.2013-3549 2-s2.0-84887495872 24194618 \n11 Milham S. Elledge W. Maternal methimazole and congenital defects in children Teratology 1972 5 1 125 125 10.1002/tera.1420050117 \n12 Hajivassiliou C. A. Intestinal obstruction in neonatal/pediatric surgery Seminars in Pediatric Surgery 2003 12 4 241 253 10.1053/j.sempedsurg.2003.08.005 2-s2.0-0348155635 14655163 \n13 Michopoulou A. T. Germanos S. S. Ninos A. P. Pierrakakis S. K. Vitelline artery remnant causing intestinal obstruction in an adult Surgery 2013 154 5 1137 1138 10.1016/j.surg.2012.06.034 2-s2.0-84886099893 22920945 \n14 Akgür F. M. Tanyel F. C. Büyükpamukçu N. Hiçsönmez A. Anomalous congenital bands causing intestinal obstruction in children Journal of Pediatric Surgery 1992 27 4 471 473 10.1016/0022-3468(92)90340-d 2-s2.0-0026576823 1522460 \n15 Lin D.-S. Wang N.-L. Huang F.-Y. Shih S.-L. Sigmoid adhesion caused by a congenital mesocolic band Journal of Gastroenterology 1999 34 5 626 628 10.1007/s005350050384 2-s2.0-0032707114 10535493 \n16 Liu C. Wu T.-C. Tsai H.-L. Chin T. Wei C. Obstruction of the proximal jejunum by an anomalous congenital band—a case report Journal of Pediatric Surgery 2005 40 3 E27 E29 10.1016/j.jpedsurg.2004.11.008 2-s2.0-15744371662 15793709 \n17 Sarkar D. Gongidi P. Presenza T. Scattergood E. Intestinal obstruction from congenital bands at the proximal jejunum: a case report and literature review Journal of Clinical Imaging Science 2012 2, article 78 10.4103/2156-7514.105130 \n18 Chua C. Gurnurkar S. Rodriguez-Prado Y. Niklas V. Prolonged ileus in an infant presenting with primary congenital hypothyroidism Case Reports in Pediatrics 2015 2015 4 584735 10.1155/2015/584735 \n19 Sadler T. W. Langman's Medical Embryology 2011 12th Philadelphia, Pa, USA Lippincott Williams & Wilkins \n20 Hoffman J. I. E. Kaplan S. The incidence of congenital heart disease Journal of the American College of Cardiology 2002 39 12 1890 1900 10.1016/s0735-1097(02)01886-7 2-s2.0-0037134945 12084585 \n21 Momotani N. Ito K. Hamada N. Ban Y. Nishikawa Y. Mimura T. Maternal hyperthyroidism and congenital malformation in the offspring Clinical Endocrinology 1984 20 6 695 700 10.1111/j.1365-2265.1984.tb00119.x 2-s2.0-0021247215 6467634 \n22 Hackmon R. Blichowski M. Koren G. The safety of methimazole and propylthiouracil in pregnancy: a systematic review Journal of Obstetrics and Gynaecology Canada 2012 34 11 1077 1086 2-s2.0-84876236129 23231846 \n23 Li H. Zheng J. Luo J. Congenital anomalies in children exposed to antithyroid drugs in-utero: a meta-analysis of cohort studies PLoS ONE 2015 10 5 e0126610 10.1371/journal.pone.0126610 \n24 Li X. Liu G. Y. Ma J. L. Zhou L. Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis Clinics 2015 70 6 453 459 10.6061/clinics/2015(06)12 26106966 \n25 Gianetti E. Russo L. Orlandi F. Pregnancy outcome in women treated with methimazole or propylthiouracil during pregnancy Journal of Endocrinological Investigation 2015 38 9 977 985 10.1007/s40618-015-0281-z 25840794\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-651X",
"issue": "2015()",
"journal": "Case reports in endocrinology",
"keywords": null,
"medline_ta": "Case Rep Endocrinol",
"mesh_terms": null,
"nlm_unique_id": "101576457",
"other_id": null,
"pages": "789762",
"pmc": null,
"pmid": "26664769",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "15793709;22920945;25840794;26106966;23231846;24963758;6467634;24194618;25747892;10535493;22547422;12084585;23393634;24622372;14655163;24151287;22869843;21787128;1522460;25974033;24662319;25866693;20668039",
"title": "Congenital Bands with Intestinal Malrotation after Propylthiouracil Exposure in Early Pregnancy.",
"title_normalized": "congenital bands with intestinal malrotation after propylthiouracil exposure in early pregnancy"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-108987",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPYLTHIOURACIL"
},
... |
{
"abstract": "BACKGROUND\nLithium has been used to treat bipolar disorder. Lithium has a narrow therapeutic index, with a therapeutic level between 0.6 and 1.5 mEq/L. The possible complications of lithium overdose include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Lithium intoxication can be fatal and is difficult to diagnose in patients without a history of lithium intake. The occurrence of serious cardiac arrhythmias is rare in lithium intoxication.\nAn 81-year-old man was brought to the emergency department because of consciousness disturbance for 2 days. According to his daughter, he had a history of hypertension and diabetes. Recently, his family also observed slurring of speech and easy choking. The physical examination findings were unremarkable.\n\n\nMETHODS\nBlood examination only revealed impaired renal function. Twelve-lead electrocardiography revealed sinus rhythm with first-degree atrioventricular block. Chest radiography revealed mediastinal widening. The blood pressures obtained from the 4 limbs showed no significant differences. Subsequently, brain computed tomography revealed no obvious intracranial lesion. A neurologist was consulted, and a recent ischemic stroke could not be ruled out. While in the observation area, his systolic blood pressure decreased to <90 mm Hg and he showed bradycardia, and 12-lead electrocardiography revealed an AV block and long pulse. Contrast-enhanced chest computed tomography revealed no evidence of aortic dissection. Another family member reported a history of lithium intake for bipolar disorder for >30 years. Blood examination revealed a lithium concentration of 2.65 mEq/L.\n\n\nMETHODS\nA nephrologist was consulted, and emergency hemodialysis was indicated. Dopamine was administered for his shock status via a right neck central venous catheter.\n\n\nRESULTS\nHis lithium level gradually declined after the hemodialysis, and blood pressure and consciousness level improved subsequently. The patient was discharged 9 days later in a stable condition.\n\n\nCONCLUSIONS\nIf an emergency physician encounters a patient with altered consciousness and arrhythmia with cardiogenic shock, the patient's drug intake history should be carefully reviewed to rule out cardiovascular problems on the basis of the patient's clinical condition.",
"affiliations": "Department of Emergency Medicine, Kaohsiung Medical University Hospital.;Department of Emergency Medicine, Kaohsiung Medical University Hospital.;Department of Emergency Medicine, Kaohsiung Medical University Hospital.",
"authors": "Chien|Shun-Ching|SC|;Liu|Kuan-Ting|KT|;Wu|Yen-Hung|YH|",
"chemical_list": "D000928:Antidepressive Agents; D002316:Cardiotonic Agents; D018020:Lithium Compounds; D004298:Dopamine",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000013129",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30407335MD-D-18-0486110.1097/MD.0000000000013129131293900Research ArticleClinical Case ReportLithium intoxication presenting as altered consciousness and arrhythmia with cardiogenic shock A case reportChien Shun-Ching MDaLiu Kuan-Ting MDabWu Yen-Hung MDa∗NA. a Department of Emergency Medicine, Kaohsiung Medical University Hospitalb School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.∗ Correspondence: Yen-Hung Wu, No. 100 Shichuan 1st Rd., Kaohsiung 80708, Taiwan (e-mail: blan32705@hotmail.com).11 2018 09 11 2018 97 45 e1312916 7 2018 12 10 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This 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. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nLithium has been used to treat bipolar disorder. Lithium has a narrow therapeutic index, with a therapeutic level between 0.6 and 1.5 mEq/L. The possible complications of lithium overdose include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Lithium intoxication can be fatal and is difficult to diagnose in patients without a history of lithium intake. The occurrence of serious cardiac arrhythmias is rare in lithium intoxication.\n\nPatient concerns:\nAn 81-year-old man was brought to the emergency department because of consciousness disturbance for 2 days. According to his daughter, he had a history of hypertension and diabetes. Recently, his family also observed slurring of speech and easy choking. The physical examination findings were unremarkable.\n\nDiagnosis:\nBlood examination only revealed impaired renal function. Twelve-lead electrocardiography revealed sinus rhythm with first-degree atrioventricular block. Chest radiography revealed mediastinal widening. The blood pressures obtained from the 4 limbs showed no significant differences. Subsequently, brain computed tomography revealed no obvious intracranial lesion. A neurologist was consulted, and a recent ischemic stroke could not be ruled out. While in the observation area, his systolic blood pressure decreased to <90 mm Hg and he showed bradycardia, and 12-lead electrocardiography revealed an AV block and long pulse. Contrast-enhanced chest computed tomography revealed no evidence of aortic dissection. Another family member reported a history of lithium intake for bipolar disorder for >30 years. Blood examination revealed a lithium concentration of 2.65 mEq/L.\n\nInterventions:\nA nephrologist was consulted, and emergency hemodialysis was indicated. Dopamine was administered for his shock status via a right neck central venous catheter.\n\nOutcomes:\nHis lithium level gradually declined after the hemodialysis, and blood pressure and consciousness level improved subsequently. The patient was discharged 9 days later in a stable condition.\n\nLessons:\nIf an emergency physician encounters a patient with altered consciousness and arrhythmia with cardiogenic shock, the patient's drug intake history should be carefully reviewed to rule out cardiovascular problems on the basis of the patient's clinical condition.\n\nKeywords\naltered mental statusarrhythmiacardiogenic shocklithium intoxicationOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nLithium has been used to treat bipolar disorder. Lithium has a narrow therapeutic index, with a therapeutic level between 0.6 and 1.5 mEq/L.[1] The possible complications of lithium overdose include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Lithium intoxication can be fatal and is difficult to diagnose in a patient without a history of lithium intake. Here, we report a case of lithium intoxication presenting with altered consciousness and arrhythmia with cardiogenic shock. According to the regulations of the institutional review board of the Kaohsiung Medical University Hospital, ethical approval for this case report article is not required. Informed consent was obtained from the patient for the publication of this case report.\n\n2 Case presentation\nAn 81-year-old man was brought to the emergency department because of conscious disturbance for 2 days. Upon arrival, his vital signs were as follows: body temperature, 37.9°C; blood pressure, 83/45 mm Hg; heart rate, 71 bpm, and Glasgow coma scale score, 9 (E3V3M3). According to his daughter, he had a history of hypertension and diabetes, with good compliance to medications. He had no history of recent trauma. Recently, his family also observed slurring of speech and easy choking. These physical examination findings were unremarkable. Blood examination, including complete blood count, renal and liver functions, electrolyte, and cardiac enzyme, revealed no elevation of leukocytosis or C-reactive protein level, normal liver function and cardiac enzyme, impaired renal function (creatinine, 2.71 mg/dL), no obvious electrolyte abnormality, and no acidosis. Twelve-lead electrocardiography revealed sinus rhythm with a first-degree atrioventricular (AV) block. Chest radiography revealed mediastinal widening (Fig. 1). Blood pressures obtained from 4 limbs showed no significant differences. Subsequently, brain computed tomography revealed no obvious intracranial lesion. A neurologist was consulted, and a recent ischemic stroke could not be ruled out; thus, admission for further examination was suggested. His blood pressure improved after hydration with normal saline. While in the observation area, his systolic blood pressure decreased to <90 mm Hg and he showed bradycardia, and 12-lead electrocardiography revealed an AV block and long pulse (Fig. 2). Atropine was prescribed, and his blood pressure was elevated for a few minutes but subsequently decreased; thus, dopamine was administered for the shock status via a right neck central venous catheter. Contrast-enhanced chest computed tomography revealed no evidence of aortic dissection. Another family member reported a history of lithium intake for bipolar disorder for >30 years. Blood examination revealed a lithium concentration of 2.65 mEq/L (normal treatment range, 0.5–1.2 mEq/L). Subsequently, a nephrologist was consulted, and emergency hemodialysis was indicated; hence, the patient was transferred to the intensive care unit for further care. His lithium level gradually declined after the hemodialysis, and his blood pressure improved subsequently. He was transferred to the ward after 4 days because of stable hemodynamic status. His consciousness level gradually improved in the ward. He was discharged 9 days later in a stable condition. Neither the patient nor his family reported a history of lithium overdose after discharge because the physician used another drug to control the patient's bipolar disorder.\n\nFigure 1 Chest radiograph showing mediastinal widening.\n\nFigure 2 A 12-lead electrocardiogram showing atrioventricular block with bradycardia and long pulse.\n\n3 Discussion\nLithium is a widely used drug for bipolar affective disorder, depression, and schizoaffective disorder. It has a narrow therapeutic level, and its levels should be monitored carefully and dosage must be adjusted if necessary.\n\nLithium intoxication is of three types, namely acute, acute on chronic, and chronic. Acute poisoning occurs in individuals who are not treated with lithium. Acute-on-chronic poisoning occurs in patients treated with lithium who take an overdose. Chronic toxicity occurs in patients receiving chronic lithium therapy. Chronic poisoning can occur in patients whose lithium dosage has been increased or in individuals whose renal function has decreased, resulting in an increase in serum lithium levels.[1]\n\nThe clinical manifestations of chronic lithium intoxication include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Serious cardiac arrhythmias are rarely seen in lithium toxicity.[2] The cardiac manifestations of lithium toxicity include junctional rhythm, atrial fibrillation, ST-T wave changes, supraventricular tachycardia, and sinus node arrest. The cardiac effects of lithium are observed over a wide range of lithium concentrations at both therapeutic and toxic levels. Its manifestations range from benign ST-segment, T-wave changes to severe manifestations such as sinus node dysfunction, atrial flutter, AV blocks, left anterior hemiblock, right bundle-branch block, ventricular tachycardia, ventricular fibrillation, and sudden cardiac arrest.[3]\n\nThe possible mechanisms of lithium-induced arrhythmia include the following: lithium causes hyperkalemia by displacing the intracellular potassium ion; lithium is not removed effectively as sodium ions enter cardiac cells during depolarization; the spontaneous rate of depolarization of the sinus node and the conduction velocity in the AV and intraventricular conduction systems are reduced; the response to adrenergic stimulation is reduced; and calcium ion influx interferes in the pacing cells of the sinus node.[4–6]\n\nLithium is concentrated within the thyroid and inhibits thyroid synthesis and release. Thus, lithium can cause hypothyroidism and hypothermia. It can also cause thyrotoxicosis and hyperthermia, as well as hyperparathyroidism and hypercalcemia.[1]\n\nFactors that increase the risk of lithium toxicity include renal insufficiency, overdose, volume depletion, infections, decreased effective circulating volume (cirrhosis, congestive heart failure, and nephrotic syndrome), medication interaction (e.g., diuretics and angiotensin-converting enzyme inhibitor), gastroenteritis, and anorexia.[1,7–9]\n\nThe treatment of chronic lithium intoxication is based on the patient's lithium level and clinical condition. The airway should be protected if consciousness is impaired. If the serum lithium level is >4 mEq/L or the patient has an unstable hemodynamic status and severe neurological symptoms with a serum lithium level of >2.5 mEq/L, hemodialysis should be considered.[10]\n\nIn this case, the initial impression was acute ischemic stroke when the patient was brought to the emergency department; however, his blood pressure was not elevated, and this was noted by the physician. The mean arterial blood pressure is usually elevated in patients with acute stroke. This may be due to chronic hypertension, which is a major risk factor for ischemic stroke. Type A aortic dissection can present as a stroke, including limb weakness or conscious disturbance with hypotension.[11] Therefore, chest computed tomography was performed because the chest radiograph showed mild mediastinum widening and hypotension, without evidence of aortic dissection. The diagnosis of chronic lithium intoxication was established when another family member reported a history of chronic lithium intake for >30 years (lithium dosage: 600 mg/day), and the lithium level was 2.65 mEq/L.\n\nThe patient underwent emergency hemodialysis with indication of an unstable hemodynamic status and severe neurological symptoms, with a serum lithium level of >2.5 mEq/L. The thyroid and calcium levels obtained before hemodialysis were within their normal ranges. Serious cardiac arrhythmias rarely occur, and in this case, the patient presented with AV block with cardiogenic shock. His arrhythmia and consciousness level improved after the lithium level decreased.\n\nIf an emergency physician encounters a patient with altered consciousness and arrhythmia with cardiogenic shock, the patient's drug intake history should be carefully reviewed to rule out cardiovascular problems on the basis of the patient's clinical condition.\n\nAuthor contributions\nResources: Yen-Hung Wu.\n\nSupervision: Kuan-Ting Liu.\n\nWriting – original draft: Shun-Ching Chien, Yen-Hung Wu.\n\nWriting – review & editing: Shun-Ching Chien, Kuan-Ting Liu, Yen-Hung Wu.\n\nAbbreviation: AV = atrioventricular.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Timmer RT Sands JM \nLithium intoxication . J Am Soc Nephrol \n1999 ;10 :666–74 .10073618 \n[2] Maddala RNM Ashwal AJ Rao MS \nChronic lithium intoxication: varying electrocardiogram manifestations . Indian J Pharmacol \n2017 ;49 :127–9 .28458438 \n[3] Tilkian AG Schroeder JS Kao JJ \nThe cardiovascular effects of lithium in man. A review of the literature . Am J Med \n1976 ;61 :665–70 .790953 \n[4] Mckusick VA \nThe effect of lithium on the electrocardiogram of animals and relation of these effects to the ratio of the intracellular and extracellular concentrations of potassium . J Clin Invest \n1954 ;33 :598–610 .13152200 \n[5] Singer I Rotenberg D \nMechanisms of lithium action . N Engl J Med \n1973 ;289 :254–60 .4351597 \n[6] Talati SN Aslam AF Vasavada B \nSinus node dysfunction in association with chronic lithium therapy: a case report and review of literature . Am J Ther \n2009 ;16 :274–8 .19352146 \n[7] Okusa MD Crystal LJ \nClinical manifestations and management of acute lithium intoxication . Am J Med \n1994 ;97 :383–9 .7942943 \n[8] Lehmann K Ritz E \nAngiotensin-converting enzyme inhibitors may cause renal dysfunction in patients on long-term lithium treatment . Am J Kidney Dis \n1995 ;25 :82–7 .7810540 \n[9] Bennett WM \nDrug interactions and consequences of sodium restriction . Am J Clin Nutr \n1997 ;65 2 suppl :678S–81S .9022564 \n[10] Ellenhorn MJ Schonwald S Ordog G \nLithium . In: Medical Toxicology: Diagnosis and Treatment of Human Poisoning , Ellenhorn MJ Schonwald S Ordog G Wasserberger J , Eds., Baltimore , Williams and Wilkins , 1997 , p. 1579.\n[11] Ying CH Sheng FS Kuan TL \nPainless acute aortic dissection may present as a stroke: risky markers that could be identified on hospital arrival . J Acute Med \n2017 ;7 :93–100 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "97(45)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000369:Aged, 80 and over; D000928:Antidepressive Agents; D001145:Arrhythmias, Cardiac; D002316:Cardiotonic Agents; D003244:Consciousness Disorders; D004298:Dopamine; D062787:Drug Overdose; D004562:Electrocardiography; D006801:Humans; D018020:Lithium Compounds; D008297:Male; D006435:Renal Dialysis; D012770:Shock, Cardiogenic",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e13129",
"pmc": null,
"pmid": "30407335",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "790953;9022564;7810540;7942943;28458438;19352146;13152200;4351597;10073618",
"title": "Lithium intoxication presenting as altered consciousness and arrhythmia with cardiogenic shock: A case report.",
"title_normalized": "lithium intoxication presenting as altered consciousness and arrhythmia with cardiogenic shock a case report"
} | [
{
"companynumb": "TW-MYLANLABS-2018M1090959",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E), autoimmune, toxic, ischemic, and metabolic etiologies including Wilson's disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.",
"affiliations": "Department of Gastroenterology and Hepatology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.;Department of Gastroenterology and Hepatology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.;Department of Pathology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.;Department of Gastroenterology and Hepatology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.",
"authors": "Namn|Yunseok|Y|0000-0002-1023-8878;Schneider|Yecheskel|Y|0000-0002-0680-3627;Cui|Isabelle H|IH|;Jesudian|Arun|A|0000-0002-8562-3375",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/3864236",
"fulltext": "\n==== Front\nCase Reports HepatolCase Reports HepatolCRIHEPCase Reports in Hepatology2090-65872090-6595Hindawi Publishing Corporation 10.1155/2017/3864236Case ReportDiphenhydramine as a Cause of Drug-Induced Liver Injury http://orcid.org/0000-0002-1023-8878Namn Yunseok \n1\n\n*\nhttp://orcid.org/0000-0002-0680-3627Schneider Yecheskel \n1\nCui Isabelle H. \n2\nhttp://orcid.org/0000-0002-8562-3375Jesudian Arun \n1\n1Department of Gastroenterology and Hepatology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA2Department of Pathology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA*Yunseok Namn: yun9007@nyp.orgAcademic Editor: Melanie Deutsch\n\n2017 26 1 2017 2017 386423618 11 2016 10 1 2017 Copyright © 2017 Yunseok Namn 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.Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E), autoimmune, toxic, ischemic, and metabolic etiologies including Wilson's disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.\n==== Body\n1. Introduction\nDrug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States, accounting for nearly 50% of cases and 10% of acute hepatitis cases [1–3]. Other etiologies of acute liver injury include viral, autoimmune, metabolic, and ischemic etiologies. When acute liver injury progresses to fulminant hepatic failure, it is associated with high mortality [4, 5]. Therefore, prompt recognition of the underlying etiology and initiation of treatment are of paramount importance. Medications such as acetaminophen, antiepileptics, and antibiotics are well known causes of DILI; however, thousands of drugs, herbs, and toxins can cause idiosyncratic liver injury. We report the first case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.\n\n2. Case\nA 28-year-old man with history of chromosomal translocation 13/14 and no prior liver disease presented to the hospital with complaint of fevers, nonbloody emesis, and dark urine. History revealed ingestion of diphenhydramine 400 mg nightly, taken for insomnia, over the previous 4 months; the medication was inspected in the hospital and confirmed not to contain acetaminophen. He denied use of herbal compounds, supplements, teas, and any other medication. The patient endorsed rare alcohol consumption and rare intranasal cocaine use in the distant past. Family history was notable for possible statin-induced liver disease and hereditary angioedema.\n\nVital signs on presentation were within normal limits. Physical exam revealed icteric conjunctiva, a 15 cm liver palpable 3 cm below the right costal margin, nonpalpable spleen, normal mentation, and neurologic exam without asterixis. Initial laboratory studies revealed aspartate aminotransferase (AST) 10,425 IU/L, alanine aminotransferase (ALT) 2,471 IU/L, alkaline phosphatase (ALP) 65 IU/L, total bilirubin 2.7 mg/dL (direct 1.4 mg/dL), INR 2.6, and a hemoglobin level of 12.7 g/dL; the remainder of the laboratory studies were normal, including creatinine, blood glucose, and lactate. Hepatology and toxicology consultations were requested, and empiric intravenous N-acetylcysteine (NAC) was initiated. By day two, his transaminases and coagulopathy worsened, with AST 20,176 IU/L, ALT 5,076 IU/L, and INR 3.1 (Figures 1(a), 1(b), and 1(c)). The patient did not exhibit signs of hepatic encephalopathy, but was transferred to the intensive care unit for closer monitoring. By the third day of NAC treatment, transaminases started to improve. A complete evaluation for causes of acute liver injury, including viral hepatitis (hepatitis A, B, C, and E), workup for other viruses (including EBV, CMV, HHV-6, and HIV), autoimmune workup (ANA, ASMA, AMA, A1AT, IgG, and LTK Ab), metabolic testing (ceruloplasmin, 24-hour urine copper, ophthalmologic examination for Keyser-Fleischer rings, MRI brain to evaluate for lenticular degeneration, and iron studies), urine toxicology, and SPEP/UPEP, was all normal and did not reveal an alternative etiology of the patient's acute liver injury. Abdominal ultrasound demonstrated a 17.4 cm liver with smooth contour and normal echogenicity with patent hepatic and portal vasculature. He underwent a transjugular biopsy which revealed centrilobular and bridging necrosis accompanied by portal and lobular inflammation, favoring drug-induced liver injury (Figures 2(a) and 2(b)). Rhodanine stain for copper and quantitative copper analysis were both negative, ruling out Wilson's disease. Iron staining was not consistent with hemochromatosis. The patient ultimately recovered completely from acute liver injury and was discharged home. Upon the 6-month outpatient follow-up, patient was asymptomatic and reported feeling well, and repeat liver function tests did not show any evidence of liver injury.\n\n3. Discussion\nAcute liver injury can be attributed to a wide array of causes, with viral and drug etiologies being the most common in adults. In the United States, acetaminophen toxicity and idiosyncratic drugs reaction are the leading causes of acute liver failure while viral hepatitis is the leading cause in Asia and Europe [4, 5].\n\nDrug-induced liver injury remains one of the most challenging diagnoses to make but must be considered in the differential diagnosis of any liver injury [6, 7]. Patients should undergo careful evaluation to exclude other causes of liver disease, including viral hepatitides (hepatitis A, B, C, and E), EBV, CMV, HHV-6, autoimmune hepatitis, and Wilson's disease if age is less than 40 [8, 9]. Offending agents can include prescription and over-the-counter medications, such as antibiotics (nitrofurantoin, isoniazid, and trimethoprim/sulfamethoxazole), immunomodulatory agents (such as infliximab), analgesics (especially those that contain acetaminophen), antineoplastic agents, antiepileptics, and statins [10, 11]. Additionally, DILI can result from herbal ingestions or dietary supplements [12, 13]. Manifestations of liver injury can range from asymptomatic transaminase elevation and/or jaundice (depending on a hepatocellular or cholestatic pattern of injury, resp.) to development of acute liver failure marked by encephalopathy and synthetic dysfunction [13, 14].\n\nDrug-induced liver injury can be divided into two classes of medication-related hepatotoxicity: intrinsic and idiosyncratic. The former, which includes acetaminophen, is often dose-dependent with predictable liver injury at hepatotoxic doses [11, 15]. Idiosyncratic DILI is not dose-dependent and thus is harder to predict. It is thought to mainly affect individuals with underlying susceptibility or predisposition and therefore, may have variable latency [11, 16].\n\nIn the presented case, multiple etiologies for the liver injury were considered and excluded. The liver biopsy was consistent with DILI and after ascertainment of an exhaustive mediation history diphenhydramine was identified as the only possible culprit. Although there are reports of diphenhydramine and acetaminophen causing liver injury when ingested together, there are no prior cases in the literature of diphenhydramine alone causing DILI. Although considered to have minimal to no hepatotoxic effects, this case suggests that diphenhydramine may be hepatotoxic at high doses with chronic use (as the patient had been taking at least 400 mg per day for over four months). It has been reported that compounds with more than 50% hepatic metabolism given at doses higher than 50 mg/day were at highest risk of hepatotoxicity [13, 17]. Diphenhydramine undergoes extensive first-pass metabolism, whereby 50–60% of ingested medication is metabolized by the liver before reaching the systemic circulation. Nearly all the available drug is metabolized by the liver within 24–48 hours, thus increasing risk for liver injury. It is unclear if a predisposition for hepatotoxicity was present in this patient given his history of a balanced chromosomal translocation. However, certain genetic predispositions have been noted to play a role in risk for DILI. For example, the HLA-1 and HLA-II genotypes have been shown to confer an increased susceptibility to DILI for patients taking amoxicillin-clavulanate [7, 17, 18].\n\nIn summary, we present a case of diphenhydramine-induced liver injury, without the concomitant use of acetaminophen. Although not previously thought to cause liver injury, this case highlights that any medication metabolized by the liver has potential to lead to liver injury when ingested at high enough doses and for long enough duration in susceptible individuals.\n\nConsent\nPatient consent was obtained for publication of case details including images.\n\nCompeting Interests\nThere is no financial support or competing interests.\n\nAuthors' Contributions\nYunseok Namn is the main author of manuscript and article guarantor; Yecheskel Schneider is the 2nd author of manuscript; Isabelle H. Cui attained and analyzed the histological slide; Arun Jesudian is the advisor.\n\nFigure 1 Linear graphs representing the trend of transaminases, INR, and direct bilirubin throughout patient's hospital course and outpatient follow-up.\n\nFigure 2 On Hematoxylin and Eosin stain (100x and 400x), there is centrilobular and bridging necrosis accompanied by portal and lobular inflammation including eosinophils and plasma cells. There is evidence of cholestasis and bile duct injury is noted in some portal tracts. Hepatocellular injury, that is, hepatocyte ballooning degeneration, is also present. Fibrosis is absent on Trichrome staining. There is no evidence of steatosis, glycogenic nuclei, Mallory's hyaline, or copper deposition. Overall, these findings favor a diagnosis of drug-induced liver injury.\n==== Refs\n1 Zimmerman H. J. Drug-induced liver disease Clinical Liver Disease 2000 4 1 73 96 10.1016/s1089-3261(05)70097-0 \n2 Ostapowicz G. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States Annals of Internal Medicine 2002 137 12 947 954 10.7326/0003-4819-137-12-200212170-00007 12484709 \n3 Larson A. M. Polson J. Fontana R. J. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study Hepatology 2005 42 6 1364 1372 10.1002/hep.20948 16317692 \n4 Gotthardt D. Riediger C. Weiss K. H. Fulminant hepatic failure: etiology and indications for liver transplantation Nephrology Dialysis Transplantation 2007 22 supplement 8 viii5 viii8 10.1093/ndt/gfm650 2-s2.0-42049085182 \n5 Stephens C. Andrade R. J. Lucena M. I. Mechanisms of drug-induced liver injury Current Opinion in Allergy and Clinical Immunology 2014 14 4 286 292 10.1097/ACI.0000000000000070 24915546 \n6 Marudanayagam R. Shanmugam V. Gunson B. Aetiology and outcome of acute liver failure HPB: The Official Journal of the International Hepato Pancreato Biliary Association 2009 11 5 429 434 19768148 \n7 Ghabril M. Chalasani N. Björnsson E. Drug-induced liver injury: a clinical update Current Opinion in Gastroenterology 2010 26 3 222 226 10.1097/MOG.0b013e3283383c7c 20186054 \n8 Leise M. D. Poterucha J. J. Talwalkar J. A. Drug-induced liver injury Mayo Clinic Proceedings 2014 89 1 95 106 10.1016/j.mayocp.2013.09.016 24388027 \n9 Kaplowitz N. Drug-induced liver injury Clinical Infectious Diseases 2004 38 2 S44 S48 10.1086/381446 14986274 \n10 Sarges P. Steinberg J. M. Lewis J. H. Drug-induced liver injury: highlights from a review of the 2015 literature Drug Safety 2016 39 9 801 821 10.1007/s40264-016-0427-8 27142208 \n11 Roth R. A. Ganey P. E. Intrinsic versus idiosyncratic drug-induced hepatotoxicity—two villains or one? Journal of Pharmacology and Experimental Therapeutics 2010 332 3 692 697 10.1124/jpet.109.162651 20019161 \n12 Reuben A. Koch D. G. Lee W. M. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study Hepatology 2010 52 6 2065 2076 10.1002/hep.23937 20949552 \n13 Lammert C. Einarsson S. Saha C. Niklasson A. Bjornsson E. Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals Hepatology 2008 47 6 2003 2009 10.1002/hep.22272 2-s2.0-46249118651 18454504 \n14 Marudanayagam R. Shanmugam V. Gunson B. Aetiology and outcome of acute liver failure HPB 2009 11 5 429 434 10.1111/j.1477-2574.2009.00086.x 19768148 \n15 Chalasani N. Bonkovsky H. L. Fontana R. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study Gastroenterology 2015 148 7 1340 1352.e7 10.1053/j.gastro.2015.03.006 2-s2.0-84930017409 25754159 \n16 Knowles S. R. Uetrecht J. Shear N. H. Idiosyncratic drug reactions: the reactive metabolite syndromes The Lancet 2000 356 9241 1587 1591 10.1016/s0140-6736(00)03137-8 2-s2.0-0034605712 \n17 Fromenty B. Drug-induced liver injury in obesity Journal of Hepatology 2013 58 4 824 826 10.1016/j.jhep.2012.12.018 23298629 \n18 Chalasani N. Bonkovsky H. L. Fontana R. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study Gastroenterology 2015 148 7 1340.e7 1352.e7 10.1053/j.gastro.2015.03.006 25754159\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6595",
"issue": "2017()",
"journal": "Case reports in hepatology",
"keywords": null,
"medline_ta": "Case Reports Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101622103",
"other_id": null,
"pages": "3864236",
"pmc": null,
"pmid": "28246565",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "14986274;16317692;19768148;20186054;23298629;20949552;11075787;18454504;25754159;12484709;24915546;20019161;27142208;24388027;11232192;17890263",
"title": "Diphenhydramine as a Cause of Drug-Induced Liver Injury.",
"title_normalized": "diphenhydramine as a cause of drug induced liver injury"
} | [
{
"companynumb": "US-PROCTER_AND_GAMBLE-GS17025069",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "Chronic myeloid leukemia cells acquire resistance to tyrosine kinase inhibitors through mutations in the ABL1 kinase domain. The T315I mutation mediates resistance to imatinib, dasatinib, nilotinib and bosutinib, whereas sensitivity to ponatinib remains. Mutation detection by conventional Sanger sequencing requires 10%-20% expansion of the mutated subclone. We studied the T315I mutation development by ultra-deep sequencing on the 454 XL+ platform (Roche) in comparison to Sanger sequencing. By ultra-deep sequencing, mutations were detected at loads of 1%-2%. We selected 40 patients who had failed first-line to third-line treatment (imatinib, dasatinib, nilotinib) and had high loads of the T315I mutation detected by Sanger sequencing. We confirmed T315I mutations by ultra-deep sequencing and investigated the mutation dynamics by backtracking earlier samples. In 20 of 40 patients, we identified the T315I three months (median) before Sanger sequencing detection limits were reached. To exclude sporadic low percentage mutation development without subsequent mutation outgrowth, we selected 42 patients without resistance mutations detected by Sanger sequencing but loss of major molecular response. Here, no mutation was detected by ultradeep sequencing. Additional non-T315I resistance mutations were found in 20 of 40 patients. Only 15% had two mutations per cell; the other cases showed multiple independently mutated clones and the T315I clone demonstrated a rapid outgrowth. In conclusion, T315I mutations could be detected earlier by ultra-deep sequencing compared to Sanger sequencing in a selected group of cases. Earlier mutation detection by ultra-deep sequencing might allow treatment to be changed before clonal increase of cells with the T315I mutation.",
"affiliations": "MLL Munich Leukemia Laboratory, Germany.;MLL Munich Leukemia Laboratory, Germany.;MLL Munich Leukemia Laboratory, Germany.;MLL Munich Leukemia Laboratory, Germany.;MLL Munich Leukemia Laboratory, Germany.;MLL Munich Leukemia Laboratory, Germany.;MLL Munich Leukemia Laboratory, Germany.;MLL Munich Leukemia Laboratory, Germany torsten.haferlach@mll.com.",
"authors": "Baer|Constance|C|;Kern|Wolfgang|W|;Koch|Sarah|S|;Nadarajah|Niroshan|N|;Schindela|Sonja|S|;Meggendorfer|Manja|M|;Haferlach|Claudia|C|;Haferlach|Torsten|T|",
"chemical_list": "D000970:Antineoplastic Agents; D003062:Codon; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2016.145888",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "101(7)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents; D060965:Clonal Evolution; D003062:Codon; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors; D012680:Sensitivity and Specificity; D055815:Young Adult",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "830-8",
"pmc": null,
"pmid": "27102501",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16522812;23223358;26603839;15215876;24993880;20008232;25239264;25367136;22160483;21990409;12399961;25652737;24180494;24550512;23897237;25629972;21818112;25132497;18054881;12077114;11840263;18603549;10557058;24365090;20607847;26437782;23803709;18615105;21562040;12204532;21856226;23794064;23190221;26297264;19282833;24131888;23716543",
"title": "Ultra-deep sequencing leads to earlier and more sensitive detection of the tyrosine kinase inhibitor resistance mutation T315I in chronic myeloid leukemia.",
"title_normalized": "ultra deep sequencing leads to earlier and more sensitive detection of the tyrosine kinase inhibitor resistance mutation t315i in chronic myeloid leukemia"
} | [
{
"companynumb": "PHHY2016DE126091",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYUREA"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nCyclosporine and infliximab (IFX) seem equally effective as rescue therapy in hospitalized patients with severe ulcerative colitis (UC), although associated hospital stay and costs may differ.\n\n\nOBJECTIVE\nThe aim of this study was to compare the duration of hospital stay and associated costs from initiation of rescue therapy to time of discharge in hospitalized patients with corticosteroid-refractory UC receiving cyclosporine or IFX. Colectomy rates after 6 months were used as the outcome parameter for treatment success.\n\n\nMETHODS\nHospital records of patients admitted between November 2003 and August 2012 at a tertiary referral center were analyzed.\n\n\nRESULTS\nForty-two patients were included (cyclosporine group: 26 patients; IFX group: 16 patients). Patient characteristics were comparable, with the exception that cyclosporine-treated patients more often had a pancolitis (89 vs. 63%, P=0.046). The median length of hospital stay was 11.0 (interquartile range 7.75-13.25) versus 4.0 days (interquartile range 4.0-5.75) in the cyclosporine and IFX group (P<0.01), respectively. The mean in-hospital costs were significantly higher in the cyclosporine-treated versus IFX-treated patients (6121 vs. 4853 euros, P<0.05), whereas the total costs up to 3 months after initiation of rescue therapy were significantly higher in the IFX group (6787 vs. 9983 euros, P<0.01). There were no significant differences in colectomy rates at 6 months (23 and 31% for cyclosporine and IFX, P=0.50). More side-effects were observed during treatment with cyclosporine.\n\n\nCONCLUSIONS\nLength of hospital stay and in-hospital costs have been reduced significantly since the introduction of IFX as rescue therapy for severe UC instead of cyclosporine. However, the total treatment costs are higher in IFX-treated patients.",
"affiliations": "aDepartment of Gastroenterology and Hepatology bTytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.",
"authors": "Löwenberg|Mark|M|;Duijvis|Nicolette W|NW|;Ponsioen|Cyriel|C|;van den Brink|Gijs R|GR|;Fockens|Paul|P|;D'Haens|Geert R A M|GR|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "26(11)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D003082:Colectomy; D003093:Colitis, Ulcerative; D016572:Cyclosporine; D016527:Drug Costs; D005260:Female; D005765:Gastrointestinal Agents; D006302:Health Services Research; D017721:Hospital Costs; D006760:Hospitalization; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D007902:Length of Stay; D008297:Male; D009426:Netherlands; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1240-6",
"pmc": null,
"pmid": "25171024",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Length of hospital stay and associated hospital costs with infliximab versus cyclosporine in severe ulcerative colitis.",
"title_normalized": "length of hospital stay and associated hospital costs with infliximab versus cyclosporine in severe ulcerative colitis"
} | [
{
"companynumb": "NL-JNJFOC-20141008723",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aims of this study were to analyze patterns of recurrence in patients with ovarian clear cell adenocarcinoma (CCA) and to evaluate the role of pelvic radiotherapy (RT).\n\n\nMETHODS\nAll patients with ovarian CCA treated at a single institution between 1989 and 2012 were identified, and their medical records were reviewed. Eligibility criteria included histologic diagnosis of pure CCA of the ovary, surgical staging for International Federation of Gynecology and Obstetrics stage I-to-IIIC disease, and adjuvant or neoadjuvant chemotherapy. Selected end points were 3-, 5-, and 8-year cumulative incidence of pelvic recurrence (CIPR).\n\n\nRESULTS\nFifty-six patients met eligibility criteria. Most received intravenous carboplatin and paclitaxel for a median of 6 cycles. Six patients (10.7%) received pelvic RT, and 50 (89.3%) did not. Pelvic RT patients had stage I-to-IIC disease. Median follow-up was 39 months (range, 1-69 months). For the group as a whole, 14 patients (25%) had initial disease recurrence involving the pelvis, whereas 6 (10.7%) had first recurrence outside the pelvis. Three-, 5- and 8-year CIPR were 28.2%, 38.5%, and 43.2%, respectively. There was no significant difference in 3-, 5-, or 8-year CIPR between the group of patients receiving RT (20%, 20%, and 20%) and a group of patients with stages I to IIC who did not receive RT (9.9%, 22.4%, and 30.2%), P = 0.22. During RT, patients developed mild grade 1-to-2 side effects. After RT, 1 patient developed lower extremity lymphedema with recurrent cellulitis. One patient who developed small bowel obstruction before RT developed small bowel radiation enteritis and obstruction after RT, ultimately requiring surgical intervention.\n\n\nCONCLUSIONS\nThese findings suggest that ovarian CCA exhibits a propensity for pelvic recurrence after surgery and chemotherapy. RT, a local treatment that can effectively sterilize microscopic tumor cells, may benefit patients with this disease. Prospective studies with sufficient statistical power are warranted to further evaluate the role of RT.",
"affiliations": "*Department of Radiation Oncology and †Department of Preventive Medicine, Division of Biostatistics, Northwestern University Feinberg School of Medicine; ‡Robert H. Lurie Comprehensive Cancer Center and §Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Northwestern University Feinberg School of Medicine; ∥Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago.",
"authors": "Macrie|Bryan D|BD|;Strauss|Jonathan B|JB|;Helenowski|Irene B|IB|;Rademaker|Alfred|A|;Schink|Julian C|JC|;Lurain|John R|JR|;Small|William|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0000000000000270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "24(9)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D018262:Adenocarcinoma, Clear Cell; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077216:Carcinoma, Ovarian Epithelial; D002641:Chicago; D003131:Combined Modality Therapy; D016889:Endometrial Neoplasms; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D010386:Pelvic Neoplasms; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1597-602",
"pmc": null,
"pmid": "25275661",
"pubdate": "2014-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Patterns of recurrence and role of pelvic radiotherapy in ovarian clear cell adenocarcinoma.",
"title_normalized": "patterns of recurrence and role of pelvic radiotherapy in ovarian clear cell adenocarcinoma"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01920",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "In female-to-male transgender individuals, testosterone is used to induce masculinization. Sex steroid therapy may increase circulating triglyceride and low-density lipoprotein cholesterol (LDL-C) levels and may decrease high-density lipoprotein cholesterol (HDL-C) levels, resulting in a more atherogenic lipid profile. These potentially adverse effects of androgen therapy may be exacerbated by the presence of familial hypercholesterolemia (FH). We describe the case of a transgender man with genetically diagnosed FH who was intolerant to statins and was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to control his lipoproteins more effectively. The 35-year-old female-to-male transgender individual was referred to our center with a history of elevated LDL-C levels. Despite treatment with high doses of high-potency statins and ezetimibe, he had never achieved a sustained reduction in LDL-C; his levels of LDL-C were fluctuating between 170 and 344 mg/dL (4.4 and 8.9 mmol/L). Moreover, he developed side effects to statins in the form of myalgia and discontinued statin treatment. At the Sahlgrenska Lipid Clinic, a genetic diagnosis of heterozygous FH was established, and PCSK9 inhibitor therapy was started. The patient's LDL-C level has been reduced by approximately 40% for 23 months, and no adverse events have been reported.",
"affiliations": "Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.;Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.;Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.;Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.",
"authors": "Pirazzi|Carlo|C|;Tavaglione|Federica|F|0000-0002-1720-4355;Tivesten|Åsa|Å|;Romeo|Stefano|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/js.2019-00070",
"fulltext": "\n==== Front\nJ Endocr SocJ Endocr SocjesJournal of the Endocrine Society2472-1972Endocrine Society Washington, DC 20190007010.1210/js.2019-00070Case ReportLipids and CardiovascularPCSK9 Inhibitors in a Statin-Intolerant Transgender Man With Heterozygous Familial Hypercholesterolemia: A Case Report Pirazzi Carlo 12http://orcid.org/0000-0002-1720-4355Tavaglione Federica 3Tivesten Åsa 145Romeo Stefano Stefano.Romeo@wlab.gu.se1261 Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden2 Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden3 Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy4 Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden5 Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden6 Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, ItalyC.P. and F.T. contributed equally to this case report.\n\nCorrespondence: Stefano Romeo, PhD, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Bruna Stråket 16, 41345, Gothenburg, Sweden. E-mail: Stefano.Romeo@wlab.gu.se.01 8 2019 06 6 2019 3 8 1461 1464 21 2 2019 31 5 2019 Copyright © 2019 Endocrine Society2019This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Abstract\nIn female-to-male transgender individuals, testosterone is used to induce masculinization. Sex steroid therapy may increase circulating triglyceride and low-density lipoprotein cholesterol (LDL-C) levels and may decrease high-density lipoprotein cholesterol (HDL-C) levels, resulting in a more atherogenic lipid profile. These potentially adverse effects of androgen therapy may be exacerbated by the presence of familial hypercholesterolemia (FH). We describe the case of a transgender man with genetically diagnosed FH who was intolerant to statins and was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to control his lipoproteins more effectively.\n\nThe 35-year-old female-to-male transgender individual was referred to our center with a history of elevated LDL-C levels. Despite treatment with high doses of high-potency statins and ezetimibe, he had never achieved a sustained reduction in LDL-C; his levels of LDL-C were fluctuating between 170 and 344 mg/dL (4.4 and 8.9 mmol/L). Moreover, he developed side effects to statins in the form of myalgia and discontinued statin treatment. At the Sahlgrenska Lipid Clinic, a genetic diagnosis of heterozygous FH was established, and PCSK9 inhibitor therapy was started. The patient’s LDL-C level has been reduced by approximately 40% for 23 months, and no adverse events have been reported.\n\ngender dysphoriatestosteronelipoproteinsfamilial hypercholesterolemiaPCSK9 inhibitorsVetenskapsrådet10.13039/5011000043592016-01527Swedish state under the Agreement between the Swedish government and the county councils (the ALF-agreement)10.13039/5011000037932018-04276Novo Nordisk Fonden10.13039/5011000097089321-430Diabetesfonden10.13039/5011000085502017-205Hjärt-Lungfonden10.13039/50110000379320120533Knut och Alice Wallenbergs Stiftelse10.13039/5011000040632017.0203\n==== Body\nIn female-to-male transgender individuals, testosterone is used to induce masculinization [1, 2]. This therapy may increase circulating triglyceride and low-density lipoprotein cholesterol (LDL-C) levels and decrease high-density lipoprotein cholesterol (HDL-C) levels, resulting in a more atherogenic lipid profile [3]. These potential adverse effects of androgen therapy may be exacerbated by the presence of familial hypercholesterolemia (FH), an autosomal-dominant genetic disease characterized by elevated LDL-C levels [4]. We describe the case of a transgender man affected by FH who is receiving treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to more effectively control his LDL-C levels. The patient provided written informed consent for the publication of this case report.\n\n1. Case Report\nA 35-year-old female-to-male transgender individual with elevated LDL-C levels was referred to the Lipid Clinic at the Cardiology Department of Sahlgrenska University Hospital, Gothenburg, Sweden. He had a family history of hypercholesterolemia and premature coronary heart disease, with his mother having an acute myocardial infarction at age 29 years. He had a history of several psychiatric hospitalizations due to attempted suicides. He had been diagnosed with bipolar disorder, borderline personality disorder, and attention-deficit/hyperactivity disorder, which were treated with methylphenidate, dexamfetamine, and alprazolam. He also experienced asthma, which was treated with a combination of budesonide/formoterol.\n\nAt the age of 30 years, he started testosterone undecanoate, 1000 mg every 12 weeks, with the administration interval adjusted on the basis of testosterone levels. His levels of testosterone had been maintained within the normal physiologic range for the affirmed gender, ranging between 317 and 808 ng/dL (11 to 28 nmol/L). He underwent bilateral mastectomy and total hysterectomy with bilateral oophorectomy at the age of 30 and 31 years, respectively. One year later, vaginectomy and creation of a neopenis were performed.\n\nAt the age of 30 years, with an LDL-C level of 321 mg/dL (8.3 mmol/L), he was started on simvastatin 40 mg/d (Fig. 1). After an initial response to therapy, his LDL-C went back to the baseline level of 344 mg/dL (8.9 mmol/L) because of lack of compliance. Thus, at the age of 33 years, he was started on rosuvastatin 40 mg/d, and ezetimibe 10 mg/d was added 5 months later. He continued this therapy for 9 months and had 220 mg/dL (5.7 mmol/L) as the lowest level of LDL-C. He developed side effects with rosuvastatin in the form of myalgia. Despite statin interruption and rechallenge, a dose reduction, and the change to atorvastatin therapy, the symptoms persisted and he discontinued statin treatment.\n\nFigure 1. Statin therapy was started in this patient in October 2011 because of an LDL-C level of 321 mg/dL (8.3 mmol/L). TC, total cholesterol; TG, triglycerides.\n\nIn the Lipid Clinic, the patient presented with xanthelasma bilaterally and a body mass index of 19.8 kg/m2; no diabetes, hypertension, or symptoms of cardiovascular disease were present. He was smoking ∼15 to 20 cigarettes a day. With ezetimibe 10 mg/d, routine laboratory tests showed the following values: total cholesterol, 360 mg/dL (9.3 mmol/L); triglycerides, 186 mg/dL (2.1 mmol/L); LDL-C, 298 mg/dL (7.7 mmol/L); HDL-C, 54 mg/dL (1.4 mmol/L); and lipoprotein(a), <0.1 g/L. Heterozygous FH was diagnosed by targeted next-generation sequencing [5]. In particular, a c.1012T>G mutation in the low-density lipoprotein receptor (LDLR), resulting in an amino acid change from cysteine to glycine at position 338 (LDLR p.Cys338Gly), was detected. No pathogenic mutations were observed in PCSK9 or APOB. Given the patient’s high LDL-C levels with genetically diagnosed FH and family history of premature cardiovascular disease, in June 2016 he was started on a PCSK9 inhibitor (evolocumab 140 mg every 2 weeks). After 1 month, his LDL-C level was 189 mg/dL (4.9 mmol/L), and it remained in this range for 22 months, with minimum and maximum values of 159 mg/dL (4.1 mmol/L) and 186 mg/dL (4.8 mmol/L), respectively. No adverse events were reported.\n\n2. Discussion\nGender-affirming treatment is a multidisciplinary effort that includes mental health care, hormone therapy, and/or surgical therapy [1]. In female-to-male transgender individuals, testosterone is the main hormonal agent used to induce virilization [2]. Potential adverse effects of excessive androgen therapy are erythrocytosis, sleep apnea, hypertension, excessive weight gain, salt retention, lipoprotein changes, and acne [1]. With regard to testosterone-induced lipoprotein changes, a recent review and meta-analysis on testosterone therapy in female-to-male transgender individuals found that sex steroid therapy was associated with a more atherogenic lipid profile, resulting in higher circulating triglyceride levels at ≥24 months (+21.4 mg/dL; 95% CI: 0.14 to 42.6 mg/dL), higher LDL-C levels at ≥24 months (+17.8 mg/dL; 95% CI: 3.5 to 32.1 mg/dL), and lower HDL-C levels at ≥24 months (−8.5 mg/dL; 95% CI: −13.0 to −3.9 mg/dL) [3].\n\nFH is a genetic disease characterized by high LDL-C levels due to decreased clearance of this lipoprotein, most commonly because of mutations in LDLR, PCSK9, or APOB [4]. This patient was a carrier of a nonsynonymous mutation, potentially inducing a loss of function in the LDLR [6]. As a result of the reduced clearance, a more pronounced deleterious effect on lipoproteins was expected with testosterone administration in this patient.\n\nIn patients with FH, intensive lipid-lowering therapy should be initiated soon after diagnosis, using high doses of high-potency statins (atorvastatin/rosuvastatin) and ezetimibe. However, in the “real world,” myalgia is often a side effect of statins, resulting in medication discontinuation or poor compliance. PSCK9 inhibitors have resulted in an LDL-C decrease of 50% to 65% in patients with FH [7] and are effective in reducing the risk of major cardiovascular events [8–10]. In this patient, LDL-C goals were not attained with statin therapy and his LDL-C levels were relapsing, most likely because of poor compliance due to the occurrence of side effects. Ezetimibe alone was not sufficient to provide adequate control of lipoprotein levels. Given his genetic diagnosis of FH, smoking habit, and premature family history of cardiovascular disease, we decided to start PCSK9 inhibitor therapy to reduce his LDL-C levels. After commencement of this therapy, the patient had a sustained 40% reduction in LDL-C levels for 23 months, ranging between 159 and 189 mg/dL (4.1 and 4.9 mmol/L). Although these LDL-C levels may still be considered suboptimal, they may also be regarded as satisfactory.\n\n3. Conclusion\nIn this case of PCSK9 inhibitor therapy in a statin-intolerant transgender man affected by FH, a sustained and well-tolerated reduction in LDL-C levels was observed.\n\nAcknowledgments\n\nFinancial Support: This work was supported by project grants from Amgen and Sanofi-Aventis, the Swedish Research Council (Vetenskapsrådet, 2016-01527), the Swedish state under the agreement between the Swedish government and the county councils [(the ALF-agreement); SU 2018-04276], a Novo Nordisk Foundation Grant for Excellence in Endocrinology (Excellence Project, 9321-430), the Swedish Diabetes Foundation (DIA 2017-205), the Swedish Heart Lung Foundation (20120533), and the Wallenberg Academy Fellows from the Knut and Alice Wallenberg Foundation (KAW 2017.0203), all to S.R.\n\n\nDisclosure Summary: S.R. has received consulting and lecturing fees from Amgen, Sanofi, and Akcea in the last 3 years. He has received consulting fees from Akcea, Astrazeneca, Pfizer, Celgene, CAMP4, and GSK. The remaining authors have nothing to disclose.\n\nAbbreviations:\nFHfamilial hypercholesterolemia\n\nHDL-Chigh-density lipoprotein cholesterol\n\nLDL-Clow-density lipoprotein cholesterol\n\nLDLRlow-density lipoprotein receptor\n\nPCSK9proprotein convertase subtilisin/kexin type 9\n==== Refs\nReferences and Notes\n1. \nHembree WC , Cohen-Kettenis PT , Gooren L , Hannema SE , Meyer WJ , Murad MH , Rosenthal SM , Safer JD , Tangpricha V , T’Sjoen GG \nT’Sjoen GG. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline . Endocr Pract . 2017 ;23 (12 ):1437 .29320642 \n2. \nVelho I , Fighera TM , Ziegelmann PK , Spritzer PM \nEffects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review . Andrology . 2017 ;5 (5 ):881 –888 .28709177 \n3. \nMaraka S , Singh Ospina N , Rodriguez-Gutierrez R , Davidge-Pitts CJ , Nippoldt TB , Prokop LJ , Murad MH \nSex steroids and cardiovascular outcomes in transgender individuals: a systematic review and meta-analysis . J Clin Endocrinol Metab . 2017 ;102 (11 ):3914 –3923 .28945852 \n4. \nGidding SS , Champagne MA , de Ferranti SD , Defesche J , Ito MK , Knowles JW , McCrindle B , Raal F , Rader D , Santos RD , Lopes-Virella M , Watts GF , Wierzbicki AS ; American Heart Association Atherosclerosis, Hypertension, and Obesity in Young Committee of Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and Council on Lifestyle and Cardiometabolic Health . The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association . Circulation . 2015 ;132 (22 ):2167 –2192 .26510694 \n5. \nMaglio C , Mancina RM , Motta BM , Stef M , Pirazzi C , Palacios L , Askaryar N , Borén J , Wiklund O , Romeo S \nGenetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing . J Intern Med . 2014 ;276 (4 ):396 –403 .24785115 \n6. \nLombardi MP , Redeker EJ , Defesche JC , Kamerling SW , Trip MD , Mannens MM , Havekes LM , Kastelein JJ \nMolecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in the Netherlands . Clin Genet . 2000 ;57 (2 ):116 –124 .10735632 \n7. \nDefesche JC , Gidding SS , Harada-Shiba M , Hegele RA , Santos RD , Wierzbicki AS \nFamilial hypercholesterolaemia . Nat Rev Dis Primers . 2017 ;3 (1 ):17093 .29219151 \n8. \nSabatine MS , Giugliano RP , Keech AC , Honarpour N , Wiviott SD , Murphy SA , Kuder JF , Wang H , Liu T , Wasserman SM , Sever PS , Pedersen TR ; FOURIER Steering Committee and Investigators . Evolocumab and clinical outcomes in patients with cardiovascular disease . N Engl J Med . 2017 ;376 (18 ):1713 –1722 .28304224 \n9. \nSchwartz GG , Steg PG , Szarek M , Bhatt DL , Bittner VA , Diaz R , Edelberg JM , Goodman SG , Hanotin C , Harrington RA , Jukema JW , Lecorps G , Mahaffey KW , Moryusef A , Pordy R , Quintero K , Roe MT , Sasiela WJ , Tamby JF , Tricoci P , White HD , Zeiher AM ; ODYSSEY OUTCOMES Committees and Investigators . Alirocumab and cardiovascular outcomes after acute coronary syndrome . N Engl J Med . 2018 ;379 (22 ):2097 –2107 .30403574 \n10. \nRidker PM , Revkin J , Amarenco P , Brunell R , Curto M , Civeira F , Flather M , Glynn RJ , Gregoire J , Jukema JW , Karpov Y , Kastelein JJP , Koenig W , Lorenzatti A , Manga P , Masiukiewicz U , Miller M , Mosterd A , Murin J , Nicolau JC , Nissen S , Ponikowski P , Santos RD , Schwartz PF , Soran H , White H , Wright RS , Vrablik M , Yunis C , Shear CL , Tardif JC ; SPIRE Cardiovascular Outcome Investigators . Cardiovascular efficacy and safety of bococizumab in high-risk patients . N Engl J Med . 2017 ;376 (16 ):1527 –1539 .28304242\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2472-1972",
"issue": "3(8)",
"journal": "Journal of the Endocrine Society",
"keywords": "PCSK9 inhibitors; familial hypercholesterolemia; gender dysphoria; lipoproteins; testosterone",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
"other_id": null,
"pages": "1461-1464",
"pmc": null,
"pmid": "31380502",
"pubdate": "2019-08-01",
"publication_types": "D002363:Case Reports",
"references": "10735632;24785115;26510694;28304224;28304242;28709177;28945852;29219151;29320642;30403574",
"title": "PCSK9 Inhibitors in a Statin-Intolerant Transgender Man With Heterozygous Familial Hypercholesterolemia: A Case Report.",
"title_normalized": "pcsk9 inhibitors in a statin intolerant transgender man with heterozygous familial hypercholesterolemia a case report"
} | [
{
"companynumb": "SE-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-229794",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"dr... |
{
"abstract": "Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP.\n\n\n\nComprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate.\n\n\n\nOne hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types.\n\n\n\nSite-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.",
"affiliations": "1 Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;1 Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;3 Chiba University, Chiba, Japan.;3 Chiba University, Chiba, Japan.;4 Osaka City General Hospital, Osaka, Japan.;4 Osaka City General Hospital, Osaka, Japan.;5 Hyogo Cancer Center, Akashi, Japan.;5 Hyogo Cancer Center, Akashi, Japan.;6 National Cancer Center Hospital East, Kashiwa, Japan.;6 National Cancer Center Hospital East, Kashiwa, Japan.;7 Kobe University Graduate School of Medicine, Kobe, Japan.;7 Kobe University Graduate School of Medicine, Kobe, Japan.;8 Shizuoka Cancer Center, Nagaizumi, Japan.;8 Shizuoka Cancer Center, Nagaizumi, Japan.;1 Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;1 Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;9 Wakayama Medical University, Wakayama, Japan.;10 Keio University, Tokyo, Japan.;11 Chuo University, Hachioji, Japan.;1 Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;1 Kindai University Faculty of Medicine, Osaka-Sayama, Japan.",
"authors": "Hayashi|Hidetoshi|H|;Kurata|Takayasu|T|;Takiguchi|Yuichi|Y|;Arai|Makoto|M|;Takeda|Koji|K|;Akiyoshi|Kohei|K|;Matsumoto|Koji|K|;Onoe|Takuma|T|;Mukai|Hirofumi|H|;Matsubara|Nobuaki|N|;Minami|Hironobu|H|;Toyoda|Masanori|M|;Onozawa|Yusuke|Y|;Ono|Akira|A|;Fujita|Yoshihiko|Y|;Sakai|Kazuko|K|;Koh|Yasuhiro|Y|;Takeuchi|Ayano|A|;Ohashi|Yasuo|Y|;Nishio|Kazuto|K|;Nakagawa|Kazuhiko|K|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016190:Carboplatin; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.18.00771",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "37(7)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016190:Carboplatin; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009382:Neoplasms, Unknown Primary; D017239:Paclitaxel; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D000077982:Progression-Free Survival; D011446:Prospective Studies; D013997:Time Factors; D059467:Transcriptome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "570-579",
"pmc": null,
"pmid": "30653423",
"pubdate": "2019-03-01",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site.",
"title_normalized": "randomized phase ii trial comparing site specific treatment based on gene expression profiling with carboplatin and paclitaxel for patients with cancer of unknown primary site"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2019INT000240",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drug... |
{
"abstract": "Erythrodermic psoriasis (EP) is the most serious type of psoriasis with high morbidity and mortality. First-line recommended therapies for EP, cyclosporine and infliximab have significant adverse effects. Cyclosporine increases the risk of hypertension, leucopenia, infections and renal failure. Infliximab increases the risk of reactivation of tuberculosis, hepatitis B and histoplasmosis, and increases risk for hepatitis, autoantibody formation, congestive heart failure, demyelinating disorders, pancytopenia, lymphoma and skin cancer. An effective drug with a much safer side effect profile will be of significant benefit in EP. The phosphodiesterase 4 inhibitor apremilast is U.S Food and Drug Administration (FDA) approved for plaque psoriasis and psoriatic arthritis. Adverse effects of apremilast reported are headache, nausea, diarrhoea, upper respiratory tract infection, potential for depression and weight loss. We report complete and long-standing resolution of EP with first-line apremilast monotherapy. Apremilast may be an effective option with comparatively minor side effects for EP.",
"affiliations": "Internal Medicine, St. Joseph Mercy Oakland Hospital, Pontiac, Michigan, USA.;Pulmonary/Critical Care, Henry Ford Hospital, Detroit, Michigan, USA.;Pathology, Henry Ford Hospital, Detroit, Michigan.",
"authors": "Krishnamoorthy|Geetha|G|;Kotecha|Aditya|A|http://orcid.org/0000-0002-0139-4406;Pimentel|Jason|J|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013792:Thalidomide; C505730:apremilast",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226959",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(1)",
"journal": "BMJ case reports",
"keywords": "dermatology; healthcare improvement and patient safety; medical management",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D003873:Dermatitis, Exfoliative; D006801:Humans; D008297:Male; D008875:Middle Aged; D011537:Pruritus; D011565:Psoriasis; D000067251:Symptom Flare Up; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30709830",
"pubdate": "2019-01-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28856115;25973439;2967779;14660268;26220911;29367871;4224242;29034298;27726163;10192155;27942369;29663615;8369577;25752640;2530253;22257911;26273164;8621827;19665821;25681953;22413927;9167333",
"title": "Complete resolution of erythrodermic psoriasis with first-line apremilast monotherapy.",
"title_normalized": "complete resolution of erythrodermic psoriasis with first line apremilast monotherapy"
} | [
{
"companynumb": "US-CELGENEUS-USA-20190201270",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"drugadditional": "3",
... |
{
"abstract": "Diarrhea after liver transplantation is a common complication. Vasoactive intestinal peptide-producing tumor (VIPoma) is a rare cause of watery diarrhea; 80% of such tumors occur in the pancreas, but it is rare in liver. Hypersecretion of vasoactive intestinal polypeptide can stimulate intestinal water and electrolyte secretion, and patients with VIPoma present with watery diarrhea, hypokalemia, and dehydration. Here we report on a 50-year-old man who presented with a 7-month history of watery diarrhea. He had undergone an orthotopic split-liver transplantation for hepatocellular carcinoma in November 2011. Two months after the liver transplantation, he presented with watery diarrhea, dehydration, and hypokalemia. Antibiotics, immunosuppressive drugs modification, antidiarrheal agents, antispasmodics, adsorbents, and fasting were alternately used to control the diarrhea, but his symptoms remained unchanged. A chromogranin examination, a marker of pancreatic neuroendocrine neoplasm, was positive in the third month of the diarrhea history and VIPoma was considered. Treatment with somatostatin immediately controlled the diarrhea, but the primary lesion could not be identified even after corresponding examinations were completed. In the ninth month of diarrhea, a 1 × 1-cm lesion was detected in the right liver by ultrasonography. Radiofrequency ablation was performed, and the diarrhea stopped. Seventeen months later, the chromogranin level decreased to normal and the patient was asymptomatic. Neither the recipient sharing the other liver portion nor the donor presented with any symptoms, so we wondered how the tumor occurred. It is possible that a small VIPoma lesion existed in the liver donor before the transplantation, and that the immunosuppressive drugs induced tumor development.",
"affiliations": "Department of Liver Transplantation Center, West China Hospital of Sichuan University, Sichuan Province, China.;Department of Liver Transplantation Center, West China Hospital of Sichuan University, Sichuan Province, China.;Department of Liver Transplantation Center, West China Hospital of Sichuan University, Sichuan Province, China.;Department of Liver Transplantation Center, West China Hospital of Sichuan University, Sichuan Province, China. Electronic address: yanlunan_688@163.com.",
"authors": "Haiqing|W|W|;Jiayin|Y|Y|;Jian|Y|Y|;Lunan|Y|Y|",
"chemical_list": "D014660:Vasoactive Intestinal Peptide; D013004:Somatostatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D003967:Diarrhea; D006801:Humans; D007008:Hypokalemia; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D013004:Somatostatin; D014660:Vasoactive Intestinal Peptide; D003969:Vipoma",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "171-3",
"pmc": null,
"pmid": "25596962",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intractable and dramatic diarrhea in liver transplantation recipient with vasoactive intestinal peptide-producing tumor after split liver transplantation: a case report.",
"title_normalized": "intractable and dramatic diarrhea in liver transplantation recipient with vasoactive intestinal peptide producing tumor after split liver transplantation a case report"
} | [
{
"companynumb": "CN-ROXANE LABORATORIES, INC.-2016-RO-00172RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditi... |
{
"abstract": "A 54-year-old man was treated with mycophenolate mofetil (MMF) after undergoing living donor renal transplantation. Two years later, he experienced repeated episodes of diarrhea, and his C-reactive protein (CRP) level was found to be 12.63 mg/dL. Ileocolonoscopy showed multiple deep, punched-out ulcers that were similar to Behçet's disease (BD) and cytomegalovirus (CMV) in the ileum. CMV infection was suspected. However, anti-cytomegalovirus agents were ineffective. The patient was subsequently diagnosed with gastrointestinal toxicity of MMF and MMF was switched to mizoribine. His symptoms improved immediately, and his CRP level normalized. Six months later, the patient's mucosa was healed.",
"affiliations": "Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.;Department of Gastroenterology, Oita University, Japan.",
"authors": "Sonoda|Akira|A|;Wada|Kurato|K|;Mizukami|Kazuhiro|K|;Fukuda|Kensuke|K|;Shuto|Mitsutaka|M|;Okamoto|Kazuhisa|K|;Ogawa|Ryo|R|;Okimoto|Tadayoshi|T|;Murakami|Kazunari|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D002097:C-Reactive Protein; D009173:Mycophenolic Acid",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.8815-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2894356610.2169/internalmedicine.8815-17Case ReportDeep Ulcers in the Ileum Associated with Mycophenolate Mofetil Sonoda Akira 1Wada Kurato 1Mizukami Kazuhiro 1Fukuda Kensuke 1Shuto Mitsutaka 1Okamoto Kazuhisa 1Ogawa Ryo 1Okimoto Tadayoshi 1Murakami Kazunari 1\n1 Department of Gastroenterology, Oita University, JapanCorrespondence to Dr. Akira Sonoda, load2akr@oita-u.ac.jp\n\n25 9 2017 1 11 2017 56 21 2883 2886 4 1 2017 6 3 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 54-year-old man was treated with mycophenolate mofetil (MMF) after undergoing living donor renal transplantation. Two years later, he experienced repeated episodes of diarrhea, and his C-reactive protein (CRP) level was found to be 12.63 mg/dL. Ileocolonoscopy showed multiple deep, punched-out ulcers that were similar to Behçet's disease (BD) and cytomegalovirus (CMV) in the ileum. CMV infection was suspected. However, anti-cytomegalovirus agents were ineffective. The patient was subsequently diagnosed with gastrointestinal toxicity of MMF and MMF was switched to mizoribine. His symptoms improved immediately, and his CRP level normalized. Six months later, the patient's mucosa was healed. \n\nmycophenolate mofetilgastrointestinal toxicityileal ulcerrenal transplantation\n==== Body\nIntroduction\nMycophenolate mofetil (MMF) is widely used for immunosuppression therapy in organ transplant recipients. Although its association with gastrointestinal (GI) toxicity (including diarrhea) is well known, there have been few reports of the associated endoscopic findings. We herein present the case of a patient who developed deep ulcers in the ileum and who improved after the withdrawal of MMF.\n\nCase Report\nA 54-year-old man underwent living donor renal transplantation in 20XX, after which he was treated with MMF (1 g/day), tacrolimus (3 mg/day), and methylprednisolone (4 mg/day). His relevant history included cholecystectomy at 44 years of age. His father was diagnosed with pulmonary tuberculosis. He had no history of non-steroidal anti-inflammatory drug use.\n\nTwo years after the transplant, the patient developed watery diarrhea, which occurred 5-6 times a day. Ileocolonoscopy showed multiple deep ulcers in the ileum (Fig. 1a-c). The pathological findings showed mild crypt distortion (Fig. 1d). Interferon gamma release assays (T-SPOTⓇ, Oxford Immunotec, Abingdon, UK) were positive, but a mucosal culture and a PCR for tuberculosis were both negative. Immunostaining for cytomegalovirus (CMV) was negative, and CMV-C7HRP-positive cells were present at only at one cell per 5×104 peripheral blood leukocytes in the patient's serum; however, CMV infection was suspected based on the form of the ulcer. However, treatment with valganciclovir (VGCV 900 mg/day) for 22 days was ineffective, and his symptoms worsened. He was then admitted to our hospital on day 22. At the time, his vital signs were normal and skin, eyes, and genitals were not involved; however, the frequency of his diarrhea episodes had increased to >10 times/day and the laboratory data showed a highly elevated C-reactive protein (CRP) level (12.63 mg/dL). On the other hand, the patient was negative for CMV-C7HRP. The other laboratory data are shown in Table. Total parenteral nutrition (TPN) improved his symptoms and CRP levels. However, bloody stools were seen and the ulcer grew larger on day 24. The antiviral agents were then switched to ganciclovir (GCV, 125 mg on the first day, and 62.5 mg daily thereafter). Oral feeding was started on day 29, and soon his symptoms and CRP level worsened. On day 32, the ulcer in the ileum became even larger and deeper (Fig. 2). Because the clinical course was considered to be unusual for a CMV infection, GI toxicity of MMF was suspected, and the patient was switched from MMF to mizoribine (MZR, 100 mg/day). His symptoms improved immediately, and his CRP level normalized. Six months later, the ileal mucosa was healed (Fig. 3). The patient's clinical course is shown in Fig. 4.\n\nFigure 1. The endoscopic and pathological findings on admission. a-c: The endoscopic findings on admission. Multiple punched-out ulcers were seen in the ileum. d: The pathological findings. Mild crypt distortion was seen.\n\nTable. Laboratory Data on Admission.\n\nWBC\t6,370/μL\tTP\t6.11 g/dL\tCRP\t12.63 mg/dL\t\nSTAB\t12.0%\tALB\t3.55 g/dL\t\t\t\nSEG\t77.0%\tT-bil\t0.53 mg/dL\tMMF\t2.3 μg/mL(1.0-3.0)\t\nLYMP\t3.0%\tAST\t22.4 IU/L\tTacrolimus\t8.6 ng/mL\t\nMONO\t5.0%\tALT\t12.9 IU/L\t\t\t\nEOS\t3.0%\tALP\t436 IU/L\tCMV-C7HRP : negative\t\nRBC\t466×104/μL\tγ-GTP\t34.5 IU/L\tIGRAs : positive\t\nHb\t13.8 g/dL\tLDH\t268 IU/L\tBlood culture : negative\t\nHCT\t39.5%\tBUN\t15.6 mg/dL\tStool culture : normal flora\t\nMCV\t84.8 fL\tCr\t1.43 mg/dL\t\t\t\nMCH\t29.6 pg\t\t\t\t\t\nMCHC\t34.9%\t\t\t\t\t\nPLT\t27.0×104/μL\t\t\t\t\t\nMMF: mycophenolate mofetil, CMV: cytomegalovirus, IGRAs: interferon-gamma release assays\n\nFigure 2. The endoscopic findings one month after the administration of antiviral agents. a, b: One month after the initiation of antiviral therapy. The patient’s ulcers were observed to have become bigger and deeper.\n\nFigure 3. Endoscopic findings at six months after the withdrawal of MMF. The ileal mucosa was observed to have healed. MMF: mycophenolate mofetil\n\nFigure 4. The clinical course of the present case. The patient’s CMV-C7HRP level became negative after the administration of antiviral therapy; however, his diarrhea and CRP levels worsened with the start of oral feeding. The symptoms improved and a negative CRP level was achieved by switching MMF to MZR. VGCV: valganciclovir, GCV: ganciclovir, MMF: mycophenolate mofetil, MZR: mizoribine, TPN: total parenteral nutrition, ICS: ileo-colonoscopy, PBLs: peripheral blood leukocytes\n\nDiscussion\nCombination therapy with prednisolone, tacrolimus, and MMF is recommended as the first-line immunosuppressive treatment to prevent rejection in patients after organ transplantation (1). GI toxicity is a well-known side effect of MMF. Diarrhea, which occurs in 8.3% of cases, is the most frequent symptom (2). The mechanism of this side effect is thought to involve an acyl glucuronide of mycophenolic acid (MPA), one of the MMF metabolites, which was found to induce the production of pro-inflammatory cytokines such as IL-6 and TNF-alpha (3).\n\nThe pathological examination of the intestinal ulcers associated with MMF reveals various findings, including neutrophil infiltration, crypt abscess, crypt distortion, crypt loss, and epithelial apoptosis (4-8). These findings are non-specific, and the condition cannot be diagnosed based on the pathological findings. In comparison, far fewer reports have described the endoscopic findings. To the best our knowledge, there have only been two case reports. One showed multiple shallow ulcers in the colon (8); the other showed a longitudinal ulcer similar to Crohn's disease in the colon (9). In the present case, endoscopy revealed deep and punched-out ulcers that were similar to Behçet's disease (BD), simple ulcer (SU), or CMV infection. In fact - despite the patient's low CMV-C7HRP level - CMV infection was initially suspected based on the form of the ulcer. The patient's CMV C7-HRP level became negative after the administration of antiviral agents, but the ulcer worsened. Furthermore, immunostaining for CMV was negative. This series of events made CMV infection unlikely. GCV and MZR are known to show anti-CMV activity and synergism, and it is difficult to rule out CMV infection completely; however, we think that it is reasonable to suggest that the patient's CMV infection was subclinical and that GI toxicity of MMF was the highly likely cause of the patient's symptoms (10).\n\nIn Japan, MZR is most often used for post-transplant patients who cannot tolerate MMF due to its side effects; thus, MMF was discontinued and MZR was started (11). In the present case, we did not observe any signs that were suggestive of BD, such as skin, oral, or genital lesions. There have been some reports of the development of oral ulcers as an adverse effect of MMF (12, 13). If oral ulcers had been seen in the present patient, it might have been difficult to distinguish his condition from BD.\n\nThe endoscopic appearance of an SU is quite similar to the appearance of an intestinal ulcer of BD. A MEDLINE search of the literature up to February 2017, which was performed using the search terms “simple ulcer” and “mycophenolate mofetil or mizoribine”, yielded no reports. Thus, there seems to be no relationship between SU and MMF or MZR.\n\nSome intestinal ulcers associated with MMF may be difficult to distinguish from BD, SU or CMV infection. It is not possible to make an accurate diagnosis based on the pathological findings and it is important to be aware that the form of ulcers associated with MMF might vary.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nThe authors would like to thank all of the staff of Oita University Hospital who took care of the patient.\n==== Refs\n1. \nChadban SJ , Barraclough KA , Campbell SB , et al \nKHA-CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients . Nephrology (Carlton) \n17 : 204 -214 , 2012 .22212251 \n2. \nIida M , Fukuda T , Ikegame K , et al \nUse of mycophenolate mofetil in patients received allogeneic hematopoietic stem cell transplantation in Japan . Int J Hematol \n93 : 523 -531 , 2011 .21465117 \n3. \nWieland E , Shipkova M , Schellhaas U , et al \nInduction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects? \nClin Biochem \n33 : 107 -113 , 2000 .10751588 \n4. \nMaes BD , Dalle I , Geboes K , et al \nErosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea . Transplantation \n75 : 665 -672 , 2003 .12640307 \n5. \nParfitt JR , Jayakumar S , Driman DK \nMycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including Graft-Versus-Host Disease-Like Changes . Am J Surg Pathol \n33 : 1355 -1363 , 2009 .19542873 \n6. \nAl-Absi AI , Cooke CR , Wall BM , et al \nPatterns of Injury in Mycophenolate mofetil-Related Colitis . Transplant Proc \n42 : 3591 -3593 , 2010 .21094821 \n7. \nLiapis G , Boletis J , Skalioti C , et al \nHistological spectrum of mycophenolate mofetil-related colitis: association with apoptosis . Histopathology \n63 : 649 -658 , 2013 .24025088 \n8. \nLiu TC , Amorosino MS , Cerda S , Farraye FA \nMycophenolate mofetil-associated enterocolitis . Gastrointest Endosc \n63 : 707 -708 , 2006 .16564882 \n9. \nDost D , van Leerdam ME , van Dekken H , et al \nCrohn's-like enterocolitis associated with mycophenolic acid treatment . Gut \n57 : 1330 , 2008 .\n10. \nKuramoto T , Daikoku T , Yoshida Y , et al \nNovel anticytomegalovirus activity of immunosuppressant mizoribine and its synergism with ganciclovir . J Pharmacol Exp Ther \n333 : 816 -821 , 2010 .20194528 \n11. \nKalluri HV , Hardinger KL \nCurrent state of renal transplant immunosuppression: present and future . World J Transplant \n2 : 51 -68 , 2012 .24175197 \n12. \nNaranjo J , Poniachik J , Cisco D , et al \nOral ulcers produced by mycophenolate mofetil in two liver transplant Patients . Transplant Proc \n39 : 612 -614 , 2007 .17445557 \n13. \nSavas N , Sevmis S , Karakayali H , Yilmaz U , Haberal M \nOrogenital ulcers in a liver transplant recipient: discerning between mycophenolate-mofetil-induced complication and Behcet's disease . Clin Transplant \n23 : 147 -149 , 2009 .19191805\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "gastrointestinal toxicity; ileal ulcer; mycophenolate mofetil; renal transplantation",
"medline_ta": "Intern Med",
"mesh_terms": "D002097:C-Reactive Protein; D006084:Graft Rejection; D006801:Humans; D007077:Ileal Diseases; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D014456:Ulcer",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2883-2886",
"pmc": null,
"pmid": "28943566",
"pubdate": "2017-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24025088;19191805;24175197;21465117;17445557;18763324;22212251;18719142;16564882;12640307;20194528;10751588;21094821",
"title": "Deep Ulcers in the Ileum Associated with Mycophenolate Mofetil.",
"title_normalized": "deep ulcers in the ileum associated with mycophenolate mofetil"
} | [
{
"companynumb": "JP-ROCHE-2033161",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"dru... |
{
"abstract": "Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2- metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial.\n\n\n\nIn the present prospective analysis of hormone receptor-positive (HR+)/HER2- and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity.\n\n\n\nWe enrolled 54 HR+ and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR+ and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR+ and TN patients, respectively). The median OS was 17.9 months for HR+ patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment.\n\n\n\nIxabepilone plus carboplatin is active even in later-line HR+ and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.",
"affiliations": "US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology, Baylor-Sammons Cancer Center, Dallas, TX. Electronic address: Cynthia.Osborne@USONCOLOGY.com.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology, Wichita Falls, KS.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Cancer Centers of North Carolina, Raleigh, NC.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology-Houston Memorial City, Houston, TX.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Kansas City Cancer Center-Southwest, Overland Park, KS.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Maryland Oncology Hematology PA, Columbia, MD.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology-Methodist Charlton Cancer Center, Dallas, TX.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology-Tyler, Tyler, TX.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology-San Antonio, San Antonio, TX.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Comprehensive Cancer Centers of Nevada, Henderson, NV.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology, Wichita Falls, KS.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Rocky Mountain Cancer Centers, Denver, CO.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX.;US Oncology Research, McKesson Specialty Health, The Woodlands, TX; Texas Oncology, Baylor-Sammons Cancer Center, Dallas, TX.",
"authors": "Osborne|Cynthia|C|;Challagalla|Jagathi D|JD|;Eisenbeis|Charles F|CF|;Holmes|Frankie Ann|FA|;Neubauer|Marcus A|MA|;Koutrelakos|Nicholas W|NW|;Taboada|Carlos A|CA|;Vukelja|Sasha J|SJ|;Wilks|Sharon T|ST|;Allison|Mary Ann|MA|;Reddy|Praveen|P|;Sedlacek|Scot|S|;Wang|Yunfei|Y|;Asmar|Lina|L|;O'Shaughnessy|Joyce|J|",
"chemical_list": "D034261:Epothilones; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016190:Carboplatin; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C430592:ixabepilone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2017.07.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "18(1)",
"journal": "Clinical breast cancer",
"keywords": "Carboplatin; HR+; Ixabepilone; MBC; TNBC",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D034261:Epothilones; D005221:Fatigue; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases; D000077982:Progression-Free Survival; D011446:Prospective Studies; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D066066:Response Evaluation Criteria in Solid Tumors; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "e89-e95",
"pmc": null,
"pmid": "28779904",
"pubdate": "2018-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer.",
"title_normalized": "ixabepilone and carboplatin for hormone receptor positive her2 neu negative and triple negative metastatic breast cancer"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US08631",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IXABEPILONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nMycotic aneurysms are an uncommon occurrence, withStaphylococcus and Salmonella species found to be the causative pathogen in up to 95% of cases. We believe this is the first described case of a common femoral artery mycotic aneurysm due to Listeria monocytogenes.\n\n\nMETHODS\nA 66-year-old male presented with a two-month history of an increasing painful mass in his left groin, on the background of immunosuppression treatment for ankylosing spondylitis. He was afebrile on assessment, with a normal white cell count. Contrast enhanced CT scan showed a common femoral artery aneurysm, with no infective features. His aneurysm was excised and repaired with a Dacron tube graft. L. monocytogenes was cultured from the aneurysm tissue, and he was commenced on appropriate antibiotic treatment. The prosthetic graft was also replaced with a venous bypass of the aneurysm.\n\n\nCONCLUSIONS\nL. monocytogenes is a rare cause of mycotic aneurysm with less than 40 cases reported in the literature. Immunosuppression is a recognised risk factor for Listerial infections. Immunocompromised patients may not display typical clinical or biochemical features associated with a mycotic aneurysm. Prosthetic graft infections are associated with significant mortality, with excision of the prosthetic material and venous reconstruction associated with good outcomes for eradicating infection.\n\n\nCONCLUSIONS\nThis report highlights the importance of obtaining intraoperative tissue samples for microbiological and histopathological assessment in immunocompromised patients. This is important for the detection of rare organisms such as L.monocytogenes, requiring targeted antibiotic therapy. Inappropriate treatment of Listerial infections can result in serious invasive illness.",
"affiliations": "Department of Vascular and Endovascular Surgery, Royal Perth Hospital, Perth, Australia. Electronic address: Tishanthan.Pathmarajah@health.wa.gov.au.;Department of Plastic and Reconstructive Surgery, Fiona Stanley Hospital, Perth, Australia.;Department of Vascular and Endovascular Surgery, Royal Perth Hospital, Perth, Australia.",
"authors": "Pathmarajah|T|T|;Chu|S|S|;Sieunarine|K|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2019.07.063",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(19)30445-610.1016/j.ijscr.2019.07.063ArticleA rare case of Listeria monocytogenes causing mycotic aneurysm of the common femoral artery: A case report Pathmarajah T. Tishanthan.Pathmarajah@health.wa.gov.aua⁎Chu S. bSieunarine K. aa Department of Vascular and Endovascular Surgery, Royal Perth Hospital, Perth, Australiab Department of Plastic and Reconstructive Surgery, Fiona Stanley Hospital, Perth, Australia⁎ Corresponding author at: 18 Rathlin Cove, Canning Vale, 6155 Australia. Tishanthan.Pathmarajah@health.wa.gov.au25 7 2019 2019 25 7 2019 61 238 241 5 3 2019 30 6 2019 22 7 2019 © 2019 The Authors2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Immunosuppressed patients may not display typical clinical or biochemical features associated with mycotic aneurysms.\n\n• Clinicians should have a high index of suspicion for infective aetiology when treating aneurysmal disease in immunocompromised patients.\n\n• It is important to obtain intraoperative tissue samples for histopathology and microbiological assessment in immunocompromised patients for detection of rare pathogens.\n\n• Autogenous vein should be used in infected surgical fields to avoid the risk of prosthetic graft infection.\n\n\n\nIntroduction\nMycotic aneurysms are an uncommon occurrence, withStaphylococcus and Salmonella species found to be the causative pathogen in up to 95% of cases. We believe this is the first described case of a common femoral artery mycotic aneurysm due to Listeria monocytogenes.\n\nPresentation of case\nA 66-year-old male presented with a two-month history of an increasing painful mass in his left groin, on the background of immunosuppression treatment for ankylosing spondylitis. He was afebrile on assessment, with a normal white cell count. Contrast enhanced CT scan showed a common femoral artery aneurysm, with no infective features. His aneurysm was excised and repaired with a Dacron tube graft. L. monocytogenes was cultured from the aneurysm tissue, and he was commenced on appropriate antibiotic treatment. The prosthetic graft was also replaced with a venous bypass of the aneurysm.\n\nDiscussion\nL. monocytogenes is a rare cause of mycotic aneurysm with less than 40 cases reported in the literature. Immunosuppression is a recognised risk factor for Listerial infections. Immunocompromised patients may not display typical clinical or biochemical features associated with a mycotic aneurysm. Prosthetic graft infections are associated with significant mortality, with excision of the prosthetic material and venous reconstruction associated with good outcomes for eradicating infection.\n\nConclusion\nThis report highlights the importance of obtaining intraoperative tissue samples for microbiological and histopathological assessment in immunocompromised patients. This is important for the detection of rare organisms such as L.monocytogenes, requiring targeted antibiotic therapy. Inappropriate treatment of Listerial infections can result in serious invasive illness.\n\nKeywords\nMycotic aneurysmListeriaGraft infectionFemoralCase report\n==== Body\n1 Introduction\nMycotic aneurysms are uncommon events, occurring in 3% of all arterial aneurysms [1]. The most common sites of mycotic aneurysm formation include the abdominal aorta (31%) and the femoral artery (38%) with the latter most commonly caused by iatrogenic or self-inflicted trauma e.g intravenous drug users. Although in the pre-antibiotic era, mycotic aneurysms were originally attributed to infective endocarditis, this is now a rare underlying cause and hematogenous seeding of a previously damaged atherosclerotic vessel is the commonest mechanism of infection. The most common organisms isolated from infected aneurysms are gram positive bacteria, accounting for 60% of cases, most commonly Staphylococci [2]. Gram negative bacteria (chiefly Salmonellae) can be isolated from 35% of cases [2]. Since the first published report of a Listeria monocytogenes infected aortic aneurysm in 1965, there have been less than 40 reported cases worldwide [[2], [3], [4], [5]] with majority involving the abdominal aorta. We believe this to be the first described case of a common femoral artery mycotic aneurysm due to L.monocytogenes.\n\nThis work has been reported in line with the SCARE criteria. [17]\n\n2 Case\nA 66-year-old male presented to his general practitioner with a two-month history of an increasing painful mass in his left groin associated with medial thigh paresthesia. He denied any fevers, infective symptoms and was otherwise systemically well. His past medical history included ankylosing spondylitis for which he was on long-term prednisolone (5 mg mane), and had commenced Infliximab infusions (400 mg 6-weekly) 10 months prior. Other significant medical history included ischemic heart disease with four coronary stents, and an open repair of an abdominal aortic aneurysm. On assessment he was hemodynamically stable and afebrile, and examination of his left groin revealed a tender pulsatile mass, with no overlying skin changes. Biochemistry revealed a normal white cell count.\n\nA duplex ultrasound showed a dilatation of the left common femoral artery suggestive of a possible pseudoaneurysm or mycotic aneurysm. This was further evaluated with a CT angiogram of the lower limbs which showed bilateral common femoral artery aneurysms associated with areas of arterial dissection. The left aneurysm extended 5.5 cm cranio-caudally, 4 cm transversely and 3.5 cm antero-posteriorly. (Fig. 1) The left distal common femoral artery was markedly stenosed as it draped over the aneurysm. The right aneurysm was 1.5 mm in maximal diameter and 2 cm in cranio-caudal length with moderate stenosis of the right distal common femoral artery. The CTA did not show any features suspicious for a mycotic aneurysm (Fig. 2)Fig. 1 A 3-dimensional reconstruction of the right femoral aneurysm in this patient as shown on CT angiogram. The actual size of the aneurysm including thrombus outlined.\n\nFig. 1Fig. 2 A 3-dimensional reconstruction of the femoral arteries showing the bilateral femoral aneurysms in this patient.\n\nFig. 2\n\nThe patient underwent an uncomplicated resection of the left common femoral artery aneurysm with repair performed using an 8 mm Dacron tube graft. Intraoperatively the vessel wall appeared normal, with no evidence of oedema or suppurative material in the surrounding tissue therefore an infective etiology was not suspected. The aneurysmal tissue specimen was sent for histopathological and microbiological testing. L. monocytogenes was cultured from this tissue. Histopathological examination of the aneurysmal wall and contents demonstrated hyaline fibrosis and focal dystrophic calcification accompanied by amorphous debris containing cholesterol crystals, foamy histiocytes, acute and chronic inflammatory cells, focal hemorrhage and neovascularization. There was also inflammation and fibrosis extending into the fatty tissue surrounding the large blood vessel.\n\nPerioperatively the patient was administered 2 g of cephalothin for surgical prophylaxis, with nil further antibiotics continued post operatively. With the isolation of L. monocytogenes, the patient was commenced on IV ampicillin 2 g QID and gentamicin 1 mg/kg/tds in accordance with the therapeutic guidelines. Due to the risk of prosthetic graft infection, the Dacron patch was replaced with a venous bypass of the aneurysm in a second operation. Microscopy and culture of the specimens taken at the second operation (femoral wall tissue, groin tissue, left groin swab and graft specimen) showed no residual evidence of L. monocytogenes. Post-operatively, the patient was continued on a total of 6 weeks of ampicillin. The contralateral aneurysm was treated at a later stage with excision and venous bypass. Microbiological testing of the aneurysmal tissue again demonstrated L. monocytogenes, which was treated in a similar manner with a prolonged course of oral antibiotics post-operatively.\n\n3 Discussion\nL. monocytogenes is a gram positive, non-sporulating, facultatively anaerobic bacillus. The organism is ubiquitous in soil and water and can be isolated in the gastrointestinal flora of animals and up to 5% of healthy human adults. L. monocytogenes is able to grow in a wide range of pH as well as at low temperatures; a feature that enables this organism to multiply in food stored at refrigeration temperatures [6,7]. The main route of transmission is via ingestion of contaminated food. Clinical manifestation of L. monocytogenes varies from self-limiting febrile gastroenteritis in normal hosts, to invasive disease including meningitis, meningoencephalitis or bacteremia in immunosuppressed adults. Ampicillin or amoxicillin has been the drug of choice in most L. monocytogenes infections. Cephalosporins have limited activity against the organism, with some patients progressing to develop listerial meningitis whilst on cephalosporin therapy. [6]\n\nThe rates of L. monocytogenes infection are highest among infants <1 month of age and adults > 60 years of age. [6] About 70% of all non-perinatal infections occur in immunosuppressed patients with hematological malignancies or AIDs, in transplant recipients and in patients on corticosteroid therapy [6]. Immunosuppressive states are also described as an independent risk factor for mycotic aneurysm formation. In a retrospective review of 43 patients treated for mycotic aneurysms, up to 70% were found to have immunosuppressive disorders [8]. Furthermore, patients with atherosclerosis, particularly older adults, are at risk for bacteremic seeding of atheromatous plaques [9]. In this case the patient had atherosclerotic disease of the arterial wall, and also systemic immunosuppression therefore increasing susceptibility to mycotic aneurysm formation.\n\nLeukocytosis is often seen in up to 70% of patients with mycotic aneurysms, however our patient had a normal white cell count. [10] In a review of 48 patients with infected aneurysms Hsu and Lin described the intraoperative presence of gross pus in 54% of patients, the authors concluding local purulent infection was associated with high risk of prosthetic graft infection and aneurysm related death [11]. Intraoperative examination of the aneurysm in our patient did not raise suspicion for an infective aetiology as there was no gross pus or necrotic tissue around the aneurysm. CT angiography is the most useful imaging modality for diagnosing an infected aneurysm, however no features of perivascular fluid collection, intramural/extravascular gas, or inflammation of the tissue surrounding the vessel was present in our case to suggest infective aetiology [12]. The lack of inflammatory response in our patient is most likely the result of his immunosuppressed state.\n\nThe management of infected aneurysms remains a challenge in current practice, with reported hospital mortality rates ranging from 16 to 44%. [13] Almost all untreated aneurysm eventually leads to rupture. No randomized controlled trials exist to guide the treatment of infected aneurysms, with management strategies primarily based upon clinical experience and available case series. The standard accepted treatment of infected aneurysms includes targeted antibiotic therapy in conjunction with surgical debridement with or without revascularization. Chu et al described 45 patients treated for infected mycotic aortic aneurysms, with 35 undergoing surgical debridement of the necrotic tissue and in-situ reconstruction with a prosthetic graft, while 11 were managed with antibiotic therapy alone. One-year mortality rate was 25% in the operative group versus 59% in the medical management group. The authors also noted that 30-day mortality rates were significantly lower in patients undergoing elective surgery in comparison to emergency surgery (0% vs 36%), highlighting urgent surgical intervention in patients with mycotic aneurysm is associated with poor prognosis [14].\n\nA significant concern with in-situ reconstruction with prosthetic graft material is the development of prosthetic graft infection. Prosthetic graft infections occur in 1%–6% of cases after vascular graft implantation procedures [13]. Intraoperative bacterial contamination is cited as the most common cause, with other causes including bacterial colonization of the thrombus or direct inoculation. Prosthetic vascular graft infection is associated with a mortality and amputation rate of up to 70% [13]. Chu et al reported 6 prosthetic graft complications (3 early and 3 late) amongst the 35 patients who underwent surgical debridement, with an associated 100% mortality rate among these patients [14]. Total excision of the infected graft, and extra-anatomical bypass is considered the gold standard of treatment; however is disadvantaged by low patency rate, re-infection of the new graft, and often persistent infection at the site of the vascular stump with blow out and life threatening haemorrhage reported in cases of aortic infection [15]. The use of rifampicin-impregnated grafts and silver coated grafts have been described for anatomical reconstruction, however they are still associated with significant rates of re-infection [16]\n\nThe use of autologous vein for arterial reconstruction for graft infection has been well described with good outcomes. Daenens et al described 49 patients with prosthetic graft infection who were successfully treated with autogenous vein reconstruction, with no incidence of reinfection. [16] Ehsan and Gibbons described a 10-year experience of using autogenous deep vein reconstruction for arterial and prosthetic graft infections, including 6 patients with mycotic aneurysm with two involving the femoral artery. The authors concluded autogenous vein was an excellent conduit for arterial reconstruction in the presence of infection, with venous bypass almost eliminating recurrent infection reducing risk of later graft rupture and minimizing mortality [15]. In this case we chose to replace the Dacron patch once infective aetiology was confirmed using an exclusion bypass of the aneurysm to minimize risk of prosthetic graft infection.\n\n4 Conclusion\nThis case highlights the need for a high index of suspicion for an infective aetiology when treating aneurysmal disease in immunocompromised patients. These patients may not display typical clinical or biochemical features seen in non-immunocompromised patients with mycotic aneurysms. It is important to obtain intraoperative specimens for microbiological and histopathological testing for unusual organisms in these patients, as routine antibiotic therapy may not be active against the causative organisms with inadequate treatment potentially resulting in more invasive illness. Furthermore, autogenous vein should be considered in infected surgical fields to avoid the risk of prosthetic graft infection.\n\nFunding\nNone.\n\nEthical approval\nThis case report was exempt from ethical approval at our institution.\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-in-Chief of this journal on request.\n\nAuthor contribution\nDr Tishanthan Pathmarajah – Study concept, gathering data, writing the paper.\n\nDr Sharon Chu – Study concept, gathering data, writing the paper.\n\nDr Kishore Sieunarine – Study concept, operating surgeon, editing the paper.\n\nRegistration of research studies\nNot applicable for this case report.\n\nGuarantor\nDr Tishanthan Pathmarajah.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nDeclaration of Competing Interest\nNone.\n==== Refs\nReferences\n1 Patra P. Ricco J.B. Costargent A. Goueffic Y. Pillet J.C. Chaillou P. Infected aneurysms of neck and limb arteries: a retrospective multicenter study Ann. Vasc. Surg. 15 2 2001 197 205 11265084 \n2 Clouse W.D. DeWitt C.C. Hagino R.T. DeCaprio J. Kashyap V.S. Rapidly enlarging iliac aneurysm secondary to listeria monocytogenes infection: a case report Vasc. Endovasc. Surg. 37 2 2003 145 149 \n3 Rohde H. Horstkotte M.A. Loeper S. Recurrent Listeria monocytogenes aortic graft infection: confirmation of relapse by molecular subtyping Diagn. Microbiol. Infect. Dis. 48 1 2004 63 67 14761724 \n4 Yokoyama E. Tsuruoka S. Saitou Y. Ichinohe S. [Isolation of Listeria monocytogenes from a patient with sealed ruptured thoracoabdominal aortic aneurysm] Kansenshogaku Zasshi 78 12 2004 1016 1019 15678977 \n5 Barkhordarian S. Harris A. Patterson R. Ruptured thoracic aortic aneurysm from listeria monocytogenes aortitis: a sentinel case Eur. J. Vasc. Endovasc. Surg. 30 1 2005 109 \n6 Lorber B. Listeriosis Clin. Infect. Dis. 24 1 1997 1 9 quiz 10-1 8994747 \n7 Wing E.J. Gregory S.H. Listeria monocytogenes: clinical and experimental update J. Infect. Dis. 185 Suppl 1 2002 S18 24 11865436 \n8 Oderich G.S. Panneton J.M. Bower T.C. Infected aortic aneurysms: aggressive presentation, complicated early outcome, but durable results J. Vasc. Surg. 34 2001 900 11700493 \n9 Kim Y.W. Infected aneurysm: current management Ann. Vasc. Dis. 3 1 2010 7 15 23555382 \n10 Hsu R.B. Chen R.J. Wang S.S. Chu S.H. Infected aortic aneurysms: clinical outcome and risk factor analysis J. Vasc. Surg. 40 2004 30 35 15218459 \n11 Hsu R.B. Lin F.Y. Surgical pathology of infected aortic aneurysm and its clinical correlation Ann. Vasc. Surg. 21 2007 742 17499963 \n12 Blair R.H. Resnik M.D. Polga J.P. CT appearance of mycotic abdominal aortic aneurysms J. Comput. Assist. Tomogr. 13 1989 101 104 2910923 \n13 Elens M. Dusoruth M. Astarci P. Mastrobuoni S. Bosiers M.J. Nardella J. Management and outcome of prosthetic vascular graft infections: a single center experience Vasc. Endovasc. Surg. 52 3 2018 181 187 \n14 Hsu R.-B. Chen R.J. Wang S.-S. Chu S.-H. Infected aortic aneurysms: clinical outcome and risk factor analysis J. Vasc. Surg. 40 2004 30 35 15218459 \n15 Ehsan O. Gibbons C.P. A 10-year experience of using femoro-popliteal vein for re-vascularisation in graft and arterial infections Eur. J. Vasc. Endovasc. Surg. 38 2 2009 172 179 19362498 \n16 Daenens K. Fourneau I. Nevelsteen A. Ten-year experience in autogenous reconstruction with the femoral vein in the treatment of aortofemoral prosthetic infection Eur. J. Vasc. Endovasc. Surg. 25 3 2003 240 245 12623336 \n17 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE group. The SCARE 2018 statement: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2210-2612",
"issue": "61()",
"journal": "International journal of surgery case reports",
"keywords": "Case report; Femoral; Graft infection; Listeria; Mycotic aneurysm",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "238-241",
"pmc": null,
"pmid": "31382235",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "11265084;11700493;11865436;12623336;12669148;14761724;15218459;15678977;17499963;19362498;23555382;2910923;29421969;30342279;8994747",
"title": "A rare case of Listeria monocytogenes causing mycotic aneurysm of the common femoral artery: A case report.",
"title_normalized": "a rare case of listeria monocytogenes causing mycotic aneurysm of the common femoral artery a case report"
} | [
{
"companynumb": "AU-BAUSCH-BL-2019-023418",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "The association of platelet reactivity and clinical outcomes, especially stent thrombosis, was not so clear. We sought to investigate whether high platelet reactivity affects clinical outcomes of patients with drug eluting stents (DESs) implantation.\n\n\n\nAll enrolled individuals treated with DESs implantation were evaluated by PL-11, using sequentially platelet counting method. The primary end point was the occurrence of definite and probable stent thrombosis at 2 years. The secondary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including all cause death, spontaneous myocardial infarction (MI), target vessel revascularization (TVR), and ischemic stroke.\n\n\n\nA total of 1331consecutive patients were enrolled at our center. There were 91 patients (6.8 %) identified with high platelet reactivity (HPR) on aspirin, and 437 patients (32.9 %) with HPR on clopidogrel. At 2-year follow-up, the incidence of stent thrombosis was significantly higher in patients with HPR on aspirin (9.9 % vs. 0.4 %, p < 0.001), and HPR on clopidogrel (3.0 % vs. 0.1 %, p < 0.001). There were increased MACCE in the HPR on aspirin group (16.5 % vs. 8.5 %, p = 0.021), mainly driven by the higher all cause death (7.7 % vs. 1.6 %, p = 0.002) and MI (9.9 % vs. 1.9 %, p < 0.001) in the HPR on aspirin group. Similarly, the rate of MACCE was higher in the HPR on clopidogrel group (12.4 % vs. 7.4 %, p = 0.004). No differences in all bleeding and hemorrhagic stroke were observed.\n\n\n\nThe present study demonstrated that high platelet reactivity on both aspirin and clopidogrel were associated with incremental stent thrombosis following DESs implantation.",
"affiliations": "Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China.;Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China.;Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China.;Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China.;Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China.;Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China.;Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China.;Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006, Nanjing, China. chmengx@126.com.",
"authors": "Zhang|Jun-Jie|JJ|;Gao|Xiao-Fei|XF|;Ge|Zhen|Z|;Tian|Nai-Liang|NL|;Liu|Zhi-Zhong|ZZ|;Lin|Song|S|;Ye|Fei|F|;Chen|Shao-Liang|SL|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1186/s12872-016-0394-0",
"fulltext": "\n==== Front\nBMC Cardiovasc DisordBMC Cardiovasc DisordBMC Cardiovascular Disorders1471-2261BioMed Central London 39410.1186/s12872-016-0394-0Research ArticleHigh platelet reactivity affects the clinical outcomes of patients undergoing percutaneous coronary intervention Zhang Jun-Jie 12Gao Xiao-Fei 1Ge Zhen 12Tian Nai-Liang 1Liu Zhi-Zhong 1Lin Song 1Ye Fei 1Chen Shao-Liang +86-25-52208048chmengx@126.com 121 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle road, 210006 Nanjing, China 2 Department of Cardiology, Nanjing Heart Center, Nanjing, China 29 11 2016 29 11 2016 2016 16 24013 9 2016 7 11 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe association of platelet reactivity and clinical outcomes, especially stent thrombosis, was not so clear. We sought to investigate whether high platelet reactivity affects clinical outcomes of patients with drug eluting stents (DESs) implantation.\n\nMethods\nAll enrolled individuals treated with DESs implantation were evaluated by PL-11, using sequentially platelet counting method. The primary end point was the occurrence of definite and probable stent thrombosis at 2 years. The secondary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including all cause death, spontaneous myocardial infarction (MI), target vessel revascularization (TVR), and ischemic stroke.\n\nResults\nA total of 1331consecutive patients were enrolled at our center. There were 91 patients (6.8 %) identified with high platelet reactivity (HPR) on aspirin, and 437 patients (32.9 %) with HPR on clopidogrel. At 2-year follow-up, the incidence of stent thrombosis was significantly higher in patients with HPR on aspirin (9.9 % vs. 0.4 %, p < 0.001), and HPR on clopidogrel (3.0 % vs. 0.1 %, p < 0.001). There were increased MACCE in the HPR on aspirin group (16.5 % vs. 8.5 %, p = 0.021), mainly driven by the higher all cause death (7.7 % vs. 1.6 %, p = 0.002) and MI (9.9 % vs. 1.9 %, p < 0.001) in the HPR on aspirin group. Similarly, the rate of MACCE was higher in the HPR on clopidogrel group (12.4 % vs. 7.4 %, p = 0.004). No differences in all bleeding and hemorrhagic stroke were observed.\n\nConclusions\nThe present study demonstrated that high platelet reactivity on both aspirin and clopidogrel were associated with incremental stent thrombosis following DESs implantation.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12872-016-0394-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nPlatelet function testHigh platelet reactivityDrug eluting stentStent thrombosisJiangsu Provincial Special Program of Medical Science grantBL2013001Chen Shao-Liang issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nStent thrombosis was recognized as an important complication of percutaneous coronary intervention (PCI), ranging around 0.5 to 2 % with the use of drug-eluting stents (DES) [1, 2], but stent thrombosis had a high risk of myocardial infarction and cardiac death [3, 4]. Effective dual anti-platelet therapy (DAPT) with aspirin and clopidogrel is mandatory after DES implantation, due to DES inducing platelet adhesion, activation and thrombus formation. Anti-platelet insufficiency, especially high platelet reactivity on aspirin and clopidogrel, has been considered to play an important role in stent thrombosis [5].\n\nThere are several studies exploring the association between platelet reactivity and stent thrombosis [5–8], however, some limitations still existed, such as low-risk population, low event rates, and conflicted results. Moreover, the VerifyNow P2Y12 assay was widely used in these studies, which has been reported to be nonflexible, very expensive, limited hematocrit and platelet count, and just moderate agreement with other platelet function tests [9, 10]. However, sequentially platelet counting method by PL-11 (SINNOWA Co., Nanjing, China) was a novel analyzer for platelet reactivity test by automatic impedance technique [11]. Therefore, this prospective study was designed to assess the association between platelet reactivity with the novel automatic platelet aggregometer and stent thrombosis among patients with DES implantation.\n\nMethods\nStudy population\nFrom July 2012 to May 2014, a total of 3600 consecutive real-world patients who treated with DES implantation from our center were considered candidates for this registry. Finally 1331 patients were included in this study according to the inclusion and exclusion criteria. Inclusion criteria were as follows: age >18 years, and successful PCI in at least one major epicardial coronary artery. Exclusion criteria were demonstrated in Fig. 1. Additional exclusion criteria included pregnancy, a platelet count < 10*109 /L and suspected intolerance to one of the study drugs.Fig. 1 Flowchart of study design. The value of ADP-MAR% was missed in three patients. AA: arachidonic acid; MAR: maximal aggregation ratio; ADP: adenosine diphosphate\n\n\n\n\nInterventional procedure and medications\nAll interventional procedures were performed in accordance with the current guidelines. The type of DES selection, procedural technique, use of glycoprotein IIb/IIIa inhibitors, intravascular ultrasound, fractional flow reserve, and optical coherence tomography were at the discretion of the operators. A loading dose of aspirin and clopidogrel of at least 300 mg were administered prior to the index procedure. Heparin was used during the procedure to maintain an activated clotting time more than 250 s. Total creatine kinase (CK), CK-MB, and troponin were dynamically measured until 72 h post-procedure. After the intervention, all patients received 100 mg/day aspirin for life and clopidogrel (75 mg/day) for at least 12 months.\n\nPlatelet function test\nPlatelet reactivity was assessed in all patients before heparin administered during procedure in the Lab room. PL-11 analyzer (SINNOWA Co., Nanjing, China) was used for the test [11, 12]. With standardized and easier test method, the analyzer gives more exact and stable results of platelet maximum aggregation ratio (MAR%). PL-11 analyzer measures the platelet function by “sequentially platelet counting method”, and the analyzer automatically and sequentially counts (impedance technology) the numbers of platelet in the citrated whole blood sample before and after adding agonists in fixed time interval during the whole testing progress. For each agonist test, 500 ul citrated whole blood sample was transferred into a test tube, then it was placed into the test position in the analyzer, press the “test button” the analyzer begins to count the platelet of the sample automatically two times and calculates the original platelet number (mean value) by the first two counts, then 40 ul of agonist was added into the sample and mixed to activate platelets aggregating. The numbers of platelet in the sample will be decreased because aggregation. More platelet aggregated, lower numbers of platelet existing in the sample. After adding agonist, the analyzer continues to measure platelet numbers in the sample for 3 times, also in fixed time interval and get three results of platelet number, the lowest platelet number of the three is used to calculate the MAR% in the following formula: (1-lowest platelet number/initial platelet number) × 100 %. The whole test progress is 12 min, the sample position keeps at 37 °C and keeps swaying during the progress, so the sample is kept in well mixed and good condition during testing. Arachidonic acid (AA, 2 mg/ml) and adenosine diphosphate (ADP, 50umol/L) were used as agonists. Additionally, high platelet reactivity (HPR) on aspirin was defined as MAR% ≥ 30 %; meanwhile, HPR on clopidogrel was defined as MAR% ≥ 55 %. All investigators were strongly encouraged not to change antiplatelet strategy according to the results of platelet function test.\n\nStudy endpoints and definitions\nThe primary end point was the occurrence of definite and probable stent thrombosis at 2 years, defined according to the Academic Research Consortium (ARC) classification [13]. The secondary endpoint was the incidence of major adverse cardiovascular and cerebrovascular events (MACCE), including all cause death, spontaneous myocardial infarction (MI), target vessel revascularization (TVR), and ischemic stroke. The safety endpoint was the risk of all bleeding and hemorrhagic stroke, defined according to the Bleeding Academic Research Consortium (BARC) classification [14]. All deaths were considered cardiac in origin unless a non-cardiac cause was confirmed clinically or at autopsy. Spontaneous MI was diagnosed in accordance with Third Universal Definition of Myocardial Infarction [15]. Target lesion revascularization and TVR were defined as repeat revascularization (including PCI and coronary artery bypass grafting) for target lesions and target vessels, respectively, in the presence of symptoms or objective signs of ischemia. Stroke was defined as global or focal cerebral, spinal cord, or retinal injury resulting in acute neurological dysfunction and was further classified into ischemic and hemorrhagic.\n\nFollow-up\nClinical follow-up was performed either by telephone or through a clinical office visit at 1, 6, 12, and 24 months. Repeat coronary angiography was scheduled at 13 months after the indexed procedure unless clinical reasons indicated earlier. All clinical events were assessed by an independent committee that was blinded to the study.\n\nStatistical analysis\nThe distribution of continuous variables was assessed by the Kolmogrov-Smirnov test. Categorical variables were expressed as frequencies or percentages and compared by Chi-square statistics or Fisher’s exact test. Continuous variables were summarized as means ± standard deviation (SD) or median and compared using Students’ t-test (for normal data) and Mann–Whitney U-test (for non-normally distributed variables). Survival curves with time-to-event data were generated by the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HR) are presented along their 95 % confidence interval (CI). Multivariable Cox proportional hazard model including platelet reactivity, other clinical and procedural variables was applied to identify the independent predictors that correlated with definite and probable stent thrombosis. Receiver-operating characteristic (ROC) curves were generated to assess the association between platelet reactivity and clinical outcomes. A p value <0.05 was considered statistically significance. All analyses were performed with the use of the statistical program SPSS 22.0 (SPSS Institute Inc, Chicago, Illinois).\n\nResults\nBaseline clinical characteristics\nA total of 1331 patients with DES implantation were finally enrolled, and baseline clinical characteristics were showed in Table 1. The median AA-MAR% of 1331 enrolled patients was 18.2 %, and the median ADP-MAR% of 1328 patients was 36.4 %. There were 91 patients (6.8 %) identified with HPR on aspirin, and 437 patients (32.9 %) with HPR on clopidogrel. 86.2 % of the individuals were admitted with acute coronary syndromes (ACS). Baseline clinical characteristics between HPR on aspirin group and normal platelet reactivity (NPR) on aspirin group were comparable. Patients in the NPR on clopidogrel group were more likely males (77.7 %) and ACS (87.8 %), when compared to the HPR on clopidogrel group (70.9 %, p = 0.008; 82.8 %, p = 0.018).Table 1 Baseline clinical characteristics\n\n\tNPR on aspirin (n = 1240)\tHPR on aspirin (n = 91)\t\nP value\tNPR on clopidogrel (n = 891)\tHPR on clopidogrel (n = 437)\t\nP value\t\nAge, yrs\t64.19 ± 10.06\t65.63 ± 9.75\t0.189\t63.96 ± 10.23\t64.98 ± 9.60\t0.082\t\nMale, n (%)\t936 (75.5)\t67 (73.6)\t0.706\t692 (77.7)\t310 (70.9)\t0.008\t\nBMI, kg/mm2\n\t24.70 ± 3.01\t24.55 ± 3.01\t0.649\t24.65 ± 2.95\t24.78 ± 3.12\t0.449\t\nHypertension, n (%)\t888 (71.6)\t66 (72.5)\t0.905\t644 (72.3)\t307 (70.3)\t0.438\t\nHyperlipidemia, n (%)\t318 (27.4)\t23 (25.6)\t0.806\t236 (28.3)\t105 (25.4)\t0.281\t\nDiabetes, n (%)\t328 (26.5)\t24 (26.4)\tNS\t239 (26.8)\t112 (25.6)\t0.691\t\nCurrent smoking, n (%)\t482 (39.2)\t33 (36.7)\t0.656\t356 (40.3)\t159 (36.7)\t0.229\t\nACS, n (%)\t1072 (86.5)\t75 (82.4)\t0.272\t782 (87.8)\t362 (82.8)\t0.018\t\neGFR < 60 ml/min/1.73 m2, n (%)\t122 (10.1)\t8 (9.2)\tNS\t94 (10.9)\t36 (8.4)\t0.170\t\nPrior stroke, n (%)\t138 (11.2)\t11 (12.2)\t0.731\t93 (10.5)\t56 (12.9)\t0.196\t\nPrior PCI, n (%)\t236 (19.2)\t15 (16.7)\t0.676\t161 (18.2)\t89 (20.6)\t0.331\t\nLVEF, %\t59.80 ± 9.33\t58.50 ± 9.89\t0.275\t59.59 ± 9.27\t59.94 ± 9.61\t0.587\t\nhsCRP, ug/ml\t31.94 ± 8.88\t32.84 ± 9.16\t0.400\t31.98 ± 8.80\t32.13 ± 9.11\t0.804\t\nAgents in hospital\t\n Aspirin, 100 mg/d\t1216 (98.1)\t90 (98.9)\tNS\t881 (98.9)\t428 (97.9)\t0.218\t\n Clopidogrel, 75 mg/d\t1203 (97.0)\t88 (96.7)\t0.751\t863 (96.9)\t426 (97.5)\t0.606\t\nAgents at 2 years\t\n Aspirin (100 mg/d), n (%)\t1142 (92.1)\t81 (89.0)\t0.317\t800 (89.8)\t398 (91.1)\t0.493\t\n Clopidogrel (75 mg/d), n (%)\t806 (65.0)\t57 (62.6)\t0.650\t570 (64.0)\t266 (61.9)\t0.277\t\n\nBMI body mass index, ACS acute coronary syndrome, eGFR estimated glomerular filtration rate, PCI percutaneous coronary intervention, LVEF left ventricular ejection fraction, hsCRP high sensitivity C reactive protein, NPR normal platelet reactivity, HPR high platelet reactivity\n\n\n\n\nLesions and procedural characteristics\nNo differences in the lesions and procedural characteristics were observed between HPR on aspirin and NPR on aspirin group (Table 2). In addition, there were also no differences between HPR on clopidogrel and NPR on clopidogrel group, except for more frequent use of glycoprotein IIb/IIIa Inhibitors for patient with NPR on clopidogrel (12.0 % vs. 8.2 %, p = 0.048).Table 2 Angiographic and procedural characteristics\n\n\tNPR on aspirin (n = 1240)\tHPR on aspirin (n = 91)\t\nP value\tNPR on clopidogrel (n = 891)\tHPR on clopidogrel (n = 437)\t\nP value\t\nMulti-vessel disease, n (%)\t517 (59.2)\t41 (63.1)\t0.601\t363 (59.6)\t194 (59.1)\t0.889\t\nBifurcation lesion, n (%)\t407 (32.8)\t35 (38.5)\t0.300\t301 (33.8)\t141 (32.3)\t0.578\t\nThrombus-containing lesions, n (%)\t113 (9.3)\t5 (5.7)\t0.336\t77 (8.9)\t41 (9.5)\t0.683\t\nIIb/IIIa Inhibitor, n (%)\t122 (10.8)\t7 (8.6)\t0.709\t96 (12.0)\t33 (8.2)\t0.048\t\nDES used, n (%)\t1240 (100)\t91 (100)\tNS\t891 (100)\t437 (100)\tNS\t\nTotal implanted stent\t2.78 ± 1.72\t2.58 ± 1.61\t0.287\t2.81 ± 1.76\t2.69 ± 1.62\t0.235\t\nMean stent diameter, mm\t3.08 ± 0.38\t3.03 ± 0.34\t0.313\t3.08 ± 0.38\t3.05 ± 0.39\t0.155\t\nTotal stent length, mm\t72.14 ± 48.69\t65.06 ± 42.73\t0.187\t72.61 ± 49.14\t69.77 ± 46.65\t0.332\t\nComplete revascularization, n (%)\t823 (67.9)\t59 (67.0)\t0.906\t598 (68.8)\t281 (65.7)\t0.256\t\nFinal TIMI grade 3, n (%)\t1199 (98.2)\t88 (98.9)\tNS\t860 (98.3)\t424 (98.1)\t0.827\t\nHeparin volume, units\t7915.11 ± 2027.05\t8085.00 ± 1945.01\t0.503\t7892.79 ± 2029.11\t7999.97 ± 2012.82\t0.421\t\n\nDES drug-eluting stent, TIMI thrombolysis in myocardial infarction, NPR normal platelet reactivity, HPR high platelet reactivity\n\n\n\n\nHigh platelet reactivity and clinical outcomes\nAfter a median follow-up of 2 years, there were 9 (9.9 %) definite and probable stent thrombosis events in the HPR on aspirin group and 5 (0.4 %) in the NPR on aspirin group (p < 0.001, Table 3, Fig. 2a), with the detailed information of these 14 patients listed in Table 4. The risk of stent thrombosis in the HPR on clopidogrel group was 3.0 %, much higher than 0.1 % in the NPR on clopidogrel group (Fig. 2b). By Cox regression multivariable analysis, the independent predictors of definite and probable stent thrombosis were AA-MAR% (HR: 1.844, 95 % CI: 1.348 to 2.522, p < 0.001), ADP-MAR% (HR: 1.680, 95 % CI: 1.128 to 2.502, p = 0.011), and total implanted stents (HR: 1.421, 95 % CI: 1.108 to 1.822, p = 0.006).Table 3 Clinical outcomes\n\n\tNPR on aspirin (n = 1240)\tHPR on aspirin (n = 91)\t\nP value\tNPR on clopidogrel (n = 891)\tHPR on clopidogrel (n = 437)\t\nP value\t\nIn hospital\t\n Definite/probable Stent thrombosis\t1\t0\tNS\t0\t1\t0.329\t\n All cause death\t0\t0\tNS\t0\t0\tNS\t\n Cardiac death\t0\t0\tNS\t0\t0\tNS\t\n Spontaneous MI\t2\t0\tNS\t0\t2\t0.108\t\n TLR\t1\t0\tNS\t0\t1\t0.329\t\n TVR\t1\t0\tNS\t0\t1\t0.329\t\n Ischemic stroke\t8 (0.6)\t0\tNS\t4 (0.4)\t4 (0.9)\t0.451\t\n All bleeding\t39 (3.1)\t3 (3.3)\t0.762\t30 (3.4)\t12 (2.7)\t0.619\t\n Hemorrhagic stroke\t3 (0.2)\t0\tNS\t3 (0.3)\t0\t0.555\t\n MACCE\t10 (0.8)\t0\tNS\t4 (0.5)\t6 (1.4)\t0.090\t\nAt 1 years\t\n Definite/probable Stent thrombosis\t3 (0.2)\t8 (8.8)\t< 0.001\t1 (0.1)\t10 (2.3)\t< 0.001\t\n All cause death\t8 (0.6)\t2 (2.2)\t0.146\t3 (0.3)\t7 (1.6)\t0.018\t\n Cardiac death\t2 (0.2)\t2 (2.2)\t0.025\t1 (0.1)\t3 (0.7)\t0.107\t\n Spontaneous MI\t17 (1.4)\t3 (3.3)\t0.152\t10 (1.1)\t10 (2.3)\t0.147\t\n TLR\t30 (2.4)\t0 (0)\t0.260\t25 (2.8)\t5 (1.1)\t0.075\t\n TVR\t31 (2.5)\t0 (0)\t0.265\t25 (2.8)\t6 (1.4)\t0.123\t\n Ischemic stroke\t9 (0.7)\t1 (1.1)\t0.509\t9 (1.0)\t1 (0.2)\t0.180\t\n All bleeding\t64 (5.2)\t3 (3.3)\t0.619\t48 (5.4)\t19 (4.3)\t0.505\t\n Hemorrhagic stroke\t5 (0.4)\t0\tNS\t3 (0.3)\t2 (0.5)\t0.666\t\n MACCE\t40 (3.2)\t5 (5.5)\t0.228\t30 (3.4)\t15 (3.4)\t0.951\t\nAt 2 years\t\n Definite/probable Stent thrombosis\t5 (0.4)\t9 (9.9)\t< 0.001\t1 (0.1)\t13 (3.0)\t< 0.001\t\n All cause death\t20 (1.6)\t7 (7.7)\t0.002\t3 (0.3)\t23 (5.3)\t< 0.001\t\n Cardiac death\t4 (0.3)\t7 (7.7)\t< 0.001\t1 (0.1)\t10 (2.3)\t< 0.001\t\n Spontaneous MI\t23 (1.9)\t9 (9.9)\t< 0.001\t11 (1.2)\t21 (4.8)\t< 0.001\t\n TLR\t60 (4.8)\t5 (5.5)\t0.799\t51 (5.7)\t14 (3.2)\t0.057\t\n TVR\t65 (5.2)\t5 (5.5)\t0.809\t51 (5.7)\t19 (4.3)\t0.360\t\n Ischemic stroke\t16 (1.3)\t2 (2.2)\t0.352\t12 (1.3)\t6 (1.4)\tNS\t\n All bleeding\t118 (10.0)\t8 (9.2)\tNS\t93 (10.9)\t33 (7.9)\t0.110\t\n Hemorrhagic stroke\t8 (0.6)\t0 (0)\tNS\t4 (0.4)\t4 (0.9)\t0.451\t\n MACCE\t106 (8.5)\t15 (16.5)\t0.021\t66 (7.4)\t54 (12.4)\t0.004\t\n\nMI myocardial infarction, TLR target lesion revascularization, TVR target vessel revascularization, MACCE adverse cardiovascular and cerebrovascular events, NPR normal platelet reactivity, HPR high platelet reactivity\n\n\nFig. 2 Definite/ probable stent thrombosis-free survival rate at 2 years. Freedom from definite/probable stent thrombosis at 2-year follow-upa between AA-MAR% ≥ 30 % (green line) and AA-MAR% < 30 % (blue line), b between ADP-MAR% ≥ 55 % (green line) and ADP-MAR% < 55 % (blue line). Abbreviations are showed in Fig. 1\n\n\n\nTable 4 Characteristics of patients with definite and probable stent thrombosis\n\nCase\tRisk factors\tLesions\tStent number\tAA-MAR, %\tADP-MAR, %\tCYP2C19 gene\tUse of antiplatelet drugs\tTime from PCI to stent thrombosis (days)\tCardiac death\t\n1\tEH\tMulti-vessel disease\t2\t15.4\t60.6\tNA\tDual-antiplatelet for 2 years\t2\t0\t\n2\tSmoking\tLeft main lesion\t3\t42.9\t60.3\tNA\tDual-antiplatelet for 2 years\t241\t1\t\n3\tEH, DM, smoking\tMulti-vessel disease\t8\t35\t58.4\tPoor metabolizer\tDual-antiplatelet for 2 years\t170\t0\t\n4\tEH, smoking\tMulti-vessel disease\t3\t20\t58.6\tNA\tDual-antiplatelet for 2 years\t1\t0\t\n5\tDM\tMulti-vessel disease\t3\t79.8\t67.9\tNA\tClopidogrel for lifelong time, aspirin for half year\t236\t1\t\n6\tEH, smoking\tPro-LAD lesion\t1\t50\t60.5\tIntermediate metabolizer\tClopidogrel for 1 year, aspirin stopped by oneself at 1 month after procedure, and aspirin re-used at 1 year\t455\t0\t\n7\tEH\tMulti-vessel disease\t3\t20.2\t63\tIntermediate metabolizer\tAspirin for lifelong time, clopidogrel for 1 year\t12\t0\t\n8\tEH, DM\tMulti-vessel disease\t2\t39\t58.7\tIntermediate metabolizer\tDual-antiplatelet for 2 years\t82\t0\t\n9\tNo\tMulti-vessel disease + left main lesion\t3\t49.8\t61.1\tNA\tDual-antiplatelet for 2 years\t94\t1\t\n10\tEH, DM\tMulti-vessel disease + left main lesion\t6\t37\t45\tPoor metabolizer\tDual-antiplatelet for 2 years\t1\t0\t\n11\tDM, smoking\tMulti-vessel disease\t4\t24.6\t56.4\tPoor metabolizer\tDual-antiplatelet for 2 years\t731\t1\t\n12\tEH, DM, smoking, CKD 4\tMulti-vessel disease + left main lesion\t7\t21.1\t68\tIntermediate metabolizer\tDual-antiplatelet for 2 years\t617\t1\t\n13\tSmoking\tMulti-vessel disease\t2\t34.6\t57.2\tIntermediate metabolizer\tDual-antiplatelet for 2 years\t42\t1\t\n14\tEH\tMulti-vessel disease\t6\t45.4\t60.3\tIntermediate metabolizer\tDual-antiplatelet for 2 years\t138\t1\t\n\nEH essential hypertension, DM diabetes mellitus, CKD chronic kidney disease, LAD left anterior descending, AA arachidonic acid, MAR maximal aggregation ratio, ADP adenosine diphosphate, PCI percutaneous coronary intervention\n\n\n\n\nThe area under ROC (AUC) of AA-MAR% predicting stent thrombosis was 0.808 (95 % CI: 0.695, 0.922; p < 0.001), with the cutoff value of 34.5 % (sensitivity: 64.3 %, specificity: 92.1 %, Additional file 1: Figure S1), which was comparable with the AUC of ADP-MAR% (0.747, 95 %: 0.623, 0.870, p = 0.001; p = 0.087 for AUC comparison), with the cutoff value of 56.4 % (sensitivity: 57.1 %, specificity: 90.7 %).\n\nThere were 15 (16.5 %) composite MACCEs in the HPR on aspirin group and 106 (8.5 %) in the NPR on aspirin group (p = 0.021, Fig. 3a), mainly driven by the higher rates of all cause death (7.7 %) and MI (9.9 %) in the HPR on aspirin group compared with those in the NPR on aspirin group (1.6 %, p = 0.002; 1.9 %, p < 0.001). Similarly, the rate of MACCE was 12.4 % in the HPR on clopidogrel group, higher than 7.4 % in the NPR on clopidogrel group (p = 0.004, Fig. 3b), mainly due to higher rates of all cause death (5.3 %) and MI (4.8 %) in the HPR on clopidogrel group.Fig. 3 MACCE-free survival rate at 2 years. Freedom from adverse cardiovascular and cerebrovascular events at 2-year follow-up a between AA-MAR% ≥ 30 % (green line) and AA-MAR% < 30 % (blue line), b between ADP-MAR% ≥ 55 % (green line) and ADP-MAR% < 55 % (blue line). Abbreviations are showed in Fig. 1\n\n\n\n\n\nNo differences in all bleeding and hemorrhagic stroke were observed between NPR on aspirin group and HPR on aspirin group, without significant difference found between NPR on clopidogrel group and HPR on clopidogrel group.\n\nDiscussion\nThe major findings of this prospective study were that: 1) There were 6.8 % identified with high platelet reactivity on aspirin, and 32.9 % with high platelet reactivity on clopidogrel among patient undergoing PCI; 2) high platelet reactivity on both aspirin and clopidogrel were independent predictors of 2-year stent thrombosis following DESs implantation; and 3) there were no significant association between high platelet reactivity on aspirin/clopidogrel and any bleeding/ hemorrhagic stroke.\n\nAntiplatelet therapy is the cornerstone of preventing stent thrombosis in patients after DESs implantation, but at the cost of higher bleeding risk, which has been the Achilles’ heel for these patients. Platelet function test focusing on the individual’s response to antiplatelet therapy, was expected to select the most optimal agents and dosage for these patients, in order to reduce the risk of stent thrombosis and bleeding. Indeed, the ADAPT-DES (Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents) study, prospectively enrolling 8665 patients after PCI, showed that high platelet reactivity on clopidogrel was an independent predictor of stent thrombosis, but was also protective against clinically relevant bleeding. However, several other studies with different population had the conflicted results [6, 8]. The present study with a novel method confirmed the data from ADAPT-DES, indicating that platelet function test, combining with clinical and procedural factors, could be at least useful for predicting stent thrombosis for PCI patients.\n\nIn contrast with our findings, ADAPT-DES study did not identify the incremental stent thrombosis in patients with high platelet reactivity on aspirin. This difference might be due to the differences in population, platelet testing methods, as well as duration of follow-up. Indeed, there are other clinical factors to affect platelet reactivity, such as current smoking, diabetes, and hyperlipidemia, which may increase the incidence of high platelet reactivity on aspirin and the risk of adverse clinical outcomes. However, multivariable Cox proportional hazard model was used in the present study to demonstrate that high platelet reactivity on aspirin was the independent predictor of stent thrombosis, apart from clinical and procedural factors. Certainly, this new findings need be verified in the further clinical trials.\n\nAlthough the preliminary association between high platelet reactivity and stent thrombosis was established, several randomized clinical trials on adjust treatment based on platelet function test in PCI patients had the negative results [16–18]. In the ARCTIC (The Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption versus Continuation 1 Year after Stenting) study [16], 2440 PCI patients were randomized to platelet function monitoring group with therapy adjustment if necessary, or conventional strategy without monitoring. After 1-year follow-up, there were no significant improvements in clinical outcomes with platelet function monitoring, compared with conventional antiplatelet therapy, which was in line with other studies [17, 18]. The negative results might be due to the low-risk population, low event rate, and inclusion of periprocedural MI, which could not be prevented by platelet function test. Of note, all these studies were performed with VerifyNow, and other platelet assays such as PL-11 require further investigation. In summary, the current randomized studies do not support the routine platelet function tests to adjust treatment for PCI patients.\n\nJust as mentioned above, there are several methods of platelet test assessing platelet reactivity. In the POPULAR (Do Platelet Function Assays Predict Clinical Outcomes in Clopidogrel-Pretreated Patients Undergoing Elective PCI) study [19], the largest head-to-head comparison among platelet test methods, only light transmittance aggregometry (LTA), VerifyNow, and Plateletworks had the modest association with the primary end point (composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke). However, none of these tests could identify patients at the higher risk of bleeding after PCI. Moreover, the study by Lemesle G [20] showed poor agreement between LTA, VerifyNow and vasodilatator-stimulated phosphoprotein for clopidogrel low-response assessment. Therefore, platelet function assays were not equally interchangeable and the correlations among them were varied. PL-11 by “sequentially platelet counting method” gives more exact and stable results of platelet counting before and after the addition of agonists in the citrated whole blood samples, which has been demonstrated to be correlated with LTA and VerifyNow [11]. Consequently, sequentially platelet counting method by PL-11 would bean optional device for platelet function tests.\n\nAnother two questions need to be discussed further. First, Sheiban et al. [21] reported that PCI on unprotected left main (ULM) disease had a safe long-term (more than 10 years) outcome despite of using first-generation DES, with low rates of recurrent events due to index revascularization. A total of 167 patients with ULM disease were involved in our study, in which 100 patients (59.9 %) received second-generation DES implantation and 67 patients (40.1 %) with first-generation DES. There was no significant difference in MACCE between first- and second-generation DES, might due to a relative small population. Second, a recent meta-analysis [22] showed that shorter DAPT duration was associated with higher rates of MI, lower rates of major bleeding, and similar rates of stent thrombosis, and cardiovascular mortality. In our study, all patients received 100 mg/day aspirin for life and clopidogrel (75 mg/day) for at least 12 months after the intervention, without shorter DAPT duration (less than 12 months). An individualized patient approach to DAPT duration by balancing risks of bleeding and stent thrombosis was recommended. Therefore, the impact of platelet reactivity test guided DAPT duration on PCI patients will be explored in our next study.\n\nOur data confirm the previous evidence from ADAPT-DES and add some novel findings. First, high platelet reactivity on aspirin was associated with stent thrombosis after drug-eluting stent implantation apart from clopidogrel, which was in accordance to the clinical hypothesis. Second, the associations between platelet function tests with 1-year thrombotic events were explored in most previous studies, but our study showed the reduced 2-year stent thrombosis with high platelet reactivity for the first time. Finally, it is the first time for PL-11 used in clinical trials, and PL-11 might bean optional device for platelet function tests.\n\nStudy limitation\nThe current study has several limitations. First, none of the 1331 patients had received therapy adjustment according to platelet function tests, and it was not available for evaluating the effects of platelet function tests-guided therapy adjustment on cardiovascular outcome. Second, all enrolled patients underwent platelet function tests before DES implantation, and it might not be possible to conduct a repeat platelet test in consideration of the short hospitalization period in patients after PCI. Third, there was the lack of platelet function tests post-discharge, and we could not find time-dependent changes in platelet activity.\n\nConclusions\nThis prospective study showed high platelet reactivity on both aspirin and clopidogrel were associated with incremental stent thrombosis following drug-eluting stent implantation.\n\nAdditional file\n\nAdditional file 1: Figure S1. Receiver-operating characteristic curve predicting stent thrombosis. (TIFF 5134 kb)\n\n\n\n\nAbbreviations\nAAArachidonic acid\n\nACSAcute coronary syndromes\n\nADPAdenosine diphosphate\n\nARCAcademic Research Consortium\n\nBARCBleeding Academic Research Consortium\n\nCKCreatine kinase\n\nDESsDrug eluting stents\n\nHPRHigh platelet reactivity\n\nLTALight transmittance aggregometry\n\nMACCEMajor adverse cardiovascular and cerebrovascular events\n\nMARMaximal aggregation ratio\n\nMIMyocardial infarction\n\nNPRNormal platelet reactivity\n\nPCIPercutaneous coronary intervention\n\nROCReceiver-operating characteristic\n\nTVRTarget vessel revascularization\n\nAcknowledgements\nThe authors deeply appreciate Ling Lin, Jing Kan, Hai-Mei Xu, and Ying-Ying Zhao for their contributions to data collection and remote monitoring.\n\nFunding\nThis study was funded with the Jiangsu Provincial Special Program of Medical Science grant (BL2013001). The funding agency did not have a role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.\n\nAvailability of data and materials\nThe raw date supporting the results and conclusions of the present study will be available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nCSL designed the statistical analysis, lead the interpretation of research findings, and revised the manuscript. ZJJ and GXF participated in the design, collected data, build datasets, statistical analysis, and drafting of the manuscript. GZ, TNL, LZZ, LS, and YF participated in the conception and design and data collection. All of the authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe study was approved by the institutional ethics committee of Nanjing First Hospital, and was carried out in accordance with the guidelines of the Declaration of Helsinki. Written informed consent was formally obtained from all participants.\n==== Refs\nReferences\n1. Kedhi E Joesoef KS McFadden E Wassing J van Mieghem C Goedhart D Smits PC Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial Lancet 2010 375 9710 201 9 10.1016/S0140-6736(09)62127-9 20060578 \n2. Mauri L Hsieh WH Massaro JM Ho KK D’Agostino R Cutlip DE Stent thrombosis in randomized clinical trials of drug-eluting stents N Engl J Med 2007 356 10 1020 9 10.1056/NEJMoa067731 17296821 \n3. Iakovou I Schmidt T Bonizzoni E Ge L Sangiorgi GM Stankovic G Airoldi F Chieffo A Montorfano M Carlino M Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents JAMA 2005 293 17 2126 30 10.1001/jama.293.17.2126 15870416 \n4. Kimura T Morimoto T Kozuma K Honda Y Kume T Aizawa T Mitsudo K Miyazaki S Yamaguchi T Hiyoshi E Comparisons of baseline demographics, clinical presentation, and long-term outcome among patients with early, late, and very late stent thrombosis of sirolimus-eluting stents: Observations from the Registry of Stent Thrombosis for Review and Reevaluation (RESTART) Circulation 2010 122 1 52 61 10.1161/CIRCULATIONAHA.109.903955 20566955 \n5. Stone GW Witzenbichler B Weisz G Rinaldi MJ Neumann FJ Metzger DC Henry TD Cox DA Duffy PL Mazzaferri E Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study Lancet 2013 382 9892 614 23 10.1016/S0140-6736(13)61170-8 23890998 \n6. Paulu P Osmancik P Tousek P Minarik M Benesova L Motovska Z Bednar F Kocka V Widimsky P Lack of association between clopidogrel responsiveness tested using point-of-care assay and prognosis of patients with coronary artery disease J Thromb Thrombolysis 2013 36 1 1 6 10.1007/s11239-012-0813-8 23054463 \n7. Price MJ Angiolillo DJ Teirstein PS Lillie E Manoukian SV Berger PB Tanguay JF Cannon CP Topol EJ Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial Circulation 2011 124 10 1132 7 10.1161/CIRCULATIONAHA.111.029165 21875913 \n8. Range G Yayehd K Belle L Thuaire C Richard P Cazaux P Barbou F Koning R Chassaing S Teiger E Thrombotic and bleeding events after coronary stenting according to clopidogrel and aspirin platelet reactivity: VerifyNow French Registry (VERIFRENCHY) Arch Cardiovasc Dis 2014 107 4 225 35 10.1016/j.acvd.2014.03.004 24794216 \n9. Paniccia R Priora R Liotta AA Abbate R Platelet function tests: a comparative review Vasc Health Risk Manag. 2015 11 133 48 10.2147/VHRM.S44469 25733843 \n10. Franchi F Rollini F Cho JR Ferrante E Angiolillo DJ Platelet function testing in contemporary clinical and interventional practice Curr Treat Options Cardiovasc Med 2014 16 5 300 10.1007/s11936-014-0300-y 24652579 \n11. Guan J Cong Y Ren J Zhu Y Li L Deng X Bai J Comparison between a new platelet count drop method PL-11, light transmission aggregometry, VerifyNow aspirin system and thromboelastography for monitoring short-term aspirin effects in healthy individuals Platelets 2015 26 1 25 30 10.3109/09537104.2013.865835 24433273 \n12. Chen S, Ma XD, Fang F, CY S. Embedded Control and Management System for Novel Automatic Platelet Aggregometer. 7th IEEE Conference on Industrial Electronics and Applications (ICIEA). 2012.\n13. Cutlip DE Windecker S Mehran R Boam A Cohen DJ van Es GA Steg PG Morel MA Mauri L Vranckx P Clinical end points in coronary stent trials: a case for standardized definitions Circulation 2007 115 17 2344 51 10.1161/CIRCULATIONAHA.106.685313 17470709 \n14. Mehran R Rao SV Bhatt DL Gibson CM Caixeta A Eikelboom J Kaul S Wiviott SD Menon V Nikolsky E Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium Circulation 2011 123 23 2736 47 10.1161/CIRCULATIONAHA.110.009449 21670242 \n15. Thygesen K Alpert JS White HD Joint ESC/ACCF/AHA/WHF Task Force for the redefinition of myocardial infarction. Universal definition of myocardial infarction Eur Heart J 2007 28 20 2525 38 10.1093/eurheartj/ehm355 17951287 \n16. Collet JP Cuisset T Range G Cayla G Elhadad S Pouillot C Henry P Motreff P Carrie D Boueri Z Bedside monitoring to adjust antiplatelet therapy for coronary stenting N Engl J Med 2012 367 22 2100 9 10.1056/NEJMoa1209979 23121439 \n17. Price MJ Berger PB Teirstein PS Tanguay JF Angiolillo DJ Spriggs D Puri S Robbins M Garratt KN Bertrand OF Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial JAMA 2011 305 11 1097 105 10.1001/jama.2011.290 21406646 \n18. Trenk D Stone GW Gawaz M Kastrati A Angiolillo DJ Muller U Richardt G Jakubowski JA Neumann FJ A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study J Am Coll Cardiol. 2012 59 24 2159 64 10.1016/j.jacc.2012.02.026 22520250 \n19. Breet NJ van Werkum JW Bouman HJ Kelder JC Ruven HJ Bal ET Deneer VH Harmsze AM van der Heyden JA Rensing BJ Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation JAMA 2010 303 8 754 62 10.1001/jama.2010.181 20179285 \n20. Lemesle G Landel JB Bauters A Delhaye C Bonello L Sudre A Susen S Bauters C Lablanche JM Poor agreement between light transmission aggregometry, Verify Now P2Y(1)(2) and vasodilatator-stimulated phosphoprotein for clopidogrel low-response assessment: a potential explanation of negative results of recent randomized trials Platelets 2014 25 7 499 505 10.3109/09537104.2013.840363 24176022 \n21. Sheiban I Moretti C D’Ascenzo F Chieffo A Taha S Connor SO Chandran S de la Torre Hernández JM Chen S Varbella F Long-term (≥10 years) safety of percutaneous treatment of unprotected left main stenosis with drug-eluting stents Am J Cardiol 2016 118 1 32 9 10.1016/j.amjcard.2016.04.007 27209125 \n22. D’Ascenzo F Moretti C Bianco M Bernardi A Taha S Cerrato E Omedè P Montefusco A Frangieh AH Lee CW Meta-analysis of the duration of dual antiplatelet therapy in patients treated with second-generation drug-eluting stents Am J Cardiol 2016 117 11 1714 23 10.1016/j.amjcard.2016.03.005 27134057\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2261",
"issue": "16(1)",
"journal": "BMC cardiovascular disorders",
"keywords": "Drug eluting stent; High platelet reactivity; Platelet function test; Stent thrombosis",
"medline_ta": "BMC Cardiovasc Disord",
"mesh_terms": "D000368:Aged; D001241:Aspirin; D001792:Blood Platelets; D000077144:Clopidogrel; D003324:Coronary Artery Disease; D054855:Drug-Eluting Stents; D005260:Female; D005500:Follow-Up Studies; D006083:Graft Occlusion, Vascular; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D013988:Ticlopidine; D013997:Time Factors",
"nlm_unique_id": "100968539",
"other_id": null,
"pages": "240",
"pmc": null,
"pmid": "27894260",
"pubdate": "2016-11-29",
"publication_types": "D016428:Journal Article",
"references": "21875913;21670242;17951287;27209125;27134057;24433273;23054463;22520250;23890998;23121439;20179285;17296821;21406646;24176022;25733843;24652579;24794216;15870416;20060578;17470709;20566955",
"title": "High platelet reactivity affects the clinical outcomes of patients undergoing percutaneous coronary intervention.",
"title_normalized": "high platelet reactivity affects the clinical outcomes of patients undergoing percutaneous coronary intervention"
} | [
{
"companynumb": "CN-SA-2016SA230984",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "A 43-year-old woman and a 73-year-old man were referred separately from primary care to the urology service with short histories of frank haematuria. In both cases, histology from transurethral resection of their bladder tumours demonstrated the rare clear cell variant of urothelial/transitional cell carcinoma. Staging scans found the former patient had low-volume local disease, and the latter had locally advanced disease. The former patient went on to have partial cystectomy and pelvic lymph node dissection (with the endoscopic portion of the partial cystectomy undertaken by holmium:YAG laser), while the latter was found to have inoperable disease, and proceeded to chemotherapy. The former patient was alive with no evidence of disease recurrence at 45 months, while the latter was alive but with extensive lymph nodal recurrence at 45 months.",
"affiliations": "MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.;Histopathology Department, NHS Forth Valley, Larbert, UK.;Histopathology Department, NHS Forth Valley, Larbert, UK.;Urology Department, NHS Forth Valley, Larbert, UK.",
"authors": "Blackmur|James P|JP|;Melquiot|Nadja|N|;Robertson|Katherine E|KE|;Teahan|Seamus|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228904",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(6)",
"journal": "BMJ case reports",
"keywords": "cancer intervention; haematuria; surgical oncology; urological cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D002295:Carcinoma, Transitional Cell; D015653:Cystectomy; D004358:Drug Therapy; D005260:Female; D006417:Hematuria; D006801:Humans; D008197:Lymph Node Excision; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D009364:Neoplasm Recurrence, Local; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31208982",
"pubdate": "2019-06-16",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article",
"references": "9451354;23372912;27207269;25124389;22325372;28753835;20216403;20096882;7802559;11444201;20372045;19060992;28601954;17083402;19450852;29085783;19492895",
"title": "Comparison of two patients presenting with the clear cell variant of urothelial cell carcinoma of the urinary bladder: laser-assisted partial cystectomy for local disease versus chemotherapy for locally advanced disease.",
"title_normalized": "comparison of two patients presenting with the clear cell variant of urothelial cell carcinoma of the urinary bladder laser assisted partial cystectomy for local disease versus chemotherapy for locally advanced disease"
} | [
{
"companynumb": "GB-PFIZER INC-2019303534",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "A woman with acute poisoning from extended-release paracetamol presented at 14.5 hours post-ingestion. The paracetamol's absorption phase and elimination half-life appeared prolonged, with peak blood concentration occurring at 20 hours post-ingestion, requiring an extended course of intravenous N-acetylcysteine. Current treatment recommendations, based on experience with a different formulation in the United States, may not be appropriate for the Australian formulation.",
"affiliations": "Medical School, Australian National University, Canberra, ACT, Australia. 1darren1@gmail.com",
"authors": "Roberts|Darren M|DM|;Buckley|Nicholas A|NA|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D003692:Delayed-Action Preparations; D000082:Acetaminophen",
"country": "Australia",
"delete": false,
"doi": "10.5694/j.1326-5377.2008.tb01629.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-729X",
"issue": "188(5)",
"journal": "The Medical journal of Australia",
"keywords": null,
"medline_ta": "Med J Aust",
"mesh_terms": "D000042:Absorption; D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D019540:Area Under Curve; D003692:Delayed-Action Preparations; D062787:Drug Overdose; D005260:Female; D006207:Half-Life; D006801:Humans",
"nlm_unique_id": "0400714",
"other_id": null,
"pages": "310-1",
"pmc": null,
"pmid": "18312200",
"pubdate": "2008-03-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged absorption and delayed peak paracetamol concentration following poisoning with extended-release formulation.",
"title_normalized": "prolonged absorption and delayed peak paracetamol concentration following poisoning with extended release formulation"
} | [
{
"companynumb": "AU-JNJFOC-20201112942",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Lateralized involuntary movements consistent with hemichorea-hemiballism (HCHB) may appear following the development of contralateral haemorrhagic or ischaemic lesions of the basal ganglia, particularly the striatum (caudate nucleus and putamen). This condition is called vascular HCHB, but the same symptoms can be caused by a completely different striatal lesion. Glycaemic HCHB may occur in patients with uncontrolled hyperglycaemia: basal ganglia hyperdensity is seen on brain CT, while increased T1 signal intensity and reduced susceptibility-weighted imaging (SWI) and gradient-echo sequences (T2*-GRE) are detected on MRI.\nAn 83-year-old man with multiple vascular risk factors and uncontrolled chronic hyperglycaemia was admitted for ischaemic stroke presenting with dysarthria and mild left hemiparesis. No involuntary movements were reported at admission. The emergent brain CT scan was negative for vascular acute lesions, while a mild bilateral hyperdensity of the striata was detectable. Involuntary movements on the left side of the body, consistent with HCHB, appeared 27 days later. The alterations on brain CT completely disappeared after 3 months. On brain MRI, the T1 signal alterations resolved after 10 months, while SWI and T2*-GRE sequences showed persisting alterations after 2 years.\nDetailed brain imaging demonstrated evolution of striatal alterations of glycaemic HCHB before the appearance of involuntary movements and during the following 2 years. The association between ischaemic stroke and glycaemic HCHB favours the hypothesis that chronic hyperglycaemia more likely determines striatal alterations and the clinical picture of HCHB when vascular hypoperfusion also occurs.\nHemichorea-hemiballism (HCHB) may appear in patients with uncontrolled hyperglycaemia accompanied by typical neuroradiological features consisting of striatal alterations detectable on brain CT and MRI, often bilaterally.Unusually, striatal alterations can be detected before the appearance of involuntary movements and are fully reversible on brain CT and T1-MRI sequences.Brain hypoperfusion may facilitate the appearance of typical HCHB in patients with chronic hyperglycaemia.",
"affiliations": "Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy.;Diabetology Clinic, Department of Internal Medicine, University of Genoa, Italy.;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy.;Department of Neuroradiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.",
"authors": "Marinelli|Lucio|L|;Maggi|Davide|D|;Trompetto|Carlo|C|;Renzetti|Paolo|P|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2019_001257",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0012571257-1-9677-1-10-20191022ArticlesNeuroradiological Evolution of Glycaemic Hemichorea-Hemiballism and the Possible Role of Brain Hypoperfusion Marinelli Lucio 12Maggi Davide 34Trompetto Carlo 12Renzetti Paolo 5\n1 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy\n2 Department of Neuroscience, IRCCS Ospedale Policlinico San Martino, Genoa, Italy\n3 Diabetology Clinic, Department of Internal Medicine, University of Genoa, Italy\n4 Diabetology Clinic, IRCCS Ospedale Policlinico San Martino, Genoa, Italy\n5 Department of Neuroradiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy2019 23 10 2019 6 11 00125721 8 2019 20 9 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseBackground\nLateralized involuntary movements consistent with hemichorea-hemiballism (HCHB) may appear following the development of contralateral haemorrhagic or ischaemic lesions of the basal ganglia, particularly the striatum (caudate nucleus and putamen). This condition is called vascular HCHB, but the same symptoms can be caused by a completely different striatal lesion. Glycaemic HCHB may occur in patients with uncontrolled hyperglycaemia: basal ganglia hyperdensity is seen on brain CT, while increased T1 signal intensity and reduced susceptibility-weighted imaging (SWI) and gradient-echo sequences (T2*-GRE) are detected on MRI.\n\nCase description\nAn 83-year-old man with multiple vascular risk factors and uncontrolled chronic hyperglycaemia was admitted for ischaemic stroke presenting with dysarthria and mild left hemiparesis. No involuntary movements were reported at admission. The emergent brain CT scan was negative for vascular acute lesions, while a mild bilateral hyperdensity of the striata was detectable. Involuntary movements on the left side of the body, consistent with HCHB, appeared 27 days later. The alterations on brain CT completely disappeared after 3 months. On brain MRI, the T1 signal alterations resolved after 10 months, while SWI and T2*-GRE sequences showed persisting alterations after 2 years.\n\nDiscussion\nDetailed brain imaging demonstrated evolution of striatal alterations of glycaemic HCHB before the appearance of involuntary movements and during the following 2 years. The association between ischaemic stroke and glycaemic HCHB favours the hypothesis that chronic hyperglycaemia more likely determines striatal alterations and the clinical picture of HCHB when vascular hypoperfusion also occurs.\n\nLEARNING POINTS\nHemichorea-hemiballism (HCHB) may appear in patients with uncontrolled hyperglycaemia accompanied by typical neuroradiological features consisting of striatal alterations detectable on brain CT and MRI, often bilaterally.\n\nUnusually, striatal alterations can be detected before the appearance of involuntary movements and are fully reversible on brain CT and T1-MRI sequences.\n\nBrain hypoperfusion may facilitate the appearance of typical HCHB in patients with chronic hyperglycaemia.\n\nHemichoreahemiballismathetosishyperglycemiahypoperfusion\n==== Body\nINTRODUCTION\nThe most frequent causes of sporadic chorea are vascular lesions of the basal ganglia; in particular, unilateral lesions of the basal ganglia may determine contralateral involuntary movement[1]. In hemichorea, lateralized movements are rapid, irregular and affect the distal parts of the limbs, while in hemiballism movements are proximal and flinging. Both types of involuntary movements often coexist in a condition called hemichorea-hemiballism (HCHB).\n\nPatients with stroke sometimes develop HCHB along with hemiparesis; in the majority of cases, involuntary movements improve only partially over time. Patients with uncontrolled hyperglycaemia may develop HCHB without evidence of vascular lesions in a condition called glycaemic HCHB[2]. In vascular hemichorea, a contralateral ischaemic or haemorrhagic lesion of the basal ganglia can be demonstrated, while neuroradiological findings are completely different in patients with glycaemic HCHB. Brain CT shows hyperdensity, while brain magnetic resonance imaging (MRI) shows T1-weighted hyperintensity usually involving the striatum contralateral to the affected side or bilaterally. Susceptibility weighted imaging (SWI) and gradient echo sequence T2*-weighted images (T2*-GRE) usually show signal reduction and negative DWI and ADC signals in the same region[3–6]. There is no mass effect and the lesions may be fully reversible[7]. The pathological mechanisms of such lesions are still elusive: some authors suggest petechial haemorrhage, metal deposition (e.g., calcium, manganese) or mild ischaemia causing astrocyte swelling[8]. The temporal evolution of the neuroimaging has not been widely studied and only one report has described typical findings on brain CT before symptom onset[9].\n\nCASE DESCRIPTION\nWe describe the case of an 83-year-old man with a history of arterial hypertension, mild chronic renal insufficiency, and prostate cancer treated with radiation therapy, bicalutamide, tamoxifen and triptorelin. He had had a previous mild ischaemic stroke with transient right facio-brachio-crural hemiparesis followed by pneumonia caused by Staphylococcus aureus with complete recovery. At that time, blood glucose levels were 114 and 99 mg/dl (normal values 65–110 mg/dl). After 6 years he presented with thrombosis of the right common iliac vein treated with low-molecular-weight heparin, closely followed by myocardial infarction, consequent coronary stent implantation and double antiplatelet therapy (dipyridamole 200 mg/day plus acetylsalicylic acid 150 mg/day).\n\nFour months later, worsening of walking ability was closely followed by dysarthria about 1 week later. The patient was admitted to our hospital where he was diagnosed with mild ischaemic stroke, showing mild left hemiparesis without sensory impairment. An emergent brain CT was negative for acute lesions and only former small chronic ischaemic lesions were reported (Fig. 1, –26 days). Later review showed mild bilateral hypodensity of the striata was already present, which became clearer on another CT scan performed 2 days later (Fig. 1, −24 days). No involuntary movements were reported at admission or during the following days while the patient was in the university neurology ward. Blood tests showed very high blood glucose (505 mg/dl) and glycated haemoglobin of 15.7% (normal values 4.3–5.8%). Subcutaneous insulin therapy was started as suggested by the consultant diabetologist. Mild dysphagia was present but no parenteral nutrition was necessary. Twenty-seven days after admission, while the patient was in the neurorehabilitation ward, he developed involuntary movements on the left side of his body, consistent with moderate HCHB. He was diagnosed with glycaemic HCHB and started treatment with olanzapine (up to 5 mg/day for 7 days), then haloperidol (up to 3 mg/day for 20 days) and finally tetrabenazine (up to 25 mg/day for about 6 months), with a partial reduction in involuntary movements.\n\nThe first brain MRI was performed 7 days after HCHB onset and confirmed an increase in signal intensity on axial T1-weighted imaging in both striata (Fig. 2). Notably, the hyperintensity was asymmetrical since the right striatum, contralateral to the affected side of the body, was clearly more hyperintense than the left striatum; DWI and ADC were negative. Such asymmetry was much less evident on CT scans. The patient underwent neurological follow-up which showed a gradual reduction in HCHB. Tetrabenazine was stopped and involuntary movement reappeared only while the patient was speaking (Video 1). This condition remained unaltered during 26 months of follow-up.\n\nTo monitor how lesions evolved, brain CT and MRI were repeated for up to 1.5 years after HCHB onset. Striatal hyperdensity on CT scans was no longer detectable after about 3 months (Fig. 1). Striatal hyperintensity on T1 MRI disappeared completely after 10 months, while striatal hypointensity on SWI and T2*-GRE still persisted 1.5 years later (Fig. 2). Table 1 shows the times and results of blood glucose and glycated haemoglobin tests and brain neuroimaging.\n\nDISCUSSION\nOur patient underwent repeated brain neuroimaging before HCHB onset and for a further 2 years. He was admitted because of clinical signs of mild hemiparesis associated with hyperglycaemia and neurological imaging showing subtle bilateral hyperdensity of the striata. Involuntary movements appeared after a mild stroke as for vascular HCHB, but with a glycaemic HCHB neuroradiological picture. Clinical and neuroradiological findings indicate that our patient had a minor stroke while striatal alterations due to chronic hyperglycaemia were already present but asymptomatic.\n\nInvoluntary movements appeared with an unusual delay. While in vascular HCHB the latency between stroke and the appearance of involuntary movement is on average 4.3±3.6 (SD) days [10], in glycaemic HCHB the clinical-neuroradiological timing is unclear. A previous study reported a 1-month delay between hyperglycaemia and hemichorea [11], but no brain neuroimaging was available before the onset of involuntary movements. The only previously described case of glycaemic HCHB with a brain CT performed before symptom onset indicates that HCHB may appear as long as 40 days after striatal hyperdensity is detected[9]. Our patient already had bilateral asymmetrical striatal CT hyperdensity 26 days before the onset of hemichorea, so our findings confirm that striatal hyperdensity may precede the onset of involuntary movements much earlier than in vascular HCHB.\n\nOur data support the hypothesis that ischaemia could have a role in determining glycaemic HCHB[8]. Indeed, there is evidence that hyperglycaemia enhances neuronal necrosis during the acute stage of ischaemic stroke[12]. Our patient had multiple vascular risk factors and developed a minor stroke while striatal alterations due to chronic hyperglycaemia were already present on brain CT. A double effect of vascular hypoperfusion and hyperglycaemia could be an unusual mechanism causing neuronal damage in glycaemic HCHB and its specific neuroradiological picture. Retrospective studies investigating the association between striatal hyperdensity, chronic hyperglycaemia and vascular risk factors could help to elucidate the pathophysiology of glycaemic HCHB.\n\nFigure 1 Unenhanced CT scans of the brain obtained with a 40-slice CT scanner Siemens (Germany). Multiplanar reconstruction (MPR), thickness 3 mm along the bicommissural plane directed through the basal ganglia. Baseline CT scans 26 days and 24 days before hemichorea-hemiballism onset. These images show bilateral striatal hyperdensity before chorea was present. CT scans 3 months later demonstrate resolution of the findings\n\nFigure 2 Brain MRI scans performed 9 days after chorea onset show increased T1 signal intensity in both striata on axial T1-weighted imaging, particularly on the right side (upper panel). MRI scans performed 10 months later demonstrate resolution of the findings. However, the same region remained hypointense on susceptibility-weighted imaging (SWI) and gradient-echo sequences (T2*-GRE) (lower panel). The MRI scanner was a 1.5T Siemens Avanto (Germany)\n\nVideo 1 Video recorded 3 months after hemichorea-hemiballism onset during a follow-up visit. Involuntary movements in the left limbs were greatly reduced but still present, mostly when the patient was speaking. Involuntary movements were mainly choreoathetoid, affecting the distal part of the upper and lower limbs\n\nWatch the video: https://youtu.be/xl4Tipdq2n4\n\nTable 1 Timing and results of blood glucose and glycated haemoglobin tests and brain neuroimaging\n\nTime with reference to HCHB onset (days)\tBlood glucose (mg/dl)\tGlycated Hgb (%)\tCT/MRI performed\tClinical event\t\n−156\t143\t\t\t\t\n−140\t186\t\t\t\t\n−26\t505\t\tCT\tMild left hemiparesis\t\n−25\t188\t15.7\t\t\t\n−24\t\t\tCT\t\t\n−23\t252\t\t\t\t\n−20\t236\t15.1\t\t\t\n−1\t112\t\t\t\t\n0\t\t\t\tHCHB onset\t\n+5\t\t\tCT\t\t\n+9\t\t\tMRI\t\t\n+21\t\t\tMRI\t\t\n+96\t\t\tCT+MRI\t\t\n+186\t\t\tMRI\t\t\n+276\t114\t8.7\t\t\t\n+282\t\t\tMRI\t\t\n+515\t\t\tMRI\t\t\n+710\t\t\tCT\t\t\nHCHB, hemichorea-hemiballism.\n==== Refs\nREFERENCES\n1 Piccolo I Defanti CA Soliveri P Volontè MA Cislaghi G Girotti F Cause and course in a series of patients with sporadic chorea J Neurol 2003 250 4 429 435 12700907 \n2 Cosentino C Torres L Nuñez Y Suarez R Velez M Flores M Hemichorea/hemiballism associated with hyperglycemia: report of 20 cases Tremor Other Hyperkinet Mov (N Y) 2016 6 402 27536463 \n3 Tocco P Barbieri F Bonetti B Barillari M Marangi A Tinazzi M Hemichorea-hemiballismus in patients with non-ketotic hyperglycemia Neurol Sci 2016 37 2 297 298 26520843 \n4 Shafran I Greenberg G Grossman E Leibowitz A Diabetic striatopathy-Does it exist in non-Asian subjects? Eur J Intern Med 2016 35 51 54 27296589 \n5 Yu F Steven A Birnbaum L Altmeyer W T2*-based MR imaging of hyperglycemia-induced hemichorea-hemiballism J Neuroradiol 2017 44 1 24 30 27836650 \n6 Goh LW Chinchure D Lim TC Clinics in diagnostic imaging (166). Nonketotic hyperglycaemic chorea-hemiballismus Singapore Med J 2016 57 3 161 164 quiz 165 26996977 \n7 Hashimoto T Hanyu N Yahikozawa H Yanagisawa N Persistent hemiballism with striatal hyperintensity on T1-weighted MRI in a diabetic patient: a 6-year follow-up study J Neurol Sci 1999 165 2 178 181 10450804 \n8 Shan D-E Hemichorea-hemiballism associated with hyperintense putamen on T1-weighted MR images: an update and a hypothesis Acta Neurol Taiwan 2004 13 4 170 177 15666692 \n9 Nakajima N Ueda M Nagayama H Katayama Y Putaminal changes before the onset of clinical symptoms in diabetic hemichorea-hemiballism Intern Med 2014 53 5 489 491 24583441 \n10 Alarcón F Zijlmans JCM Dueñas G Cevallos N Post-stroke movement disorders: report of 56 patients J Neurol Neurosurg Psychiatry 2004 75 11 1568 1574 15489389 \n11 Lin C-J Huang P Delayed onset diabetic striatopathy: hemichorea-hemiballism one month after a hyperglycemic episode Am J Emerg Med 2017 35 7 1036.e3 1036.e4 \n12 Sulter G Elting JW De Keyser J Increased serum neuron specific enolase concentrations in patients with hyperglycemic cortical ischemic stroke Neurosci Lett 1998 253 1 71 73 9754808\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(11)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Hemichorea; athetosis; hemiballism; hyperglycemia; hypoperfusion",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001257",
"pmc": null,
"pmid": "31890704",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "24583441;26520843;27536463;26996977;15489389;9754808;28202297;15666692;10450804;27296589;27836650;12700907",
"title": "Neuroradiological Evolution of Glycaemic Hemichorea-Hemiballism and the Possible Role of Brain Hypoperfusion.",
"title_normalized": "neuroradiological evolution of glycaemic hemichorea hemiballism and the possible role of brain hypoperfusion"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-121219",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPYRIDAMOLE"
},
... |
{
"abstract": "Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.",
"affiliations": "Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany.;University Medical Center Groningen, Groningen, The Netherlands.;CHU Rennes, University of Rennes, Inserm & EFS, Rennes, France.;On Behalf of HOVON/LLPC (Lunenburg Lymphoma Phase I/II Consortium).;CHU Bordeaux, Service d'Hématologie et Thérapie Cellulaire, Bordeaux, France.;On Behalf of HOVON/LLPC (Lunenburg Lymphoma Phase I/II Consortium).;Université de Paris, AP-HP, Hôpital Saint Louis, Hemato-Oncology, DMU HI, Research Unit NF-kappaB, Différenciation et Cancer, Paris, France.;NCT/UCC Early Clinical Trial Unit, University Hospital Carl Gustav Carus, Dresden, Germany.;The University of British Columbia, Vancouver, Canada.;Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.;University Hospital Essen, Essen, Germany.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;Kite, A Gilead Company, Santa Monica, CA, USA.;On Behalf of HOVON/LLPC (Lunenburg Lymphoma Phase I/II Consortium).",
"authors": "Topp|Max S|MS|;van Meerten|Tom|T|;Houot|Roch|R|;Minnema|Monique C|MC|;Bouabdallah|Krimo|K|;Lugtenburg|Pieternella J|PJ|0000-0002-6735-8651;Thieblemont|Catherine|C|;Wermke|Martin|M|;Song|Kevin W|KW|;Avivi|Irit|I|;Kuruvilla|John|J|0000-0002-6117-320X;Dührsen|Ulrich|U|0000-0002-4034-9472;Zheng|Yan|Y|;Vardhanabhuti|Saran|S|;Dong|Jinghui|J|;Bot|Adrian|A|;Rossi|John M|JM|;Plaks|Vicki|V|;Sherman|Marika|M|;Kim|Jenny J|JJ|;Kerber|Anne|A|;Kersten|Marie José|MJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17673",
"fulltext": "\n==== Front\nBr J Haematol\nBr J Haematol\n10.1111/(ISSN)1365-2141\nBJH\nBritish Journal of Haematology\n0007-1048\n1365-2141\nJohn Wiley and Sons Inc. Hoboken\n\n34590303\n10.1111/bjh.17673\nBJH17673\nResearch Paper\nHaematological malignancy‐Clinical\nEarlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B‐cell lymphoma\nEarly Corticosteroid Use in a ZUMA‐1 Safety Cohort\nM. S. Topp et al.\nTopp Max S. 1 topp_m@ukw.de\n\nvan Meerten Tom 2 3\nHouot Roch 4\nMinnema Monique C. 3 5\nBouabdallah Krimo 6\nLugtenburg Pieternella J. https://orcid.org/0000-0002-6735-8651\n3 7\nThieblemont Catherine 8\nWermke Martin 9\nSong Kevin W. 10\nAvivi Irit 11\nKuruvilla John https://orcid.org/0000-0002-6117-320X\n12\nDührsen Ulrich https://orcid.org/0000-0002-4034-9472\n13\nZheng Yan 14\nVardhanabhuti Saran 14\nDong Jinghui 14\nBot Adrian 14\nRossi John M. 14\nPlaks Vicki 14\nSherman Marika 14\nKim Jenny J. 14\nKerber Anne 14\nKersten Marie José 3 15\n1 Medizinische Klinik und Poliklinik II Universitätsklinikum Würzburg Würzburg Germany\n2 University Medical Center Groningen Groningen The Netherlands\n3 On Behalf of HOVON/LLPC (Lunenburg Lymphoma Phase I/II Consortium)\n4 CHU Rennes University of Rennes Inserm & EFS Rennes France\n5 University Medical Center Utrecht Utrecht The Netherlands\n6 CHU Bordeaux, Service d’Hématologie et Thérapie Cellulaire Bordeaux France\n7 Erasmus MC Cancer Institute University Medical Center Rotterdam Rotterdam The Netherlands\n8 Université de Paris, AP‐HP, Hôpital Saint Louis, Hemato‐Oncology, DMU HI, Research Unit NF‐kappaB, Différenciation et Cancer Paris France\n9 NCT/UCC Early Clinical Trial Unit University Hospital Carl Gustav Carus Dresden Germany\n10 The University of British Columbia Vancouver Canada\n11 Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel\n12 Princess Margaret Cancer Centre University of Toronto Toronto Canada\n13 University Hospital Essen Essen Germany\n14 Kite, A Gilead Company Santa Monica CA USA\n15 Amsterdam UMC University of Amsterdam Amsterdam The Netherlands\n* Correspondence: Max S. Topp, Department of Hematology, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany.\nE‐mail: topp_m@ukw.de\n\n29 9 2021\n11 2021\n195 3 10.1111/bjh.v195.3 388398\n24 3 2021\n09 6 2021\n© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nSummary\n\nAxicabtagene ciloleucel (axi‐cel) is an autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed or refractory large B‐cell lymphoma (R/R LBCL). To reduce axi‐cel–related toxicity, several exploratory safety management cohorts were added to ZUMA‐1 (NCT02348216), the pivotal phase 1/2 study of axi‐cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti‐CD19 CAR T cells/kg after conditioning chemotherapy. Forty‐one patients received axi‐cel. Incidences of any‐grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone‐equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA‐1 cohorts. With a median follow‐up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi‐cel.\n\nlarge B‐cell lymphoma\naxi‐cel\nCAR T\ncorticosteroids\ntoxicity\nKite, a Gilead Company source-schema-version-number2.0\ncover-dateNovember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:18.07.2022\n==== Body\npmcIntroduction\n\nAxicabtagene ciloleucel (axi‐cel), an autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy, is approved for treatment of relapsed/refractory large B‐cell lymphoma (R/R LBCL) after ≥ 2 previous systemic therapies. 1 , 2 Regulatory approvals were based on results from cohorts 1 + 2 (N = 101) of ZUMA‐1 (NCT02348216), which evaluated the efficacy and safety of axi‐cel in patients with refractory LBCL. 3 At a median follow‐up of 27·1 months (N = 101), axi‐cel demonstrated objective response, complete response (CR), and ongoing response rates of 83%, 58%, and 39%, respectively. 4 After a median of 51·1 months, median overall survival (OS) was 25·8 months, and the Kaplan–Meier (KM) estimate of the four‐year OS rate was 44%. 5\n\nCytokine release syndrome (CRS) and neurologic events (NEs) are common in patients receiving anti‐CD19 CAR T‐cell therapies and may be severe or life‐threatening. 6 , 7 , 8 At the two‐year follow‐up of the combined phase 1 + 2 ZUMA‐1 data (N = 108; data cutoff, August 11, 2018), grade ≥ 3 CRS was reported in 11% and grade ≥ 3 NEs were reported in 32% of patients. 4 Most CRS cases and NEs were manageable and reversible. 4 CRS and NEs are thought to initiate by T‐cell activation after CAR engagement of cognate antigen on target cells, leading to CAR T‐cell activation, proliferation, and cytokine release. Subsequent activation of a broad range of ‘bystander’ immune cells, including non‐CAR T cells and myeloid cells, may contribute to efficacy but also amplify these adverse events (AEs). 8 , 9 The interleukin (IL)‐6/IL‐6 receptor pathway has been directly implicated in pathogenesis of severe CRS, 3 , 10 and tocilizumab—a monoclonal antibody against IL‐6 receptor—is indicated for treatment of severe CAR T‐cell–induced CRS. 11\n\nThe etiology of NEs is incompletely elucidated and appears to be mediated by excess activation and mobilisation of T and myeloid cells, initiated by strong CAR‐triggered signaling in T cells. 12 , 13 Proposed mechanisms include peripheral cytokine release followed by cytokine diffusion across a breached blood‐brain‐barrier and/or translocation of activated anti‐CD19 CAR T cells and other immune cells—most notably myeloid cells—across the blood‐brain‐barrier, aided by vascular‐occlusive inflammatory injury and leading to a local inflammatory effect. 14 Recent evidence suggests that CD19 expression on brain mural cells, which surround the endothelium and are important for blood‐brain‐barrier integrity, may play a role in NEs associated with CAR T‐cell therapy. 15 Although unclear whether this occurs in all patients, increased blood‐brain‐barrier permeability has been reported in CAR T‐cell–treated patients with severe NEs or oedema. 16 In ZUMA‐1 cohorts 1 + 2, higher levels of CAR T‐cell expansion and serum proinflammatory cytokines (IL‐15, IL‐2, granulocyte‐macrophage colony‐stimulating factor [GM‐CSF]), were more tightly associated with severe NEs versus CRS. Other cytokines—such as interferon (IFN)‐γ, IL‐6, CXCL10, and CCL2—were significantly associated with both severe NEs and CRS. 3 Higher tumour burden (TB) was positively associated with higher rates of NEs and negatively associated with ongoing response rates at one year, 17 and with OS and progression‐free survival (PFS). 18\n\nExploratory safety management cohorts were added to phase 2 of ZUMA‐1 to evaluate toxicity management strategies in axi‐cel–treated patients. Cohort 3, which evaluated prophylactic tocilizumab on day 2 and the anticonvulsant levetiracetam starting on day 0, appeared to decrease rates of grade ≥ 3 CRS but not grade ≥ 3 NEs. 12 In addition to indicating differences in the pathogenesis of CRS and NEs, these data suggest that down‐modulating additional immune pathways may be required to reduce the rates of severe CRS and NEs. The impact of levetiracetam prophylaxis and earlier corticosteroid and tocilizumab intervention on the incidence and severity of CRS and NEs was assessed in cohort 4, reported herein.\n\nMethods\n\nZUMA‐1 is a single‐arm, multicentre, registrational study of axi‐cel in R/R LBCL being conducted in the United States, Europe, Canada, and Israel. Cohort 4 procedures were similar to those described for cohorts 1 + 2 3 but differed in the use of levetiracetam prophylaxis and earlier corticosteroid and tocilizumab intervention for managing CRS and NEs (Fig 1).\n\nFig 1 Protocol‐specified AE management in cohorts 1 + 2 and cohort 4 of ZUMA‐1. (A) Comparison of AE management in cohorts 1 + 2 and cohort 4 of ZUMA‐1. ‘Yes’ or ‘No’ indicates whether tocilizumab or corticosteroid was or was not administered, respectively. (B) Tocilizumab and corticosteroid guidelines for AE management in cohort 4 of ZUMA‐1. *Only in case of comorbidities or older age. †Only if no improvement with tocilizumab; use standard dose. ‡If no improvement after three days. §Therapy to be tapered upon improvement of symptoms at investigator’s discretion. ||Not to exceed 800 mg. AE, adverse event; CRS, cytokine release syndrome; HD, high dose; IV, intravenously; N/A, not applicable; NE, neurologic event; Mgmt, management.\n\nPatients\n\nEligible patients in cohort 4 had R/R LBCL after ≥ 2 systemic lines of therapy or were refractory to first‐line therapy (i.e., best response of progressive disease (PD) or stable disease (SD) to ≥ 4 cycles of first‐line therapy with SD duration ≤ 6 months). See Data S1 for additional eligibility criteria. The study was approved by the institutional review board or ethics commission at each site and was conducted in accordance with the Good Clinical Practice guidelines of the International Conference on Harmonisation. All patients provided written informed consent.\n\nTreatment\n\nCohort 4 patients received a conditioning regimen of cyclophosphamide (500 mg/m2/day) and fludarabine (30 mg/m2/day) on days −5 to −3, and one dose of axi‐cel (target dose, 2 × 106 CAR T cells/kg; maximum flat dose for patients > 100 kg, 2 × 108 CAR T cells) on day 0. Bridging therapy prior to initiation of conditioning chemotherapy (Table SI) was allowed per investigator’s discretion (e.g., bulky disease or rapidly progressing disease at screening or baseline). Patients received levetiracetam (750 mg orally or intravenously twice daily) starting on day 0 and at the onset of grade ≥ 2 neurologic toxicities if NEs occurred after the discontinuation of prophylactic levetiracetam. If a patient did not experience any grade ≥ 2 neurologic toxicities, levetiracetam was tapered and discontinued as clinically indicated. Corticosteroid therapy was initiated to manage all grade 1 CRS if there was no improvement after three days and for all grade ≥ 1 NEs (Fig 1). Tocilizumab was initiated at grade 1 CRS if there was no improvement after three days, at grade ≥ 2 CRS, and at grade ≥ 2 NE (Fig 1).\n\nEndpoints and analysis\n\nNo formal hypothesis was tested; all endpoints were analysed descriptively. The primary endpoint was the incidence and severity of CRS and NEs. CRS was graded per modified Lee et al. criteria 19 and NEs were graded per Common Terminology Criteria for Adverse Events version 4.03. 20 Key secondary endpoints, and clinical pharmacology and biomarker analyses, are described in Data S1.\n\nThe modified intent‐to‐treat population included patients enrolled and treated with an axi‐cel dose of ≥ 1 × 106 anti‐CD19 CAR T cells/kg. This analysis set was used for all objective response analyses and endpoints based on objective response. The safety analysis set included all patients treated with any dose of axi‐cel. For patients who received bridging therapy (excluding corticosteroids only), TB was measured after bridging but before conditioning chemotherapy. The cumulative corticosteroid dose was calculated by conversion to a systemic cortisone‐equivalent dose during the initial hospitalisation period.\n\nPropensity score matching (PSM) analysis\n\nExploratory PSM analysis 21 , 22 was performed to allow a descriptive comparison of results for patients in cohort 4 versus cohorts 1 + 2 (median follow‐up, 15·4 months 3 ) after balancing for the following baseline characteristics: age, Eastern Cooperative Oncology Group (ECOG) performance status, TB, International Prognostic Index score, number of prior lines of chemotherapy, prior platinum use, disease stage, and lactate dehydrogenase (LDH) level (Data S1). Standardised mean difference 23 , 24 within ± 0·2 between cohort 4 and matched cohorts 1 + 2 was used as a criterion to assess covariate balance after PSM.\n\nResults\n\nPatient disposition, baseline and product characteristics\n\nCohort 4 enrollment commenced in February 2018. Forty‐six patients were enrolled and leukapheresed; 41 patients received the minimum target dose of axi‐cel and comprised both the modified intent‐to‐treat and safety analysis sets (Figure S1). Sixty‐eight percent of patients (n = 28/41) received bridging therapy before axi‐cel with a median reduction in TB among the 17 evaluable patients of 10%. As of the 6 November 2019 data cutoff, the median follow‐up was 14·8 months (range, 8·9–19·9 months).\n\nAmong treated patients, the median age was 61 years (range, 19–77; Table I). The most common disease subtype was diffuse LBCL (63%). Most patients (71%) had disease stage III or IV, 63% had had ≥ 3 previous therapies, and 37% had a best response of PD to their most recent chemotherapy. Product characteristics were largely comparable with those previously reported in ZUMA‐1 (Table SII). 3\n\nTABLE 1 Baseline characteristics.\n\nCharacteristic\tCohorts 1 + 2 (N = 101) 3\tCohort 4 (N = 41)\t\nDisease type, n (%)\t\nDLBCL\t77 (76)\t26 (63)\t\nPMBCL\t8 (8)\t2 (5)\t\nTFL\t16 (16)\t10 (24)\t\nHGBCL\tNA*\t3 (7)\t\nAge\t\nMedian (range), years\t58·0 (23–76)\t61·0 (19–77)\t\n ≥65 years, n (%)\t24 (24)\t13 (32)\t\nMale sex, n (%)\t68 (67)\t28 (68)\t\nECOG performance status score of 1, n (%)\t59 (58)\t20 (49)\t\nDisease stage, n (%)\t\nI or II\t15 (15)\t11 (27)\t\nIII or IV\t86 (85)\t29 (71)\t\nIPI score, n (%)\t\n0–2\t55 (54)\t21 (51)\t\n3–4\t46 (46)\t20 (49)\t\nCD19 positivity, n/N (%) †\t\nYes\t74 (73)\t22/24 (92)\t\nNo\t8 (8)\t2/24 (8)\t\nNumber of previous lines of chemotherapy, n (%)\t\n1\t3 (3)\t0\t\n2\t28 (28)\t15 (37)\t\n3\t29 (29)\t15 (37)\t\n4\t29 (29)\t8 (20)\t\n≥ 5\t12 (12)\t3 (7)\t\nPrevious SCT, n (%)\t25 (25)\t14 (34)\t\nPD as best response to most recent chemotherapy, n (%) ‡\t67 (66)\t15 (37)\t\nMedian (range) tumour burden by SPD, § mm2\t3721 (171–23 297)\t2100 (204–24 758)\t\nMedian (range) LDH, U/l\t356 (116–7802)\t263 (145–4735)\t\nMedian (range) ferritin, ng/ml\t786 (0·78–10 576)\t393 (23–3457)\t\nRefractory subgroup, n (%)\t\nPrimary refractory\t3 (3)\t0 (0)\t\nRefractory ≥ 2nd‐line therapy\t77 (76)\t28 (68)\t\nRelapsed ≥ 2nd‐line therapy\t0 (0)\t5 (12)\t\nRelapsed post‐ASCT\t21 (21)\t8 (20)\t\nASCT, autologous stem cell transplant; DLBCL, diffuse large B‐cell lymphoma; ECOG, Eastern Cooperative Oncology Group; HGBCL, high‐grade B‐cell lymphoma; IPI, International Prognostic Index; LDH, lactate dehydrogenase; NA, not applicable; PD, progressive disease; PMBCL, primary mediastinal B‐cell lymphoma; SCT, stem cell transplant; SPD, sum of the products of diameters; TFL, transformed follicular lymphoma.\n\n* As ZUMA‐1 was initiated under the 2008 World Health Organisation classifications of B‐cell lymphomas, high‐grade subtypes were not considered separate entities in standard of care practice and therefore not identified in cohorts 1 + 2; rather, such patients were considered to have DLBCL not otherwise specified or DLBCL which was unclassifiable when using the 2008 criteria.\n\n† For cohort 4, archival and on‐study pretreatment tumour biopsy ascertainment rate was 59% (24/41) by central confirmation of diagnosis. Two additional patients had missing confirmatory diagnosis due to absence of tumour tissue within the biopsy specimen sent for central assessment.\n\n‡ For patients who had not relapsed post‐ASCT.\n\n§ For cohort 4, at the last observation before conditioning chemotherapy; may have been measured before or after bridging in patients who received bridging.\n\nJohn Wiley & Sons, Ltd\n\nSafety\n\nAll patients experienced AEs, with 98% experiencing at least one grade ≥ 3 event—most frequently neutropenia (39%), decreased neutrophil count (29%), anaemia (24%), and pyrexia (24%; Table II). Any‐grade infection was reported in 25 (61%) patients, with worst grade 3, 4, and 5 occurring in eight (20%), one (2%), and one (2%) patient, respectively. There were two deaths due to AEs and both were reported as related to conditioning chemotherapy (day 13 pneumonia) or previous chemotherapy (day 354 acute myeloid leukaemia; shown by retrospective analysis to have transformed from underlying myelodysplastic syndrome already present at leucapheresis). Grade ≥ 3 cytopenias present on or after day 30 were reported in 39% of patients (Table SIII).\n\nTABLE 2 Incidence and severity of TEAEs.*\n\n\tCohort 4 (N = 41)\t\nAny grade\tWorst grade 3\tWorst grade 4\t\nAny, n (%)\t41 (100)\t12 (29)\t22 (54)\t\nPyrexia\t39 (95)\t10 (24)\t0 (0)\t\nDiarrhoea\t25 (61)\t4 (10)\t0 (0)\t\nHypotension\t25 (61)\t4 (10)\t0 (0)\t\nAnaemia\t19 (46)\t10 (24)\t0 (0)\t\nFatigue\t19 (46)\t3 (7)\t0 (0)\t\nHeadache\t16 (39)\t1 (2)\t0 (0)\t\nNeutropenia\t16 (39)\t4 (10)\t12 (29)\t\nNausea\t12 (29)\t0 (0)\t0 (0)\t\nNeutrophil count decreased\t12 (29)\t1 (2)\t11 (27)\t\nChills\t11 (27)\t0 (0)\t0 (0)\t\nCough\t10 (24)\t0 (0)\t0 (0)\t\nPlatelet count decreased\t10 (24)\t2 (5)\t2 (5)\t\nSomnolence\t8 (20)\t3 (7)\t0 (0)\t\nDizziness\t7 (17)\t0 (0)\t0 (0)\t\nEncephalopathy\t7 (17)\t2 (5)\t0 (0)\t\nLeucopenia\t7 (17)\t1 (2)\t5 (12)\t\nTachycardia\t7 (17)\t1 (2)\t0 (0)\t\nThrombocytopenia\t7 (17)\t4 (10)\t1 (2)\t\nBack pain\t6 (15)\t0 (0)\t0 (0)\t\nConstipation\t6 (15)\t0 (0)\t0 (0)\t\nHypocalemia\t6 (15)\t1 (2)\t0 (0)\t\nHypophosphataemia\t6 (15)\t4 (10)\t0 (0)\t\nHypoxia\t6 (15)\t3 (7)\t0 (0)\t\nTremor\t6 (15)\t0 (0)\t0 (0)\t\nVomiting\t6 (15)\t1 (2)\t0 (0)\t\nWhite blood cell count decreased\t6 (15)\t1 (2)\t5 (12)\t\nTEAE, treatment‐emergent adverse event.\n\n* TEAEs that occurred in ≥ 15% of patients and includes all grade ≥ 3 events that occurred in > 10% of patients.\n\nJohn Wiley & Sons, Ltd\n\nThe overall incidence of CRS was 93%, grade 3 CRS occurred in only 2% of patients (Table III), and there were no grade 4 CRS events or deaths in the setting of CRS. The most common grade 3 symptoms of CRS were pyrexia (24%), hypotension (8%), and hypoxia (5%). The median time to onset of CRS was two days, with a median duration of 6·5 days, and all CRS events resolved by the data cutoff. NEs occurred in 61% of patients, with an incidence of grade ≥ 3 NEs of 17% (Table III). The most common grade ≥ 3 NEs in cohort 4 were somnolence (7%), confusional state (7%), and encephalopathy (5%). There were no grade 4 or 5 NEs. Notably, grade ≥ 3 NEs were limited to patients who received bridging therapy. The median time to onset of NEs was six days, with a median duration of eight days. Three patients had ongoing NEs as of the data cutoff (Table SIV). Bridging therapy did not contribute to a reduction in the incidence of grade ≥ 3 CRS (bridging, 1/28 [4%]; no bridging, 0/13 [0%]) or NEs (bridging, 7/28 [25%]; no bridging, 0/13 [0%]). A total of 73% of patients received corticosteroids. Among those who received corticosteroids, the cumulative cortisone‐equivalent corticosteroid dose was 939 mg, and 43% received ≥ 5 doses (Table SV). Tocilizumab was administered to 76% of patients.\n\nTABLE 3 Incidence, severity, onset, and duration of CRS and NEs.\n\nTEAE\tCohort 4 (N = 41)\t\nCRS\t\nAny, n (%)\t38 (93)\t\nWorst grade 1, n (%)\t13 (32)\t\nWorst grade 2, n (%)\t24 (59)\t\nWorst grade 3, n (%)\t1 (2)\t\nWorst grade 4, n (%)\t0\t\nWorst grade 5, n (%)\t0\t\nMedian (range) time to onset of any grade CRS, days\t2·0 (1·0–8·0)\t\nMedian (range) duration, days\t6·5 (2·0–16·0)\t\nNEs\t\nAny, n (%)\t25 (61)\t\nWorst grade 1, n (%)\t14 (34)\t\nWorst grade 2, n (%)\t4 (10)\t\nWorst grade 3, n (%)\t7 (17)\t\nWorst grade 4, n (%)\t0\t\nWorst grade 5, n (%)\t0\t\nMedian (range) time to onset of any grade NE, days\t6·0 (1·0–93·0)\t\nMedian (range) duration, days\t8·0 (1·0–144·0)\t\nCRS, cytokine release syndrome; NE, neurologic event; TEAE, treatment‐emergent adverse event.\n\nJohn Wiley & Sons, Ltd\n\nEfficacy\n\nThe investigator‐assessed objective response rate (ORR) in cohort 4 was 73%, with a CR rate of 51% (Fig 2). While the study was not designed to evaluate the effect of bridging therapy, comparable ORRs were observed in patients who did and did not receive bridging therapy (71% vs. 77%, respectively), although the CR rate was numerically lower in patients who received bridging therapy (46% vs. 62%). The KM estimate of the 12‐month duration of response rate was 71%, and 51% of treated patients remained in response as of the data cutoff date. Response did not appear to be affected by corticosteroid use (Figure S2). Median PFS was not reached (95% CI, 3·0 months—not estimable [NE]; Figure S3A), and the KM estimate of the 12‐month PFS rate was 57%. Median PFS in patients who achieved CR, partial response, or no response was not reached (95% CI, NE–NE), 6·1 months (95% CI, 1·3 months—NE), and 1·4 months (95% CI, 0·2–1·9 months), respectively (Figure S3B). Among all patients, median OS was not reached (95% CI, 15·8 months—NE), and the KM estimate of the 12‐month OS rate was 68%.\n\nFig 2 ORR and duration of response. (A) ORR of patients in cohort 4 and rates of SD and PD. Response could not be evaluated in two patients: one patient died of pneumonia before the first assessment, and one patient had a positive result from positron emission tomography with suspected inflammation. (B) Kaplan–Meier curve of duration of response. CR, complete response; NE, not estimable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.\n\nBiomarker analyses\n\nMedian peak CAR T‐cell expansion for cohort 4 was 52·9 cells/μl blood and was observed within 14 days after axi‐cel infusion (Fig 3A). Post‐treatment median levels of key inflammatory serum biomarkers associated with CRS and/or NEs—including IFN‐γ, IL‐2, IL‐6, IL‐8, IL‐15, MCP‐1, GM‐CSF, C‐reactive protein (CRP), and ferritin 3 —peaked during the first week after axi‐cel infusion (Fig 3B; Table SVI). Cohort 4 patients with evaluable samples and grade ≥ 3 NEs had numerically greater post‐infusion (day 5) cerebrospinal fluid levels of IFN‐γ, IL‐15, IL‐2Rα, IL‐6, IL‐8, CRP, and ferritin versus those with grade 0–1 NEs, despite low and comparable baseline levels (Figure S4). A similar pattern was observed for serum biomarkers (Figure S5).\n\nFig 3 CAR T‐cell expansion and key soluble serum biomarker levels over time. (A) Median (Q1, Q3) blood levels of CAR T cells over time. (B) Median (Q1, Q3) levels of key soluble serum inflammatory biomarkers plotted against time. BL, baseline; CAR, chimeric antigen receptor; CRP, C‐reactive protein; GM‐CSF, granulocyte‐macrophage colony–stimulating factor; IFN, interferon; IL, interleukin; MCP‐1, monocyte chemoattractant protein‐1.\n\nPSM analysis\n\nThe incidence of grade ≥ 3 CRS and grade ≥ 3 NEs observed in cohort 4 (2% and 17%, respectively) was numerically lower than in cohorts 1 + 2 (12% and 29%, respectively). 3 Because cohort 4 was not designed for statistical comparison with cohorts 1 + 2, an exploratory PSM analysis 21 , 22 was used to match these cohorts with respect to key baseline characteristics. Following PSM, baseline disease and product characteristics were generally similar between patients in cohort 4 and cohorts 1 + 2, although fewer cohort 4 patients had baseline ECOG performance status of 1 (49% vs. 68%; Table SVII). Notably, the differences in grade ≥ 3 CRS and NEs observed between patients in cohorts 1 + 2 and cohort 4 before PSM were maintained after matching. Although CR rates after PSM were numerically lower in cohort 4 versus cohorts 1 + 2, ongoing response rates remained comparable. Clinical outcomes were corroborated by lower levels of key inflammatory soluble biomarkers associated with CAR‐related inflammatory events (e.g., IFN‐γ, IL‐2, IL‐8, C‐reactive protein, ferritin, GM‐CSF), 3 , 10 and by generally comparable peak CAR T‐cell levels in cohort 4 versus cohorts 1 + 2 before and after PSM. The median cumulative cortisone‐equivalent corticosteroid dose required to manage CRS or NEs remained lower in cohort 4 (939 mg) than in matched cohorts 1 + 2 (6886 mg; Table SVIII).\n\nDiscussion\n\nAE management in CAR T‐cell therapy is an evolving field with ongoing efforts to improve the safety profile of this treatment without compromising the durable clinical benefit. To this end, ZUMA‐1 cohort 4 patients received corticosteroid and/or tocilizumab intervention earlier than the pivotal cohorts 1 + 2. 3 , 4 Numerically lower rates of grade ≥ 3 CRS and NEs were observed in cohort 4 (2% and 17%, respectively) than in cohorts 1 + 2 (12% and 29%), suggesting that earlier intervention with corticosteroids and/or tocilizumab has the potential to improve the safety profile of axi‐cel in patients with R/R LBCL. In patients treated with corticosteroids, the median cumulative cortisone‐equivalent dose was 939 mg in cohort 4 versus 6388 mg in cohorts 1 + 2, suggesting that earlier corticosteroid use does not increase cumulative corticosteroid dose. Furthermore, this revised safety management regimen did not appear to negatively affect the ongoing response rate at one year (cohort 4: 51%; cohorts 1 + 2: 42%), although additional follow‐up is needed to assess the long‐term durability of responses.\n\nDifferences in baseline characteristics and cohort sizes should be considered when comparing cohort 4 with cohorts 1 + 2. Cohort 4 patients had lower levels of inflammatory serum biomarkers (e.g., ferritin or LDH) at baseline, and a lower proportion of patients had PD in response to the most recent line of therapy. 4 , 25 Cohort 4 also had lower TB, which has previously been associated with lower rates of NEs and increased efficacy. 17 , 18 To overcome these limitations and reduce bias in the absence of a randomised trial, PSM 21 , 22 was applied to cohorts 1 + 2 and cohort 4. This statistical method adjusts for potential imbalances in baseline disease characteristics between cohorts, thereby providing a more balanced and robust comparison. 23 , 26 It should be noted that although PSM controls for known imbalances between cohorts, other sources of bias may exist due to unmeasured confounding variables. Although minor differences in pretreatment characteristics remained after matching, the aforementioned differences in toxicity outcomes observed between patients in cohort 4 and cohorts 1 + 2 before PSM were maintained after matching, supporting the benefit of earlier corticosteroid and/or tocilizumab. PSM also had little effect on peak CAR T‐cell levels, and ongoing response rates at one year remained comparable, suggesting no negative impact of earlier corticosteroid and/or tocilizumab use on long‐term outcomes.\n\nDespite the theoretical concern that immunosuppressive agents may abrogate CAR T‐cell expansion and anti‐tumour response, 27 earlier and measured introduction of corticosteroid in cohort 4 did not substantially affect either. Cohort 4 showed generally comparable peak CAR T‐cell levels versus cohorts 1 + 2 but lower levels of key inflammatory serum biomarkers associated with CAR‐related inflammatory events (e.g., IFN‐γ, IL‐2, IL‐8, and GM‐CSF). 3 , 10 These findings corroborated clinical outcomes, suggesting that early use of corticosteroids may have a greater impact on immune cell cytokine production than on CAR T‐cell expansion and anti‐tumour activity. Furthermore, corticosteroids are known to modulate T‐cell and myeloid cell activity, thereby decreasing proinflammatory cytokine levels with potential beneficial impact on blood‐brain‐barrier permeability and local inflammatory processes. 28\n\nThe results presented here are consistent with the primary analysis of ZUMA‐1 (cohorts 1 + 2), which suggested no substantial effect of corticosteroid use on ORR (corticosteroid, 78% [58–91%]; no corticosteroid, 84% [73–91%]). 3 Retrospective analyses of real‐world data have delivered conflicting results regarding the impact of corticosteroid use on clinical outcomes after axi‐cel in R/R LBCL. 29 , 30 However, in the larger of these two studies (N = 298), multivariate analysis demonstrated no significant difference in PFS, CR rates, or OS in patients treated with corticosteroids versus treated without. 30 It is important to note that the clinical applicability of these studies is unclear given their retrospective nature and potential imbalances in baseline characteristics (e.g., TB) 17 , 18 , 31 , 32 in patients requiring corticosteroids versus those not requiring corticosteroids. Although studies of other CAR T‐cell products in B‐cell acute lymphoblastic leukaemia have also not been designed to assess the impact of corticosteroid use, published analyses have shown no substantial effect of corticosteroid use on CAR T‐cell expansion or anti‐tumour response. 33 , 34\n\nFinally, we cannot fully rule out the contribution of additional differences in intervention beyond corticosteroid and/or tocilizumab use. However, it is unlikely that prophylactic levetiracetam resulted in fewer grade ≥ 3 NEs in cohort 4 versus cohorts 1 + 2, given that prophylactic levetiracetam was used in ZUMA‐1 safety management cohort 3, which actually demonstrated a numerical increase in grade ≥ 3 NEs. 12 While cohort 4 patients could receive bridging therapy, bridging was not associated with a reduction in the incidence of grade ≥ 3 CRS or NEs in cohort 4. It should also be noted that, at time of enrollment, none of the 40 cohort 4 sites were considered a CAR T‐experienced centre, and 90% had never before treated a patient with CAR T cells. Thus, the experience of the investigators is unlikely to have contributed to the improved safety of axi‐cel in cohort 4.\n\nIn conclusion, earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs through down‐modulating key proinflammatory soluble serum biomarkers, including cytokines, without notably affecting CAR T‐cell expansion and ongoing response rates in patients with R/R LBCL receiving axi‐cel. This approach offers important additive information to further inform patient care.\n\nData sharing statement\n\nGilead is committed to sharing clinical trial data with external medical experts and scientific researchers in the interest of advancing public health. As such, Gilead shares anonymised individual patient data (IPD) upon request or as required by law and/or regulation. Qualified external researchers may request IPD for studies of Gilead compounds approved in the United States and the European Union with a marketing authorisation date on or after 1 January 2014, and are publicly listed on clinicaltrials.gov or the European Union‐Clinical Trials Register (EU CTR). For studies of newly approved compounds or indication, the IPD will be available for request six months after approval from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Such requests are at Gilead’s discretion and are dependent on the nature of the request, the merit of the research proposed, availability of the data, and the intended use of the data. If Gilead agrees to the release of clinical data for research purposes, the requestor will be required to sign a data‐sharing agreement, to ensure protection of patient confidentiality before the release of any data.\n\nFunding\n\nThe study was supported by Kite, a Gilead Company.\n\nAuthor contributions\n\nMST, AB, AK, and MJK conceived and designed the study; all authors provided study material or patients, collected or assembled data, participated in drafting and revising the manuscript, approved the final version of the manuscript, and are accountable for all aspects of this work.\n\nConflict of interest\n\nMST has served in a consultancy or advisory role for Amgen, Kite, a Gilead Company, Celgene, Regeneron and Roche, and received research funding from Amgen, Kite, a Gilead Company, Regeneron, Roche and MacroGenics. TvM has received honoraria from Kite, a Gilead Company, and has served in a consultant or advisory role for Janssen. RH has received honoraria from Bristol Myers Squibb, Novartis, Celgene, Janssen, MSD, Kite, a Gilead Company, Roche, and ADC Therapeutics and has served in a consultancy or advisory role for Kite, a Gilead Company. MCM has served in a consultancy or advisory role for Janssen‐Cilag, Gilead, and Alnylam and has received travel support from Celgene. KB has served in a consultancy or advisory role for Kite, a Gilead Company, Roche, Sandoz, and Takeda; received honoraria from Kite, a Gilead Company, Celgene, Roche and Takeda; and received travel support from Roche. PJL has served in a consultancy or advisory role for Takeda, Servier, Roche, Bristol Myers Squibb, Celgene, Sandoz, and Genmab and received research funding from Takeda and Servier. CT has served in a consultancy or advisory role for Novartis, Roche, Celgene, and Janssen; received honoraria from Gilead, Novartis, Roche, Celgene and Janssen; received research funding from Roche; and received travel support from Gilead, Novartis, Roche and Janssen. MW has served in a consultancy or advisory role for Kite, a Gilead Company, Novartis, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, Genmab and Boehringer Ingelheim; received honoraria from Novartis, Bristol Myers Squibb, AstraZeneca, Pfizer and Merck; and received travel support from Novartis, Bristol Myers Squibb and AstraZeneca. KWS has received honoraria from and has served in a consultancy or advisory role for Kite, a Gilead Company. JK has served in a consultancy or advisory role for AbbVie, Bristol Myers Squibb, Gilead, Karyopharm, Merck, Roche and Seattle Genetics; received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Gilead, Janssen, Karyopharm, Merck, Novartis, Roche and Seattle Genetics; and received research funding from Roche and Janssen. UD served in a consultancy or advisory role for AbbVie, Amgen, CPT, Gilead, Janssen, Novartis and Takeda; received honoraria from AbbVie, Amgen, Celgene, CPT, Gilead, Janssen, Novartis, Roche and Takeda; received research funding from Amgen, Celgene and Roche; and received travel support from AbbVie and Janssen. YZ, MS, JJK, and AK are employed by Kite, a Gilead Company, and have stock or other ownership in Gilead Sciences. SV is employed by and has received research funding and travel support from Kite, a Gilead Company, and has stock or other ownership in Gilead Sciences. JD is employed by Kite, a Gilead Company; has served in a consultancy or advisory role for GliaCure/Tufts; and has received patents, royalties or other intellectual property from Patent US8598141 (Dec 03, 2013). AB is employed by Kite, a Gilead Company, and has stock or other ownership in, has served in a consultancy or advisory role for, and received travel support from Gilead Sciences. JMR is employed by Kite, a Gilead Company. VP is employed by and has received honoraria and travel support from Kite, a Gilead Company; has stock or other ownership in Gilead Sciences; and has patents, royalties or other intellectual property from Genentech. MJK has served in a consultancy or advisory role for and received honoraria from Kite, a Gilead Company, Novartis and Miltenyi; received research funding from Roche, Takeda and Celgene; and received travel support from Kite, a Gilead Company, Novartis and Miltenyi. The remaining author (IA) declares no competing financial interests.\n\nSupporting information\n\nData S1. Supplemental methods\n\nTable SI. Bridging therapy regimens.*\n\nTable SII. Summary of product characteristics.\n\nTable SIII. Incidence of worst grade ≥ 3 neutropenia, thrombocytopenia, and anaemia present on or after day 30 following axi‐cel infusion.\n\nTable SIV. Summary of neurologic events unresolved at data cutoff.\n\nTable SV. Cumulative dose and frequency of corticosteroid use.\n\nTable SVI. Summary of serum biomarkers.\n\nTable SVII. Comparison of baseline and product characteristics between patients in cohorts 1 + 2 and cohort 4 before and after propensity score matching.\n\nTable SVIII. Comparison of efficacy and safety outcomes and CAR T‐cell and soluble serum biomarker levels between patients in cohorts 1 + 2 and cohort 4 before and after propensity score matching.\n\nFig S1. Patient disposition diagram.\n\nFig S2. Best response by corticosteroid use.\n\nFig S3. Progression‐free survival in cohort 4. (A) All treated patients. (B) Best overall response subgroups.\n\nFig S4. Selected CSF analysis at baseline and day 5 and association with neurologic events.\n\nFig S5. Selected serum analysis at baseline and day 5 and association with neurologic events.\n\nClick here for additional data file.\n\nAcknowledgements\n\nWe thank all investigators, coordinators, study‐site personnel, and the patients and their families for participating in this study. Kite, a Gilead Company, was involved in the development of the study protocol and in data collection, analysis, and interpretation. We would like to acknowledge Drs. Zahid Bashir, Justin Chou, Aurora Liao, and Yan Zheng for their contributions to data analysis and interpretation. Editorial and writing assistance during the development of this article was provided by Skye Geherin, PhD, and Ashley Skorusa, PhD, of Nexus Global Group Science, a Vaniam Group Company, and funded by Kite, a Gilead Company.\n==== Refs\nReferences\n\n1 YESCARTA® (axicbatagene ciloleucel) Summary of product characteristics. Kite Pharma EU B.V.; 2021.\n2 YESCARTA® (axicabtagene ciloleucel) Prescribing information. Kite Pharma, Inc; 2021.\n3 Neelapu SS , Locke FL , Bartlett NL , Lekakis LJ , Miklos DB , Jacobson CA , et al. Axicabtagene ciloleucel CAR T‐cell therapy in refractory large B‐cell lymphoma. N Engl J Med. 2017;377 (26 ):2531–44.29226797\n4 Locke FL , Ghobadi A , Jacobson CA , Miklos DB , Lekakis LJ , Oluwole OO , et al. Long‐term safety and activity of axicabtagene ciloleucel in refractory large B‐cell lymphoma (ZUMA‐1): a single‐arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20 (1 ):31–42.30518502\n5 Jacobson C , Locke FL , Ghobadi A , Miklos DB , Lekakis LJ , Oluwole OO , et al. Long‐term survival and gradual recovery of B cells in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi‐cel). Blood. 2020;136 (Suppl 1 ):40–2.\n6 Maruffi M , Sposto R , Oberley MJ , Kysh L , Orgel E . Therapy for children and adults with mixed phenotype acute leukemia: a systematic review and meta‐analysis. Leukemia. 2018;32 (7 ):1515–28.29550836\n7 Sun W , Malvar J , Sposto R , Verma A , Wilkes JJ , Dennis R , et al. Outcome of children with multiply relapsed B‐cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study. Leukemia. 2018;32 (11 ):2316–25.29728694\n8 Santomasso B , Bachier C , Westin J , Rezvani K , Shpall EJ . The other side of CAR T‐cell therapy: cytokine release syndrome, neurologic toxicity, and financial burden. Am Soc Clin Oncol Educ Book. 2019;39 :433–44.31099694\n9 Chen P‐H , Lipschitz M , Weirather JL , Jacobson C , Armand P , Wright K , et al. Activation of CAR and non‐CAR T cells within the tumor microenvironment following CAR T cell therapy. JCI Insight. 2020;5 (12 ):e134612.\n10 Teachey DT , Lacey SF , Shaw PA , Melenhorst JJ , Maude SL , Frey N , et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6 (6 ):664–79.27076371\n11 ACTEMRA (tocilizumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2018.\n12 Locke FL , Neelapu SS , Bartlett NL , Lekakis LJ , Jacobson CA , Braunschweig I , et al. Preliminary results of prophylactic tocilizumab after axicabtagene ciloleucel (axi‐cel; KTE‐C19) treatment for patients with refractory, aggressive non‐Hodgkin lymphoma (NHL). Blood. 2017;130 (Suppl 1 ):1547.\n13 Brudno JN , Lam N , Vanasse D , Shen Y‐W , Rose JJ , Rossi J , et al. Safety and feasibility of anti‐CD19 CAR T cells with fully human binding domains in patients with B‐cell lymphoma. Nat Med. 2020;26 (2 ):270–80.31959992\n14 Brudno JN , Kochenderfer JN . Recent advances in CAR T‐cell toxicity: mechanisms, manifestations and management. Blood Rev. 2019;34 :45–55.30528964\n15 Parker KR , Migliorini D , Perkey E , Yost KE , Bhaduri A , Bagga P , et al. Single‐cell analyses identify brain mural cells expressing CD19 as potential off‐tumor targets for CAR‐T immunotherapies. Cell. 2020;183 (1 ):126–42.e17.32961131\n16 Gust J , Hay KA , Hanafi L‐A , Li D , Myerson D , Gonzalez‐Cuyar LF , et al. Endothelial activation and blood‐brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR‐T cells. Cancer Discov. 2017;7 (12 ):1404–19.29025771\n17 Locke F , Rossi J , Neelapu S , Jacobson CA , Miklos D , Ghobadi A , et al. Tumor burden, inflammation, and product attributes determine outcomes of axi‐cel in large B‐cell lymphoma. Blood Adv. 2020;4 (19 ):4898–911.33035333\n18 Dean EA , Mhaskar RS , Lu H , Mousa MS , Krivenko GS , Lazaryan A , et al. High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B‐cell lymphoma. Blood Adv. 2020;4 (14 ):3268–76.32702097\n19 Lee DW , Gardner R , Porter DL , Louis CU , Ahmed N , Jensen M , et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124 (2 ):188–95.24876563\n20 U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2010. National Institutes of Health National Cancer Institute.\n21 Rosenbaum PR , Rubin DB . The central role of the propensity score in observational studies for causal effects. Biometriks. 1983;70 (1 ):41–55.\n22 Austin PC . An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46 (3 ):399–424.21818162\n23 Austin PC . A critical appraisal of propensity‐score matching in the medical literature between 1996 and 2003. Stat Med. 2008;27 (12 ):2037–49.18038446\n24 Imai K , King G , Stuart EA . Misunderstandings between experimentalists and observationalists about causal inference. J R Stat Soc. 2008;171 :481–502.\n25 Topp M , Van Meerten T , Houot R , Minnema MC , Milpied N , Lugtenburg PJ , et al. Earlier steroid use with axicabtagene ciloleucel (Axi‐Cel) in patients with relapsed/refractory large B cell lymphoma. Blood. 2019;134 (Suppl 1 ):243.\n26 Zhang Z , Kim HJ , Lonjon G , Zhu Y . Balance diagnostics after propensity score matching. Ann Transl Med. 2019;7 (1 ):16.30788363\n27 Davila ML , Riviere I , Wang X , Bartido S , Park J , Curran K , et al. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6 (224 ):224ra25.\n28 Zielińska KA , Van Moortel L , Opdenakker G , De Bosscher K , Van den Steen PE . Endothelial response to glucocorticoids in inflammatory diseases. Front Immunol. 2016;7 :592.28018358\n29 Strati P , Ahmed S , Furqan F , Fayad LE , Lee HJ , Iyer SP , et al. Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor T‐cell therapy in large B‐cell lymphoma. Blood. 2021;137 (23 ):3272–6. Online ahead of print.33534891\n30 Nastoupil LJ , Jain MD , Feng L , Spiegel JY , Ghobadi A , Lin YI , et al. Standard‐of‐care axicabtagene ciloleucel for relapsed or refractory large B‐cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020;38 (27 ):3119–28. [online ahead of print].32401634\n31 Gauthier J , Hirayama AV , Hay KA , Li D , Sheih A , Wu V , et al. Factors associated with duration of response after CD19‐specific CAR‐T cell therapy for refractory/relapsed B‐cell non‐Hodgkin lymphoma. J Clin Oncol. 2018;36 (Suppl 15 ):7567.\n32 Jacobson CA , Hunter B , Armand P , Kamihara Y , Ritz J , Rodig SJ , et al. Axicabtagene ciloleucel in the real world: outcomes and predictors of response, resistance and toxicity. Blood. 2018;132 (Suppl 1 ):92.\n33 Gardner RA , Ceppi F , Rivers J , Annesley C , Summers C , Taraseviciute A , et al. Preemptive mitigation of CD19 CAR T‐cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019;134 (24 ):2149–58.31697826\n34 Liu S , Deng B , Yin Z , Pan J , Lin Y , Ling Z , et al. Corticosteroids do not influence the efficacy and kinetics of CAR‐T cells for B‐cell acute lymphoblastic leukemia. Blood Cancer J. 2020;10 (2 ):15.32029707\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0007-1048",
"issue": "195(3)",
"journal": "British journal of haematology",
"keywords": "CAR T; axi-cel; corticosteroids; large B-cell lymphoma; toxicity",
"medline_ta": "Br J Haematol",
"mesh_terms": null,
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "388-398",
"pmc": null,
"pmid": "34590303",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma.",
"title_normalized": "earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large b cell lymphoma"
} | [
{
"companynumb": "DE-NOVARTISPH-NVSC2021DE226070",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "... |
{
"abstract": "A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).",
"affiliations": "Diagnostic Pathology Clinic, Pathos Tsutsumi, Nagoya, Aichi, Japan.;Department of Diagnostic Pathology, Shimada Municipal Hospital, Shimada, Shizuoka, Japan.;Department of Dermatology, Shimada Municipal Hospital, Shimada, Shizuoka, Japan.;Department of Dermatology, Shimada Municipal Hospital, Shimada, Shizuoka, Japan.;Department of Diagnostic Pathology, Shimada Municipal Hospital, Shimada, Shizuoka, Japan.",
"authors": "Tsutsumi|Yutaka|Y|https://orcid.org/0000-0002-4136-9678;Odani|Kentaro|K|https://orcid.org/0000-0003-4379-7112;Kaneko|Yasuhito|Y|https://orcid.org/0000-0001-7052-801X;Hashizume|Hideo|H|;Tachibana|Mitsuhiro|M|https://orcid.org/0000-0002-1041-0391",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/8819560",
"fulltext": "\n==== Front\nCase Rep Pathol\nCase Rep Pathol\nCRIPA\nCase Reports in Pathology\n2090-6781 2090-679X Hindawi \n\n10.1155/2021/8819560\nCase Report\nCutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression\nhttps://orcid.org/0000-0002-4136-9678Tsutsumi Yutaka pathos223@kind.ocn.ne.jp\n1\n\n2\n https://orcid.org/0000-0003-4379-7112Odani Kentaro \n2\n\n3\n https://orcid.org/0000-0001-7052-801XKaneko Yasuhito \n4\n Hashizume Hideo \n4\n https://orcid.org/0000-0002-1041-0391Tachibana Mitsuhiro \n2\n \n1Diagnostic Pathology Clinic, Pathos Tsutsumi, Nagoya, Aichi, Japan\n\n2Department of Diagnostic Pathology, Shimada Municipal Hospital, Shimada, Shizuoka, Japan\n\n3Department of General Medicine, Shimada Municipal Hospital, Shimada, Shizuoka, Japan\n\n4Department of Dermatology, Shimada Municipal Hospital, Shimada, Shizuoka, Japan\nAcademic Editor: Denise Tostes Oliveira\n\n\n2021 \n29 1 2021 \n2021 881956021 5 2020 8 1 2021 22 1 2021 Copyright © 2021 Yutaka Tsutsumi et al.2021This 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.A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).\n==== Body\n1. Introduction\nImmunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.\n\n2. Case Report\nA 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.\n\nFour months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.\n\nMicrobial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).\n\nClarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.\n\nMetformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.\n\nFor characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.\n\n3. Discussion\nOpportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].\n\nOpportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.\n\nVaried nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].\n\n\nM. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].\n\nThe cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.\n\nLipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].\n\nImmunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].\n\n4. Conclusion\nWe reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.\n\nAcknowledgments\nThe authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.\n\nConsent\nThe patient gave written informed consent to publication of the case report.\n\nDisclosure\nThe present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.\n\nConflicts of Interest\nThe authors do not have any conflict of interest in the present report.\n\nAuthors' Contributions\nWe declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.\n\nFigure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.\n\nFigure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).\n\nFigure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.\n\nFigure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.\n\nFigure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.\n\nFigure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.\n\nTable 1 Antibodies used in the present study.\n\nTarget antigen\tAnimal/clone\tDilution\tAntigen retrieval\tSource\t\nBacillus Calmette-Guérin (BCG)\tRabbit antiserum\t1 : 10,000\tNone\tAgilent\t\nMPT64 (RV1980C, 24 kDa protein)\tRabbit antiserum\t1 : 800\tHIER in 10 mM CB (pH 6)\tAbcam\t\nLAM (lipoarabinomannan)\tMouse TMDU3\t1 : 1,000\tHIER in 10 mM CB (pH 6)\tMBL\t\nPAB (Propionibacterium acnes-specific lipoteichoic acid)\tMouse TMDU2\t1 : 4,000\tHIER in 10 mM CB (pH 6)\tMBL\t\nBacillus cereus\tRabbit antiserum\t1 : 500\tHIER in 10 mM CB (pH 6)\tAbcam\t\nTreponema pallidum\tRabbit antiserum\t1 : 1,000\tHIER in 1 mM EDTA (pH 8)\tBM\t\nEscherichia coli\tRabbit antiserum\t1 : 20,000\tProteinase K digestion\tAgilent\t\nMPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines).\n==== Refs\n1 Tappero J. W. Perkins B. A. Wenger J. D. Berger T. G. Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus Clinical Microbiology Reviews 1995 8 3 440 450 10.1128/CMR.8.3.440 7553576 \n2 Cunliffe T. Opportunistic skin infections 2015 http://www.pcds.org.uk/clinical-guidance/mycoses-uncommon-types \n3 Kozono K. Nakahara T. Kikuchi S. Itoh E. Kido-Nakahara M. Furue M. Pyoderma gangrenosum with increased levels of serum cytokines Journal of Dermatology 2015 42 12 1186 1188 10.1111/1346-8138.12970 2-s2.0-84955178499 26047254 \n4 Neuschlova M. Vladarova M. Kompanikova J. Sadlonova V. Novakova E. Pokorski M. Identification of Mycobacterium species by MALDI-TOF mass spectrometry Pulmonary Care and Clinical Medicine 2017 1021 Champions Springer 37 42 Advances in Experimental Medicine and Biology 10.1007/5584_2017_26 2-s2.0-85030636286 \n5 Tsutsumi Y. Low-Specificity and High-Sensitivity Immunostaining for Demonstrating Pathogens in Formalin-Fixed, Paraffin-Embedded Sections Immunohistochemistry - The Ageless Biotechnology 2020 London, UK IntechOpen p. 46 10.5772/intechopen.85055 \n6 Kawai K. Tsutsumi Y. Immunoperoxidase visualization of acid-fast bacilli. A comparison with conventional acid-fast staining Byori-to-Rinsho 1984 2 862 867 (in Japanese) \n7 Myneedu V. P. Arora J. Kumar G. Verma A. K. Bhalla M. Sarin R. Utility of MPT64 antigen detection for rapid confirmation of Mycobacterium tuberculosis complex Journal of Global Infectious Diseases 2015 7 2 66 69 10.4103/0974-777X.154443 2-s2.0-84930470954 26069425 \n8 Sakakibara Y. Suzuki Y. Fujie T. Radiopathological features and identification of mycobacterial infections in granulomatous nodules resected from the lung Respiration 2017 93 4 264 270 10.1159/000456550 2-s2.0-85013685259 28219077 \n9 Negi M. Takemura T. Guzman J. Localization of Propionibacterium acnes in granulomas supports a possible etiologic link between sarcoidosis and the bacterium Modern Pathology 2012 25 9 1284 1297 10.1038/modpathol.2012.80 2-s2.0-84865702362 22596102 \n10 Tsutsumi Y. Pathology of Skin Infections 2013 NY, USA Nova Biomedical https://pathos223.com/bookintroduction/pathology_of_skin_infectious.html \n11 Ruocco E. Sangiuliano S. Gravina A. G. Miranda A. Nicoletti G. Pyoderma gangrenosum: an updated review Journal of the European Academy of Dermatology and Venereology 2009 23 9 1008 1017 10.1111/j.1468-3083.2009.03199.x 2-s2.0-68749094383 19470075 \n12 Partridge A. C. R. Bai J. W. Rosen C. F. Walsh S. R. Gulliver W. P. Fleming P. Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic review of observational studies and clinical trials British Journal of Dermatology 2018 179 290 295 10.1111/bjd.16485 2-s2.0-85052205824 \n13 Choi Y. L. Kim J. A. Jang K. T. Characteristics of cutaneous cytomegalovirus infection in non-acquired immune deficiency syndrome, immunocompromised patients British Journal of Dermatology 2006 155 5 977 982 10.1111/j.1365-2133.2006.07456.x 2-s2.0-33749832582 \n14 Mishra K. Jandial A. Bal A. Verrucous skin lesions in a case of acute lymphoblastic leukemia: a rare manifestation of cytomegalovirus infection Indian Journal of Hematology and Blood Transfusion 2018 34 2 378 380 10.1007/s12288-017-0855-3 2-s2.0-85026468540 29622895 \n15 Ballestero-Díez M. Alvarez-Ruiz S. B. Aragüés Montanés M. Fraga J. Septal panniculitis associated with cytomegalovirus infection Histopathology 2005 46 6 720 722 10.1111/j.1365-2559.2005.02037.x 2-s2.0-20644445863 15910612 \n16 Grushchak S. Hutchens K. A. Joy C. Peterson A. Speiser J. Mudaliar K. Cutaneous cytomegalovirus infection in an immunocompetent patient: innocent bystander or culprit? American Journal of Dermatopathology 2018 40 4 295 298 10.1097/DAD.0000000000001009 2-s2.0-85052582786 28937438 \n17 Kullavanijaya P. Atypical mycobacterial cutaneous infection Clinics in Dermatology 1999 17 2 153 158 discussion 105–106 10.1016/S0738-081X(99)00008-5 2-s2.0-0032704995 10330598 \n18 Forbes B. A. Hall G. S. Miller M. B. Practical Guidance for clinical microbiology laboratories: Mycobacteria Clinical Microbiological Reviews 2018 31 2, article e00038 10.1128/CMR.00038-17 2-s2.0-85041549480 29386234 \n19 Hori H. Kokashiwa H. Nishina M. Tawada Y. Aono M. Nagano T. A case of M. chelonae infection detected by prolonged culture Modern Media 2006 52 131 134 (in Japanese) \n20 Friedmann F. F. Spontane Lungentuberkulose bei Schildkröten und die Stellung des Tuberkelbazillus im system Zeitschrift für Tuberkulose 1903 4 439 451 (in German) \n21 De Groote M. A. Huitt G. Infections due to rapidly growing Mycobacteria Clinical Infectious Diseases 2006 42 12 1756 1763 10.1086/504381 2-s2.0-33744798461 16705584 \n22 Fogelson S. B. Camus A. C. Lorenz W. W. Variation among human, veterinary and environmental Mycobacterium chelonae-abscessus complex isolates observed using core genome phylogenomic analysis, targeted gene comparison, and anti-microbial susceptibility patterns PLoS One 2019 14 3, article e0214274 10.1371/journal.pone.0214274 2-s2.0-85063444837 30908517 \n23 Cusumano L. R. Tran V. Tlamsa A. Rapidly growing Mycobacterium infections after cosmetic surgery in medical tourists: the Bronx experience and a review of the literature International Journal of Infectious Diseases 2017 63 1 6 10.1016/j.ijid.2017.07.022 2-s2.0-85027500666 28780185 \n24 Gable A. D. Marsee D. K. Milner D. A. Granter S. R. Suppurative inflammation with microabscess and pseudocyst formation is a characteristic histologic manifestation of cutaneous infections with rapid-growing Mycobacterium species American Journal of Clinical Pathology 2008 130 4 514 517 10.1309/DPCLAWWQNTB74JNB 2-s2.0-54049113485 18794042 \n25 Fowler J. Mahlen S. D. Localized cutaneous infections in immunocompetent individuals due to rapidly growing mycobacteria Archives of Pathology and Laboratory Medicine 2014 138 8 1106 1109 10.5858/arpa.2012-0203-RS 2-s2.0-84907270594 25076301 \n26 Chandler L. Young D. S. Chapter 20. Challenges in clinical microbiology testing Accurate Results in the Clinical Laboratory. A Guide to Error Detection and Correction 2013 Amsterdam, the Netherland Elsevier 315 326 10.1016/B978-0-12-415783-5.00020-7 2-s2.0-84902066343 \n27 Marrakchi H. Lanéelle M.-A. Daffé M. Mycolic acids: structures, biosynthesis, and beyond Cell Chemical Biology 2014 21 1 67 85 10.1016/j.chembiol.2013.11.011 2-s2.0-84892635980 24374164 \n28 Schorey J. S. Sweet L. The mycobacterial glycopeptidolipids: structure, function, and their role in pathogenesis Glycobiology 2008 18 11 832 841 10.1093/glycob/cwn076 2-s2.0-54549117073 18723691 \n29 Fujii M. Mizutani Y. Sakuma T. \nCorynebacterium kroppenstedtii in granulomatous mastitis: analysis of formalin-fixed, paraffin-embedded biopsy specimens by immunostaining using low-specificity bacterial antisera and real-time polymerase chain reaction Pathology International 2018 68 7 409 418 10.1111/pin.12683 2-s2.0-85049506505 29862601 \n30 Collins M. D. Falsen E. Akervall E. Sjoden B. Alvarez A. Note: Corynebacterium kroppenstedtii sp. nov., a novel corynebacterium that does not contain mycolic acids International Journal of Systematic Bacteriology 1998 48 4 1449 1454 10.1099/00207713-48-4-1449 2-s2.0-0031754648 9828448 \n31 Roberts J. A. Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient Critical Care Medicine 2009 37 3 840 851 quiz 859 10.1097/CCM.0b013e3181961bff 2-s2.0-62849095029 19237886 \n32 Franck N. Cabie A. Villette B. Amor B. Lessana-Leibowitch M. Escande J. P. Treatment of Mycobacterium chelonae -induced skin infection with clarithromycin Journal of the American Academy of Dermatology 1993 28 6 1019 1021 10.1016/S0190-9622(08)80660-3 2-s2.0-0027253829 8496448 \n33 Terry S. Timotby N. H. Zurio J. J. Manders E. K. \nMycobacterium chelonae : nonhealing leg ulcers treated successfully with an oral antibiotic Journal of the American Board of Family Practice 2001 14 457 461 \n34 Levine N. Rothschild J. G. Treatment of Mycobacterium chelonae infection with controlled localized heating Journal of the American Academy of Dermatology 1991 24 5 867 870 10.1016/0190-9622(91)70135-O 2-s2.0-0025898742 2050854 \n35 Eishi Y. Propionibacterium acnes as a cause of sarcoidosis 2013 London, UK InTechOpen 10.5772/55073\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-679X",
"issue": "2021()",
"journal": "Case reports in pathology",
"keywords": null,
"medline_ta": "Case Rep Pathol",
"mesh_terms": null,
"nlm_unique_id": "101576609",
"other_id": null,
"pages": "8819560",
"pmc": null,
"pmid": "33564484",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "10330598;28219077;22596102;24374164;11757889;29622895;19470075;17034528;15910612;16705584;26069425;9828448;2050854;18723691;30908517;25076301;18794042;19237886;28937438;28780185;29862601;29386234;28623484;26047254;8496448;7553576;29478243",
"title": "Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.",
"title_normalized": "cutaneous coinfection of cytomegalovirus and mycobacterium chelonae accelerated by immunosuppression"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2021SP026426",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"d... |
{
"abstract": "Paraquat is a herbicide of great toxicological importance because it is associated with high mortality rates, mainly due to respiratory failure. We report the case of a 28-year-old man admitted to the casualty department at Ngwelezana Hospital, Empangeni, KwaZulu-Natal, South Africa, with a history of vomiting and abdominal pain after ingestion of ~100 mL of an unknown substance, later identified as paraquat, together with an unknown amount of alcohol, in a suicide attempt. He developed respiratory distress associated with lung parenchymal infiltrates that required ventilatory support and later a spontaneous pneumothorax, and died in the intensive care unit. We discuss the importance of a high index of suspicion of paraquat poisoning in rural areas, where paraquat is readily available as a herbicide on farms, in patients with a similar presentation. We further stress the importance of identifying the classic radiological progression after paraquat poisoning, to help avoid a delay in diagnosis if the culprit substance is not known (as happened in our case). Lastly, we look at the importance of avoiding oxygen supplementation, and early administration of immunosuppressive therapy, to improve outcome.",
"affiliations": "Department of Internal Medicine, Ngwelezana Hospital, Empangeni, KwaZulu-Natal, South Africa. sipho.duncan@gmail.com.",
"authors": "Ntshalintshali|Sipho D|SD|;Manzini|Thandekile C|TC|",
"chemical_list": "D006540:Herbicides; D010269:Paraquat",
"country": "South Africa",
"delete": false,
"doi": "10.7196/SAMJ.2017.v107i5.12306",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "107(5)",
"journal": "South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde",
"keywords": null,
"medline_ta": "S Afr Med J",
"mesh_terms": "D055371:Acute Lung Injury; D000328:Adult; D003951:Diagnostic Errors; D018450:Disease Progression; D004435:Eating; D017809:Fatal Outcome; D006540:Herbicides; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D010269:Paraquat; D011030:Pneumothorax; D013902:Radiography, Thoracic; D012128:Respiratory Distress Syndrome; D013019:South Africa; D013405:Suicide",
"nlm_unique_id": "0404520",
"other_id": null,
"pages": "399-401",
"pmc": null,
"pmid": "28492119",
"pubdate": "2017-04-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paraquat poisoning: Acute lung injury - a missed diagnosis.",
"title_normalized": "paraquat poisoning acute lung injury a missed diagnosis"
} | [
{
"companynumb": "ZA-LHC-2017109",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"drugadmin... |
{
"abstract": "Surveillance for mid- and long-term antiretroviral therapy (ART) toxicity in children is important for informing treatment guidelines. We assessed the safety of darunavir (DRV) and atazanavir (ATV), commonly used as second-line protease inhibitors following lopinavir/ritonavir, in Europe and Thailand.\n\n\n\nCohorts contributed individual patient data on adverse events (AE) in those aged <18 years taking DRV and ATV, respectively, to 02/2014. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory AEs were calculated.\n\n\n\nOf 431 patients on DRV and 372 on ATV, 317 (74%) and 301 (81%), respectively, had weight and dose data available, of whom 56 (18%) and 33 (9%) took the drugs at a non-approved age or dose. Median age at DRV and ATV start was 14.8 years (IQR 12.8-16.1) and 13.5 years (11.4-15.2); 43% and 26% had received ≥8 ART drugs previously. Overall rates of grade ≥3 AEs for absolute neutrophils, total cholesterol, triglycerides, pancreatic amylase, lipase and alanine aminotransferase (ALT) were ≤3/100 person-years (PY) on approved doses of both drugs, but 66/100 PY (95% CI 52, 84) for bilirubin after <12 months on ATV declining to 32/100 PY (95% CI 23, 44) after >24 months. Five serious drug-related clinical AEs were reported in four patients on ATV (one discontinued) and three in three patients on DRV (all discontinued), and did not substantially differ in those on approved compared to non-approved doses. Proportions on the drugs at last follow-up were 89% (383/431) for DRV and 81% (301/372) for ATV (including 73/92 with grade ≥3 hyperbilirubinaemia).\n\n\n\nAEs were few in number and comparable for the two drugs, with the exception of high rates of hyperbilirubinaemia for ATV; few patients discontinued due to toxicity.",
"affiliations": null,
"authors": "|||",
"chemical_list": "D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D000069454:Darunavir",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "21(4)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000293:Adolescent; D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D002648:Child; D015331:Cohort Studies; D000069454:Darunavir; D005060:Europe; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D013785:Thailand",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "353-8",
"pmc": null,
"pmid": "26561496",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety of darunavir and atazanavir in HIV-infected children in Europe and Thailand.",
"title_normalized": "safety of darunavir and atazanavir in hiv infected children in europe and thailand"
} | [
{
"companynumb": "GB-CIPLA LTD.-2015GB08933",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional": null,
... |
{
"abstract": "Aripiprazole, a dopamine stabilizing atypical antipsychotic is used in treatment of tardive dyskinesia caused by other neuroleptics. Tardive dyskinesia is rarely caused by Aripiprazole and has only been documented in high risk patients i.e., female gender, advanced age, affective illness, coexisting neurological disorders. Here the author describes two atypical cases of tardive dyskinesia associated with Aripiprazole. First case of tardive dyskinesia was observed in a neuroleptic naïve young adult male with paranoid illness after six months of treatment with Aripiprazole upon addition of Fluoxetine and the second case was a middle aged female with affective illness where dyskinetic movements appeared after stopping Aripiprazole. The role of Fluoxetine in causing tardive dyskinesia with Aripiprazole and covert dyskinesia due to Aripiprazole with appropriate management is discussed.",
"affiliations": "Department of Psychiatry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India. patrasuravi@gmail.com.",
"authors": "Patra|Suravi|S|",
"chemical_list": "D014150:Antipsychotic Agents; D000068180:Aripiprazole",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886310666150921104343",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "11(1)",
"journal": "Current drug safety",
"keywords": null,
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D004409:Dyskinesia, Drug-Induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071057:Tardive Dyskinesia; D055815:Young Adult",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "102-3",
"pmc": null,
"pmid": "26391425",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tardive Dyskinesia and Covert Dyskinesia with Aripiprazole: A Case Series.",
"title_normalized": "tardive dyskinesia and covert dyskinesia with aripiprazole a case series"
} | [
{
"companynumb": "IN-WATSON-2016-07180",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional": nul... |
{
"abstract": "Thrombotic thrombocytopenia purpura (TTP) is an infrequent but serious disease. Pregnancy is a known risk factor for presentation or relapse of TTP. Difficulties in differentiating TTP from preeclampsia/HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, and current treatment recommendations are discussed in this case report. A woman with previously treated and stable TTP had a relapse at 36 weeks' gestation. Careful surveillance led to an early diagnosis. Severe disease in the peripartum period was treated successfully with cryosupernatant plasma-based plasmapheresis and platelet transfusion, with good maternal and neonatal outcomes. Cryosupernatant plasma is a viable alternative to fresh frozen plasma for plasmapheresis for TTP and may offer some therapeutic and logistical advantages. Platelet transfusion can be undertaken safely if needed to prevent or treat significant hemorrhage.",
"affiliations": "Division of Maternal-Fetal Medicine, Royal Alexandra Hospital, University of Alberta, Edmonton, Alberta, Canada.",
"authors": "Fyfe-Brown|Ashley|A|;Clarke|Gwen|G|;Nerenberg|Kara|K|;Chandra|Sujata|S|;Jain|Venu|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0032-1331380",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2157-7005",
"issue": "3(1)",
"journal": "AJP reports",
"keywords": "HELLP syndrome; TTP; cryosupernatant plasma; fresh frozen plasma; platelet transfusion; preeclampsia",
"medline_ta": "AJP Rep",
"mesh_terms": null,
"nlm_unique_id": "101569862",
"other_id": null,
"pages": "45-50",
"pmc": null,
"pmid": "23943710",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports",
"references": "18456236;17240195;21133861;16672704;17683359;12969811;15890682;19210323;12130486;9299856;7197306;16905949;8759902;19190814;20686117;21275971;2363411;19160220;7188723;15883960;10942361;15265118;16635066;8770709;12393399;8413457",
"title": "Management of pregnancy-associated thrombotic thrombocytopenia purpura.",
"title_normalized": "management of pregnancy associated thrombotic thrombocytopenia purpura"
} | [
{
"companynumb": "CA-ROXANE LABORATORIES, INC.-2014-BI-44080GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nTo report a case of idiosyncratic hepatotoxicity associated with metformin in the treatment of type 2 diabetes with nonalcoholic fatty liver disease (NAFLD).\n\n\nMETHODS\nA 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin. Laboratory findings revealed aminotransferase values 10-15 times the upper limit of normal. Potential causative agents, including metformin, simvastatin, and Niaspan (extended-release niacin), were discontinued. Two months later, the patient's signs and symptoms had resolved and aminotransferase values returned to normal. An objective causality assessment revealed that the adverse reaction was probably associated with metformin.\n\n\nCONCLUSIONS\nSince numerous medications and disease states can cause abnormalities in liver enzymes, it is important for providers to be able to distinguish the cause(s) and take appropriate actions. This can take a great deal of time and effort in patients with multiple medications and comorbidities. In this patient's case, viral hepatitis, worsening NAFLD, and the concomitant drugs were highly suspected. As hydroxymethylglutaryl coenzyme A reductase inhibitors offer substantial cardiovascular benefits and as metformin is a first-line agent in helping to lower blood glucose concentrations and to normalize the metabolic profile in type 2 diabetes, reintroduction of metformin and simvastatin would likely be beneficial.\n\n\nCONCLUSIONS\nThis is a case report of metformin-induced hepatotoxicity. As the prevalence of type 2 diabetes and subsequent metabolic effects increases in the US, metformin use will likewise increase. As potential for increased idiosyncratic hepatotoxicity associated with metformin use is likely to occur, clinicians should be vigilant.",
"affiliations": "University of New Mexico, Albuquerque, USA. CJCone@salud.unm.edu",
"authors": "Cone|Catherine J|CJ|;Bachyrycz|Amy M|AM|;Murata|Glen H|GH|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin; D000637:Transaminases",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1P099",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "44(10)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D003924:Diabetes Mellitus, Type 2; D005234:Fatty Liver; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D009765:Obesity; D000637:Transaminases",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1655-9",
"pmc": null,
"pmid": "20647417",
"pubdate": "2010-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease.",
"title_normalized": "hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease"
} | [
{
"companynumb": "PHHY2017US122171",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function.",
"affiliations": "Liver Surgery and Liver Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.;Department of Care of Organ Failures and Transplants, Internal Medicine for the Treatment of Severe Organ Failures, University Hospital - Policlinico S.Orsola-Malpighi, Bologna, Italy.;Hepatology Unit, Liver Transplant Department, Cardarelli Hospital, Naples, Italy.;Unit of internal Medicine and Hepatology (UIMH), University of Padua, Rome, Italy.;Gastroenterology Unit, University Hospital - Policlinico S.Orsola-Malpighi, Bologna, Italy.;Infectious Diseases-Hepatology, National Institute for Infectious Diseases Spallanzani, Rome, Italy.;Hepatology Unit, Department of Medicine, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo, Italy.;Hepatology and Transplant Unit, Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy.;Hepatology Unit, AORN Sant'Anna e San Sebastiano, Caserta, Italy.;Gastroenterology/Multivisceral Transplant Unit, University Hospital Padua, Padua, Italy.;Internal Medicine and Liver Unit, Gragnano Hospital (NA), Udine, Italy.;Italian Drug Agency (AIFA), Roma, Italy.;Italian Drug Agency (AIFA), Roma, Italy.;Italian Drug Agency (AIFA), Roma, Italy.;Italian Drug Agency (AIFA), Roma, Italy.;Italian Drug Agency (AIFA), Roma, Italy.;Italian Drug Agency (AIFA), Roma, Italy.;Gastrohepatology Unit, AOU Città della Salute e della Scienza di Torino, Turin, Italy.;Department of Medical Area (DAME), Medical Liver Transplant Section, Internal Medicine, Azienda Ospedaliero-Universitaria, Udine, Italy.",
"authors": "Carrai|Paola|P|;Morelli|Cristina|C|;Cordone|Gabriella|G|;Romano|Antonietta|A|;Tamé|Mariarosa|M|;Lionetti|Raffaella|R|http://orcid.org/0000-0003-2827-4591;Pietrosi|Giada|G|;Lenci|Ilaria|I|;Piai|Guido|G|;Russo|Francesco Paolo|FP|;Coppola|Carmine|C|;Melazzini|Mario|M|;Montilla|Simona|S|;Pani|Luca|L|;Petraglia|Sandra|S|;Russo|Pierluigi|P|;Trotta|Maria Paola|MP|;Martini|Silvia|S|;Toniutto|Pierluigi|P|http://orcid.org/0000-0002-2566-3041;|||",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1111/tri.13018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "30(12)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "cholestatic hepatitis; hepatitis C; liver transplantation; sofosbuvir",
"medline_ta": "Transpl Int",
"mesh_terms": "D000704:Analysis of Variance; D000998:Antiviral Agents; D015331:Cohort Studies; D057176:Compassionate Use Trials; D016001:Confidence Intervals; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D007558:Italy; D008103:Liver Cirrhosis; D008111:Liver Function Tests; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D011379:Prognosis; D012008:Recurrence; D012254:Ribavirin; D018570:Risk Assessment; D012720:Severity of Illness Index; D000069474:Sofosbuvir; D016896:Treatment Outcome",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "1253-1265",
"pmc": null,
"pmid": "28799277",
"pubdate": "2017-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "The Italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.",
"title_normalized": "the italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis c clinical and virological outcomes"
} | [
{
"companynumb": "IT-TEVA-814184ACC",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nUrachal carcinoma is a rare tumor that is usually associated with a poor prognosis, especially the pathological type, urachal mucinous adenocarcinoma. Surgery remains the primary treatment in prolonging the overall survival time of patients.\n\n\nMETHODS\nWe report on a 41-year-old woman with urachal mucinous adenocarcinoma who underwent three surgeries and several courses of chemotherapy over a 42-month period. The first surgery, involving en-bloc excision of the urachal mass, partial urinary bladder, urachal ligament, and umbilicus was performed in May 2007. It is well known that the correct surgical scheme plays a key role in preventing recurrence or metastasis. However, a second debulking surgery with only a single salpingo-oophorectomy may have contributed directly to the patient's subsequent left ovarian metastasis. Therefore, we strongly recommend performing a bilateral salpingo-oophorectomy once ovarian metastasis has been detected, even if the metastasis is only present on one side. Although postoperative adjuvant chemotherapy regimens, first with Taxol, carboplatin, gemcitabine, and cisplatin, and then with IFO, EPI, and mesna were consecutively administered after the first and second surgeries, they seemed less effective, since recurrence and metastasis occurred shortly after each surgical treatment. After a third debulking surgery in June 2009, docetaxel, oxaliplatin, and capecitabine were administered. This chemotherapy regimen was chosen based on an immunohistochemical test that involved the multidrug resistance gene; this test indicated that the urachal mucinous adenocarcinoma was resistant to the two chemotherapy regimens used previously. Surprisingly, the patient exhibited a marker response to the new regimen and the metastatic foci entered into a stable disease stage. However, the patient still died of diffuse metastatic disease 1.5 years later. During the whole period of treatment, we found that serum tumor markers including CA724, CA125, CA19-9, and CEA were elevated in a linear pattern, with parallel increases in line with peritoneal carcinomatosis and parallel reductions in line with response to personalized chemotherapy.\n\n\nCONCLUSIONS\nPersonalized treatment can be given to those patients who experience a poor response to initial therapy. Moreover, an immunohistochemical test for the multidrug resistance gene and serum tumor markers may supply key information in the choice of reasonable chemotherapeutics.",
"affiliations": null,
"authors": "Zong|Liang|L|;Chen|Ping|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1477-7819-11-170",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central 1477-7819-11-1702391484910.1186/1477-7819-11-170Case ReportSurgical and chemotherapeutic experience regarding a urachal carcinoma with repeated relapse: case report and literature review Zong Liang 1250537471@qq.comChen Ping 1chen86ky@126.com1 Department of Surgery, Su Bei People’s Hospital of JiangSu Province, Yangzhou University, Yangzhou 225001, Jiangsu Province, China2013 1 8 2013 11 170 170 6 12 2012 26 7 2013 Copyright ©2013 Zong and Chen; licensee BioMed Central Ltd.2013Zong and Chen; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nUrachal carcinoma is a rare tumor that is usually associated with a poor prognosis, especially the pathological type, urachal mucinous adenocarcinoma. Surgery remains the primary treatment in prolonging the overall survival time of patients.\n\nCase presentation\nWe report on a 41-year-old woman with urachal mucinous adenocarcinoma who underwent three surgeries and several courses of chemotherapy over a 42-month period. The first surgery, involving en-bloc excision of the urachal mass, partial urinary bladder, urachal ligament, and umbilicus was performed in May 2007. It is well known that the correct surgical scheme plays a key role in preventing recurrence or metastasis. However, a second debulking surgery with only a single salpingo-oophorectomy may have contributed directly to the patient’s subsequent left ovarian metastasis. Therefore, we strongly recommend performing a bilateral salpingo-oophorectomy once ovarian metastasis has been detected, even if the metastasis is only present on one side. Although postoperative adjuvant chemotherapy regimens, first with Taxol, carboplatin, gemcitabine, and cisplatin, and then with IFO, EPI, and mesna were consecutively administered after the first and second surgeries, they seemed less effective, since recurrence and metastasis occurred shortly after each surgical treatment. After a third debulking surgery in June 2009, docetaxel, oxaliplatin, and capecitabine were administered. This chemotherapy regimen was chosen based on an immunohistochemical test that involved the multidrug resistance gene; this test indicated that the urachal mucinous adenocarcinoma was resistant to the two chemotherapy regimens used previously. Surprisingly, the patient exhibited a marker response to the new regimen and the metastatic foci entered into a stable disease stage. However, the patient still died of diffuse metastatic disease 1.5 years later. During the whole period of treatment, we found that serum tumor markers including CA724, CA125, CA19-9, and CEA were elevated in a linear pattern, with parallel increases in line with peritoneal carcinomatosis and parallel reductions in line with response to personalized chemotherapy.\n\nConclusion\nPersonalized treatment can be given to those patients who experience a poor response to initial therapy. Moreover, an immunohistochemical test for the multidrug resistance gene and serum tumor markers may supply key information in the choice of reasonable chemotherapeutics.\n\nChemotherapySurgeryUrachal carcinoma\n==== Body\nBackground\nUrachal carcinoma is a rare form of tumor that usually originates in the bladder, and represents 0.01% of all cancers. Moreover, this lesion accounts for 0.34-0.7% of all bladder carcinomas [1]. Pathologically, a recent population-based analysis has revealed that adenocarcinoma is very common among urachal carcinomas and represents approximately 10% of all bladder adenocarcinomas [2]. The most common histological type of urachal adenocarcinoma is mucinous adenocarcinoma [3]. However, the rare variant form known as signet-ring cell carcinoma accounts for only a small proportion of the urachal mucinous adenocarcinomas. Until now, urachal adenocarcinoma has been regarded as associated with poor prognosis, especially in the case of urachal mucinous adenocarcinoma [4,5]. Surgery remains the primary treatment for prolonging the overall survival time of patients. However, the appropriate initial surgical treatment is a matter of controversy. No standard chemotherapy regimens for advanced urachal carcinoma have yet been established.\n\nCase presentation\nIn June 2007, a 41-year-old woman was referred to our hospital with a palpable mass in her lower abdomen. Computed tomography showed a large mass located in the anterior pelvic cavity just superior to the bladder, but no other positive findings elsewhere. Because of the limited clinical evidence for diagnosis, laparotomy was performed for this patient. Laparotomy revealed a 12.0 × 12.0 × 9.0 cm solid lesion, which extended from the vertex of the bladder to the umbilicus. The lesion was removed en bloc together with the umbilicus, bladder dome, and adjacent peritoneum. Pathological diagnosis confirmed it to be a urachal mucinous adenocarcinoma (Figure 1A). At 1 month after diagnosis, this patient received adjuvant chemotherapy consisting of four cycles of Taxol and carboplatin. However, this regimen seemed ineffective in preventing disease progression because multiple hepatic metastases were found at only 6 months after surgery (Figure 2A). Accordingly, a revised chemotherapeutic strategy with four cycles of gemcitabine and cisplatin, as well as one cycle of interventional therapy, was administered sequentially. However, a symptom involving lower abdominal compression was gradually felt over a 1-year period. Because of this, the patient was again admitted to our hospital. Physical examination showed a large abdominal mass lying between the xiphoid process of the sternum and the umbilicus, without obvious tenderness. Abdominal computed tomography with peripheral enhancement using contrast material in the delayed phase revealed extrinsic multi-organ compression because of a giant mass, 27.0 × 17.0 cm, in the abdominal cavity (Figure 2B). At laparotomy, a giant tumor was discovered adhering to the right ovary, as well as multiple metastases in the greater omentum and liver (Figure 3). Moreover, about 300 ml of mucus was found in the pelvic cavity, suggesting seeded metastasis. We removed the tumor en bloc and resected the right ovary and greater omentum. In addition, we performed a complete dissection of the lymph node around the tumor. At the end of the surgery, we implanted a sustained-release preparation of 5-fluorouracail into the surroundings of the recurrent tumor, hepatic surface and other suspected metastatic sites in the abdominal cavity. Pathological analysis confirmed the tumor to be a recurrent carcinoma since it was located in the original tumor site (Figure 1B). Systemic chemotherapy, consisting of four cycles of IFO, mesna, and EPI, was given as a persistent treatment at 1 month after the second surgery. However, 1.5 years later, this patient was referred to our department for the third time with distension of the lower abdomen. Ultrasound detected a new mass lying in the pelvic cavity. Physical examination revealed a large abdominal mass of about 10 × 10 cm located in the lower abdomen. During laparotomy, a metastatic mass measuring 2 cm in diameter was excised. When the abdominal cavity was entered, a 10 × 10 × 8 cm solid mass was found tightly adhering to the left ovary, as well as multiple hepatic metastases. A debulking operation was performed to remove the recurrent tumor and the left ovary. During the third surgery, a sustained-release preparation of 5-fluorouracail was also implanted into the recurrent rumor site, the hepatic surface, and the bottom of the pelvic cavity. Pathological analysis supported the finding that the lesion was a stable urachal mucinous adenocarcinoma (Figure 1C). An immunohistochemical test involving the multidrug resistance gene was carried out, in which glutathione s-transferase was found to be strongly positive. Based on the detection of multidrug resistance using the gene test, four cycles of docetaxel, oxaliplatin, and capecitabine were given persistently. After the first cycle, the progression of multi-liver-foci stopped, and after the fourth cycle, 20% of these foci had disappeared. Although the docetaxel, oxaliplatin, and capecitabine regimen was efficacious in treating the tumor, temporary myelosuppression was observed, which was offset by colony-stimulating factor. However, the patient died of diffuse metastatic disease at 18 months after individualized treatment.\n\nFigure 1 Pathological section with hematoxylin and eosin staining after surgery. (A) First surgery. (B) Second surgery. (C) Third surgery.\n\nFigure 2 Computed tomography. (A) Multiple hepatic metastases. (B) giant local recurrent tumor infiltrating right ovary.\n\nFigure 3 27.0 × 17.0 cm giant recurrent tumor. (A) A giant tumor covered by abundant mucus. (B) A giant tumor lying in abdominal cavity. (C) A giant tumor adhering to the right ovary. (D) A giant tumor after resection.\n\nConclusion\nIt is sometimes difficult to differentiate between urachal and non-urachal carcinomas based only on symptoms. This is primarily because there is no specific symptom for urachal carcinoma. Furthermore, most of the tumors may develop in the submucosa or muscularis, and do not invade the mucosa of the bladder in the early stage, so symptoms are not prominent. According to the latest reports, several different imaging methods may be useful in aiding diagnosis. Ultrasound can demonstrate a tumor in the bladder dome associated with a mass containing calcification [6]. Computed tomography can identify the extent of the palpable suprapubic mass, localize calcification, and determine the involvement of local nodes. In addition, cystoscopy can reveal a tumor in the bladder dome, and concurrent bimanual examination can detect a suprapubic mass. Occasionally, biopsy may be performed via cystoscopy to confirm a diagnosis before surgery. However, for a few of the complicated cases or metastatic cases, a limited number of useful positive findings can only be made using imaging modalities; under such conditions laparotomy is necessary.\n\nTo date, the criteria for making a diagnosis of urachal carcinoma are not uniform, but clinical findings and histological evidence are both key factors. The typical criteria [1,7-9] should include: (a) a tumor in the dome of the bladder; (b) the presence of urachal residua; (c) an absence of cystitis cystica and cystitis glandularis; (d) a sharp demarcation between the tumor and the surface epithelium of the bladder; (e) the invasion of deeper muscular tissues with intact or ulcerated epithelium; (f) an extension of the tumor through the Retzius space; and (g) no evidence of a primary tumor outside of the bladder.\n\nOur case was consistent with the typical criteria. However, for a few uncommon cases, this system is too restrictive to fulfill all the prognostic criteria. Two simpler criteria sets, which are more closely related to clinical practice, have been suggested by some scientists. The first set [4] is: (a) a tumor in the dome of the bladder; (b) the presence of urachal residua; and (c) the absence of cystitis cystica and cystitis glandularis. The second set [10] is: (a) a tumor in the dome of the bladder; (b) a sharp demarcation between the tumor and the surface epithelium of bladder; and (c) no evidence of a primary tumor outside of the bladder.\n\nSurgical treatment plays a dominant role in the management of patients with urachal carcinoma. The achievement of a complete urachectomy including umbilectomy and negative surgical margins, and extended partial or total cystectomy, are crucial to long-term survival [1,11]. The surgical resection margin is one of the most important iatrogenic factors for prognosis, so resection must be technically feasible and frozen sections must reveal the negative resected margins [6]. If only the resection margin is clear, another important prognostic factor is tumor staging [11]. Until now, tumors have been staged using two different staging systems: the Sheldon staging system and the Mayo staging system. Both systems have predicted cancer-specific survival equally well, but we recommend the use of the Mayo staging system in future studies owing to its simplicity (Table 1). However, both systems need to be validated in future large trials.\n\nTable 1 Mayo staging system for urachal carcinoma\n\nStage\tDefinition\t\nI\tTumors confined to the urachus and or bladder\t\nII\tTumors extending beyond the muscular layer of the urachus or the bladder\t\nIII\tTumors infiltrating the regional lymph nodes\t\nIV\tTumors infiltrating non-regional lymph nodes or other distant sites\t\nLate presentation of symptoms and fast progression leading to advanced tumor stage at diagnosis have resulted in a poor prognosis for urachal carcinoma, which is consequently uniformly fatal. Moreover, urachal adenocarcinomas show a tendency to local recurrence and distant metastasis after surgical treatment, most often (81%) in the first 2 years [1]. It has been revealed that postoperative local recurrence takes place earlier than distant metastasis. The most common sites of local recurrence are the pelvis, bladder, abdominal wall, and wounds. Distant metastases have been reported in a number of organs, including the lung, brain, omentum, liver, bone, and lymph nodes [1,12-14]. However, ovarian metastasis seems to be rare. In reviewing the literature, only eight cases with ovarian metastasis have been previously reported [15-22] (Table 2). Possible mechanisms of urethral recurrence are thought to include hematogenous metastasis; dissemination via the retrograde lymphatic route; and intravesical dissemination. Current research is focused on the differentiation of primary and metastatic ovarian tumors. Since the urachal adenocarcinoma metastasizes to the ovary it may mimic primary ovarian mucinous carcinoma, and this can lead to misdiagnosis. Among the eight reported cases [15-22], three were identified simultaneously with the primary urachal carcinoma and one was detected as a primary tumor before urachal adenocarcinoma was confirmed. Half of the eight cases were histologically identified as mucinous adenocarcinomas. Furthermore, frequent findings with regard to the metastatic carcinomas were bilaterality, microscopic surface involvement of epithelial cells, and an infiltrative pattern of stromal invasion. Less frequent findings that were exclusive or almost exclusive to metastatic carcinoma were a nodular invasive pattern, ovarian hilar involvement, single cell invasion, signet-ring cells, vascular invasion, and microscopic surface mucin. However, bilateral presentation of primary ovarian mucinous carcinoma is uncommon. When bilateral ovarian mucinous carcinoma is considered in the diagnosis, it is essential to exclude the possibility of metastatic carcinoma completely. The most common primary sites for metastatic ovarian mucinous carcinoma include the colon, pancreas, gallbladder, stomach, appendix, and uterine cervix [23-25]. Bladder adenocarcinoma, including urachal carcinoma, is a less common candidate for the primary tumor on these occasions.\n\nTable 2 Summary of key data from eight reported cases of urachal adenocarcinoma metastatic to the ovaries\n\nReference\tMetastasis site\tAge\tSerum tumor marker\tStatus with primary urachal carcinoma\tPathology\tImmunohistochemistry (positive or negative)\tTreatment\tFollow-up result\t\n[15]\tRight ovary\t50\tCEA 27.9 ng/m\tSimultaneous finding\tNot available\t-\tSurgery\tNot available\t\n[16]\tBoth ovaries, bone, lymph nodes\t50\tCEA 27.9 ng/ml\tSimultaneous finding\tHigh-grade mucinous adenocarcinoma\tCytokeratin 20 and CEA, cytokeratin 7\tSurgery and irradiation\tAlive with disease (6 months)\t\n[17]\tRight ovary, peritoneum, sigmoid colon\t54\t-\tSimultaneous finding\tModerately differentiated mucinous adenocarcinoma\t–\tSurgery and chemotherapy\tAlive with disease (55 months)\t\n[18]\tBoth ovaries, abdominal wall, colon mass, uterosacral ligament, bladder\t64\tNormal\tSecondary metastasis\tBorderline malignant mucinous adenocarcinoma\t–\tSurgery and chemotherapy\tAlive with disease (3 months)\t\n[19]\tBoth ovaries, bladder\t39\tNormal\tSecondary metastasis\tWell-differentiated mucinous adenocarcinoma\t–\tSurgery and chemotherapy\tDied of disease (38 months)\t\n[20]\tBoth ovaries, peritoneum, bone\t26\t-\tSecondary metastasis\t-\t–\tSurgery and chemotherapy\tDied of disease (26 months)\t\n[21]\tLeft ovary, right lung\t30\t-\tSecondary metastasis\tWell-differentiated mucinous adenocarcinoma\t–\tSurgery and chemotherapy\tAlive without disease (11 years)\t\n[22]\tBoth ovaries\t72\t-\tPre-finding\tModerately differentiated mucinous adenocarcinoma\t–\tSurgery and chemotherapy\tAlive with disease (36 months)\t\nImmunohistochemistry is always one important method for differentiating between primary and metastatic ovarian mucinous tumors, although there is a considerable overlap in their immunohistochemical staining patterns. In line with the latest findings, Lee [22] has recommended using a panel of CK7, CK20, CDX2, MUC2, 34βE12, and β-catenin to assist in the discrimination of urachal adenocarcinoma metastasis from primary ovarian mucinous carcinoma, and metastatic carcinoma from other organs. In Lee’s opinion [22], the coordinated expression of CK7, CK20, and CDX2 might be helpful in differentiating metastatic urachal carcinoma from primary ovarian mucinous tumor. Firstly, CK20 and CDX-2 are diffusely and strongly positive in urachal carcinoma, while about 50% of urachal carcinomas are positive for CK7, so there are two possible profiles for urachal carcinoma (CK7−/CK20+/CDX2+ vs. CK7+/CK20+/CDX2+). Secondly, CK7 − CK20+ is rarely seen in primary ovarian mucinous tumor, but CK7+/CK20+ is present in both the primary ovarian tumor and lower intestinal tract tumors. Thus, a finding of diffusely and strongly positive CDX2 plays a key role in excluding the primary ovarian tumor. In addition, because urachal carcinoma is expressed immunohistochemically as a unique colonic epithelial epitope that mimics the immunochemical profile of colonic cancer, its presence could be further confirmed by means of MUC2. Then, the only remaining issue is to discriminate a urachal origin from a lower gastrointestinal origin. However, 34βE12–/β-catenin + is rarely expressed in lower gastrointestinal tract tumors, which may help to ensure the urachal origin of metastatic ovarian tumors [9]. In this case, the immunochemical findings were partly compatible with the Lee’s diagnostic criteria [22]. CK7 and CK20 were both negative in our case, but positive CDX2 and MUC2 confirmed the tumor’s urachal origin (Figure 4). However, because only a limited number of studies with small sample size have been published on the immunohistochemical profiles of urachal carcinomas, a further large trial is need to provide more reliable data.\n\nFigure 4 Immunohistochemical test. (A) Positive staining for CDX2. (B) Positive staining for MUC2.\n\nIf suspected metastasis is encountered in the ovary, whether or not it occurs on one or both sides, it should be fully investigated and complete resection should be performed to prolong the patient’s overall survival time [26,27]. In many conditions, bilateral salpingo-oophorectomy is essential, since bilateral ovarian metastasis is the common clinical model. However, with regard to suspected single metastasis, there is still a debate on the scope of surgical resection. Kawakami et al. [21] reported that the use of single salpingo-oophorectomy enabled the achievement of a long survival period of more than 11 years. Conversely, Young [17] performed bilateral salpingo-oophorectomy, which was followed by early postoperative multiple metastasis at 7 months. Of course, a systematic analysis is required to obtain absolute results, including tumor stage or presence of local recurrence. Although single salpingo-oophorectomy was performed when metastasis occurred in the right ovary in our case, we support the use of bilateral salpingo-oophorectomy even for single metastasis in the ovary, especially for cases with local recurrence.\n\nAlthough the role of chemotherapy and radiotherapy still remain unclear and the effects of other treatments have not been established, varied chemotherapy regimens have been reported to have some presumptive advantage [28-31] (Table 3). However, in our case, traditional chemotherapy regimens such as paclitaxel and carboplatin, 5-fluorouracail, gemcitabine, and cisplatin, and 5-fluorouracail, IFO, EPI, and mesna seemed less effective in controlling disease progression. Rapid progression of disease suggested that our patient’s carcinoma might have been chemoresistant to these chemotherapeutics. Under such an adverse condition, an individualized treatment was put forward, to achieve an improved remission. Therefore, an immunohistochemical test involving a multidrug resistance gene was carried out, in which glutathione s-transferase scored as strongly positive. This finding may explain why the initial chemotherapy regimen was less efficacious than expected. Based on this finding, a regimen of oxaliplatin, capecitabine, and docetaxel was prescribed as a salvage treatment. To our surprise, the liver metastatic foci responded well to this chemotherapy regimen and there was a 10-month remission, despite the fact that this patient experienced temporal myelosuppression, which was offset by colony-stimulating factor.\n\nTable 3 Summary of response to chemotherapy in reported cases of urachal carcinoma\n\nReference\tNumber of patients\tChemotherapy and status at last follow-up\tResponse\tFollow-up result\t\n[18]\t1\tPaclitaxel and carboplatin\tStable\tAlive with disease (3 months)\t\n[19]\t1\t5-flourouracil, cisplatin, and gemcitabine\tComplete response\tDied of disease (38 months)\t\n[20]\t1\t5-fluorouracil, folinic acid, and oxaliplatin\tComplete response\tDied of disease (26 months)\t\n[28]\t3\t5-fluorouracil, doxorubicin, and mitomycin C\tPartial response\tDied of disease (12 months)\t\n[29]\t1\t5-fluorouracil, mitomycin C, and mitoxantrone,\tComplete response\tDied of disease (28 months)\t\n[21]\tPatient 1\t5-fluorouracil, doxorubicin, and cisplatin;\tComplete response\tAlive without disease (11 years)\t\n5-fluorouracil, doxorubicin, and etoposide;\t\n5-fluorouracil, cisplatin, and α interferon\t\n[21]\tPatient 2\tDoxorubicin, cisplatin, and mitomycin C\tComplete response\tAlive without disease (10 years)\t\n[22]\t1\tDocetaxel and carboplatin\tComplete response\tAlive with disease (36 months)\t\n[30]\t1\tTegafur, gimeracil, oteracil, and cisplatin\tComplete response\tAlive without disease (30 months)\t\n[31]\t1\tCisplatin, Adriamycin, vinblastine, and methotrexate\tPartial response\tAlive with disease (13 months)\t\nDuring the whole period of treatment, serum tumor markers might be one of the most important prognostic factors that can reflect the efficacy of chemotherapy and tumor recurrence. Consistent with other enteric-type adenocarcinomas, urachal adenocarcinoma might express detectable serum levels of CEA, CA125, and CA19-9 [32]. In our case, with the development of disease, these markers, including CA724, CA125, CA19-9, and CEA, were elevated in a linear pattern (Figure 5). Their levels were increased in parallel with peritoneal carcinomatosis and in parallel with a reduction in response to personal chemotherapy. Among all of the tumor markers, the most significant elevation was achieved in CA724 level prior to local recurrence and ovary metastasis (Table 4).\n\nFigure 5 Tumor markers changing at different follow-up dates.\n\nTable 4 Laboratory findings related to tumor markers at different follow-up dates\n\nTumor markers\tIndex change in follow-up date\tNormal range\t\n \t30 April 2007\t8 August 2008\t3 December 2008\t3 June 2009\t20 December2009\t \t\nCA19-9\t88.38 kU/l\t43.80 kU/l\t158.30 kU/l\t57.15 kU/l\t23.44 kU/l\t<37.00\t\nCA724\t15.24 kU/l\t73.42 kU/l\t2352.0 kU/l\t1237.0 kU/l\t47.50 kU/l\t<6.00\t\nCA125\t60.00 kU/l\t19.11 kU/l\t309.60 kU/l\t79.20 kU/l\t10.00 kU/l\t<35.00\t\nCA15-3\t4.32 kU/l\t5.91 kU/l\t10.83 kU/l\t11.56 kU/l\t10.83 kU/l\t<30.00\t\nCEA\t9.49 ng/ml\t4.08 ng/ml\t43.62 μg/ml\t13.87 μg/ml\t3.06 μg/ml\t<5.00\t\nAFP\t2.00 ng/ml\t2.55 ng/ml\t2.03 μg/ml\t3.39 μg/ml\t7.66 μg/ml\t<20.00\t\nIn conclusion, urachal carcinoma is not only a rare form of tumor, but also a difficult-to-treat disease. We support standard and radical resection to achieve a negative margin. However, even an enlarged or consecutive operation is encouraged when recurrence or peritoneal carcinomatosis occurs with a laparotomy. It is difficult to make an exact diagnosis preoperatively and a systematic review of all of the data is always essential in making a correct diagnosis based on the Mayo criteria. A standard chemotherapeutic strategy still needs to be explored in future studies, but personalized treatment can be given to those patients who experience a poor response to initial therapy. Moreover, an immunohistochemical test for multidrug resistance gene and serum tumor markers may supply key information in the choice of reasonable chemotherapeutics.\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-in-chief of this journal.\n\nCompeting interests\nBoth authors declare that they have no conflicts of interest in the following areas: employment; consultancies; stock ownership; honoraria; paid expert testimony; patent applications or registrations; grants or other funding.\n\nAuthors’ contributions\nThe patient was examined and operated by PC and LZ, who are responsible for the postoperative care, follow-up, and clinical information. PC examined the patient and reviewed the patient’s files. LZ performed histopathological examination. The manuscript was drafted by LZ and critically reviewed by PC. Both authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Dr. Gouqing Li, Department of Pathology, and Su Bei People’s Hospital, Yangzhou University, Yangzhou, China for their technical help with the immunohistochemistry studies.\n==== Refs\nSheldon CA Clayman RV Gonzalez R Williams RD Fraley EE Malignant urachal lesions J Urol 1984 11 1 1 8 6361280 \nWright JL Porter MP Li CI Lange PH Lin DW Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder Cancer 2006 11 4 721 728 10.1002/cncr.22059 16826584 \nPaul AB Hunt CR Harney JM Jenkins JP McMahon RF Stage 0 mucinous adenocarcinoma in situ of the urachus J Clin Pathol 1998 11 483 484 10.1136/jcp.51.6.483 9771454 \nHenly DR Farrow GM Zincke H Urachal cancer: role of conservative surgery Urology 1993 11 635 639 10.1016/0090-4295(93)90526-G 8256396 \nSiefker-Radtke AO Gee J Shen Y Wen S Daliani D Millikan RE Pisters LL Multimodality management of urachal carcinoma: the M. D. Anderson Cancer Center experience J Urol 2003 11 1295 1298 10.1097/01.ju.0000054646.49381.01 12629346 \nRavi R Shrivastava BR Chandrasekhar GM Prahlad S Balasubramanian KV Mallikarjuna VS Adenocarcinoma of the urachus J Surg Oncol 1992 11 3 201 203 10.1002/jso.2930500315 1619945 \nWheeler JD Hill WT Adenocarcinoma involving the urinary bladder Cancer 1954 11 1 119 135 10.1002/1097-0142(195401)7:1<119::AID-CNCR2820070113>3.0.CO;2-8 13126906 \nMostofi FK Thomson RV JrDean AL Mucous adenocarcinoma of the urinary bladder Cancer 1955 11 4 741 758 10.1002/1097-0142(1955)8:4<741::AID-CNCR2820080417>3.0.CO;2-C 13240656 \nGopalan A Sharp DS Fine SW Tickoo SK Herr HW Reuter VE Olgac S Urachal carcinoma: a clinicopathologic analysis of 24 cases with outcome correlation Am J Surg Pathol 2009 11 5 659 668 10.1097/PAS.0b013e31819aa4ae 19252435 \nAnderstrom C Johansson SL Von Schultz L Primary adenocarcinoma of the urinary bladder. A clinicopathologic and prognostic study Cancer 1983 11 7 1273 1280 10.1002/1097-0142(19831001)52:7<1273::AID-CNCR2820520724>3.0.CO;2-7 6883290 \nSantucci RA True LD Lange PH Is partial cystectomy the treatment of choice for mucinous adenocarcinoma of the urachus? Urology 1997 11 4 536 540 10.1016/S0090-4295(96)00574-2 9111622 \nKakizoe T Matsumoto K Andoh M Nishio Y Kishi K Adenocarcinoma of urachus. Report of 7 cases and review of literature Urology 1983 11 4 360 366 10.1016/0090-4295(83)90152-8 6836822 \nYu JS Kim KW Lee HJ Lee YJ Yoon CS Kim MJ Urachal remnant diseases: spectrum of CT and US findings Radiographics 2001 11 2 451 461 11259707 \nDunnick NR McCallum RW Sandler CM Grayson TH The urinary bladder Textbook of uroradiography 1991 Baltimore: Williams & Wilkins 337 338 \nYanagisawa S Fujinaga Y Kadoya M Urachal mucinous cystadenocarcinoma with a cystic ovarian metastasis AJR Am J Roentgenol 2003 11 4 1183 1184 10.2214/ajr.180.4.1801183 12646487 \nOhira S Shiohara S Itoh K Ashida T Fukushima M Konishi I Urachal adenocarcinoma metastatic to the ovaries: case report and literature review Int J Gynecol Pathol 2003 11 2 189 193 10.1097/00004347-200304000-00013 12649676 \nYoung RH Urachal adenocarcinoma metastatic to the ovary simulating primary mucinous cystadenocarcinoma of the ovary: report of a case Virchows Arch 1995 11 5 529 532 7633664 \nJo EJ Choi CH Bae DS Park SH Hong SR Lee JH Metastatic urachal carcinoma of the ovary J Obstet Gynaecol Res 2011 11 12 1833 1837 10.1111/j.1447-0756.2011.01615.x 21794003 \nEl-Ghobashy A Ohadike C Wilkinson N Lane G Campbell JD Recurrent urachal mucinous adenocarcinoma presenting as bilateral ovarian tumors on cesarean delivery Int J Gynecol Cancer 2009 11 9 1539 1541 10.1111/IGC.0b013e3181a84177 19955933 \nTrastour C Desprez B Delotte J Bongain A Rahili A Bernard JL Benchimol D Ovarian metastases from an urachal adenocarcinoma Eur J Obstet Gynecol Reprod Biol 2006 11 1 143 144 10.1016/j.ejogrb.2005.09.014 16257483 \nKawakami S Kageyama Y Yonese J Fukui I Kitahara S Arai G Hyouchi N Suzuki M Masuda H Hayashi T Okuno T Kihara K Successful treatment of metastatic adenocarcinoma of the urachus: report of 2 cases with more than 10-year survival Urology 2001 11 3 462 11549502 \nLee W Urachal adenocarcinoma metastatic to the ovaries resembling primary ovarian mucinous carcinoma: a case report with the immunohistochemical study Int J Clin Exp Pathol 2010 11 1 118 123 21228934 \nKhunamornpong S Lerwill MF Siriaunkgul S Suprasert P Pojchamarnwiputh S Chiangmai WN Young RH Carcinoma of extrahepatic bile ducts and gallbladder metastatic to the ovary: a report of 16 cases Int J Gynecol Pathol 2008 11 3 366 379 10.1097/PGP.0b013e31815d6903 18580314 \nKhunamornpong S Siriaunkgul S Suprasert P Pojchamarnwiputh S Na Chiangmai W Young RH Intrahepatic cholangiocarcinoma metastatic to the ovary: a report of 16 cases of an underemphasized form of secondary tumor in the ovary that may mimic primary neoplasia Am J Surg Pathol 2007 11 12 1788 1799 10.1097/PAS.0b013e3180674ded 18043033 \nVang R Gown AM Barry TS Wheeler DT Yemelyanova A Seidman JD Ronnett BM Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases Am J Surg Pathol 2006 11 9 1130 1139 16931958 \nHerr HW Urachal carcinoma: the case for extended partial cystectomy J Urol 1994 11 2 365 366 8283526 \nTomita K Tobisu KI Kume H Fujimoto H Kakizoe T Long survival with extended surgery for urachal carcinoma involving adjacent organs J Urol 1998 11 4 1298 10.1016/S0022-5347(01)63588-2 9507860 \nLogothetis CJ Samuels ML Ogden S Chemotherapy for adenocarcinomas of bladder and urachal origin: 5-fluorouracil, doxorubicin, and mitomycin-C Urology 1985 11 3 252 255 10.1016/0090-4295(85)90121-9 3929441 \nQuilty PM Urachal carcinoma: a response to chemotherapy Br J Urol 1987 11 4 372 10.1111/j.1464-410X.1987.tb04992.x 3690215 \nKojima Y Yamada Y Kamisawa H Sasaki S Hayashi Y Kohri K Complete response of a recurrent advanced urachal carcinoma treated by S-1/cisplatin combination chemotherapy Int J Urol 2006 11 8 1123 1125 10.1111/j.1442-2042.2006.01487.x 16903943 \nIchiyanagi O Sasagawa I Suzuki Y Iijima Y Kubota Y Nakada T Arai S Successful chemotherapy in a patient with recurrent carcinoma of the urachus Int Urol Nephrol 1998 11 5 569 573 10.1007/BF02550547 9934799 \nO’Leary M Foley M A case of urachal carcinoma J Obstet Gynaecol 2004 11 3 332 333 10.1080/01443610410001661138 15203656\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-7819",
"issue": "11()",
"journal": "World journal of surgical oncology",
"keywords": null,
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D002288:Adenocarcinoma, Mucinous; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D010052:Ovariectomy; D011379:Prognosis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101170544",
"other_id": null,
"pages": "170",
"pmc": null,
"pmid": "23914849",
"pubdate": "2013-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9507860;3690215;12649676;18580314;21228934;19955933;13240656;6883290;6836822;3929441;13126906;9771454;16826584;11259707;8256396;12646487;15203656;18043033;19252435;16257483;1619945;8283526;16931958;9111622;7633664;21794003;6361280;11549502;16903943;9934799;12629346",
"title": "Surgical and chemotherapeutic experience regarding a urachal carcinoma with repeated relapse: case report and literature review.",
"title_normalized": "surgical and chemotherapeutic experience regarding a urachal carcinoma with repeated relapse case report and literature review"
} | [
{
"companynumb": "CN-CIPLA LTD.-2018CN10342",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "BACKGROUND\nHyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined the risk and predictors of hyponatremia and other electrolyte abnormalities in a 'real-world' sample of patients receiving ICIs to treat advanced malignancies.\n\n\nMETHODS\nThis was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018. Patients were followed for 12 months after initiation of ICIs or until death. Common Terminology for Cancer Adverse Events version 5.0 criteria were used to grade the severity of hyponatremia and other electrolyte abnormalities. The predictors of severe (Grade 3 or 4) hyponatremia were determined using a multivariable logistic regression model. The etiology of Grade 3 or 4 hyponatremia was determined by chart review.\n\n\nRESULTS\nA total of 2458 patients were included. Their average age was 64 years [standard deviation (SD) 13], 58% were male and 90% were white. In the first year after starting ICIs, 62% experienced hyponatremia (sodium <134 mEq/L) and 136 (6%) experienced severe hyponatremia (<124 mEq/L). Severe hyponatremia occurred on average 164 days (SD 100) after drug initiation. Only nine cases of severe hyponatremia were due to endocrinopathies (0.3% overall incidence). Risk factors for severe hyponatremia included ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) use, diuretic use and non-White race. Other severe electrolyte abnormalities were also commonly observed: severe hypokalemia (potassium <3.0 mEq/L) occurred in 6%, severe hyperkalemia (potassium ≥6.1 mEq/L) occurred in 0.6%, severe hypophosphatemia (phosphorus <2 mg/dL) occurred in 17% and severe hypocalcemia (corrected calcium <7.0 mg/dL) occurred in 0.2%.\n\n\nCONCLUSIONS\nHyponatremia is common in cancer patients receiving ICIs. However, endocrinopathies are an uncommon cause of severe hyponatremia.",
"affiliations": "Department of Internal Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA.;Department of Internal Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA.;Department of Internal Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA.;Department of Internal Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.;Department of Internal Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.;Department of Internal Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.;Department of Internal Medicine, Division of Endocrinology, Massachusetts General Hospital, Boston, MA, USA.;Department of Internal Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.;Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA.;Department of Internal Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA.",
"authors": "Seethapathy|Harish|H|;Rusibamayila|Nifasha|N|;Chute|Donald F|DF|;Lee|Meghan|M|;Strohbehn|Ian|I|0000-0003-2167-2896;Zubiri|Leyre|L|;Faje|Alexander T|AT|;Reynolds|Kerry L|KL|;Jhaveri|Kenar D|KD|;Sise|Meghan E|ME|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ndt/gfaa272",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-0509",
"issue": "36(12)",
"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": "electrolytes; hypokalemia; hyponatremia; hypophosphatemia; hypophysitis; immune checkpoint inhibitor",
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": null,
"nlm_unique_id": "8706402",
"other_id": null,
"pages": "2241-2247",
"pmc": null,
"pmid": "33374011",
"pubdate": "2021-12-02",
"publication_types": "D016428:Journal Article",
"references": "31343665;28973656;29762725;28076863;3015384;31672794;32138574;24359982;31694698;30693099;27282937;2158808;29567705;30197346;20516446;29710180;16737547;32150268;31896554;19699382;26317459;31176301;29320654;32416348;29093678;26027431",
"title": "Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors.",
"title_normalized": "hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-008569",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "M. bovis strain Bacillus Calmette-Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death outcome.",
"affiliations": "Key Laboratory of Dependable Service Computing in Cyber Physical Society, Ministry of Education, College of Computer Science, Chongqing University, Chongqing, China.;College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, United States of America.;College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, United States of America.;Unit for Laboratory Animal Medicine, Department of Microbiology and Immunology, Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.",
"authors": "Xie|Jiangan|J|;Codd|Christopher|C|;Mo|Kevin|K|;He|Yongqun|Y|",
"chemical_list": "D001500:BCG Vaccine; D019496:Cancer Vaccines; D032581:Tuberculosis Vaccines; D002097:C-Reactive Protein",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0164792",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2774992310.1371/journal.pone.0164792PONE-D-16-29443Research ArticleMedicine and Health SciencesOncologyCancer PreventionCancer VaccinesBiology and Life SciencesImmunologyVaccination and ImmunizationVaccinesCancer VaccinesMedicine and Health SciencesImmunologyVaccination and ImmunizationVaccinesCancer VaccinesMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationVaccinesCancer VaccinesBiology and Life SciencesImmunologyVaccination and ImmunizationVaccinesMedicine and Health SciencesImmunologyVaccination and ImmunizationVaccinesMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationVaccinesMedicine and Health SciencesOncologyCancers and NeoplasmsGenitourinary Tract TumorsBladder CancerMedicine and Health SciencesUrologyBladder CancerMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisBiology and Life SciencesImmunologyVaccination and ImmunizationMedicine and Health SciencesImmunologyVaccination and ImmunizationMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsMedicine and Health SciencesOncologyCancer TreatmentResearch and Analysis MethodsMathematical and Statistical TechniquesStatistical MethodsMeta-AnalysisPhysical SciencesMathematicsStatistics (Mathematics)Statistical MethodsMeta-AnalysisDifferential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis Differential Adverse Event Profiles Associated with BCG Tuberculosis or Bladder Cancer VaccineXie Jiangan 12Codd Christopher 3Mo Kevin 3He Yongqun 2*1 \nKey Laboratory of Dependable Service Computing in Cyber Physical Society, Ministry of Education, College of Computer Science, Chongqing University, Chongqing, China2 \nUnit for Laboratory Animal Medicine, Department of Microbiology and Immunology, Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America3 \nCollege of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, United States of AmericaTyagi Anil Kumar EditorUniversity of Delhi - South Campus, INDIACompeting Interests: The authors have declared that no competing interests exist.\n\nConceptualization: JX CC KM YH.\n\nData curation: JX CC KM.\n\nFormal analysis: JX YH.\n\nFunding acquisition: JX YH.\n\nInvestigation: JX CC KM.\n\nMethodology: JX YH.\n\nProject administration: JX YH.\n\nResources: JX CC KM YH.\n\nSoftware: JX YH.\n\nSupervision: YH.\n\nValidation: JX CC KM YH.\n\nVisualization: JX YH.\n\nWriting – original draft: JX CC.\n\nWriting – review & editing: JX YH.\n\n\n\n* E-mail: yongqunh@med.umich.edu17 10 2016 2016 11 10 e016479225 7 2016 2 10 2016 © 2016 Xie et al2016Xie 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.M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death outcome.\n\nhttp://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious Diseases1R01AI081062He Yongqun China Scholarship Council PhD exchange program201406050119Xie Jiangan JX is a joint PhD student in the University of Michigan Medical School and was funded by a China Scholarship Council PhD studentship (Grant Reference: 201406050119). The OAE research was partly supported by the NIH National Institute of Allergy and Infectious Diseases grant 1R01AI081062. CC and KM were supported by the undergraduate research opportunity program (UROP) in the University of Michigan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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\nBacillus Calmette–Guérin (BCG), a live attenuated strain of Mycobacterium bovis, has been the only officially registered human vaccine against tuberculosis (TB) for almost a century [1, 2]. TB is a serious infectious disease induced by Gram-positive bacterium M. tuberculosis that is estimated to cause more than 2 million human deaths each year. In 2014, there were 9.6 million new cases of TB reported globally, with 5.4 million cases in adult males, 3.2 million in adult females, and 1 million in children. The World Health Organization (WHO) recommends that the BCG vaccine should be given to all infants as soon as possible after birth in countries with a high burden of TB [3].\n\nIn addition to be a TB vaccine, BCG can also serve as a bladder cancer immunotherapeutic vaccine [4, 5]. In 1929, Pearl published his autopsy study results demonstrating a lower frequency of cancer in patients with TB [6]. Since then many studies have showed the benefits of BCG usage against bladder cancer [5]. In 1990, the US Food and Drug Administration (FDA) approved the general use of intravesical BCG in patients with superficial bladder cancer. Over 20 years of usage have further proven the efficiency and superior status of the BCG therapy compared to other intravesical agents for bladder cancer.\n\nDespite the usefulness of the BCG vaccine in preventing TB and treating bladder cancer, BCG vaccination has been reported to be associated with various adverse events (AEs) including some serious AEs (SAEs) [7–9]. As shown in the literature, the most commonly reported AEs for the BCG vaccine include injection site abscess, lymphadenitis, and severe local reactions [7]. The most severe AE associated with the BCG vaccine is death [8]. Besides literature records, post-licensure safety surveillance programs have been a major source of reporting and collecting BCG vaccine AEs. In the US, the Vaccine Adverse Event Reporting System (VAERS) is a spontaneous vaccine AE case reporting system used to report and monitor AE cases associated with all licensed vaccines [10]. VAERS has received AE reports from health care providers, vaccine recipients or their parents, vaccine manufacturers, and other interested parties. Since 1990’s, VAERS has collected millions of vaccine AE case reports. Although VAERS data does not support the identification of AE causality, statistical VARES data analysis has provided ways to develop hypotheses on AE causality and has greatly supported AE studies and vaccine safety [11].\n\nNo study has been reported to compare the AEs associated with the BCG TB vaccine and the BCG therapy for bladder cancer. The BCG TB vaccine is typically given in the infants who are at a healthy condition. In contrast, the BCG cancer therapy is mainly used for adults or geriatric patients who have been diagnosed with bladder cancer. Although we expect that different AE profiles may be resulted from these two types of vaccinations, VAERS categorizes these two vaccination types under the same “BCG” and does not separate them based on the purpose of the vaccination. Such a combined categorization can be confusing. However, since the same live attenuated BCG vaccine strain is used, it would be very interesting to identify the exact AE profiles associated with these two different types of vaccinations. We hypothesized that preventive BCG TB vaccination and therapeutic BCG cancer treatment would result in many distinct AE profiles as well as some shared AEs in administered human populations. Such a hypothesis is addressed in the current study.\n\nTo analyze AEs from different resources, it is critical to normalize the results using a standard controlled terminology. The Medical Dictionary of Regulatory Activities (MedDRA) is an international medical terminology dictionary used by regulatory authorities in the pharmaceutical industry during regulatory processes including AE result presentation and evaluation [12]. MedDRA is the standard controlled terminology system used by the VAERS vaccine AE reporting and analysis. However, MedDRA has many issues by itself including its lack of term definitions, poor hierarchical classification, and lack of robust relations among AEs [13]. To address these issues, a community-based biomedical ontology in the domain of AE terminology − Ontology of Adverse Events (OAE) has been developed [14]. A biomedical ontology is a human- and computer-interpretable set of terms and relations that represent entities in a specific biomedical domain and how these entities relate to each other. After an AE term mapping between MedDRA and OAE, OAE can be used to classify VAERS reported AEs represented with MedDRA terms [15, 16]. Empirical evidences have shown that OAE performs better than MedDRA in the area of AE classification [15, 17].\n\nAlthough many literature papers and the VAERS database have provided various reports of AEs associated with the BCG vaccine, a systematic comparative study on the AEs associated with the BCG as a preventive TB vaccine or therapeutic bladder cancer vaccine has not been reported. The objective of this project is based on OAE classification method to systematically collect and comparatively analyze various AE data associated with these two types of BCG vaccine that extracted from the VAERS database and PubMed literature.\n\nMaterials and Methods\nBCG Adverse Event Data Extraction from VAERS\nUsing the CDC Wonder data access program (http://wonder.cdc.gov/vaers.html), the VAERS database was searched for all BCG-associated AE case reports. Current VAERS database allows query of AE case report data starting from 1990. In order to include every possible case report for BCG, we queried AE case reports from all locations, and the AE reported time was set from July 1990 through May 2016. Categories of search included symptom, vaccine, age, gender, territory, and VAERS ID.\n\nThe BCG vaccine category under VAERS database includes three subcategories: “BCG (MYCOBAX)”, “BCG (NO BRAND NAME)”, and “BCG (TICE)”. Since VAERS does not label each AE case report involved in a BCG TB preventive or bladder cancer therapeutic vaccination, we manually checked every BCG AE case report and identified the vaccine type for each case report based on the administration route and other descriptions in the each AE case report.\n\nStatistical analysis with PRR, Chi-square test, and base level filtration\nTo identify statistically significant AEs, three standard methods were applied, including the Proportional Reporting Ratio (PRR) [18], Chi-square test [19], and base level filtration [20]. PRR is a statistical method used to measure if an AE is more likely to result from one specific vaccine (or a vaccine type) than from the whole class of vaccines. Chi-square is used to determine whether there is a significant difference between observed values and expected values in an area of interest. A Chi-square score of 4 is equivalent to a p-value of 0.05. Base level filtration usually used a minimal sample size cutoff for filtering out background noise. Specifically, to be classified as a statistically significant AE, three criteria had to be met: minimal case report number ≥ 3, PRR score ≥ 2, and Chi-square score ≥ 4 [18, 20].\n\nOAE- or MedDRA-based AE group classification\nFor MedDRA-based AE classification, the hierarchical structure of AE terms was extracted from the BioPortal MedDRA website (https://bioportal.bioontology.org/ontologies/MEDDRA, accessed at 1st June, 2016) and displayed with the Protégé-OWL editor [21]. For OAE-based AE classification, statistically significant AE terms were first mapped from MedDRA to OAE. After the MedDRA-OAE term mapping, the subset hierarchies that include BCG vaccine type-specific AEs and their parent terms were extracted from OAE using the OntoFox program [22]. The hierarchical structures of these terms were also visualized using the Protégé-OWL editor.\n\nExamination of BCG-associated death AE in VAERS\nTo in-depth study BCG-associated death AE in VAERS database, vaccinee’s age, territory, gender, time elapsed, co-administered vaccines, and current illness in each death AE case report were all further investigated to understand whether any of these factors might significantly influence the chances of vaccinee suffering this AE. The values of these variables in each case report indicating death or sudden death was extracted and studied.\n\nMeta-analysis of BCG-associated AEs from PubMed literature\nA meta-analysis of previous written studies on BCG-associated AEs was performed by following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [23, 24]. The PRISMA checklist is provided in S1 File. Briefly, the meta-analysis was done by searching the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed) with the search keywords (‘BCG’ and ‘adverse events’). The abstracts and full text of the articles were retrieved and annotated independently by two reviewers, and any disagreements resolved by discussions and analysis with a third reviewer. Those articles without any related real AE data were excluded from further study. In the eligible papers, BCG-related AEs and BCG vaccine types were manually identified, extracted, and analyzed.\n\nResults\nIdentification and differentiation of 397 VAERS BCG AE case reports associated with 857 unique AEs\nFrom July 1990 through May 2016, our query of the VAERS database identified 397 AE case reports for BCG usage. After manual checking of each of 397 BCG AE case reports, we found that 47 BCG AE reports under the BCG vaccine subcategory “BCG (MYCOBAX)” were associated with the usage of BCG as the TB vaccine, and only 6 reports associated with the cancer vaccine. Meanwhile, we found that 52 reports under the subcategory “BCG (TICE)” were related to the use of BCG as the cancer vaccine, and 24 related to the TB vaccine. The BCG subcategory of “BCG (NO BRAND NAME)” included 217 case reports with the TB vaccine and 51 with the cancer vaccine. In total, 288 AE case reports were associated with BCG as a preventive TB vaccine and 109 AE case reports associated with BCG as a therapeutic cancer vaccine. The detailed VAERS case report IDs and their associated vaccine types are recorded in the S2 File.\n\nAll the AE symptoms in each AE case report were collected and matched to the MedDRA AE codes. In total, 857 unique AEs with their corresponding MedDRA terms were identified from all the 397 case reports. It is cautious here that the identification of these AEs does not mean that each of these AEs is caused by BCG. It only means that these AEs occur shortly after the BCG vaccination, and the temporal association between the vaccination and the AE may or may not be causally related to the vaccination in individual patients.\n\nStatistical analysis of BCG-associated AE terms using VAERS data\nOf all 857 BCG AEs, 206 had minimal 3 case reports associated with either the BCG TB vaccine or the BCG bladder cancer vaccine. Out of these 206 AEs, 47 AEs (e.g., pathology test and hemoglobin normal) were ambiguous or not considered to be AEs and then be excluded for further analysis. By adopting the screening criteria include PRR score (≥ 2) and Chi-square score (≥ 4), our statistical analysis eventually identified 64 and 14 AEs significantly associated with the BCG as TB vaccine (Table 1 and S1 Fig) and bladder cancer vaccine (Table 2 and S2 Fig), respectively. Complementary to Tables 1 and 2, S1 and S2 Figs provide intermediate level terms in the ontological hierarchy of different AEs.\n\n10.1371/journal.pone.0164792.t001Table 1 Sixty-four statistically significant AEs associated with BCG as TB vaccine.\nAdverse Event\tCount\tPRR\tChi-square\t\nbehavioral and neurological AE (5)\t\n chills\t6\t7.65\t34.63\t\n cold sweat\t3\t3.51\t5.38\t\n depression\t3\t5.07\t9.78\t\n irritability\t9\t2.30\t6.68\t\n psychomotor retardation\t5\t164.92\t750.07\t\ncardiovascular AE (5)\t\n bradycardia\t3\t5.55\t11.18\t\n epistaxis\t3\t6.23\t13.14\t\n hemorrhage\t4\t9.15\t28.96\t\n hypertension\t4\t3.48\t7.10\t\n tachycardia\t4\t2.75\t4.48\t\ndigestive AE (6)\t\n gastroenteritis*\t4\t8.01\t24.49\t\n hematochezia*\t10\t9.40\t74.94\t\n intussusception*\t7\t6.81\t34.66\t\n diarrhea\t18\t2.26\t13.03\t\n feces discolored\t3\t10.38\t25.31\t\n mucous stool\t3\t11.39\t28.28\t\ngustatory system AE (1)\t\n hypophagia\t5\t8.97\t35.33\t\nhematopoietic system AE (4)\t\n anemia\t8\t12.70\t85.86\t\n sedimentation rate increased\t8\t8.22\t50.72\t\n splenomegaly\t3\t28.84\t79.46\t\n thrombocytopenia\t4\t5.92\t16.34\t\nhepatobiliary or pancreatic AE (1)\t\n hepatomegaly*\t4\t30.25\t111.41\t\nimmune system AE (8)\t\n hepatosplenomegaly*\t3\t74.54\t209.52\t\n immunodeficiency*\t3\t98.95\t276.61\t\n meningitis*\t3\t4.63\t8.53\t\n abscess\t10\t26.68\t244.11\t\n allergy\t4\t4.51\t10.94\t\n granuloma\t9\t136.65\t1131.39\t\n lymphadenitis\t12\t67.52\t760.10\t\n lymphadenopathy\t32\t8.21\t204.38\t\ninfection AE (3)\t\n disseminated BCG infection*\t14\t13391.58\t23432.45\t\n tuberculosis*\t10\t910.99\t6158.04\t\n respiratory tract infection\t3\t21.34\t57.53\t\ninvestigation result abnormal AE (6)\t\n aspartate aminotransferase level increased\t3\t3.46\t5.26\t\n blood bilirubin level increased\t3\t12.50\t31.57\t\n blood creatinine level decreased\t3\t10.72\t26.34\t\n C-reactive protein (CRP) increased\t6\t4.90\t18.66\t\n hemoglobin level decreased\t3\t4.33\t7.68\t\n hypocalcemia\t3\t95.65\t267.64\t\nmetabolism, endocrine or exocrine system AE (1)\t\n necrosis\t3\t38.779\t108.25\t\nmusculoskeletal or connective tissue AE (3)\t\n osteomyelitis*\t8\t170.05\t1234.93\t\n hypotonia\t9\t2.87\t11.09\t\n joint swelling\t4\t3.96\t8.84\t\nrespiratory system AE (8)\t\n apnea*\t3\t6.90\t15.10\t\n pneumonia*\t11\t6.53\t51.61\t\n respiratory failure*\t6\t16.73\t87.73\t\n cough\t30\t4.52\t83.84\t\n lung disorder\t5\t11.68\t48.60\t\n nasal congestion\t4\t3.23\t6.17\t\n respiratory disorder\t8\t14.86\t102.81\t\n respiratory rate increased\t17\t59.13\t943.37\t\nserious AE (3)\t\n death*\t17\t13.48\t195.97\t\n disability*\t5\t40.53\t188.86\t\n sudden death*\t6\t93.32\t522.63\t\nskin AE (8)\t\n cyanosis\t7\t3.04\t9.61\t\n flushing\t4\t2.88\t4.92\t\n skin discoloration\t4\t2.66\t4.17\t\n skin exfoliation\t3\t8.25\t19.04\t\n skin lesion\t5\t4.10\t11.72\t\n skin mass\t4\t4.46\t10.73\t\n skin ulceration\t7\t4.68\t20.32\t\n thrombocytopenic purpura\t3\t9.33\t22.23\t\nsyndrome AE (1)\t\n cachexia*\t3\t168.80\t459.88\t\ntumor AE (1)\t\n axillary mass\t4\t55.86\t209.44\t\nNote:\n\n* = serious adverse event (SAE). Specific AEs are labeled with MedDRA terms. The top-level categories follow the OAE hierarchy.\n\n10.1371/journal.pone.0164792.t002Table 2 Fourteen statistically significant AEs associated with BCG as bladder cancer vaccine.\nAdverse Event\tCount\tPRR\tChi-square\t\nbehavioral and neurological AE (3)\t\n back pain\t6\t5.27\t20.93\t\n chills\t17\t4.80\t52.86\t\n skin burning sensation\t5\t38.82\t183.06\t\ninfection AE (1)\t\n bacterial infection\t4\t15.74\t55.15\t\ninvestigation result abnormal AE (1)\t\n urine analysis result abnormal\t3\t20.30\t54.90\t\nmusculoskeletal or connective tissue AE (1)\t\n arthralgia\t9\t2.83\t10.94\t\nsyndrome AE (1)\t\n flu-like syndrome\t10\t11.01\t91.58\t\nsystematic AE (1)\t\n condition aggravated\t4\t3.79\t8.30\t\nurinary system (6)\t\n hematuria*\t13\t167.21\t2080.51\t\n urinary incontinence*\t3\t16.72\t44.26\t\n dysuria\t20\t227.18\t4313.62\t\n pollakiuria\t14\t176.92\t2367.87\t\n urgent urination\t5\t227.69\t1080.07\t\n urinary tract infection\t5\t24.63\t113.03\t\nNote:\n\n* = serious adverse event (SAE). Specific AEs are labeled with MedDRA terms. The top-level categories follow the OAE hierarchy.\n\nThe 64 AEs associated with the TB vaccine were categorized into 16 OAE AE classes (Table 1). Based on the case report numbers, the most reported AEs were lymphadenopathy (32 reports), following by cough (30 reports) and diarrhea (18 reports). The most frequently observed AE groups were ‘immune system AE’, ‘respiratory system AE’, and ‘skin AE’, each with 8 specific AE classes. The 14 statistically significant AEs associated with the bladder cancer vaccine were enriched in the urinary system (Table 2 and S2 Fig). There were 6 urinary system AEs, including hematuria, urinary incontinence, dysuria, pollakiuria, urgent urination, and urinary tract infection. In addition, the urine analysis result abnormal is also related to the urinary system AE.\n\nAE profiles associated with BCG vaccine based on literature meta-analysis\nThe inclusion criteria for selection of eligible articles from PubMed and the final results are provided in the PRISMA flowchart (Fig 1). The selection criteria are two-fold. First, the articles were all searchable in PubMed by using the keywords “BCG” and “adverse events”. With this criterion, our literature search identified 204 potentially eligible articles on June 1, 2016. The second article inclusion criterion is the identification from the article of specific AEs detected from randomized controlled trials or spontaneous case report studies. With this criterion, the number of related articles was reduced to 87. From these 87 articles, our PubMed literature meta-analysis eventually identified a total of 41 peer-reviewed journal articles that contained specific BCG-associated AEs. The details of these articles and the AEs identified from each articles are provided in S3 File. Note that we have examined all the 41 eligible peer-reviewed articles in PubMed as well as the VAERS BCG-associated AE case reports, and we have not found any information in terms of latent tuberculosis screening in these case reports and articles.\n\n10.1371/journal.pone.0164792.g001Fig 1 PRISMA flowchart of the selection of relevant papers.\nIn 27/41 (65.9%) of these articles, TB vaccination was the reason for BCG usage; in the remaining 14/41 (34.1%), BCG was used to treat bladder cancer. From these papers, we identified 48 AEs associated with BCG as a TB vaccine (Table 3 and S3 Fig) and 43 AEs were associated with BCG as a cancer vaccine (Table 3 and S4 Fig). The comparison of these results clearly show significant differences in the AE profiles associated with the two BCG vaccine types. For example, compared with the cancer vaccine, the TB vaccine was significantly more associated with skin AEs (11 vs 1) and lymphatic immune system AEs (6 vs 0) (Table 3 and S3 Fig). In particular, there had no report on any urinary system AE associated with the TB vaccine (Table 3). However, 14 urinary system AEs associated with the cancer vaccine were reported (Table 3).\n\n10.1371/journal.pone.0164792.t003Table 3 BCG-associated AEs from literature meta-analysis.\nAEs associated with BCG used as TB vaccine\tAEs associated with BCG used as bladder cancer vaccine\t\nbehavioral and neurological AE (8)\tbehavioral and neurological AE (7)\t\n dizziness\t chills\t\n fatigue\t headache\t\n gastrointestinal pain\t kidney pain\t\n headache\t lower abdominal pain\t\n malaise\t malaise\t\n musculoskeletal pain\t miction pain\t\n myalgia\t urethral pain\t\n seizure\tcardiovascular AE (1)\t\ncardiovascular AE (2)\t hypertension\t\n hematoma\tdigestive system AE (1)\t\n hemorrhage\t diarrhea\t\nhematopoietic system AE (1)\tgustatory system (1)\t\n sedimentation rate increased\t anorexia\t\nhomeostasis AE (2)\thematopoietic system AE (1)\t\n edema\t pancytopenia\t\n fever\thomeostasis AE (1)\t\nimmune system AE (14)\t fever\t\n hepatosplenomegaly*\timmune system AE (9)\t\n meningitis*\t hepatitis*\t\n pneumonia*\t pneumonia*\t\n vasculitis*\t allergy\t\n abscess\t bacterial cystitis\t\n axillary lymphadenitis\t chemical cystitis\t\n axillary lymphadenopathy\t cystitis\t\n hepatic abscess\t granuloma\t\n hepatosplenic granuloma\t granulomatous cystitis\t\n lymphadenitis\t granulomatous prostatitis\t\n lymphadenopathy\tinfection AE (3)\t\n osteitis\t sepsis*\t\n staphylococcal abscess\t bacterial infection\t\n suppurative lymphadenitis\t lung infection\t\ninfection AE (1)\tinvestigation result abnormal AE (1)\t\n disseminated BCG infection*\t CRP increased\t\ninvestigation result abnormal AE (1)\tmusculoskeletal or connective tissue AE (2)\t\n CRP increased\t arthralgia\t\nlocal AE (2)\t asthenia\t\n injection site discharge\tskin AE (1)\t\n injection site ulcer\t rash\t\nmusculoskeletal or connective tissue AE (2)\tsyndrome AE (1)\t\n osteomyelitis*\t flu-like syndrome\t\n asthenia\turinary system AE (14)\t\nnervous system AE (1)\t hematuria*\t\n paresthesia\t macroscopic hematuria*\t\nserious AE (1)\t urinary incontinence*\t\n death*\t bladder atrophy\t\nskin AE (11)\t bladder spasm\t\n acute cutaneous erythema\t contracted bladder\t\n eczema\t dysuria\t\n induration\t irritative bladder symptom\t\n keloid\t lower urinary tract symptom\t\n papule\t nocturia\t\n pruritus\t pollakiuria\t\n purpura\t pyuria\t\n pustule\t urinary frequency\t\n scab\t urinary tract infection\t\n scar\t\t\n urticaria\t\t\nsyndrome AE (2)\t\t\n immune reconstitution inflammatory syndrome*\t\t\n Kawasaki disease*\t\t\nNote:\n\n* = serious adverse event (SAE). Specific AEs are labeled with MedDRA terms. The top-level categories follow the OAE hierarchy.\n\nTable 4 includes a list of the 12 most commonly reported AEs based on the total numbers of articles reporting individual AEs. Out of these 41 annotated journal articles, the most frequently reported AEs were fever and hematuria, mentioned in 16 and 11 articles, respectively (Table 4). Three AEs (i.e., fever, malaise, and headache) were associated with both BCG vaccine types. Note that among the 6 TB vaccine-specific AEs, injection site ulcer and erythema were reported in VAERS, but they were not statistically significant (so unavailable in Table 1).\n\n10.1371/journal.pone.0164792.t004Table 4 Twelve most commonly reported BCG AEs from the literature.\nAdverse event\tCount\tTB vaccine\tbladder cancer vaccine\t\nAEs shared by TB vaccinees and bladder cancer patients (all in\nTable 1):\t\nfever\t16 (39%)\t6 (37.5%)\t10 (62.5%)\t\nmalaise\t8 (20%)\t1 (12.5%)\t7 (87.5%)\t\nheadache\t4 (10%)\t3 (75%)\t1 (25%)\t\nAEs only found in TB vaccinees (all in\nTable 1\nexcept injection site ulcer and erythema):\t\nlymphadenitis\t10 (24%)\t10 (100%)\t0 (0%)\t\ninjection site ulcer\t9 (22%)\t9 (100%)\t0 (0%)\t\nabscess\t8 (20%)\t8 (100%)\t0 (0%)\t\ndisseminated BCG infection\t5 (12%)\t5 (100%)\t0 (0%)\t\nlymphadenopathy\t5 (12%)\t5 (100%)\t0 (0%)\t\nerythema\t4 (10%)\t4 (100%)\t0 (0%)\t\nAEs only found in bladder cancer patients (all in\nTable 2):\t\nhematuria\t11 (27%)\t0 (0%)\t11 (100%)\t\ncystitis\t6 (15%)\t0 (0%)\t6 (100%)\t\nsepsis\t5 (12%)\t0 (0%)\t5 (100%)\t\nFig 2 is a summary Venn diagram that compares four groups of the AEs (Tables 1–3) associated with BCG TB vaccine or bladder cancer vaccine using VAERS and literature resources. It is surprising that none of the AEs was conserved in all the four AE groups. Only three AEs (i.e., chills, pneumonia, and C-reactive protein increased) were shared by the BCG TB vaccine and bladder cancer vaccine (Fig 2). C-reactive protein (CRP) is produced by the liver in response to inflammation. Further investigation found that those AEs shown in the literature but not from VAERS statistical analysis indeed existed in the VAERS case report database. They were not shown in the Tables 1 and 2 because they did not pass the statistical filtering cutoffs. In summary, our comparative study indicates that the BCG TB vaccine and cancer vaccine were associated with quite different AE profiles, the two profiles could be identified from both VAERS statistic data analysis and literature reports although specific lists of AEs might differ from the analyses of these two resources.\n\n10.1371/journal.pone.0164792.g002Fig 2 Venn diagram summary of the BCG-associated AEs from VAERS statistical analysis and literature meta-analysis.\nTB-V: AEs associated with BCG TB vaccine from VAERS statistical analysis. TB-L: AEs associated with BCG TB vaccine from literature meta-analysis. BC-V: AEs associated with BCG bladder cancer vaccine from VAERS statistical analysis. BC-L: AEs associated with BCG bladder cancer vaccine from literature meta-analysis. Three AEs (i.e., chills, pneumonia, and CRP level increased) are shared by the BCG TB vaccine and bladder cancer vaccine.\n\nDifferential BCG TB and bladder cancer vaccine-specific SAE profiles\nAmong all the AEs specific to the BCG TB vaccine, 20 unique AEs including 17 AEs from VAERS (Table 1) and 9 AEs from literature reports (Table 3) were further classified as SAEs [9]. For BCG as a bladder cancer vaccine, our meta-analysis identified 6 unique SAEs including 2 SAEs (Table 2) from VAERS and 6 SAEs from literature reports (Table 3). Specifically, pneumonia was the only AE shared by both BCG vaccine types. Overall, a total of 25 SAEs associated with BCG usage.\n\nFor better understanding of the SAEs, all the SAEs were classified and compared as subsets of the complete MedDRA and OAE hierarchies (Fig 3). Obviously, the MedDRA subset hierarchy (Fig 3A) appears to be much larger and complicated than the OAE subset hierarchy (Fig 3B). Actually, MedDRA has many drawbacks in terms of AE classification. First, MedDRA includes many terms ended with “NEC” (i.e., “not elsewhere classified”), such as ‘Meningitis NEC’, in its hierarchical structures (Fig 3A). Such an “NEC” term is defined arbitrarily and ambiguously, and its usage often leads to confusing and unclear classification results. Second, MedDRA often misses obvious parent-child term logic. For example, in MedDRA, ‘Sudden death’ is listed as a sibling class of ‘Death’, and both are listed as subclasses of ‘Death and sudden death’ (Fig 3A). This is confusing and logically incorrect since a sudden death should be a special subtype of death. Additionally, MedDRA also contains many redundant terms, such as the terms ‘Disability issues’ and ‘Disability’ (Fig 3A). In comparison, all these drawbacks have been avoided in the OAE ontology (Fig 3B).\n\n10.1371/journal.pone.0164792.g003Fig 3 Hierarchical classification of 25 BCG-associated SAEs and their related top level classes using MedDRA and OAE.\n(A) MedDRA-based classification. All oval circle highlighted terms are discussed in the main text. (B) Asserted OAE hierarchy of the 25 SAEs and related top level classes. (C) Inferred OAE hierarchy after reasoning with the ELK reasoner (version 0.4.10, downloaded from website: https://www.cs.ox.ac.uk/isg/tools/ELK/). The SAE labeled with “t” and “c” represents the SAE associated with BCG as a tuberculosis and bladder cancer vaccine, respectively. After reasoning, two classes of terms were inferred to under different parent terms as highlighted in dotted oval circles.\n\nAs a biomedical ontology, OAE supports asserted hierarchy and inferred hierarchy. An asserted hierarchy is the hierarchy asserted by OAE developers. An inferred hierarchy is one after the execution with an ontology reasoner [25]. Many AE terms are often classified under two or more parent terms. For example, ‘immune reconstitution inflammatory syndrome AE’ is a subclass of ‘immune system AE’ or ‘syndrome AE’ (Fig 3B and 3C). The approach of asserting more than one parent term in ontology is called multiple inheritance [26], which often makes an ontology difficult to maintain and update. To avoid the multiple inheritance shortcomings, OAE asserts only one parent term and allows the other term(s) to be inferred as parent(s) through semantic reasoning. In the above example, ‘immune reconstitution inflammatory syndrome AE’ is asserted as a subclass of ‘syndrome AE’ (Fig 3B). After reasoning (based on the internal logical axiom definition of this AE occurring in the immune system), this term is inferred to be a subclass of ‘immune system AE’ as well (Fig 3C). Such a feature does not exist in MedDRA.\n\nThe OAE hierarchical classification (Fig 3B and 3C) clearly shows the patterns of the 25 SAEs associated with the BCG TB vaccine and the cancer vaccine. Among the 6 BCG bladder cancer vaccine-associated SAEs, three (i.e., hematuria AE, macroscopic hematuria AE, and urinary incontinence AE) all belong to the urinary system AE. The hepatitis and pneumonia AEs are both inflammation AEs. Sepsis AE is a special infection AE, likely due to the BCG infection. Among the 20 SAEs associated with the BCG TB vaccine, 6 belong to immune system AEs (Fig 3C), and 4 of these 6 immune system AEs show different types of inflammation. In addition to the immune system, 20 SAEs were found to occur in the digestive and respiratory systems (Fig 3B and 3C). Interestingly, none of the 20 SAEs is related to the urinary system.\n\nSpecial profiles associated with 24 BCG-associaed death AE\nAs of June 1, 2016, VAERS reported 1,272 total death events associated with 101 vaccines, with the average of approximately 12 deaths each vaccine. For the BCG vaccine, a total of 24 death cases (including 6 sudden death cases) were reported (Table 5). This number of BCG-associated deaths doubles the average of 12 deaths per vaccine reported in VAERS. Since death is the most severe AE, we investigated each of BCG-associated death cases with a focus on identifying contributions of different variables to the death outcome (Table 5).\n\n10.1371/journal.pone.0164792.t005Table 5 BCG-associated death AE case reports from VAERS.\nVAERS ID\tAge (years)\tTerritory\tGender\tTime elapsed\tCo-administered vaccines\tCurrent illness\t\n18 death cases\t\n318242\t<0.5\tForeign\tFemale\t4–5 hours\tDTaP, Hib, PCV7, IPV\tRhinorrhea\t\n353252\t0.5–1\tForeign\tMale\t7 months\tNone\tN/A\t\n368158\t<0.5\tForeign\tFemale\t< 2 days\tHepB\tN/A\t\n383583\t3–5\tForeign\tMale\tN/A\tNone\tChronic granulomatous disease\t\n383596\t<0.5\tForeign\tMale\tN/A\tNone\tSCID, FHID\t\n383598\t<0.5\tForeign\tMale\tN/A\tNone\tImmunodeficiency disorder\t\n383599\t0.5–1\tForeign\tFemale\tN/A\tNone\tSCID\t\n383601\t<0.5\tForeign\tFemale\tN/A\tNone\tSCID, FHID\t\n383602\t<0.5\tForeign\tFemale\tN/A\tNone\tSCID, FHID\t\n383604\t<0.5\tForeign\tMale\tN/A\tNone\tSCID\t\n383634\t<0.5\tForeign\tFemale\tN/A\tNone\tImmunodeficiency disorders, FHID\t\n431084\t<0.5\tForeign\tFemale\t1.5 hours\tHEP B\tN/A\t\n488670\t<0.5\tForeign\tFemale\t< 1 day\tDTaP+Hib+IPV, HepB, PCV7, IPV, PRV\tHIV+, Premature birth, Respiratory distress, Vomiting\t\n491427*\t65+\tForeign\tMale\t< 1 day\tNone\tBladder cancer\t\n522465\t0.5–1\tForeign\tMale\t< 1 day\tDTaP + IPV, HepB, PRV\tAsteatosis, Eczema\t\n530241\t40–49\tMichigan\tFemale\tN/A\tDTP\tN/A\t\n533126\t<0.5\tForeign\tFemale\t>107 days\tHepB\tN/A\t\n549045\t0.5–1\tUnknown\tMale\tN/A\tOPV\tSCID\t\n6 sudden death cases\t\n414170\t<0.5\tForeign\tMale\t2 days\tDTaP + IPV +Hib, PRV\tN/A\t\n414704\t<0.5\tForeign\tMale\t2 d\tDTaP + IPV +Hib, PRV\tN/A\t\n418242\t<0.5\tForeign\tMale\t2 d\tHib\tN/A\t\n431084\t<0.5\tForeign\tFemale\t1.5 h\tHepB\tN/A\t\n433276\t<0.5\tForeign\tMale\tN/A\tHepB\tN/A\t\n433278\t<0.5\tForeign\tMale\tN/A\tHepB\tN/A\t\nNote:\n\n*The only one case where BCG vaccine was used for bladder cancer treatment. In all other 23 cases, BCG was used as a TB vaccine. SCID: severe combined immunodeficiency; FHID: family history of immunodeficiency.\n\nAs shown in Table 5, out of 12 cases with reported time relapsed, 10 cases reported patient death within 2 days after BCG vaccination. The fact that 21 of 24 (87.5%) cases occurred in patients younger than one year old indicates patient age was an important factor for death outcome. Gender was unlikely an important factor since these 24 cases were almost evenly split with 11 females and 13 males. Most of patients were suffering some current illness, especially severe combined immunodeficiency (SCID) and family history of immunodeficiency (FHID), when they were vaccinated with BCG vaccine. Therefore, personal health issue likely influenced the death outcome for BCG vaccination. Twelve patients were co-immunized with other vaccines, including HepB (8 patients), DTAP (3 patients), IPV (5 patients), PCV7 (2 patients), PRV (4 patients), Hib (5 patients), and OPV (one patient). Furthermore, out of 24 death cases, 22 cases were occurred at territory with “foreign” (i.e., countries outside of the USA); the rest of two cases, one occurred in an “Unknown” territory, and the other occurred in Michigan, USA.\n\nDiscussion\nThe data resources and methods used in our study are relatively novel. To our best knowledge, our paper is the first report focusing on the systematic analysis of AE profiles associated with two different types of BCG vaccine. Our study is also the first to utilize the VAERS database for BCG AE data analysis. One difficulty in our data collection is that VAERS does not differentiate the type (for TB prevention or cancer treatment) of usage for the BCG vaccine. Therefore, we had to manually check each case report to identify the vaccine type. It would be helpful for future studies if clear differentiation of the BCG vaccine type is made in VAERS. Meanwhile, we also collected and analyzed related papers from the PubMed literature database. Compared to providing lists of BCG AEs from other BCG AE papers, our ontology-based AE analysis allowed classification of AEs, leading to more specific insights.\n\nOur comparative results on the differential AE profiles associated with two types of BCG vaccine not only keep consistent with the results from existing reports, but also contain more specific details. The US FDA has reported many BCG AEs based on randomized and well-controlled critical trials [27, 28]. Specifically, for the BCG vaccination against TB, the FDA package insert document reports many AEs including moderate axillary or cervical lymphadenopathy and induration and subsequent pustule formation at the injection site, and disseminated BCG infection as the most serious complication of BCG TB vaccination [27]. For the intravesical BCG use for cancer treatment, the most common complaints for BCG use were malaise, fatigue and lethargy, fever, and abdominal pain. Some serious but uncommon adverse reactions, such as disseminated sepsis and epididymitis have also been reported [28]. Compared the FDA package insert information, our study identified more AEs coming from spontaneous case reports and literature survey. Many other BCG AE reports are also available. For example, Clothier et al. recently surveyed the BCG AEs from a VAERS-like vaccine AE case report database, and their study identified abscess and lymphadenopathy as two predominant BCG AEs [29]. These two AEs were also found in our study. Retrospective BCG AE studies were also conducted in many other countries, for example, Brazil [30], French [31], Ireland [32], Singapore [33], and China (paper written in Chinese) [34]. The BCG AEs reported in these literature articles were collected in our literature meta-analysis study and analyzed again. Our comparative and ontology-based classification also provides more specific details as shown in the Results section.\n\nThere are likely many reasons behind the differential AE profiles associated with the use of BCG as a tuberculosis preventive vaccine or bladder cancer therapeutic vaccine. First, the route of administration appears to be an important factor. When BCG is used for TB vaccination, percutaneous or intradermal route is applied [35, 36]. The percutaneous method is recommended for the vaccination of the US FDA-licensed TICE-BCG [27]. One main reason of the preferred usage of the percutaneous method is that the intradermal method is associated with elevated incidences of AEs such as keloid reactions [35]. In contrast, for bladder cancer treatment, BCG is administered intravesically [28]. With this intravesical administration method, BCG is put into a catheter and injected directly into the bladder. Instilled into the bladder, BCG is able to sensitize T cells, activate macrophages, and induce cytokines, and these cellular responses cooperate to kill cancer cells, reduce tumor recurrences, delay cancer progress, and improve survival [5, 37]. Under this situation, it is reasonable to expect the bladder and its nearby systems to experience most of the complications. Second, patient health conditions likely have an important effect on the AE outcomes. The vaccinees to be vaccinated with the TB vaccine are expected to be healthy before the vaccination. However, the patients to be treated with the bladder cancer vaccine have already had a sick bladder. This weakened bladder is likely more susceptible to more AEs compared to that of healthy people. Thirdly, the age is likely another factor since the BCG TB vaccine is frequently used in children and the BCG bladder cancer vaccine is usually used in adults. How each or a combination of these factors contributes to the AE outcomes deserves further investigation.\n\nOur analysis of 24 reported cases of death from VAERS suggests that three factors, including age, health condition, and vaccine co-administration, contribute to the occurrence of BCG-associated death. Our comparative analysis shows that children, patients co-administered with BCG and other vaccine(s), and immunocompromised patients were more susceptible to the death AE after BCG vaccination (Table 5). Of these death cases, many patients suffered from one or more immune system disorders, especially the Severe Combined Immunodeficiency (SCID) (Table 5). A weakened immune system might greatly increase a person’s chance of experiencing a severe AE such as death. SCID is a primary immune deficiency characterized by a severe defect in both T- and B-lymphocyte systems. The annual incidence of SCID is estimated to be one case per 40,000–100,000 live births [38]. SCID patients have been found to be very sensitive to pathogen infections and vaccinations (e.g., rotavirus vaccines) [38]. Our study indicated that SCID patients were very sensitive to BCG, suggesting the importance of listing SCID as a contraindication for the BCG administration. In fact, the BCG package insert from FDA indicates that BCG vaccine should not be used in infants, children, or adults with severe immune deficiency syndromes [27]. All the death cases associated with the immunocompromised health condition occurred in the territory of “Foreign”, suggesting that the BCG immunization in the “Foreign” territory more likely did not follow the guideline from the package insert document.\n\nOverall, this study allows us to address the hypothesis of differential and shared AEs resulted from the preventive BCG TB vaccination and therapeutic BCG cancer treatment. The above discussion focuses on the differential AEs out of these two types of vaccinations. Meanwhile, our study also shows that these two procedures resulted in three shared AEs, i.e., chills (a feeling of coldness occurring during a high fever), pneumonia, and elevated CRP level in blood (indicating the occurrence of inflammation). These three AEs are not directly related to the local percutaneous or intradermal route for TB vaccination or intravesical site for bladder cancer treatment. Instead, such AEs are out of the systemic effects of the BCG vaccination in vivo to vaccinees with different health conditions. These results demonstrate that any of these vaccination routes would result in systemic proinflammatory responses in the blood and lung of human vaccinees. How BCG causes such inflammatory effects from different routes deserves further investigations.\n\nVaccine AE data standardization and classification have been a major research topic in vaccine safety research [39–41]. Our ontology-based BCG AE study demonstrates the ontological and semantic features of OAE in AE classification. A previous study by Sarntivijai et al. first applied the MedDRA-OAE mapping and the following OAE AE classification to study the AEs associated with live attenuated and killed influenza vaccines [15]. By comparing OAE, MedDRA, and SNOMED-CT [42], the study by Sarntivijai et al. showed many advantages of OAE in AE term classification [15]. By analyzing FAERS-reported drug AEs associated with tyrosine kinase inhibitors and monoclonal antibodies, a recent FDA-led research demonstrated that OAE can serve as a semantic framework to link MedDRA-coded clinical AE phenotypes to biological mechanisms [16]. Our current study provides new empirical evidence on the feasibility and advantages of using OAE in AE classification and clustering analysis after the MedDRA-OAE term mappings. Such a method can also be used to study AEs associated with other licensed vaccines. Currently OAE has a lower coverage of AE terms than MedDRA. To ensure all possible MedDRA-OAE mappings and better support AE classification, an increased coverage of OAE is needed.\n\nThe information learned from this study is useful for future clinical or basic research. First of all, although the same live attenuated BCG vaccine is used in both the TB vaccination and bladder cancer treatment, our research demonstrates that these two types of vaccination result in many differential AEs and three shared AEs. Second, for better categorization of the BCG-associated AEs from clinical AE reports, our study suggests the necessity of separating these two vaccination types in VAERS in order to avoid possible misinterpretation of BCG-associated AEs. Third, this study also provides a new standard operating procedure in systematically analyzing AEs using VAERS and literature reports. Furthermore, our OAE and MedDRA comparison provides a strong empirical evidence of the benefits of using OAE for more accurate AE classification and new information discovery.\n\nConclusion\nIn this study, we systematically analyzed and compared differential AE profiles associated with the BCG preventive TB vaccine and therapeutic bladder cancer vaccine using two data resources: the VAERS database and the meta-analyzed PubMed literature. The statistical analysis combined with ontology-based AE classification clearly showed that the BCG for TB prevention and cancer treatment were associated with two distinct AE profiles with minimal overlaps. Specifically, when BCG was used as a preventive TB vaccine, those AEs were enriched in immune system, skin, and respiratory system. When BCG was used as a therapeutic bladder cancer vaccine, the major group of associated AEs occurred in the urinary system. Meanwhile, three AEs (i.e., chills, pneumonia, and CRP level increased) were found to be commonly associated with the two vaccine types. In addition, the detailed analysis of BCG-related death cases found that the death outcome was primarily related to patient age, patient immunosuppressive status, and co-administered vaccines. At last, our comparative study for BCG-associated 25 SAEs empirically confirmed the advantages of OAE over MedDRA in AE classification. Overall, our research results facilitate BCG vaccine safety surveillance and benefit rational design of more secure and effective vaccines, and the research methods used in this study can also be applied to study adverse events associated with other licensed vaccines.\n\nSupporting Information\nS1 Fig OAE-based classification of 64 statistically significant AEs associated with BCG as a TB vaccine.\n(TIF)\n\nClick here for additional data file.\n\n S2 Fig OAE-based classification of 14 statistically significant AEs associated with BCG as a bladder cancer treatment vaccine.\n(TIF)\n\nClick here for additional data file.\n\n S3 Fig Classification of 48 AEs associated with the BCG TB vaccine using OAE.\n(TIF)\n\nClick here for additional data file.\n\n S4 Fig Classification of 43 AEs associated with the BCG cancer vaccine using OAE.\n(TIF)\n\nClick here for additional data file.\n\n S1 File PRISMA checklist.\n(DOC)\n\nClick here for additional data file.\n\n S2 File The detailed information of BCG-associated AE case reports in VAERS.\n(XLSX)\n\nClick here for additional data file.\n\n S3 File The details of 41 peer-reviewed journal articles and BCG-associated AEs identified from these articles.\n(DOCX)\n\nClick here for additional data file.\n\n We thank the anonymous reviewers for their valuable comments and suggestions on an earlier version of this paper. The publication fee was paid by the discretionary fund from Dr. Robert Dysko, the director of the Unit for Laboratory Animal Medicine (ULAM) in the University of Michigan Medical School.\n==== Refs\nReferences\n1 Luca S , Mihaescu T . History of BCG Vaccine . Maedica . 2013 ;8 (1 ):53 –8 . 24023600 \n2 Andersen P , Doherty TM . The success and failure of BCG—implications for a novel tuberculosis vaccine . Nature reviews Microbiology . 2005 ;3 (8 ):656 –62 . 10.1038/nrmicro1211 .16012514 \n3 WHO . Weekly epidemiological record: relevé épidémiologique hebdomadaire . World Health Organization 2006 .\n4 Paterson DL , Patel A . Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer: review of complications and their treatment . The Australian and New Zealand journal of surgery . 1998 ;68 (5 ):340 –4 . .9631906 \n5 Herr HW , Moralest A . History of bacillus Calmette-Guerin and bladder cancer: An immunotherapy success story . J Urology . 2008 ;179 (1 ):53 –6 . 10.1016/j.juro.2007.08.122 . WOS:000251650200012. 17997439 \n6 Pearl R . Cancer and tuberculosis . Am J Hygiene . 1929 ;9 :97 .\n7 Turnbull F , McIntyre P , Achat H , Wang H , Stapledon R , Gold M , et al\nNational study of adverse reactions after vaccination with bacille Calmette-Guérin . Clinical infectious diseases . 2002 ;34 (4 ):447 –53 . 10.1086/338462 \n11797170 \n8 Toida I , Nakata S . Severe adverse reactions after vaccination with Japanese BCG vaccine: a review . Kekkaku: Tuberculosis . 2007 ;82 (11 ):809 –24 . 18078106 \n9 FDA. What is a Serious Adverse Event? Available: http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm (Accessed: 5th October 2016).\n10 Chen RT , Rastogi SC , Mullen JR , Hayes SW , Cochi SL , Donlon JA , et al\nThe vaccine adverse event reporting system (VAERS) . Vaccine . 1994 ;12 (6 ):542 –50 . 8036829 \n11 Iskander J , Pool V , Zhou W , English-Bullard R . Data mining in the US using the vaccine adverse event reporting system . Drug safety . 2006 ;29 (5 ):375 –84 . 16689554 \n12 Brown EG , Wood L , Wood S . The medical dictionary for regulatory activities (MedDRA) . Drug safety . 1999 ;20 (2 ):109 –17 . Epub 1999/03/19. .10082069 \n13 Brown EG . Methods and pitfalls in searching drug safety databases utilising the Medical Dictionary for Regulatory Activities (MedDRA) . Drug safety . 2003 ;26 (3 ):145 –58 . Epub 2003/02/13. 260302 [pii]. .12580645 \n14 He YQ , Sarntivijai S , Lin Y , Xiang ZS , Guo A , Zhang S , et al\nOAE: The Ontology of Adverse Events . J Biomed Semant . 2014 ;5 :29 . WOS:000343711400001.\n15 Sarntivijai S , Xiang ZS , Shedden KA , Markel H , Omenn GS , Athey BD , et al\nOntology-Based Combinatorial Comparative Analysis of Adverse Events Associated with Killed and Live Influenza Vaccines . Plos One . 2012 ;7 (11 ):e49941 WOS:000312601700028. 10.1371/journal.pone.0049941 \n23209624 \n16 Sarntivijai S , Zhang S , Jagannathan DG , Zaman S , Burkhart KK , Omenn GS , et al\nLinking MedDRA®-Coded Clinical Phenotypes to Biological Mechanisms by the Ontology of Adverse Events: A Pilot Study on Tyrosine Kinase Inhibitors . Drug safety . 2016 :1 –11 .26597283 \n17 He Y . Ontology-based vaccine and drug adverse event representation and theory-guided systematic causal network analysis toward integrative pharmacovigilance research . Current Pharmacology Reports . 2016 ;2 (3 ):113 –28 . 10.1007/s40495-016-0055-0 \n27458549 \n18 Evans SJW , Waller PC , Davis S . Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports . Pharmacoepidemiology and Drug Safety . 2001 ;10 (6 ):483 –6 . WOS:000173426600001. 10.1002/pds.677 \n11828828 \n19 Yates F . Contingency tables involving small numbers and the χ2 test . Supplement to the Journal of the Royal Statistical Society . 1934 ;1 :217 –35 .\n20 Banks D , Woo EJ , Burwen DR , Perucci P , Braun MM , Ball R . Comparing data mining methods on the VAERS database . Pharmacoepidem Dr S . 2005 ;14 (9 ):601 –9 . WOS:000231913600002.\n21 Rubin DL , Noy NF , Musen MA . Protege: a tool for managing and using terminology in radiology applications . Journal of digital imaging . 2007 ;20 \nSuppl 1 :34 –46 . 10.1007/s10278-007-9065-0 \n17687607 \n22 Xiang Z , Courtot M , Brinkman RR , Ruttenberg A , He Y . OntoFox: web-based support for ontology reuse . BMC research notes . 2010 ;3 (1 ):175 .20569493 \n23 Moher D , Shamseer L , Clarke M , Ghersi D , Liberati A , Petticrew M , et al\nPreferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement . Systematic reviews . 2015 ;4 (1 ):1 .25554246 \n24 Liberati A , Altman DG , Tetzlaff J , Mulrow C , Gøtzsche PC , Ioannidis JP , et al\nThe PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration . Annals of internal medicine . 2009 ;151 (4 ):W –65 .\n25 He Y . Ontology-supported research on vaccine efficacy, safety and integrative biological networks . Expert review of vaccines . 2014 ;13 (7 ):825 –41 . 10.1586/14760584.2014.923762 \n24909153 \n26 Smith B. Invited Papers from the 10th International Conference in Logic Methodology and Philosophy of Science, Oviedo, Spain [Internet]2003.\n27 FDA. BCG vaccine for percutaneous use—U.S. Food and Drug Administration. Available: http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM202934.pdf (Aceessed 5 October 2016).\n28 FDA. BCG live for intravesical use—U.S. Food and Drug Administration. Available: http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM163039.pdf (Aceessed 5 October 2016).\n29 Clothier HJ , Hosking L , Crawford NW , Russell M , Easton ML , Quinn JA , et al\nBacillus Calmette-Guerin (BCG) vaccine adverse events in Victoria, Australia: analysis of reports to an enhanced passive surveillance system . Drug safety . 2015 ;38 (1 ):79 –86 . 10.1007/s40264-014-0248-6 .25475539 \n30 Dourado I , Rios MH , Pereira SM , Cunha SS , Ichihara MY , Goes JC , et al\nRates of adverse reactions to first and second doses of BCG vaccination: results of a large community trial in Brazilian schoolchildren . The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease . 2003 ;7 (4 ):399 –402 . .12729348 \n31 Mayet A , Duron S , Meynard JB , Koeck JL , Deparis X , Migliani R . Surveillance of adverse events following vaccination in the French armed forces, 2011–2012 . Public health . 2015 ;129 (6 ):763 –8 . 10.1016/j.puhe.2015.03.003 .25890634 \n32 Bolger T , O'Connell M , Menon A , Butler K . Complications associated with the bacille Calmette-Guerin vaccination in Ireland . Archives of disease in childhood . 2006 ;91 (7 ):594 –7 . 10.1136/adc.2005.078972 \n16547086 \n33 Thoon KC , Soh SB , Liew WK , Gunachandran A , Tan NW , Chong CY , et al\nActive surveillance of adverse events following childhood immunization in Singapore . Vaccine . 2014 ;32 (39 ):5000 –5 . 10.1016/j.vaccine.2014.07.020 .25045811 \n34 Wu WD , Liu DW , Li L . [Literature review of adverse events following immunization of Bacillus Calemtte-Guerin vaccine ]. Zhongguo yi miao he mian yi . 2009 ;15 (6 ):491 –5 . .20518321 \n35 Bricks LF . Percutaneous or intradermal BCG vaccine? \nJornal de pediatria . 2004 ;80 (2 ):93 –8 . 15079177 \n36 Davids V , Hanekom WA , Mansoor N , Gamieldien H , Sebastian JG , Hawkridge A , et al\nThe effect of bacille Calmette-Guerin vaccine strain and route of administration on induced immune responses in vaccinated infants . Journal of Infectious Diseases . 2006 ;193 (4 ):531 –6 . 10.1086/499825 \n16425132 \n37 Redelman-Sidi G , Glickman MS , Bochner BH . The mechanism of action of BCG therapy for bladder cancer—a current perspective . Nature reviews Urology . 2014 ;11 (3 ):153 –62 . 10.1038/nrurol.2014.15 .24492433 \n38 Centers for Disease C, Prevention . Addition of severe combined immunodeficiency as a contraindication for administration of rotavirus vaccine . MMWR Morbidity and mortality weekly report . 2010 ;59 (22 ):687 –8 . .20535093 \n39 Kohl KS , Bonhoeffer J , Braun MM , Chen RT , Duclos P , Heijbel H , et al\nThe Brighton Collaboration: Creating a Global Standard for Case Definitions (and Guidelines) for Adverse Events Following Immunization In: Henriksen K , Battles JB , Marks ES , Lewin DI , editors. Advances in Patient Safety: From Research to Implementation (Volume 2: Concepts and Methodology). Advances in Patient Safety . Rockville (MD) 2005 .\n40 Singleton JA , Lloyd JC , Mootrey GT , Salive ME , Chen RT . An overview of the vaccine adverse event reporting system (VAERS) as a surveillance system. VAERS Working Group . Vaccine . 1999 ;17 (22 ):2908 –17 . .10438063 \n41 He Y , Rappuoli R , De Groot AS , Chen RT . Emerging vaccine informatics . J Biomed Biotechnol . 2010 ;2010 :218590 Epub 2010/01/01. 10.1155/2010/218590 \n21772787 \n42 Brown SH , Elkin PL , Bauer BA , Wahner-Roedler D , Husser CS , Temesgen Z , et al\nSNOMED CT: utility for a general medical evaluation template . AMIA Annu Symp Proc . 2006 :101 –5 . Epub 2007/01/24. 86443 [pii]. .17238311\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(10)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D001500:BCG Vaccine; D002097:C-Reactive Protein; D019496:Cancer Vaccines; D016208:Databases, Factual; D053159:Dysuria; D006801:Humans; D000072281:Lymphadenopathy; D011014:Pneumonia; D012883:Skin Ulcer; D032581:Tuberculosis Vaccines; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0164792",
"pmc": null,
"pmid": "27749923",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis",
"references": "10082069;10438063;11797170;11828828;12580645;12729348;15079177;15954077;16012514;16425132;16547086;16689554;17238311;17687607;17997439;18078106;19622512;20518321;20535093;20569493;21772787;23209624;24023600;24492433;24909153;25045811;25093068;25475539;25554246;25890634;27003817;27458549;8036829;9631906",
"title": "Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis.",
"title_normalized": "differential adverse event profiles associated with bcg as a preventive tuberculosis vaccine or therapeutic bladder cancer vaccine identified by comparative ontology based vaers and literature meta analysis"
} | [
{
"companynumb": "CN-SA-2016SA202690",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
... |
{
"abstract": "Patients with β-thalassemia require iron chelation therapy to protect against progressive iron overload and non-transferrin-bound iron. Some patients fail to respond adequately to deferoxamine and deferasirox monotherapy while others have side effects which limit their use of these drugs. Since combining deferiprone and deferoxamine has an additive effect, placing all patients into net negative iron balance, we investigated the possibility that combining deferasirox and deferoxamine would lead to similar results. We conducted 34-day metabolic iron balance studies in six patients in whom the relative effectiveness of deferasirox (30 mg/kg/day) and deferoxamine (40 mg/kg/day) was compared, alone and in combination. Patients consumed fixed low-iron diets; daily urinary and stool iron excretion were determined by atomic absorption. Red blood cell transfusions were given prior to each drug treatment to minimize the effects of ineffective erythropoiesis. Serial safety measures, hematologic parameters, serum chemistries, ferritin levels and urinalyses were determined. All patients were in negative iron balance when treated with deferoxamine alone while four of six patients remained in positive balance when deferasirox monotherapy was evaluated. Daily use of both drugs had a synergistic effect in two patients and an additive effect in three others. Five of six patients would be in negative iron balance if they used the combination of drugs just 3 days a week. No significant or drug-related changes were observed in the blood work-ups or urinalyses performed. We conclude that supplementing the daily use of deferasirox with 2 - 3 days of deferoxamine therapy would place all patients into net negative iron balance thereby providing a convenient way to tailor chelation therapy to the individual needs of each patient.",
"affiliations": "Division of Pediatric Hematology/Oncology, New York Presbyterian Hospital, New York, NY, USA. rwgrady13@gmail.com",
"authors": "Grady|Robert W|RW|;Galanello|Renzo|R|;Randolph|Rachel E|RE|;Kleinert|Dorothy A|DA|;Dessi|Carlo|C|;Giardina|Patricia J|PJ|",
"chemical_list": "D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D003676:Deferoxamine; D000077588:Deferasirox",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2012.070607",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "98(1)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000328:Adult; D001565:Benzoates; D000077588:Deferasirox; D003676:Deferoxamine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007501:Iron; D007502:Iron Chelating Agents; D008297:Male; D014230:Triazoles; D017086:beta-Thalassemia",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "129-35",
"pmc": null,
"pmid": "22875626",
"pubdate": "2013-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "12241655;17372174;20492011;19236376;18298856;8695819;16373663;2695408;21072825;20884710;12817519;20553089;7877649;16227677;16352812;4416298;12763939;19996412;21615376;20217085;19912219;8560288;19724055;16956824;11703317;10885361;12100170;17951527;16818273;19187278;8604587;16531476;15846581;16627763;21628399;21813448;20678715;18537970;12745268;21509263;20627190;12747879;2884415;2112268;18281442;19815834;18055982;20712765;21668502;11605170;21523808",
"title": "Toward optimizing the use of deferasirox: potential benefits of combined use with deferoxamine.",
"title_normalized": "toward optimizing the use of deferasirox potential benefits of combined use with deferoxamine"
} | [
{
"companynumb": "NVSC2020US035367",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEFEROXAMINE MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND Histoplasmosis results from the inhalation of spores from the fungus, Histoplasma capsulatum. A case is presented of pulmonary histoplasmosis associated with altered mental state and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). CASE REPORT A 75-year-old man with a five-day history of AML treated with allogeneic hematopoietic stem cell transplantation, presented with weakness, fatigue, and slow mentation. Computed tomography (CT) of the brain was unremarkable. Laboratory investigations showed serum albumin of 2.9 g/dL, calcium of 11.6 mg/dL, ionized calcium of 1.55 mmol/L, parathyroid hormone (PTH) <6.3 pg/mL, and 25-hydroxy vitamin D of 14.4 ng/mL. Treatment began with intravenous cefepime 1 gm bid, normal saline, and the bisphosphonate, pamidronate, administered as a single dose. Three days later, his clinical status declined. He developed a dry productive cough, his oxygen saturation (O₂ Sat) was 90%, and his mental status worsened. Chest CT showed diffuse bilateral lung infiltrates with ground glass opacities. Bronchioalveolar lavage and transbronchial biopsy were negative for Pneumocystis jiroveci pneumonia (PJP). The CMV rival load was 195 IU/mL. Urinalysis for Histoplasma antigen and the Fungitell® assay were positive. Treatment commenced with intravenous voriconazole (250 mg, bid) and ganciclovir (5 mg/kg, bid). A left lower lobe transbronchial lung biopsy was positive for Histoplasma capsulatum and negative for CMV. CONCLUSIONS This case report has highlighted the need for awareness of the diagnosis of histoplasmosis in patients with allogeneic hematopoietic stem cell transplantation who present with an altered mental state in the setting of hypercalcemia.",
"affiliations": "Department of Internal Medicine, Memorial Hospital West, Memorial Healthcare System, Pembroke Pines, FL, USA.;Department of Internal Medicine, Memorial Hospital West, Memorial Healthcare System, Pembroke Pines, FL, USA.;Division of Infectious Disease, Memorial Regional Hospital, Memorial Healthcare System, Hollywood, FL, USA.;Division of Infectious Disease, Memorial Regional Hospital, Memorial Healthcare System, Hollywood, FL, USA.;Office of Human Research, Memorial Healthcare System, Hollywood, FL, USA.",
"authors": "Rodriguez|Jose A|JA|;Ivancic|Stipe|S|;Eckardt|Paula A|PA|;Lemos-Ramirez|Juan C|JC|;Niu|Jianli|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.919724",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3195517810.12659/AJCR.919724919724ArticlesA Case of Pulmonary Histoplasmosis Presenting with Hypercalcemia and Altered Mental Status in a Patient Following Allogeneic Hematopoietic Stem Cell Transplantation Rodriguez Jose A. BEF1Ivancic Stipe BEF1Eckardt Paula A. AD2Lemos-Ramirez Juan C. DE2Niu Jianli EG3\n1 Department of Internal Medicine, Memorial Hospital West, Memorial Healthcare System, Pembroke Pines, FL, U.S.A.\n2 Division of Infectious Disease, Memorial Regional Hospital, Memorial Healthcare System, Hollywood, FL, U.S.A.\n3 Office of Human Research, Memorial Healthcare System, Hollywood, FL, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Jose A. Rodriguez, e-mail: alfonsorc90@hotmail.com2020 19 1 2020 21 e919724-1 e919724-4 28 8 2019 16 10 2019 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 75-year-old\n\nFinal Diagnosis: Pulmonary histoplasmosis\n\nSymptoms: Altered mental status • cough • shortness of breath\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Pulmonology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nHistoplasmosis results from the inhalation of spores from the fungus, Histoplasma capsulatum. A case is presented of pulmonary histoplasmosis associated with altered mental state and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML).\n\nCase Report:\nA 75-year-old man with a five-day history of AML treated with allogeneic hematopoietic stem cell transplantation, presented with weakness, fatigue, and slow mentation. Computed tomography (CT) of the brain was unremarkable. Laboratory investigations showed serum albumin of 2.9 g/dL, calcium of 11.6 mg/dL, ionized calcium of 1.55 mmol/L, parathyroid hormone (PTH) <6.3 pg/mL, and 25-hydroxy vitamin D of 14.4 ng/mL. Treatment began with intravenous cefepime 1 gm bid, normal saline, and the bisphosphonate, pamidronate, administered as a single dose. Three days later, his clinical status declined. He developed a dry productive cough, his oxygen saturation (O2 Sat) was 90%, and his mental status worsened. Chest CT showed diffuse bilateral lung infiltrates with ground glass opacities. Bronchioalveolar lavage and transbronchial biopsy were negative for Pneumocystis jiroveci pneumonia (PJP). The CMV viral load was 195 IU/mL. Urinalysis for Histoplasma antigen and the Fungitell® assay were positive. Treatment commenced with intravenous voriconazole (250 mg, bid) and ganciclovir (5 mg/kg, bid). A left lower lobe transbronchial lung biopsy was positive for Histoplasma capsulatum and negative for CMV.\n\nConclusions:\nThis case report has highlighted the need for awareness of the diagnosis of histoplasmosis in patients with allogeneic hematopoietic stem cell transplantation who present with an altered mental state in the setting of hypercalcemia.\n\nMeSH Keywords:\nHistoplasmosisHypercalcemiaStem Cell Transplantation\n==== Body\nBackground\nHistoplasmosis is the most common endemic mycosis in the US and results from the inhalation of spores from the fungus, Histoplasma capsulatum [1]. A case is presented of pulmonary histoplasmosis presenting with nonspecific symptoms and hypercalcemia in the setting of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). Few cases have previously been reported of pulmonary histoplasmosis in patients following allogeneic hematopoietic stem cell transplantation [2].\n\nCase Report\nA 75-year-old man with a history of acute myeloid leukemia (AML), and resolved hepatitis C virus (HCV) and hepatitis B virus (HBV) infection received induction chemotherapy with idarubicin and consolidation therapy with cytarabine. A follow-up bone marrow biopsy showed complete remission. He underwent allogeneic hematopoietic stem cell transplantation following a reduced-intensity conditioning regimen with cyclophosphamide, fludarabine, and total body irradiation. After 144 days, he presented with a five-day history of weakness, fatigue, and slow mentation. He denied skin rash, abdominal pain, diarrhea, shortness of breath, cough, sputum production, or other symptoms. His vital signs were normal, with a blood pressure of 97/58 mmHg, a temperature 36.2°C, a pulse rate of 87 bpm, a respiratory rate of 18 breaths per minute, and oxygen saturation (O2 Sat) of 97% in room air.\n\nOn physical examination, he was somnolent, unable to recognize his spouse, but was without focal neurological deficit. Computed tomography (CT) of the brain was unremarkable. Laboratory investigations were significant for a white blood cell count (WCC) of 5.2×103/ul, an absolute neutrophil count (ANC) of 3.3×109/L, a hemoglobin of 10.7 g/dL, hematocrit of 12.6%, platelet count of 37 × 103/ul, blood urea nitrogen (BUN) of 30 mg/dL, creatinine of 1.26 mg/dL, albumin of 2.9 g/dL, calcium 11.6 mg/dL, ionized calcium of 1.55 mmol/L, parathyroid hormone (PTH) <6.3 pg/mL, 25-hydroxy vitamin D of 14.4 ng/mL. Fifteen days before admission, his calcium levels were at 9.0 mg/dL. Serologic tests for Cryptococcal antigen and Aspergillus galactomannan were negative, and EBV serology was positive. A lumbar puncture test was unremarkable. Treatment began with intravenous cefepime 1 gm bid, normal saline at 150 ml/h per 1 L, and the bisphosphonate, pamidronate, administered as a single dose of 90 mg.\n\nThree days later, the patient’s clinical status continued to decline. He developed a dry productive cough. His O2 Sat was 90%, and his mental status declined. A chest CT showed bilateral diffuse lung infiltrates with ground glass opacities (Figure 1).\n\nTreatment with trimethoprim/sulfamethoxazole (TMP/SMX) at 5 mg/kg tid commenced for possible Pneumocystis jiroveci pneumonitis (PJP). Bronchioalveolar lavage and transbronchial biopsy were negative for PJP, and the CMV viral load was 195 IU/mL. Urinalysis for Histoplasma antigen and the Fungitell® assay were positive.\n\nOn further review of the patient’s history, he had spent most of his life in the Ohio River Valley area. A provisional diagnosis of pulmonary histoplasmosis and CMV pneumonitis was made. TMP/SMX was discontinued and treatment with intravenous voriconazole (250 mg, bid) and ganciclovir (5 mg/kg, bid) commenced. A left lower lobe transbronchial biopsy showed small budding yeast forms, which showed positive histochemical staining for Histoplasma capsulatum (Figure 2). The lung biopsy was negative for CMV.\n\nThe diagnosis of pulmonary histoplasmosis was confirmed. The patient’s mental status progressively improved as the hypercalcemia resolved to a calcium level of 8.56 mg/dL. The patient was discharged from hospital on a seven-day course of ciprofloxacin, a six to 12-week course of voriconazole, and prophylactic HBV therapy with entecavir, prophylactic PJP therapy with atovaquone, and prophylactic HSV therapy with acyclovir. At one-month outpatient follow-up, the patient was noted to have persistently elevated liver enzyme levels. Voriconazole was discontinued, and posaconazole, a triazole antifungal agent, 400 mg every 12 hours, was commenced for a duration of 12 weeks. Repeat serum and urinalysis for Histoplasma antigen remained negative. The patient’s treatment was transitioned to a reduced secondary prophylactic dose of posaconazole. At a two-month outpatient follow-up, the patient remained asymptomatic but continued anti-infection prophylactic medications.\n\nDiscussion\nA case report is presented that highlights one of many diverse presentations of histoplasmosis. This patient initially presented with the main complaint of altered mental status. General physical examination, review of his medications, and initial laboratory investigations were normal apart from hypercalcemia. Brain computed tomography (CT) imaging without contrast was negative for intracranial mass or hemorrhage. Lumbar puncture was negative for infection. However, only when the patient developed respiratory compromise and following further review of the patient’s history, which identified he had lived in an endemic area in Ohio, that a diagnosis of histoplasmosis was considered. The correlation between hypercalcemia and altered mental status was supported by the improvement in neurologic function when effective treatment commenced.\n\nAlthough the presentation in this case was atypical, it was consistent with a diagnosis of acute pulmonary histoplasmosis. Although histoplasmosis can be self-limiting, patients with significant bilateral chest infiltrates or who are immunosuppressed require active treatment [3]. First-line therapy for pulmonary histoplasmosis is either with amphotericin B, fluconazole, or itraconazole. Typically, amphotericin B commences at one to two weeks and is replaced by itraconazole for an additional 12 weeks of therapy [3]. In this case, amphotericin treatment was not begun due to the moderate severity of the illness and possible drug interactions. This patient had a left ventricular ejection fraction (LVEF) of 34%. Voriconazole was chosen as the first-line treatment, due to the black box warning regarding itraconazole in patients with underlying congestive heart failure [4,5]. The triazole antifungal agent, posaconazole was used as salvage therapy and had a lower profile for causing hepatic damage when compared with voriconazole. The patient continued to be at risk for developing chronic pulmonary histoplasmosis, given his underlying immunodeficiency state. Patients treated for histoplasmosis are typically maintained on antifungal therapy for at least 12–24 months, with follow-up chest CT at 6-monthly intervals [3]. In this case, follow-up chest CT (Figure 3) showed a significant resolution of the initial lung abnormalities while the patient was receiving posaconazole maintenance therapy.\n\nThere have been at least six previously reported cases of histoplasmosis associated with allogeneic hematopoietic stem cell transplantation [2]. There have been previously published cases of histoplasmosis associated with hypercalcemia [6]. The diagnosis of histoplasmosis relies on a multidisciplinary approach that includes histopathology and microbiology examination, urine, and serology antibody tests [7]. Progressive disseminated histoplasmosis can present with hypercalcemia, which is attributed to increased vitamin D production from fungal granulomas [6]. In this case, the differential diagnoses on the initial presentation may have included malignancy and other granulomatous diseases, both of which are associated with hypercalcemia.\n\nConclusions\nA case is presented of pulmonary histoplasmosis associated with altered mental state and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). Although hypercalcemia a rare manifestation of histoplasmosis, lack of awareness of this association may lead to a delay in diagnosis and compromise patient outcome. This case report has highlighted the need for awareness of the diagnosis of histoplasmosis in patients with allogeneic hematopoietic stem cell transplantation who present with an altered mental state in the setting of hypercalcemia.\n\nConflict of interest\n\nNone.\n\nFigure 1. Computed tomography (CT) imaging of a 75-year-old man with pulmonary histoplasmosis and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). Diffuse bilateral lung infiltrates with ground glass opacities.\n\nFigure 2. Photomicrograph of the bronchial culture of a lung sample from a 75-year-old man with pulmonary histoplasmosis and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). The filamentous form of Histoplasmosis capsulatum is shown by lactophenol cotton blue staining for chitin in the wall of the fungus.\n\nFigure 3. Computed tomography (CT) 3 months follow up imaging of a 75-year-old man with pulmonary histoplasmosis and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). Major improvement of previous diffuse bilateral lung infiltrates with ground glass opacities.\n==== Refs\nReferences:\n1. Chu J Feudtner C Heydon K Hospitalizations for endemic mycoses: A population-based national study Clin Infect Dis 2006 42 6 822 25 16477560 \n2. Natarajan M Swierzbinski MJ Maxwell S Pulmonary histoplasma infection after allogeneic hematopoietic stem cell transplantation: Case report and review of the literature Open Forum Infect Dis 2017 4 2 ofx041 28470019 \n3. Wheat LJ Azar MM Bahr NC Histoplasmosis Infect Dis Clin North Am 2016 30 1 207 27 26897068 \n4. Freifeld A Proia L Andes D Voriconazole use for endemic fungal infections Antimicrob Agents Chemother 2009 53 4 1648 51 19139290 \n5. Ahmad SR Singer SJ Leissa BG Congestive heart failure associated with itraconazole Lancet 2001 357 9270 1766 67 11403818 \n6. Khasawneh FA Ahmed S Halloush RA Progressive disseminated histoplasmosis presenting with cachexia and hypercalcemia Int J Gen Med 2013 6 79 83 23467543 \n7. Hage CA Ribes JA Wengenack NL A multicenter evaluation of tests for diagnosis of histoplasmosis Clin Infect Dis 2011 53 5 448 54 21810734\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D018380:Hematopoietic Stem Cell Transplantation; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D006934:Hypercalcemia; D016867:Immunocompromised Host; D015470:Leukemia, Myeloid, Acute; D008172:Lung Diseases, Fungal; D008297:Male; D001523:Mental Disorders",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e919724",
"pmc": null,
"pmid": "31955178",
"pubdate": "2020-01-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16477560;26897068;23467543;21810734;19139290;28470019;11403818",
"title": "A Case of Pulmonary Histoplasmosis Presenting with Hypercalcemia and Altered Mental Status in a Patient Following Allogeneic Hematopoietic Stem Cell Transplantation.",
"title_normalized": "a case of pulmonary histoplasmosis presenting with hypercalcemia and altered mental status in a patient following allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "US-009507513-2005USA002934",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "POSACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Dabigatran is a novel direct thrombin inhibitor that has proven effective in the prevention of vascular events in patients with nonvalvular atrial fibrillation. Not much is known about the clearance capability with extracorporeal techniques of dabigatran. This review showcases the pharmacokinetics and a perusal of the current literature regarding cases that involved the clearance of the drug in patients with normal renal function and end-stage renal disease. Renal replacement therapy represents a therapeutic option to eliminate dabigatran and decreased the risk of bleeding in patients undergoing emergent surgical procedures on dabigatran.",
"affiliations": "1Division of Nephrology and Hypertension, Allegheny General Hospital, Temple University School of Medicine, Pittsburgh, PA; and 2Division of Nephrology and Hypertension, University of Miami, Miller School of Medicine, Miami, FL.",
"authors": "Muddana|Neeharika|N|;Thuyanh|Culver|C|;Nayer|Ali|A|;Nashar|Khaled|K|;Ortega|Luis M|LM|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000082",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001281:Atrial Fibrillation; D000069604:Dabigatran; D005260:Female; D006801:Humans; D008657:Metabolic Clearance Rate; D006435:Renal Dialysis",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e485-8",
"pmc": null,
"pmid": "24987943",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Use of Extracorporeal Techniques in the Removal of Dabigatran.",
"title_normalized": "use of extracorporeal techniques in the removal of dabigatran"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-31672GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "The SARS-CoV-2 virus causing Coronavirus Disease 2019 (COVID-19) is a global pandemic with almost 30 million confirmed worldwide cases. Prothrombotic complications arising from those affected with severe symptoms have been reported in various medical journals. Currently, clinical trials are underway to address the questions regarding anticoagulation dosing strategies to prevent thrombosis for these critically ill patients. However, given the increasing use of therapeutic anticoagulation in patients admitted with COVID-19 to curtail this prothrombotic state, our institution has witnessed six cases of devastating intracranial hemorrhage as well as thrombosis leading to five fatalities and we examine their hospital course and anticoagulation used.",
"affiliations": "Loyola University Medical Center Department of Neurology USA. Electronic address: Fady.Mousa-Ibrahim001@lumc.edu.;Loyola University Medical Center Department of Internal Medicine Division of Hematology and Oncology, Loyola University Chicago Assistant Professor of Medicine USA. Electronic address: stephanie.berg@lumc.edu.;Loyola University Medical Center Department of Internal Medicine USA. Electronic address: Oluwatobi.Odetola@lumc.edu.;Loyola University Medical Center Department of Neurology USA. Electronic address: michael.teicher@lumc.edu.;Loyola University Medical Center Department of Neurology, Loyola University Chicago Professor of Neurology USA. Electronic address: sruland@lumc.edu.",
"authors": "Mousa-Ibrahim|Fady|F|;Berg|Stephanie|S|;Od TPDetola|Oluwatobi|O|;Teitcher|Michael|M|;Ruland|Sean|S|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2020.105428",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "30(1)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Anticoagulation; COVID-19; Intracranial hemorrhage; SARS-CoV-2",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D000086382:COVID-19; D017809:Fatal Outcome; D005260:Female; D005343:Fibrinolytic Agents; D006760:Hospitalization; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "105428",
"pmc": null,
"pmid": "33161349",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "32031570;32109013;32616524;32525049;32474093;32322398;32338827;32291094;32220112;32485418;32492712;32689643;32310017",
"title": "Intracranial Hemorrhage in Hospitalized SARS-CoV-2 Patients: A Case Series.",
"title_normalized": "intracranial hemorrhage in hospitalized sars cov 2 patients a case series"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202100605",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null... |
{
"abstract": "Reactivation of latent infection is considered to be the main mechanism underlying the development of Pneumocystis pneumonia in immunosuppressed patients. We retrospectively assessed the effects of prophylactic administration of sulfamethoxazole-trimethoprim on the development of P. pneumonia and airway colonization with P. jirovecii in patients undergoing examinations to diagnose or rule out P. pneumonia. Polymerase chain reaction was performed to detect P. jirovecii in bronchoalveolar lavage fluid or sputum of 60 consecutive patients between 2004 and 2012. No patients who received the prophylactic administration of sulfamethoxazole-trimethoprim (n = 10) developed P. pneumonia or demonstrated airway colonization with P. jirovecii, and none of the patients who developed P. pneumonia (n = 11) or showed colonization (n = 9) had received prophylactic treatment. Furthermore, 20 (40%) of 50 patients without prophylactic treatment showed positive results on the P. jirovecii DNA polymerase chain reaction, but all 10 patients who had prophylactic treatment showed negative results (Fisher's exact test, P = 0.02). Therefore, the prophylactic administration of sulfamethoxazole-trimethoprim has potential to be effective in preventing P. pneumonia as well as eliminating airway colonization with P. jirovecii. Further studies targeting large cohorts of patients with a variety of underlying diseases are required to develop recommendations regarding the prophylactic administration of sulfamethoxazole-trimethoprim.",
"affiliations": "Department of Respiratory Medicine, Oita University Hospital.",
"authors": "Kushima|Hisako|H|;Ishii|Hiroshi|H|;Tokimatsu|Issei|I|;Umeki|Kenji|K|;Sato|Takako|T|;Kadota|Jun-Ichi|J|",
"chemical_list": "D000935:Antifungal Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Japan",
"delete": false,
"doi": "10.7883/yoken.JJID.2014.546",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6304",
"issue": "69(3)",
"journal": "Japanese journal of infectious diseases",
"keywords": null,
"medline_ta": "Jpn J Infect Dis",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D016867:Immunocompromised Host; D008168:Lung; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D065129:Pre-Exposure Prophylaxis; D012189:Retrospective Studies; D013183:Sputum; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "100893704",
"other_id": null,
"pages": "252-5",
"pmc": null,
"pmid": "26255727",
"pubdate": "2016-05-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effects of Sulfamethoxazole-Trimethoprim on Airway Colonization with Pneumocystis jirovecii.",
"title_normalized": "effects of sulfamethoxazole trimethoprim on airway colonization with pneumocystis jirovecii"
} | [
{
"companynumb": "JP-JNJFOC-20160611181",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum.\n\n\nMETHODS\nHIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated.\n\n\nRESULTS\nEighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60-.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing.\n\n\nCONCLUSIONS\nOverall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctrough was reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy.\n\n\nBACKGROUND\nNCT00825929 and NCT000422890.",
"affiliations": "Department of Pharmacy.;UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences & School of Medicine, University of California San Diego.;Department of Pharmacy Department of Pharmacology and Toxicology, Radboud university medical center, Nijmegen.;Center for Biostatistics in AIDS Research, Harvard School of Public Health.;Maternal Child and Adolescent/Adult Center, University of Southern California School of Medicine, Los Angeles.;Department of Infectious Diseases, Hospital Universitario Virgen de las Nieves Granada, Spain.;Chelsea and Westminster Hospital.;Imperial College Healthcare NHS Trust, London, United Kingdom.;HIV/AIDS Research Department, Irmandade da Santa Casa de Misericordia de Porto Alegre, Brazil.;Boston Children's Hospital, Harvard Medical School.;Department of Infectious Diseases, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.;Department of Infectious Diseases, Saint-Pierre University Hospital, Brussels, Belgium.;Department of Internal Medicine, St Elisabeth Ziekenhuis, Tilburg, The Netherlands.;Maternal, Adolescent, and Pediatric Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.;UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences & School of Medicine, University of California San Diego.;Department of Pharmacy.;Boston University School of Medicine, Massachusetts.",
"authors": "Colbers|Angela|A|;Best|Brookie|B|;Schalkwijk|Stein|S|;Wang|Jiajia|J|;Stek|Alice|A|;Hidalgo Tenorio|Carmen|C|;Hawkins|David|D|;Taylor|Graham|G|;Kreitchmann|Regis|R|;Burchett|Sandra|S|;Haberl|Annette|A|;Kabeya|Kabamba|K|;van Kasteren|Marjo|M|;Smith|Elizabeth|E|;Capparelli|Edmund|E|;Burger|David|D|;Mirochnick|Mark|M|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/civ587",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "61(10)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HIV; MTCT; maraviroc; pharmacokinetics; pregnancy",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D001774:Blood Chemical Analysis; D003510:Cyclohexanes; D005060:Europe; D005260:Female; D015658:HIV Infections; D006801:Humans; D000077592:Maraviroc; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D014230:Triazoles; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1582-9",
"pmc": null,
"pmid": "26202768",
"pubdate": "2015-11-15",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11590515;11800526;14982771;16176115;16988514;17825649;18532888;20696881;21383098;22174038;22515555;23295922;23535879;23676668;23945605;24566097;25425722",
"title": "Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women.",
"title_normalized": "maraviroc pharmacokinetics in hiv 1 infected pregnant women"
} | [
{
"companynumb": "NL-VIIV HEALTHCARE LIMITED-NL2015GSK174851",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MARAVIROC"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nTo research an efficient treatment for the management of bisphosphonate-associated osteonecrosis.\n\n\nBACKGROUND\nNecrosis of the jawbone has recently been described in association with systemic bisphosphonate therapy with drugs including zoledronic acid, pamidronate, and alendronate. The extent and clinical characteristics of bisphosphonate-associated osteonecrosis (BON) of the jaw are extremely variable, and range from the presence of fistulae in the oral mucosa or orofacial tissues, to large exposed areas of necrotic bone within the oral cavity. Clinical signs and symptoms commonly reported include pain, swelling, the presence of pus, loose teeth, ill-fitting dentures, and paresthesias of the inferior alveolar nerve when the necrosis affects the mandible. Fractures have also been reported. The treatment of BON of the jaw is still controversial since no therapy has proven to be efficacious as shown by the literature on the subject.\n\n\nMETHODS\nIn this study we report results achieved with 28 patients affected by BON of the jaw, who received treatment with the Nd:YAG laser alone or in combination with conventional medical or surgical treatment. Clinical variables such as severity of symptoms, presence of pus, and closure of mucosal flaps before and after therapy were evaluated to establish the effectiveness of laser irradiation. The 28 patients with BON were subdivided into four groups: eight patients were treated with medical therapy only (antibiotics with or without antimycotics and/or antiseptic rinses), six patients were treated with medical and surgical therapy (necrotic bone removal and bone curettage), six patients were treated with medical therapy associated with laser biostimulation, and eight patients were treated with medical therapy associated with both surgical therapy and laser biostimulation.\n\n\nRESULTS\nOf the 14 patients who underwent laser biostimulation, nine reported complete clinical success (no pain, symptoms of infection, or exposed bone or draining fistulas), and three improved their symptomatology only, with a follow-up of between 4 and 7 mo.\n\n\nCONCLUSIONS\nWhile the results reported in this study are not conclusive, they indicate that laser therapy has potential to improve management of BON.",
"affiliations": "Unit of Oral Pathology and Medicine, Section of Dentistry, Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Parma, Italy. paolo.vescovi@unipr.it",
"authors": "Vescovi|Paolo|P|;Merigo|Elisabetta|E|;Manfredi|Maddalena|M|;Meleti|Marco|M|;Fornaini|Carlo|C|;Bonanini|Mauro|M|;Rocca|Jean Paul|JP|;Nammour|Samir|S|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "United States",
"delete": false,
"doi": "10.1089/pho.2007.2181",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1549-5418",
"issue": "26(1)",
"journal": "Photomedicine and laser surgery",
"keywords": null,
"medline_ta": "Photomed Laser Surg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D015331:Cohort Studies; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007568:Jaw; D028022:Low-Level Light Therapy; D008297:Male; D008875:Middle Aged; D010020:Osteonecrosis; D016896:Treatment Outcome",
"nlm_unique_id": "101222340",
"other_id": null,
"pages": "37-46",
"pmc": null,
"pmid": "18248160",
"pubdate": "2008-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nd:YAG laser biostimulation in the treatment of bisphosphonate-associated osteonecrosis of the jaw: clinical experience in 28 cases.",
"title_normalized": "nd yag laser biostimulation in the treatment of bisphosphonate associated osteonecrosis of the jaw clinical experience in 28 cases"
} | [
{
"companynumb": "IT-PFIZER INC-19055",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
"drugadditional": null,
... |
{
"abstract": "All antipsychotics are associated with extrapyramidal symptoms (EPS). These can present as dysphagia, esophageal dysmotility, or aspiration, all of which may not be recognized as EPS.\nA 62-year-old with schizophrenia, prescribed olanzapine 5 mg daily, presented agitated and endorsed difficulty swallowing. Speech therapy suggested her complaints were related to either reflux or dysmotility. Esophageal manometry showed her lower esophageal sphincter was not fully relaxing, and identified an esophagogastric junction outflow obstruction. Despite therapeutic dilation, oral intake remained poor. Following an increase in olanzapine, she developed EPS, her dysphagia worsened, and she was choking on food. Following a switch to aripiprazole her EPS and appetite improved, and she ceased complaining of dysphagia.\nDysphagia has been reported with first- and second-generation antipsychotics. A review of the second-generation antipsychotic literature identified case reports of dysphagia with clozapine (n = 5), risperidone (n = 5), olanzapine (n = 2), quetiapine (n = 2), aripiprazole (n = 1), and paliperidone (n = 1). Postulated mechanisms of antipsychotic-induced dysphagia include that it may be an extrapyramidal adverse reaction or related to anticholinergic effects of antipsychotics. Management of dysphagia includes discontinuing the antipsychotic, reducing the dose, dividing the dose, or switching to another antipsychotic. Complications of dysphagia include airway obstruction (eg, choking, asphyxia), aspiration pneumonia, and weight loss. Additional complications include dehydration, malnutrition, and nonadherence to oral medications.\nIt is important to recognize symptoms of dysphagia and esophageal dysmotility in antipsychotic-treated patients. Intervention is necessary to prevent complications.",
"affiliations": "Clinical Pharmacy Specialist-Psychiatry, Virginia Commonwealth University Health System, Richmond, Virginia, ericka.crouse@vcuhealth.org.;Clinical Pharmacist-Psychiatry, Morton Plant North Bay Hospital, BayCare Health System, New Port Richey, Florida.;PGY-2 Psychiatric Pharmacy Resident, Virginia Commonwealth University Health System, Richmond, Virginia.;PGY-3 Psychiatry Resident Physician, Virginia Commonwealth University Health System, Richmond, Virginia.",
"authors": "Crouse|Ericka L|EL|0000-0003-0732-0093;Alastanos|Jennifer N|JN|0000-0003-3578-8427;Bozymski|Kevin M|KM|0000-0002-6505-8719;Toscano|Robert A|RA|0000-0001-5696-2186",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.9740/mhc.2017.03.056",
"fulltext": "\n==== Front\nMent Health ClinMent Health ClinmhclThe Mental Health Clinician2168-9709College of Psychiatric & Neurologic Pharmacists 10.9740/mhc.2017.03.056mhcl-07-02-09Geropsych UpdateDysphagia with second-generation antipsychotics: A case report and review of the literature http://orcid.org/0000-0003-0732-0093Crouse Ericka L. PharmD, BCPP, CGP, FASHP1http://orcid.org/0000-0003-3578-8427Alastanos Jennifer N. PharmD, BCPP2http://orcid.org/0000-0002-6505-8719Bozymski Kevin M. PharmD, BCPS3http://orcid.org/0000-0001-5696-2186Toscano Robert A. DO4\n1 Clinical Pharmacy Specialist–Psychiatry, Virginia Commonwealth University Health System, Richmond, Virginia, ericka.crouse@vcuhealth.org\n\n2 Clinical Pharmacist–Psychiatry, Morton Plant North Bay Hospital, BayCare Health System, New Port Richey, Florida\n\n3 PGY-2 Psychiatric Pharmacy Resident, Virginia Commonwealth University Health System, Richmond, Virginia\n\n4 PGY-3 Psychiatry Resident Physician, Virginia Commonwealth University Health System, Richmond, Virginia\n3 2017 23 3 2018 7 2 56 64 © 2017 CPNP.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nAll antipsychotics are associated with extrapyramidal symptoms (EPS). These can present as dysphagia, esophageal dysmotility, or aspiration, all of which may not be recognized as EPS.\n\nCase Report:\nA 62-year-old with schizophrenia, prescribed olanzapine 5 mg daily, presented agitated and endorsed difficulty swallowing. Speech therapy suggested her complaints were related to either reflux or dysmotility. Esophageal manometry showed her lower esophageal sphincter was not fully relaxing, and identified an esophagogastric junction outflow obstruction. Despite therapeutic dilation, oral intake remained poor. Following an increase in olanzapine, she developed EPS, her dysphagia worsened, and she was choking on food. Following a switch to aripiprazole her EPS and appetite improved, and she ceased complaining of dysphagia.\n\nDiscussion:\nDysphagia has been reported with first- and second-generation antipsychotics. A review of the second-generation antipsychotic literature identified case reports of dysphagia with clozapine (n = 5), risperidone (n = 5), olanzapine (n = 2), quetiapine (n = 2), aripiprazole (n = 1), and paliperidone (n = 1). Postulated mechanisms of antipsychotic-induced dysphagia include that it may be an extrapyramidal adverse reaction or related to anticholinergic effects of antipsychotics. Management of dysphagia includes discontinuing the antipsychotic, reducing the dose, dividing the dose, or switching to another antipsychotic. Complications of dysphagia include airway obstruction (eg, choking, asphyxia), aspiration pneumonia, and weight loss. Additional complications include dehydration, malnutrition, and nonadherence to oral medications.\n\nConclusion:\nIt is important to recognize symptoms of dysphagia and esophageal dysmotility in antipsychotic-treated patients. Intervention is necessary to prevent complications.\n\nKeywords\ndysphagiaantipsychoticolanzapineesophageal dysmotility\n==== Body\nBackground\nExtrapyramidal symptoms (EPS) are known adverse effects of antipsychotics. These can present as dysphagia, esophageal dysmotility, or aspiration, which may not be recognized as EPS. If untreated it can increase the risk for aspiration pneumonia, airway obstruction (eg, choking), or metabolic abnormalities that result from failure to thrive. Historical causes of sudden death in psychiatric hospitals included asphyxiation or choking. In April 2005 a warning was added to atypical antipsychotics regarding increased risk of death in elderly patients with dementia, which was updated in June 2008 to include all antipsychotics.1-3\n\nA patient with a history of schizophrenia presenting with complaints of swallowing difficulty is discussed. Additionally, a literature review summarizing case reports of antipsychotic-induced dysphagia is presented along with potential mechanisms of this adverse effect.\n\nCase Report\nA 62-year-old African American woman with a history of schizophrenia, hypertension, hypothyroidism, and gastroesophageal reflux disease (GERD) was admitted to the geriatric psychiatry service secondary to increased agitation and yelling, with a chief complaint of pain secondary to her GERD. Earlier in the day, she presented to an outside gastroenterology office without a scheduled appointment and became very disruptive when she could not be seen, shouting she could not swallow. She was subsequently referred to the emergency department for psychiatric evaluation. She made illogical statements in the emergency department, including that her jaw was slipping up and down, and that God was speaking to her about healing her. She continued to perseverate on her GERD. She reported recently stopping her psychotropic medications secondary to difficult, painful swallowing. Her husband confirmed that she was unable to swallow because of tightness in her esophagus, resulting in recent weight loss.\n\nHer oral medications on admission included olanzapine orally disintegrating tablets (ODT) 5 mg at bedtime, escitalopram 10 mg daily, lorazepam 0.5 mg three times daily, mirtazapine 30 mg at bedtime, temazepam 7.5 mg at bedtime as needed (PRN) for insomnia, levothyroxine 25 mcg daily, metoprolol tartrate 25 mg every 12 hours, potassium chloride 10 mEq daily, pantoprazole 40 mg daily, and losartan 25 mg daily. She had previously been treated with risperidone 3 mg two times daily, but this was changed to olanzapine ODT during a recent hospitalization 1 month prior to this admission. Her nonpsychiatric medications were continued along with olanzapine ODT 5 mg at bedtime. Because of her hyperreligious presentation along with agitation, her mirtazapine and escitalopram were discontinued.\n\nHer labs on admission were significant for hypokalemia (2.9 mmol/L) and mild thrombocytopenia (platelet count = 124 × 109/L). Her urinalysis and urine drug screen were both negative. Her thyroid-stimulating hormone was within normal limits at 1.2 milli–international units per liter.\n\nOn day 2, speech therapy suggested her complaints of difficulty swallowing were consistent with esophageal dysphagia related to either reflux or dysmotility. An esophagram from 1 year prior showed marked esophageal dysmotility while being treated with risperidone. Speech therapy recommended a full liquid diet, aspiration precautions, and a gastrointestinal (GI) consult. On day 4, her esophageal manometry showed her lower esophageal sphincter was not fully relaxing and identified an esophagogastric junction outflow obstruction.\n\nBecause of her continued delusions and behaviors she was continued on olanzapine ODT 5 mg at bedtime for 1 week. During this week she also received an average of 2 to 4 mg of intramuscular (IM) haloperidol PRN. Her intake remained poor, and she required intravenous fluids for tachycardia and dehydration (blood urea nitrogen = 14 mg/dL; serum creatinine = 0.7 mg/dL). On day 8, her olanzapine ODT was increased to 5 mg two times daily, and PRN was changed to olanzapine ODT and olanzapine IM. That day, she received a total of 12.5 mg of olanzapine, including PRNs. Oral benztropine 1 mg twice daily was also added to her regimen. On day 9, she began refusing her olanzapine secondary to choking. She continued to intermittently refuse her olanzapine and other medications during the next 2 days. During this time, she regularly ate 0% of her meals. A therapeutic dilation procedure was attempted during endoscopy on day 10 to improve her esophagogastric junction outflow obstruction.\n\nShe was adherent to her levothyroxine, pantoprazole, and docusate, but continued to refuse her oral olanzapine days 12 to 14. She did receive PRN olanzapine 2.5 mg IM during this time per involuntary administration order (maximum of 5 mg IM per day). Following the therapeutic dilation of her esophagus, along with her intermittent refusal of olanzapine, her intake increased to approximately 25% of meals; however, she continued to complain of difficulty swallowing. Her labs remained within normal limits. On days 15 and 16 she took 10 mg/d olanzapine. On day 17 she received olanzapine 2.5 mg IM in the morning and 10 mg orally at bedtime. Because of her continued poor intake she required 2 more intravenous fluid boluses for dehydration. She underwent a repeat manometry, which showed little change from the previous study. The GI service suggested the next step may be to consider Botox injections or surgical intervention. Following the increased dose of olanzapine, she was noted to have increased EPS, including parkinsonism, a shuffling gait, and a stooped/hunched posture. She continued to perseverate on her inability to swallow. The care partner working with her expressed concerns that she was choking on her food.\n\nOn day 19 the decision was made to switch her olanzapine to aripiprazole 10 mg daily secondary to lack of improvement in psychotic symptoms and increased adverse effects to olanzapine. During the next 48 hours her EPS improved, and she began eating 100% of meals, which remained consistent until discharge on day 25. Her repeat upper GI series on day 22 showed no esophageal obstruction lesions, no evidence of obstruction, and that she passed her barium swallow without difficulty. Her labs returned to baseline (blood urea nitrogen = 7 mg/dL; serum creatinine = 0.6 mg/dL). Speech therapy had been advancing her diet, and she tolerated solids without pain or any difficulty swallowing. Prior to discharge she ceased complaining of dysphagia. She was ultimately discharged on aripiprazole long-acting injection 400 mg monthly, with a 2-week oral overlap of aripiprazole 10 mg daily.\n\nDiscussion\nThis case describes a patient with schizophrenia who continued to complain of difficulty swallowing and the extensive workup performed trying to identify the cause. In retrospect, it appeared her dysphagia worsened with the change from risperidone to olanzapine a few weeks prior to admission. Her oral intake decreased on admission after reinitiation of her olanzapine and worsened with increased dosage. Although structural changes may have been related to her dysphagia, resolution of her dysphagia and EPS was not seen until her antipsychotic was changed from olanzapine to aripiprazole.\n\nDysphagia has been associated with many first-generation antipsychotics, including loxapine, fluphenazine, trifluoperazine, thioridazine, chlorpromazine, and haloperidol, in patients ages 38 to 79 years.1,4 Esophageal dysmotility with second-generation antipsychotics in the general adult population has been detailed in multiple case reports (Table),5-17 but less information is available regarding the geriatric population. Three cases were described in older adults (>60 years),5-7 and an additional 11 in the younger adult population. Our review of the literature with second-generation antipsychotics identified case reports with clozapine (n = 5), risperidone (n = 5), olanzapine (n = 2), quetiapine (n = 2), aripiprazole (n = 1), and paliperidone (n = 1). Four citations were not included in the Table because dysphagia was related to neuroleptic malignant syndrome (olanzapine and risperidone [n = 1]),18 angioedema (risperidone [n = 1]),19 scleroderma (haloperidol decanoate [n = 1]),20 and haloperidol rather than risperidone (n = 1).21 The 3 reports in patients older than 60 years are detailed below.\n\nTABLE: Case reports of dysphagia with second-generation antipsychotics\n\nMaddalena et al5 described a case of clozapine-induced dysphagia in a 64-year-old man with chronic schizophrenia managed on clozapine for 30 years. The patient had suffered from swallowing difficulties 4 years prior to this admission while on clozapine 375 mg daily. The decision was therefore made to slowly taper clozapine to 300 mg daily. Peristalsis recovery and improved esophageal motility was shown on repeat manometry 6 weeks later.5\n\nKohen and Lester6 described a case of quetiapine-induced dysphagia in a 66-year-old woman with a history of bipolar disorder managed on quetiapine 200 mg daily for several months who was admitted to an inpatient psychiatric facility for worsening depressive symptoms. She did not exhibit any other EPS. Quetiapine was tapered off, and 1 month later a repeat modified barium swallow demonstrated improvement.6\n\nFinally, Stewart7 described a case of risperidone-induced dysphagia in a 76-year-old man with history of Alzheimer dementia. Three months after his risperidone dose was increased by 0.5 mg/d, he experienced new difficulties with choking on food and weight loss of 12 pounds. Because of the new onset of swallowing difficulties, risperidone was discontinued and olanzapine 2.5 mg at bedtime was initiated. A repeat modified barium swallow 6 months later revealed oral and pharyngeal phases had completely normalized.7\n\nBecause there are minimal reports of this side effect published in medical journals, the Web site eHealthMe.com was searched for additional reports. This Web site attempts to capture real-word use of medications and identify rare or infrequent adverse effects. The Web site analyzes data from the US Food and Drug Administration along with social media. Patients and providers can also report adverse effects to the Web site. The percentage of patients experiencing an adverse effect is based on the number of reports of that specific adverse effect divided by the total number of adverse effect reports for that drug. Each second-generation antipsychotic was searched both as brand and generic, along with the keyword dysphagia. For example, as of September 16, 2016, a total of 14 579 patients have reported an adverse effect with olanzapine, and 1.26% (n = 183) reported dysphagia.22\nDysphagia was reported as an adverse event with aripiprazole, asenapine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone.22 Rates of reporting dysphagia ranged from 0.43% of adverse effect reports to 2.08% of adverse effect reports.22 Most reports occurred within the first 6 months of treatment, with the highest frequency occurring within the first month of therapy. There are some limitations to using this Web site as a reference, including the facts that the source of each report is unknown, dosage is not reported, and it is unknown if any reports are duplicated. The Web site does report top concurrently used medications, but it does not confirm which is more likely to be the causative agent of an adverse effect.\n\nPostulated mechanisms of antipsychotic-induced dysphagia include that it may be an extrapyramidal adverse reaction, because dopamine blockade can cause dysphagia or laryngospasm.4,23 Some patients may experience dysphagia in combination with other EPS symptoms, whereas with others dysphagia may be the only EPS experienced.4 In this case, dysphagia was present with low-dose olanzapine 5 mg, and additional EPS were seen when the dosage was increased to 10 mg/d. Similarly, patients with Parkinson disease may develop oropharyngeal dysphasia or achalasia.24 Achalasia makes it harder for food to move from the esophagus to the stomach. In patients with achalasia, the lower esophageal sphincter does not relax well and esophageal peristalsis may be reduced.25 This patient's original esophageal manometry showed her lower esophageal sphincter was not fully relaxing. On the contrary, the anticholinergic effects of antipsychotics can impair the coordinated action of swallowing by weakening the parasympathetic signals, which are transmitted by muscarinic acetylcholine receptors.23 Dysphagia may also be a result of the concurrent dopamine blocking activity and anticholinergic effects.23 This patient was treated with olanzapine, one of the most anticholinergic second-generation agents, in combination with benztropine. Lastly, it has been postulated that dysphagia may be related to inhibition of the cough reflex, gag reflex, or swallow reflex.1\n\nMedical causes of dysphagia include tachypnea secondary to chronic obstructive pulmonary disease or severe GERD.4 Reduced esophageal motility in elderly patients with GERD can lead to delayed esophageal clearance and increased exposure to esophageal acid, and therefore result in dysphagia.24 Other at-risk populations include individuals with neurologic degenerative disease, dementia, stroke, Parkinson disease, and myasthenia gravis.23,24 Furthermore, elderly patients older than 75 years may be at increased risk secondary to muscle atrophy, structural changes in the oropharynx, reduced esophageal peristalsis, or cognitive impairment.6,23,24 This patient had severe GERD complaints, which were most likely worsened by esophageal dysmotility contributing to her dysphagia. Continuing pantoprazole was an important part of her treatment plan.\n\nComplications of dysphagia include airway obstruction (eg, choking, asphyxia), aspiration pneumonia, and weight loss.4,23 Additional complications include dehydration, malnutrition, and, similar to this case, nonadherence to oral medications.23 Often antipsychotics with strong antihistamine properties, like olanzapine, are chosen in a certain subset of patients because of the potentially beneficial side effect of appetite stimulation. In the event that oral intake is reduced or weight loss occurs, it is important to consider evaluating for medication-induced dysphagia.\n\nManagement of dysphagia includes discontinuing the antipsychotic, reducing the dose, dividing the dose, or switching to another antipsychotic.4-8,10-17 In this case, symptoms improved with the switch from olanzapine to aripiprazole.\n\nConclusion\nAlthough this article focuses primarily on second-generation antipsychotics, dysphagia can occur with any antipsychotic treatment. Although the elderly may be more susceptible to the complications associated with dysphagia, this adverse effect can impact any age group treated with antipsychotics. Elderly patients with comorbid GERD may be at even higher risk of developing dysphagia. It is important to recognize the symptoms of dysphagia and esophageal dysmotility in antipsychotic-treated patients. Intervention is necessary to reduce the risk of aspiration pneumonia; metabolic derangements secondary to reduced nutrition or dehydration; and choking or sudden death secondary to airway obstruction.\n==== Refs\nReferences\n1 \nFioritti A ,\nGiaccotto L ,\nMelega V .\n \nChoking incidents among psychiatric patients: retrospective analysis of thirty-one cases from west Bologna psychiatric wards .\nCan J Psychiatry .\n1997 ;\n42 \n5 :\n515 -\n50 .\nPubMed PMID: 9220116 .\n9220116 \n2 \nOlanzapine prescribing information [Internet] .\nIndianapolis (IN): Eli Lily and Co .\n2016 \nJune [cited 2016 Aug 17]. Available from: http://www.dailymed.nlm.nih.gov \n\n3 \nSafety alerts [Internet] .\nSilver Spring (MD): US Food and Drug Administration .\n2008 \nJune [cited 2016 Dec 15]. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm110212.htm \n\n4 \nDziewas R ,\nWarnecke T ,\nSchnabel M ,\nRitter M ,\nNabavi DG ,\nSchilling M , \nNeuroleptic-induced dysphagia: case report and literature review .\nDysphagia .\n2007 ;\n22 \n1 :\n63 -\n7 .\nDOI: 10.1007/s00455-006-9032-9. PubMed PMID: 17024549 .\n17024549 \n5 \nMaddalena AS ,\nFox M ,\nHofmann M ,\nHock C .\n \nEsophageal dysfunction on psychotropic medication: a case report and literature review .\nPharmacopsychiatry .\n2004 ;\n37 \n3 :\n134 -\n8 .\nDOI: 10.1055/s-2004-818993. PubMed PMID: 15138897 .\n15138897 \n6 \nKohen I ,\nLester P .\n \nQuetiapine-associated dysphagia .\nWorld J Biol Psychiatry .\n2009 ;\n10 \n4 Pt 2 :\n623 -\n5 .\nDOI: 10.1080/15622970802176495. PubMed PMID: 18615368 .\n18615368 \n7 \nStewart JT .\n \nDysphagia associated with risperidone therapy .\nDysphagia .\n2003 ;\n18 \n4 :\n274 -\n5 .\nDOI: 10.1007/s00455-003-0006-x. PubMed PMID: 14571332 .\n14571332 \n8 \nLin TW ,\nLee BS ,\nLiao YC ,\nChiu NY ,\nHsu WY .\n \nHigh dosage of aripiprazole-induced dysphagia .\nInt J Eat Disord .\n2011 ;\n45 \n2 :\n305 -\n6 .\nDOI: 10.1002/eat.20934. PubMed PMID: 21541978 .\n21541978 \n9 \nPearlman C .\n \nClozapine, nocturnal sialorrhea, and choking .\nJ Clin Psychopharmacol .\n1994 ;\n14 \n4 :\n283 \nDOI: 10.1097/00004714-199408000-00013. PubMed PMID: 7962689 .\n7962689 \n10 \nMcCarthy RH ,\nTerkelsen KG .\n \nEsophageal dysfunction in two patients after clozapine treatment .\nJ Clin Psychopharmacol .\n1994 ;\n14 \n4 :\n281 -\n3 .\nDOI: 10.1097/00004714-199408000-00012. PubMed PMID: 7962688 .\n7962688 \n11 \nSagar R ,\nVarghese ST ,\nBalhara YP .\n \nDysphagia due to olanzapine, an antipsychotic medication .\nIndian J Gastroenterol .\n2005 ;\n24 \n1 :\n37 -\n8 .\nPubMed PMID: 15778537 .\n\n12 \nMendhekar DN ,\nAgarwal A .\n \nPaliperidone-induced dystonic dysphagia .\nJ Neuropsychiatry Clin Neurosci .\n2010 ;\n22 \n4 :\n451 -\nv.e37 \n-451.e37. DOI: 10.1176/appi.neuropsych.22.4.451-v.e37. PubMed PMID: 21037154 .\n\n13 \nArmstrong D ,\nAhuja N ,\nLloyd AJ .\n \nQuetiapine-related dysphagia .\nPsychosomatics .\n2008 ;\n49 \n5 :\n450 -\n2 .\nDOI: 10.1176/appi.psy.49.5.450-a. PubMed PMID: 18794516 .\n\n14 \nBrahm NC ,\nFast GA ,\nBrown RC .\n \nRisperidone and dysphagia in a developmentally disabled woman .\nPrim Care Companion J Clin Psychiatry .\n2007 ;\n9 \n4 :\n315 -\n6 .\nPubMed PMID: 17934560 .\n17934560 \n15 \nDuggal HS ,\nMendhekar DN .\n \nRisperidone-induced tardive pharyngeal dystonia presenting with persistent Dysphagia: a case report .\nPrim Care Companion J Clin Psychiatry .\n2008 ;\n10 \n2 :\n161 -\n2 .\nDOI: 10.4088/PCC.v10n0213b. PubMed PMID: 18458730 .\n18458730 \n16 \nNair S ,\nSaeed O ,\nShahab H ,\nSedky K ,\nGarver D ,\nLippmann S .\n \nSudden dysphagia with uvular enlargement following the initiation of risperidone which responded to benztropine: was this an extrapyramidal side effect? \nGen Hosp Psychiatry .\n2001 ;\n23 \n4 :\n231 -\n2 .\nDOI: 10.1016/S0163-8343(01)00145-1. PubMed PMID: 11569473 .\n11569473 \n17 \nVarghese ST ,\nBalhara YP ,\nGeorge SA ,\nSagar R .\n \nRisperidone and dysphagia .\nJ Postgrad Med .\n2006 ;\n52 \n4 :\n327 -\n8 .\nPubMed PMID: 17102565 .\n17102565 \n18 \nYu M ,\nTadin D ,\nConrad EJ ,\nLopez FA .\n \nClinical case of the month: a 48-year-old man with fever and abdominal pain of one day duration .\nJ La State Med Soc .\n2015 ;\n167 \n5 :\n237 -\n40 .\nPubMed PMID: 27159603 .\n27159603 \n19 \nGüneş F ,\nBatgi H ,\nAkbal A ,\nCanatan T .\n \nAngioedema--an unusual side effect of risperidone injection .\nClin Toxicol (Phila) .\n2013 ;\n51 \n2 :\n122 -\n3 .\nDOI: 10.3109/15563650.2013.765010. PubMed PMID: 23336748 .\n23336748 \n20 \nShibley H ,\nPelic C ,\nKahn DA .\n \nA case of paranoid schizophrenia complicated by scleroderma with associated esophageal dysmotility .\nJ Psychiatr Pract .\n2008 ;\n14 \n2 :\n126 -\n30 .\nDOI: 10.1097/01.pra.0000314321.32910.34. PubMed PMID: 18360200 .\n18360200 \n21 \nLee JC ,\nTakeshita J .\n \nAntipsychotic-induced dysphagia: a case report .\nPrim Care Companion CNS Disord .\n2015 ;\n17 \n5 \nDOI: 10.4088/PCC.15IO1792. PubMed PMID: 26835168 .\n\n22 \neHealthMe [Internet] .\nMountain View (CA): eHealthMe \n[cited \n2016 \nAug 9 and Sept 16]. Available from: http://www.ehealthme.com \n\n23 \nVisser HK ,\nWigington JL ,\nKeltner NL ,\nKowalski PC .\n \nBiological perspectives: choking and antipsychotics: is this a significant concern? \nPerspect Psychiatr Care .\n2014 ;\n50 \n2 :\n79 -\n82 .\nDOI: 10.1111/ppc.12062. PubMed PMID: 24606560 .\n24606560 \n24 \nSchnoll-Sussman F ,\nKatz PO .\n \nManaging esophageal dysphagia in the elderly .\nCurr Treat Options Gastroenterol .\n2016 ;\n14 \n3 :\n315 -\n26 .\nDOI: 10.1007/s11938-016-0102-2. PubMed PMID: 27423892 .\n27423892 \n25 \nMedlinePlus [Internet] .\nBethesda (MD) :\nNational Library of Medicine \n[cited \n2016 \nOct 18]. Available from: http://medlineplus.gov/ency/article/000267.htm\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2168-9709",
"issue": "7(2)",
"journal": "The mental health clinician",
"keywords": "antipsychotic; dysphagia; esophageal dysmotility; olanzapine",
"medline_ta": "Ment Health Clin",
"mesh_terms": null,
"nlm_unique_id": "101728585",
"other_id": null,
"pages": "56-64",
"pmc": null,
"pmid": "29955499",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "11569473;14571332;17934560;18360200;15138897;23336748;24606560;9220116;18458730;21541978;17024549;27423892;18615368;7962689;27159603;17102565;7962688;15778537;26835168;21037154;18794516",
"title": "Dysphagia with second-generation antipsychotics: A case report and review of the literature.",
"title_normalized": "dysphagia with second generation antipsychotics a case report and review of the literature"
} | [
{
"companynumb": "US-APOTEX-2021AP042828",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BENZTROPINE"
},
"drugadditional": null,
... |
{
"abstract": "We present the case of a 68-year-old man admitted to hospital with severe acute kidney injury secondary to statin-induced rhabdomyolysis. Five weeks previously, the patient started a course of clarithromycin for infection of a finger wound with Mycobacterium marinum. His current medications included simvastatin, which he continued along with clarithromycin. The severity of the acute kidney injury necessitated initial continuous venovenous haemofiltration followed by 12 haemodialysis sessions before a spontaneous improvement in renal function occurred. Statins are widely prescribed and we report this case to encourage increased vigilance in avoiding drug interactions known to increase the risk of statin-induced myopathy, including macrolide antibiotics, calcium channel antagonists and amiodarone. The authors would also like to highlight recent guidance on atorvastatin as the statin of choice in patients with chronic kidney disease, and of the need for dose adjustment in those with an estimated glomerular filtration rate less than 30 mLs/min/1.73 m².",
"affiliations": "Renal Department, Newcastle Upon Tyne Hospitals, Newcastle Upon Tyne, UK.;Renal Department, Newcastle Upon Tyne Hospitals, Newcastle Upon Tyne, UK.;Institute of Cellular Medicine, Newcastle Upon Tyne, UK.",
"authors": "Hill|Fay Joanne|FJ|;McCloskey|Sarah Jane|SJ|;Sheerin|Neil|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004977:Ethambutol; D019821:Simvastatin; D017291:Clarithromycin; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D004347:Drug Interactions; D004977:Ethambutol; D005383:Finger Injuries; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D006435:Renal Dialysis; D012206:Rhabdomyolysis; D012293:Rifampin; D019821:Simvastatin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26106178",
"pubdate": "2015-06-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16581329;18701534;21067805;24918167;25221728",
"title": "From a fish tank injury to hospital haemodialysis: the serious consequences of drug interactions.",
"title_normalized": "from a fish tank injury to hospital haemodialysis the serious consequences of drug interactions"
} | [
{
"companynumb": "GB-SA-2015SA127785",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Strongyloidiasis, due to infection with the nematode Strongyloides stercoralis, affects millions of people in the tropics and subtropics. Strongyloides has a unique auto-infective lifecycle such that it can persist in the human host for decades. In immunosuppressed patients, especially those on corticosteroids, potentially fatal disseminated strongyloidiasis can occur, often with concurrent secondary infections. Herein, we present two immunocompromised patients with severe strongyloidiasis who presented with pneumonia, hemoptysis, and sepsis. Both patients were immigrants from developing countries and had received prolonged courses of corticosteroids prior to admission. Patient 1 also presented with a diffuse abdominal rash; a skin biopsy showed multiple intradermal Strongyloides larvae. Patient 1 had concurrent pneumonic nocardiosis and bacteremia with Klebsiella pneumoniae and Enterococcus faecalis. Patient 2 had concurrent Aspergillus and Candida pneumonia and developed an Aerococcus meningitis. Both patients had negative serologic tests for Strongyloides; patient 2 manifested intermittent eosinophilia. In both patients, the diagnosis was afforded by bronchoscopy with lavage. The patients were successfully treated with broad-spectrum antibiotics and ivermectin. Patient 1 also received albendazole. Strongyloidiasis should be considered in the differential diagnosis of hemoptysis in immunocompromised patients with possible prior exposure to S. stercoralis.",
"affiliations": "Covenant Medical Group, Infectious Diseases, Division of Internal Medicine, Lubbock, TX 79410, USA. drprakashshrestha@gmail.com.;Texas Center for Infectious Diseases, San Antonio, TX 78223, USA. Sean.oneil@dshs.texas.gov.;Department of Medicine, Division of Infectious Diseases, University of Texas Health, San Antonio, TX 78229, USA. TaylorB4@uthscsa.edu.;Department of Pathology, University of Texas Health, San Antonio, TX 78229, USA. BodeOmoleye@uthscsa.edu.;Department of Medicine, Division of Infectious Diseases, University of Texas Health, San Antonio, TX 78229, USA. anstead@uthscsa.edu.",
"authors": "Shrestha|Prakash|P|;O'Neil|Sean E|SE|;Taylor|Barbara S|BS|;Bode-Omoleye|Olaoluwa|O|;Anstead|Gregory M|GM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/tropicalmed4010035",
"fulltext": "\n==== Front\nTrop Med Infect DisTrop Med Infect DistropicalmedTropical Medicine and Infectious Disease2414-6366MDPI 10.3390/tropicalmed4010035tropicalmed-04-00035Case ReportHemoptysis in the Immunocompromised Patient: Do Not Forget Strongyloidiasis Shrestha Prakash 1†O’Neil Sean E. 2†Taylor Barbara S. 3Bode-Omoleye Olaoluwa 4https://orcid.org/0000-0002-5473-9375Anstead Gregory M. 35*1 Covenant Medical Group, Infectious Diseases, Division of Internal Medicine, Lubbock, TX 79410, USA; drprakashshrestha@gmail.com2 Texas Center for Infectious Diseases, San Antonio, TX 78223, USA; Sean.oneil@dshs.texas.gov3 Department of Medicine, Division of Infectious Diseases, University of Texas Health, San Antonio, TX 78229, USA; TaylorB4@uthscsa.edu4 Department of Pathology, University of Texas Health, San Antonio, TX 78229, USA; BodeOmoleye@uthscsa.edu5 Medicine Service, Division of Infectious Diseases, South Texas Veterans Healthcare System, San Antonio, TX 78229, USA* Correspondence: anstead@uthscsa.edu; Tel.: +1-210-567-4666; Fax: +1-210-567-4670† These authors contributed equally to this work.\n\n12 2 2019 3 2019 4 1 3531 12 2018 29 1 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Strongyloidiasis, due to infection with the nematode Strongyloides stercoralis, affects millions of people in the tropics and subtropics. Strongyloides has a unique auto-infective lifecycle such that it can persist in the human host for decades. In immunosuppressed patients, especially those on corticosteroids, potentially fatal disseminated strongyloidiasis can occur, often with concurrent secondary infections. Herein, we present two immunocompromised patients with severe strongyloidiasis who presented with pneumonia, hemoptysis, and sepsis. Both patients were immigrants from developing countries and had received prolonged courses of corticosteroids prior to admission. Patient 1 also presented with a diffuse abdominal rash; a skin biopsy showed multiple intradermal Strongyloides larvae. Patient 1 had concurrent pneumonic nocardiosis and bacteremia with Klebsiella pneumoniae and Enterococcus faecalis. Patient 2 had concurrent Aspergillus and Candida pneumonia and developed an Aerococcus meningitis. Both patients had negative serologic tests for Strongyloides; patient 2 manifested intermittent eosinophilia. In both patients, the diagnosis was afforded by bronchoscopy with lavage. The patients were successfully treated with broad-spectrum antibiotics and ivermectin. Patient 1 also received albendazole. Strongyloidiasis should be considered in the differential diagnosis of hemoptysis in immunocompromised patients with possible prior exposure to S. stercoralis.\n\nstrongyloidiasisStrongyloides stercoralishemoptysiseosinophiliaivermectinalbendazolecorticosteroids\n==== Body\n1. Introduction\nAn estimated 370 million people in tropical and subtropical regions of the world are infected with the nematode Strongyloides stercoralis [1,2,3,4]. (For a map of endemic areas, see Siddiqui et al., 2010 [4]). In the United States, the highest rates of infection occur in immigrants, refugees, travelers, and military personnel who have been to endemic areas and in residents of the Southeastern USA [5,6,7,8].\n\nStrongyloides stercoralis differs from other common nematodes by its unique auto-infective lifecycle [9]. Human infection initially results from contact with soil contaminated with human feces containing the infective filariform larvae. The filariform larvae penetrate the skin or mucous membranes and migrate through the veins or lymphatics to the lungs. From there, the larvae migrate through capillaries into the alveoli, move up the trachea, are swallowed by the host, and then localize to the small intestine. There, the female worms mature and lay eggs, which hatch into rhabditiform larvae. Only female adult worms are present in chronic strongyloidiasis; subsequent reproduction occurs by parthenogenesis (the development of an embryo from an unfertilized ovum). Some of the larvae are passed in the stool and begin the external life cycle, while others develop into infective filariform larvae within the host and penetrate the intestinal mucosa and the skin, bypassing the respiratory tract, and establish themselves in the small intestine. By this autoinfection cycle, Strongyloides can multiply indefinitely within its host [3,10], and cases of strongyloidiasis have been noted as long as 75 years after leaving an endemic area [11].\n\n2. Case Presentations\n2.1. Case 1\nA 46-year old Asian male presented to the emergency department with recurrent hemoptysis. The patient had been diagnosed with dermatomyositis and IgM nephropathy 10 months prior to presentation, and was started on prednisone (50 mg/day; 0.9 mg/kg/day). In an attempt to limit corticosteroid exposure, two weeks after starting prednisone the patient was given azathioprine for two weeks, but he could not tolerate its adverse effects. As a result, he resumed high-dose prednisone (40 mg/day) up to the time of the current hospital admission.\n\nThe patient had presented a month prior to the current admission with a cough productive of clear sputum with streaks of bright red blood. A CT scan of the chest at that time showed interstitial thickening and a left lower lobe pulmonary nodule versus atelectasis. Bronchoscopy revealed no endobronchial lesions. Bronchoalveolar lavage fluid grew Candida albicans and usual respiratory flora. Serologic testing for infection with Coccidioides, Histoplasma, Strongyloides (IgG by ELISA, ARUP Laboratories, Salt Lake City, UT, USA), and Cryptococcus was all negative. An interferon-gamma release assay for the diagnosis of latent tuberculosis conducted one month prior to the current admission was indeterminate, and three sputa for acid-fast bacilli were negative by smear and culture. A urine culture grew Klebsiella pneumoniae and Escherichia coli. The hemoptysis resolved and the patient was discharged on ciprofloxacin for the urinary tract infection. The patient then presented with hemoptysis of three days duration, associated with fever and chills. He also noticed a rash on his abdomen two days prior to presentation.\n\nThe patient was born in Laos and had spent three years in a refugee camp in Thailand before emigrating to the United States 25 years ago. He had lived primarily in San Antonio, Texas, but had travelled to New York City multiple times to work at a landfill. The patient had a 25 pack-year history of smoking, but no history of incarceration or alcohol or recreational drug use.\n\nOn presentation, the patient was lethargic and appeared unwell. Vital signs were: Temperature 38.4 °C, blood pressure 70/40 mm Hg, pulse 125/min, and respiratory rate 20 breaths per minute. On exam, the patient had bilateral coarse crackles, diffuse abdominal tenderness, and a purpuric rash on the anterior trunk extending to the flanks, suprapubic area, groin, and upper thighs (Figure 1). An electrocardiogram showed atrial fibrillation with rapid ventricular response.\n\nInitial laboratory results were: White cell count 19.5 K/µL (reference range (RR) 3.4–10.4 K/µL) with 51% bands, 38% neutrophils, 3% lymphocytes, 1% eosinophils; hemoglobin 11.8 g/dL (RR 12.8-17.1); platelets 214 K/µL (RR 140-377 K/µL); creatinine 1.2 mg/dL (RR 0.6–1.3 mg/dL), bilirubin 1.2 mg/dL (RR 0.2–1.2 mg/dL); alanine aminotransferase 71 IU/L (RR <46 IU/L); aspartate aminotransferase 47 IU/L (RR <36 IU/L) and alkaline phosphatase 124 IU/L (RR 45–117 IU/L). A CT scan of the chest showed interval development of diffuse ground glass opacities (likely alveolar hemorrhage), interlobular septal thickening, and a single 9 mm right middle lobe cavitary lesion (Figure 2A,B). The patient was admitted to the medical intensive care unit with septic shock. He was started on cefepime, vancomycin, and metronidazole. The next day he required intubation for hypoxemic respiratory failure. Bronchoscopy showed a normal airway with fresh and old blood present, but without an obvious source of bleeding. The differential diagnosis for the hemoptysis considered at the time was tuberculosis, atypical mycobacterial infection, bacterial pneumonia, vasculitis, and Pneumocystis jiroveci pneumonia. A punch biopsy of the abdominal rash was performed.\n\nBlood cultures from the day of admission grew K. pneumoniae and Enterococcus faecalis. The grossly bloody bronchoalveolar lavage fluid (Figure 3) grew Nocardia asteroides and also revealed the presence of S. stercoralis larvae. Histopathologic exam of the skin biopsy showed multiple intradermal helminths consistent with Strongyloides (Figure 4). A stool exam conducted on hospital day 13 was also positive for Strongyloides.\n\nStarting on hospital day 3, the patient was treated with ivermectin 200 µg/kg/day and albendazole 400 mg twice daily through a nasogastric tube. The patient received albendazole for 21 days and ivermectin for 32 days. The ivermectin was continued until serial sputum and stool studies were negative for the presence of Strongyloides. The patient also received cefepime and vancomycin for the polymicrobial bacteremia and trimethoprim-sulfamethoxazole for the nocardiosis. The prednisone dose was decreased to 20 mg per day during the hospitalization. Due to altered mental status, the patient was evaluated by an MRI of the brain and a lumbar puncture, but there was no evidence of CNS infection. The patient was extubated after 10 days of mechanical ventilation. The patient gradually improved and was discharged to a rehabilitation facility in stable condition.\n\n2.2. Case 2\nThe patient is a 36-year old Hispanic man with a history of acute lymphoblastic leukemia that had been diagnosed 14 months prior to the current admission. At that time, he had received induction chemotherapy with cyclophosphamide, vincristine, doxorubicin, dexamethasone, and rituximab (hyper-CVAD-R) and intrathecal chemotherapy, which he finished four months prior to the current admission. He was maintained on monthly 6-mercaptopurine, vincristine, methotrexate, and prednisone (200 mg per day for five days of each month). He had been admitted to the hospital three weeks prior to the current admission for chest pain, malaise, weight loss, and a persistent cough productive of yellow sputum. At that time, he was febrile to 38.4 °C and was initially given vancomycin, piperacillin-tazobactam, and azithromycin. He was found to have diffuse infiltrates on chest X-ray. Sputum culture grew Pseudomonas aeruginosa and the patient was transitioned to ciprofloxacin. A nasopharyngeal respiratory pathogen polymerase chain reaction panel (Biofire, Salt Lake City, UT, USA) was positive for Rhinovirus and Enterovirus. Serologic studies for Histoplasma, Cryptococcus, Strongyloides (IgG by ELISA, ARUP Laboratories) and Coccidioides were negative, as were stains of the sputum for fungal and acid-fast organisms. Given the patient’s immunocompromised condition, the diffuse pulmonary infiltrates raised concern for Pneumocystis infection. Trimethoprim-sulfamethoxazole (TMP-SMX) and corticosteroids were started empirically with rapid improvement, and the patient was discharged to finish 21 days of TMP-SMX and 14 days of tapering prednisone. The patient presented for the current admission with worsening dyspnea, malaise, fever, and hemoptysis four days after completing ciprofloxacin and TMP-SMX.\n\nThe patient was born in Honduras and had emigrated to the United States 16 years prior. The patient lived in San Antonio, Texas, and worked as an electrical technician. He had no animal exposure and no history of incarceration, homelessness, or recreational drug or alcohol use.\n\nOn exam, the patient was tachypneic; vital signs were: Temperature 37 °C, pulse 112/min, respiratory rate 30 breaths/min, oxygen saturation of 88% on room air, and a blood pressure 80s/30s mm Hg. Pulmonary exam revealed diffuse rales and expiratory wheezes. The remainder of the exam was unremarkable.\n\nHematologic results were: White cell count 5.3 K/µL with 36% neutrophils, 6% lymphocytes, 18% eosinophils, 20% bands, and 8% metamyelocytes; hemoglobin 9.7 g/dL; and platelets 138 K/µL. Serum chemistry values were: Sodium 120 mmol/L (RR 135-145 mmol/L) and bilirubin 1.6 mg/dL (0.2–1.2 mg/dL); creatinine, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were all within normal limits. A CT scan of the chest showed interval worsening as compared to three weeks prior, with extensive ground glass and patchy parenchymal opacities throughout the bilateral lungs, suggestive of multi-lobar Pneumocystis pneumonia (see Figure 5).\n\nThe patient was admitted to the intensive care unit with septic shock. The initial differential diagnosis for the patient’s respiratory distress included viral or bacterial pneumonia, vasculitis, malignancy, and P. jirovecii pneumonia. He was started on cefepime, vancomycin, TMP-SMX, metronidazole, and azithromycin, and received five liters of normal saline and norepinephrine for blood pressure support. Prednisone was held. Sputum cultures again grew P. aeruginosa with the same susceptibility pattern as in previous cultures. A nasopharyngeal swab for viral respiratory pathogens was again positive for Rhinovirus and Enterovirus. Sputum cytology was also obtained to evaluate for malignancy. The patient improved after 24 days and was transferred to the ward.\n\nSputum cytology revealed helminth larvae consistent with S. stercoralis (Figure 6). The patient was started on ivermectin (200 µg/kg/d) and continued to improve. Sputum cultures also grew Aspergillus flavus and Candida tropicalis. Bronchoscopy was performed and the lavage fluid grew A. terreus; C. guilliermondii grew from tissue from a transbronchial biopsy, and he was started on voriconazole. He was discharged in stable condition. At clinic three weeks later, the patient reported a constant dull headache and a lumbar puncture showed neutrophilic pleocytosis; a CSF culture grew Aerococcus viridans. He was successfully treated with a 14-day course of vancomycin. He continued ivermectin until two weeks of serial sputum and stool samples were negative for the presence of Strongyloides (64 total days of treatment).\n\n3. Discussion\nHemoptysis is the expectoration of blood originating in the lower respiratory tract. Hemoptysis due to alveolar hemorrhage has an extensive differential diagnosis of infectious, autoimmune, neoplastic, cardiovascular, and miscellaneous causes. The most frequent conditions causing hemoptysis are bronchiectasis, tuberculosis, mycoses, necrotizing pneumonia, and malignancy [13]. In the immunocompromised patient with hemoptysis, an infectious cause is a major concern, including infection with cytomegalovirus, adenovirus, Aspergillus, Mycoplasma, Legionella, and Strongyloides [14]. For those patients who have lived in a developing country, strongyloidiasis should be included in the differential diagnosis for hemoptysis. Pulmonary strongyloidiasis typically has an asthma-like presentation, but 10% of patients suffer hemoptysis [15]. Diffuse alveolar hemorrhage from strongyloidiasis may have a fatal outcome [16,17,18]. We cannot rule out that the pulmonary co-infections (with A. terreus, A. flavus, and N. asteroides) may have contributed to the hemoptysis; however, compared with Strongyloides, reports of these other pathogens causing pulmonary hemorrhage are infrequent.\n\nIn immunocompetent persons, S. stercoralis may cause mild intestinal discomfort, urticaria, or asymptomatic carriage for decades. However, in patients with iatrogenic or disease-induced immunosuppression, including human T-lymphotrophic virus-1 (HTLV-1) infection, corticosteroid use, organ transplantation, or tumor necrosis factor antagonist use, potentially fatal hyperinfection syndrome or dissemination may occur. In these patients Strongyloides infection can cause more severe symptoms, including nausea, diarrhea, gastrointestinal and alveolar bleeding, weight loss, small bowel obstruction, and severe abdominal pain as adult parasites invade the duodenal and jejunal mucosa. Strongyloides hyperinfection syndrome is an accelerated autoinfection process, with proliferation of the previously stable population of worms to a level which adversely affects the health of the host. Detection of abundant larvae in the stool or sputum is indicative of hyperinfection [19]. During disseminated strongyloidiasis, large numbers of worms (primarily filariform larvae) reach extra-intestinal organs, including the skin, lungs, peritoneum, liver, kidneys, and central nervous system. A pathognomonic sign of disseminated strongyloidiasis is larva currens, a serpiginous cutaneous lesion of the buttocks, groin, perineum, and/or trunk; however, it is not a common finding [20]. A peri-umbilical purpuric rash, as in Case 1, has been previously described in disseminated strongyloidiasis and is a sign of poor prognosis [12,21]. The purpura has been attributed to the invasion of the dermis by larvae that have migrated through the vessel walls. The periumbilical distribution may be due to retrograde venous migration. Additionally, the larvae may penetrate into the skin from the abdominal cavity, following migration through the wall of the colon [12]. However, there is typically a blending of hyperinfection and dissemination, so it is simpler to categorize strongyloidiasis as “uncomplicated” or “severe\" [4,5].\n\nSecondary infections are common in severe strongyloidiasis due to bacterial translocation from the gut by the hematogenously migrating larvae and underlying immunosuppression [3,11,22,23]. The bacterial infections (primarily bacteremia, pneumonia, and meningitis) that often accompany severe strongyloidiasis are a major factor in the shock, multi-organ failure, and death due to this infection [23]. Chest radiographic findings in severe strongyloidiasis are non-specific; there may be pulmonary infiltrates, consolidation, and occasional cavitation or abscess formation. The variable radiographic appearance is due to concurrent superinfection by other organisms [4].\n\nSeveral immunosuppressive medications and underlying conditions are associated with Strongyloides hyperinfection [24]. Due to the risk of hyperinfection and dissemination in the immunocompromised patient, American and British guidelines recommend that all patients from endemic areas be screened serologically for Strongyloides infection prior to commencement of immunosuppressive therapy [24,25]. Patients found to have strongyloidiasis upon screening can be treated with ivermectin in order to prevent future hyperinfection after immunosuppression [26]. It has been proposed that the increased risk of hyperinfection in patients taking corticosteroids is not due to immunosuppression per se but that corticosteroids mimic the ecdysteroid molting hormones of Strongyloides [27]. Thus, the administration of exogeneous corticosteroids promotes the transformation of the rhabditiform larvae into invasive filariform larvae [3].\n\nA diagnosis of strongyloidiasis is typically confirmed if the rhabditiform larvae are seen with a microscopic exam of stool specimens or respiratory samples. However, a single stool exam is diagnostic in only one-third of patients. Serial stool examinations increase the sensitivity of stool exams but may be impractical. It is estimated that seven stool exams would provide close to 100% sensitivity [4,28]. In a series of patients with known chronic strongyloidiasis (i.e., passing of larvae in the stools), 95% were serologically positive and 83% had eosinophilia [29]. However, in patients with severe strongyloidiasis that have received corticosteroids or other immunosuppressive agents, serologic tests may be falsely negative [30]. During hyperinfection, eosinophilia is usually absent [5,31], but patients that maintain eosinophilia during hyperinfection have a better prognosis [23,32]. The agar plate culture of feces method (with observation of the tracks of bacteria arising from migrating larvae) has the highest detection rate for strongyloidiasis in immunocompromised patients, whereas serologic testing has a low yield in this setting [33]. In addition to the usual methods of sputum and stool detection, skin biopsy or observing the larvae in bronchoalveolar lavage fluid, ascites, pleural fluid, urine, or cerebrospinal fluid may also be diagnostic [4].\n\nAcute uncomplicated strongyloidiasis is treated with one to two doses of ivermectin, with reports of over 90% efficacy [1]. However, recent studies using molecular methods for detection have suggested that traditional dosing of ivermectin may not be sufficient to eradicate Strongyloides [34]. An alternative treatment is albendazole 400 mg twice daily for seven days, although the parasitologic cure rate (63.3%) is lower than that of ivermectin [35,36]. However, the optimal treatment for critically ill patients with severe strongyloidiasis is uncertain, and data regarding the ideal drug(s), doses, duration of treatment, and route of administration are limited. In an analysis of 244 cases of severe strongyloidiasis abstracted from the medical literature, it was uniformly fatal without treatment. Ivermectin or thiabendazole (currently unavailable in the USA) administration reduced the mortality rate to 47% and 51%, respectively, but in the albendazole group, 73% died [2,36]. However, not all published case series of severe strongyloidiasis carry a high mortality rate; in one series of nine patients with severe Strongyloides infection with respiratory failure, the mortality rate was 33% [32]. In another group of 16 patients with severe strongyloidiasis, in which all the patients were treated with ivermectin, the mortality rate was significantly lower (11.1%) [37].\n\nIn severe strongyloidiasis some experts recommend five to seven days of ivermectin or combining ivermectin with albendazole until the patient responds clinically and daily stool examinations have been negative for at least two weeks (one autoinfection cycle), with ongoing monthly ivermectin if the patient remains immunosuppressed [10,24,38]. Rectal ivermectin has been used in patients with severe strongyloidal colitis [39], but rectal administration may not achieve therapeutically sufficient serum levels of the drug [40]. In cases of severe strongyloidiasis in which anti-helminthic drug administration by the enteric route is not feasible due to ileus, subcutaneous injection of the parenteral veterinary formulation of ivermectin has been advocated [36,38]. Whenever possible, immunosuppressive agents should be discontinued or decreased to lowest possible dose. In particular, continued corticosteroid use is associated with a poor outcome. In severe strongyloidiasis, broad spectrum antibiotics that cover enteric gram-negative bacteria should also be administered empirically during the period of severe illness or for the standard duration necessary to treat any diagnosed intercurrent infections. There is no definitive test of cure following treatment of strongyloidiasis, but in those patients with pre-treatment eosinophilia and positive IgG serologic tests, resolution of eosinophilia and a decline in IgG antibody levels after an average of 96 and 270 days, respectively, indicates successful treatment [8,24,29].\n\n4. Conclusions\nThese cases illustrate that patients from Strongyloides-endemic areas should be serologically screened prior to commencement of immunosuppressive therapy and receive ivermectin if such screening is positive. Furthermore, strongyloidiasis should be considered in the differential diagnosis for hemoptysis in immunocompromised patients that have lived in or traveled to endemic areas. In immunocompromised patients, eosinophilia and serologic studies are not sensitive diagnostic tests [31], and the examination of stool, sputum, bronchial washings, and cutaneous biopsy specimens may be necessary to afford the diagnosis. The patients of these two cases had classic risk factors for the development of severe Strongyloides infection. Both patients were immigrants from endemic countries and both had been treated with extended courses of corticosteroids. The patient of Case 1 received high-dose corticosteroids for nine months for dermatomyositis and IgM nephropathy prior to presentation. The patient of Case 2 received scheduled cytotoxic chemotherapy including corticosteroids for over one year. Both patients had prodromal respiratory illnesses in the month prior to their critical illness, but in each case, the diagnosis of strongyloidiasis was not initially pursued beyond serologic testing. In both cases, serological tests were negative and in Case 1 either the immunocompromised state of the patient or the high doses of prednisone blunted the eosinophilic response often observed in immunocompetent persons with strongyloidiasis. In Case 2, eosinophilia was retrospectively identified by the infectious diseases specialists in the periods between cycles of chemotherapy administration. Both patients suffered multiple concurrent infections (Klebsiella/Enterococcus bacteremia and Nocardia pneumonia in Case 1 and Pseudomonas/viral/fungal pneumonia and Aerococcus meningitis in Case 2). Aggressively seeking and treating concurrent infections in patients with strongyloidiasis is necessary to optimize patient outcomes.\n\nAuthor Contributions\nP.S., B.T., and O.B. contributed to the care of patient #1; S.O. and G.M.A. contributed to the care of patient #2. The cases were discussed amongst all authors to design the case studies. S.O., P.S., O.B., and G.M.A. took the lead in writing the manuscript, with B.T. editing the article. All authors agreed on the final version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Case 1: Photograph of the peri-umbilical petechial abdominal rash.\n\nFigure 2 Case 1: CT scan of the chest showing diffuse ground glass airspace opacities, interlobular septal thickening (A), and a right middle lobe cavitary lesion (B). The airspace opacities suggested diffuse alveolar hemorrhage.\n\nFigure 3 Case 1: Grossly bloody bronchoalveolar lavage fluid.\n\nFigure 4 Case 1. (A) Longitudinal section of infective filariform Strongyloides stercoralis within subcutaneous tissue in skin biopsy of abdominal wall, stained with H&E. Image taken at 200× magnification. Note the absence of inflammatory cells [12]. (B) Cross section of infective filariform Strongyloides stercoralis within subcutaneous tissue in skin biopsy of abdominal wall, stained with H&E. Image taken at 400× magnification.\n\nFigure 5 Case 2: CT of the chest showing extensive ground glass and patchy parenchymal opacities throughout the bilateral lungs; the differential diagnosis included opportunistic infections (pneumocytosis, cytomegalovirus), alveolar hemorrhage, and pulmonary edema.\n\nFigure 6 Case 2: Cytologic exam of sputum showing S. stercoralis.\n==== Refs\nReferences\n1. Bisoffi Z. Buonfrate D. Montresor A. Requena-Mendez A. Munoz J. Krolewiecki A.J. Gotuzzo E. Mena M.A. Chiodini P.L. Anselmi M. Strongyloides stercoralis : A plea for action PLoS Negl. Trop. Dis. 2013 7 e2214 10.1371/journal.pntd.0002214 23675546 \n2. Buonfrate D. Requena-Mendez A. Angheben A. Muñoz J. Gobbi F. Van Den Ende J. Bisoffi Z. Severe strongyloidiasis: A systematic review of case reports BMC Infect. Dis. 2013 13 78 10.1186/1471-2334-13-78 23394259 \n3. Genta R.M. Global prevalence of strongyloidiasis: Critical review with epidemiologic insights into the prevention of disseminated disease Rev. Infect. Dis. 1989 11 755 767 10.1093/clinids/11.5.755 2682948 \n4. Siddiqui A.A. Genta R.M. Maguilnik I. Berk S.L. Strongyloidiasis Tropical Infectious Diseases: Principles, Pathogens, and Practice 3rd ed. Guerrant R.L. Walker D.H. Weller P.F. Churchill Livingstone Philadelphia, PA, USA 2010 805 812 \n5. Grove D.I. Human strongyloidiasis Adv. Parasitol. 1996 38 251 309 8701797 \n6. Croker C. Reporter R. Redelings M. Mascola L. Strongyloidiasis-related deaths in the United States, 1991–2006 Am. J. Trop. Med. Hyg. 2010 83 422 426 10.4269/ajtmh.2010.09-0750 20682893 \n7. Posey D.L. Blackburn B.G. Weinberg M. Flagg E.W. Ortega L. Wilson M. Secor W.E. Sanders-Lewis K. Won K. Maguire J.H. High prevalence and presumptive treatment of schistosomiasis and strongyloidiasis among African refugees Clin. Infect. Dis. 2007 45 1310 1315 10.1086/522529 17968826 \n8. Nuesch R. Zimmerli L. Stockli R. Gyr N. Christoph Hatz F.R. Imported strongyloidosis: A longitudinal analysis of 31 cases J. Travel Med. 2005 12 80 84 10.2310/7060.2005.12204 15996452 \n9. Centers for Disease Control and Prevention Parasites—Strongyloides Available online: http://www.cdc.gov/parasites/strongyloides/biology.html (accessed on 4 June 2018) \n10. Greaves D. Coggle S. Pollard C. Aliyu S.H. Moore E.M. Strongyloides stercoralis infection BMJ 2013 347 f4610 10.1136/bmj.f4610 23900531 \n11. Prendki V. Fenaux P. Durand R. Thellier M. Bouchaud O. Strongyloidiasis in man 75 years after initial exposure Emerg. Infect. Dis. 2011 17 931 932 10.3201/eid1705.100490 21529417 \n12. Salluh J.I. Bozza F.A. Pinto T.S. Toscano L. Weller P.F. Soares M. Cutaneous periumbilical purpura in disseminated strongyloidiasis in cancer patients: A pathognomonic feature of potentially lethal disease? Braz. J. Infect. Dis. 2005 9 419 424 10.1590/S1413-86702005000500010 16410894 \n13. Larici A.R. Franchi P. Occhipinti M. Contegiacomo A. del Ciello A. Calandriello L. Storto M.L. Marano R. Bonomo L. Diagnosis and management of hemoptysis Diagn. Intervent. Radiol. 2014 20 299 309 10.5152/dir.2014.13426 24808437 \n14. von Ranke F.M. Zanetti G. Hochhegger B. Marchiori E. Infectious diseases causing diffuse alveolar hemorrhage in immunocompetent patients: A state-of-the-art review Lung 2013 191 9 18 10.1007/s00408-012-9431-7 23128913 \n15. Woodring J.H. Halfhill H. 2nd Berger R. Reed J.C. Moser N. Clinical and imaging features of pulmonary strongyloidiasis South Med. J. 1996 89 10 19 10.1097/00007611-199601000-00002 8545686 \n16. Setoyama M. Fukumaru S. Takasaki T. Yoshida H. Kanzaki T. SLE with death from acute massive pulmonary hemorrhage caused by disseminated strongyloidiasis Scand. J. Rheumatol. 1997 26 389 391 10.3109/03009749709065706 9385354 \n17. El-Sameed Y.A. Beejay N. Al Maashari R. Diffuse alveolar haemorrhage and severe hypoxemia from Strongyloides stercoralis hyperinfection syndrome Clin. Respir. J. 2015 9 489 492 10.1111/crj.12169 24902477 \n18. Patel T. Singh R. Reddy V. Hodowanec A. Singh K. Photo quiz: Sepsis, confusion, rash, and pulmonary hemorrhage in a 36-year-old man with lymphoma J. Clin. Microbiol. 2015 53 758 10.1128/JCM.01090-13 \n19. Keiser P.B. Nutman T.B. Strongyloides stercoralis in the immunocompromised population Clin. Microbiol. Rev. 2004 17 208 217 10.1128/CMR.17.1.208-217.2004 14726461 \n20. Fardet L. Généreau T. Cabane J. Kettaneh A. Severe strongyloidiasis in corticosteroid-treated patients Clin. Microbiol. Infect. 2006 12 945 947 10.1111/j.1469-0691.2006.01443.x 16961629 \n21. Weiser J.A. Scully B.E. Bulman W.A. Husain S. Grossman M.E. Periumbilical parasitic thumbprint purpura: Strongyloides hyperinfection syndrome acquired from a cadaveric renal transplant Transplant Infect. Dis. 2011 13 58 62 10.1111/j.1399-3062.2010.00516.x 20525017 \n22. Zaha O. Hirata T. Kinjo F. Saito A. Strongyloidiasis-progress in diagnosis and treatment Intern. Med. 2000 39 695 700 10.2169/internalmedicine.39.695 10969899 \n23. Geri G. Rabbat A. Mayaux J. Zafrani L. Chalumeau-Lemoine L. Guidet B. Azoulay E. Pène F. Strongyloides stercoralis hyperinfection syndrome: A case series and a review of the literature Infection 2015 43 691 698 10.1007/s15010-015-0799-1 26008854 \n24. Mejia R. Nutman T.B. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis Curr. Opin. Infect. Dis. 2012 25 458 463 10.1097/QCO.0b013e3283551dbd 22691685 \n25. Checkley A.M. Chiodini P.L. Dockrell D.H. Bates I. Thwaites G.E. Booth H.L. Brown M. Wright S.G. Grant A.D. Mabey D.C. British Infection Society and Hospital for Tropical Diseases. Eosinophilia in returning travellers and migrants from the tropics: UK recommendations for investigation and initial management J. Infect. 2010 60 1 20 10.1016/j.jinf.2009.11.003 19931558 \n26. Santiago M. Leitão B. Prevention of strongyloides hyperinfection syndrome: A rheumatological point of view Eur. J. Intern. Med. 2009 20 744 748 10.1016/j.ejim.2009.09.001 19892301 \n27. Genta R.M. Dysregulation of strongyloidiasis: A new hypothesis Clin. Microbiol. Rev. 1992 5 345 355 10.1128/CMR.5.4.345 1423214 \n28. Nielsen P.B. Mojon M. Improved diagnosis of Strongyloides stercoralis by seven consecutive stool specimens Zentralbl. Bakteriol. Mikrobiol. Hyg. A 1987 263 616 618 10.1016/S0176-6724(87)80207-9 3604502 \n29. Loutfy M.R. Wilson M. Keystone J.S. Kain K.C. Serology and eosinophil count in the diagnosis and management of strongyloidiasis in a non-endemic area Am. J. Trop. Med. Hyg. 2002 66 749 752 10.4269/ajtmh.2002.66.749 12224585 \n30. Albonico M. Becker S.L. Odermatt P. Angheben A. Anselmi M. Amor A. Barda B. Buonfrate D. Cooper P. Gétaz L. StrongNet: An international network to improve diagnostics and access to treatment for strongyloidiasis control PLoS Negl. Trop. Dis. 2016 10 e0004898 10.1371/journal.pntd.0004898 27607192 \n31. Valerio L. Roure S. Fernández-Rivas G. Basile L. Martínez-Cuevas O. Ballesteros Á.L. Ramos X. Sabrià M. North Metropolitan Working Group on Imported Diseases. Strongyloides stercoralis , the hidden worm. Epidemiological and clinical characteristics of 70 cases diagnosed in the North Metropolitan Area of Barcelona, Spain, 2003–2012 Trans. R. Soc. Trop. Med. Hyg. 2013 107 465 470 23783760 \n32. Newberry A.M. Williams D.N. Stauffer W.M. Boulware D.R. Hendel-Paterson B.R. Walker P.F. Strongyloides hyperinfection presenting as acute respiratory failure and gram-negative sepsis Chest 2005 128 3681 3684 10.1378/chest.128.5.3681 16304332 \n33. Luvira V. Trakulhun K. Mungthin M. Naaglor T. Chantawat N. Pakdee W. Phiboonbanakit D. Dekumyoy P. Comparative Diagnosis of Strongyloidiasis in Immunocompromised Patients Am. J. Trop. Med. Hyg. 2016 95 401 414 10.4269/ajtmh.16-0068 27296387 \n34. Repetto S.A. Ruybal P. Batalla E. López C. Fridman V. Sierra M. Radisic M. Bravo P.M. Risso M.G. González Cappa S.M. Strongyloidiasis outside endemic areas: Long-term parasitological and clinical follow-up after ivermectin treatment Clin. Infect. Dis. 2018 66 1558 1565 10.1093/cid/cix1069 29360939 \n35. Suputtamongkol Y. Premasathian N. Bhumimuang K. Waywa D. Nilganuwong S. Karuphong E. Anekthananon T. Wanachiwanawin D. Silpasakorn S. Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis PLoS Negl. Trop. Dis. 2011 5 e1044 10.1371/journal.pntd.0001044 21572981 \n36. Henriquez-Camacho C. Gotuzzo E. Echevarria J. White A.C. Jr. Terashima A. Samalvides F. Pérez-Molina J.A. Plana M.N. Ivermectin versus albendazole or thiabendazole for Strongyloides stercoralis infection Cochrane Database Syst. Rev. 2016 1 CD007745 10.1002/14651858.CD007745.pub3 26778150 \n37. Martinez-Perez A. Díez S.R. Belhasen-Garcia M. Torrús-Tendero D. Perez-Arellano J.L. Cabezas T. Soler C. Díaz-Menéndez M. Navarro M. Treviño B. Management of severe strongyloidiasis attended at reference centers in Spain PLoS Negl. Trop. Dis. 2018 12 e0006272 10.1371/journal.pntd.0006272 29474356 \n38. Pornsuriyasak P. Niticharoenpong K. Sakapibunnan A. Disseminated strongyloidiasis successfully treated with extended duration ivermectin combined with albendazole: A case report of intractable strongyloidiasis Southeast Asian J. Trop. Med. Public Health 2004 35 531 534 15689061 \n39. Tarr P.E. Miele P.S. Peregoy K.S. Smith M.A. Neva F.A. Lucey D.R. Case report: Rectal administration of ivermectin to a patient with Strongyloides hyperinfection syndrome Am. J. Trop. Med. Hyg. 2003 68 453 455 10.4269/ajtmh.2003.68.453 12875295 \n40. Bogoch I.I. Khan K. Abrams H. Nott C. Leung E. Fleckenstein L. Keystone J.S. Failure of ivermectin per rectum to achieve clinically meaningful serum levels in two cases of Strongyloides hyperinfection Am. J. Trop. Med. Hyg. 2015 93 94 96 10.4269/ajtmh.15-0077 25918215\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2414-6366",
"issue": "4(1)",
"journal": "Tropical medicine and infectious disease",
"keywords": "Strongyloides stercoralis; albendazole; corticosteroids; eosinophilia; hemoptysis; ivermectin; strongyloidiasis",
"medline_ta": "Trop Med Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101709042",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30759812",
"pubdate": "2019-02-12",
"publication_types": "D002363:Case Reports",
"references": "10969899;12224585;12875295;1423214;14726461;15689061;15996452;16304332;16410894;16961629;17968826;19892301;19931558;20525017;20682893;21529417;21572981;22691685;23128913;23394259;23675546;23783760;23900531;24808437;24902477;25617439;25918215;26008854;26778150;2682948;27296387;27607192;29360939;29474356;3604502;8545686;8701797;9385354",
"title": "Hemoptysis in the Immunocompromised Patient: Do Not Forget Strongyloidiasis.",
"title_normalized": "hemoptysis in the immunocompromised patient do not forget strongyloidiasis"
} | [
{
"companynumb": "US-BAUSCH-BL-2020-008682",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Following on from the recently published articles reported side effects occurring due to donation of stem cells, we describe a case of a donor with transient, biopsy-proved acute focal segmental proliferative glomerulonephritis (GN) due to peripheral blood stem cells (PBSC) mobilization with granulocyte colony-stimulating factor (G-CSF). A 44-year-old woman with no relevant past medical history suffering from obesity and hypertension well controlled with metoprolol without hypertensive retinopathy was admitted to our hospital as a donor of PBSC. She received G-CSF subcutaneously-filgrastim (Amgen)-at a dose of 5 microg/kg twice a day for 6 days. The macroscopic hematuria and proteinuria occurred on 5th day of G-CSF administration. Due to mobilization and collection of stem cells, proteinuria was becoming more intense and reached the nephrotic range. The immunological, infectious, urological and gynecological causes of such complication were excluded. The final histological recognition was early stage of focal segmental proliferative GN. To our knowledge this a first report of GN in a donor due to mobilization of PBSC confirmed with renal biopsy. These findings suggest that filgrastim may induce transient urinary excretion of protein and hematuria in PBSC donors as the symptoms of acute GN without adversely affecting renal function.",
"affiliations": "Department of Stem Cell Transplantation, Institute of Hematology and Blood Transfusion Medicine, I.Gandhi Str. 14, 02-776, Warsaw, Poland. barbaramail@poczta.onet.pl",
"authors": "Nasilowska-Adamska|B|B|;Perkowska-Ptasinska|A|A|;Tomaszewska|A|A|;Serwacka|A|A|;Marianska|B|B|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-010-0730-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "92(5)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells; D006801:Humans; D014019:Tissue Donors",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "765-8",
"pmc": null,
"pmid": "21120643",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12389618;10194429;17563736;18721778;14561987;10931006;19059940;18057230;12555210",
"title": "Acute glomerulonephritis in a donor as a side effect of allogeneic peripheral blood stem cell mobilization with granulocyte colony-stimulating factor.",
"title_normalized": "acute glomerulonephritis in a donor as a side effect of allogeneic peripheral blood stem cell mobilization with granulocyte colony stimulating factor"
} | [
{
"companynumb": "PL-PFIZER INC-202200358680",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "1",
... |
{
"abstract": "Cutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin's lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential adverse events (graft versus host disease) due to manipulation of the immune system with use of checkpoint inhibitors.\n\n\n\nWe describe a patient with relapsed refractory CTCL (Sézary Syndrome) who underwent allo-HCT with persistence of disease post-transplant. The patient additionally developed a progressively worsening lesion on the right shoulder which was biopsied and showed poorly differentiated carcinoma (cSCC). Pembrolizumab was started for the treatment of cSCC. After second cycle of treatment, the cSCC lesion responded dramatically to the use of immune checkpoint inhibitor. Also, the patient experienced significant resolution of pruritus and generalized erythema. During 24 months of follow up after initial treatment with checkpoint inhibition immunotherapy, the patient showed durable response of both cSCC and CTCL, as well as restoration of full donor chimerism, without obvious worsening of graft versus host disease (GVHD).\n\n\n\nThis is the first case to our knowledge of rapid and durable response of both cSCC and CTCL to immune checkpoint inhibition after allo-HCT. Although this report highlights the potential for significant response to this class of medication, further studies are required to confirm the efficacy and safety of this approach in patients with CTCL after allo-HCT given the potential concern of GVHD.",
"affiliations": "Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO, 63110, USA.;Division of Dermatology, Department of Medicine, Washington University in Saint Louis, St. Louis, USA.;Division of Dermatology, Department of Medicine, Washington University in Saint Louis, St. Louis, USA.;Alvin J. Siteman Cancer Center, St. Louis, USA.;Division of Medical Oncology, Bone Marrow Transplantation and Leukemia, Department of Medicine, Washington University in Saint Louis, St. Louis, USA.;Alvin J. Siteman Cancer Center, St. Louis, USA.;Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO, 63110, USA. gasnsstas@wustl.edu.",
"authors": "Khaddour|Karam|K|0000-0001-6697-3516;Musiek|Amy|A|;Cornelius|Lynn A|LA|;Dehdashti|Farrokh|F|;Westervelt|Peter|P|;Fields|Ryan|R|;Ansstas|George|G|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological",
"country": "England",
"delete": false,
"doi": "10.1186/s40425-019-0801-z",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 80110.1186/s40425-019-0801-zCase ReportRapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for sézary syndrome http://orcid.org/0000-0001-6697-3516Khaddour Karam 12Musiek Amy 3Cornelius Lynn A. 34Dehdashti Farrokh 54Westervelt Peter 24Fields Ryan 64Ansstas George 314-362-5677gasnsstas@wustl.edu 141 0000 0001 2355 7002grid.4367.6Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO 63110 USA 2 0000 0001 2355 7002grid.4367.6Division of Medical Oncology, Bone Marrow Transplantation and Leukemia, Department of Medicine, Washington University in Saint Louis, St. Louis, USA 3 0000 0001 2355 7002grid.4367.6Division of Dermatology, Department of Medicine, Washington University in Saint Louis, St. Louis, USA 4 0000 0001 2355 7002grid.4367.6Alvin J. Siteman Cancer Center, St. Louis, USA 5 0000 0001 2355 7002grid.4367.6Division of Nuclear Medicine, Department of Radiology, Washington University in Saint Louis, St. Louis, USA 6 0000 0001 2355 7002grid.4367.6Section of Surgical Oncology, Department of Surgery, Washington University in Saint Louis, St. Louis, USA 4 12 2019 4 12 2019 2019 7 33823 8 2019 30 10 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\nCutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin’s lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential adverse events (graft versus host disease) due to manipulation of the immune system with use of checkpoint inhibitors.\n\nCase presentation\nWe describe a patient with relapsed refractory CTCL (Sézary Syndrome) who underwent allo-HCT with persistence of disease post-transplant. The patient additionally developed a progressively worsening lesion on the right shoulder which was biopsied and showed poorly differentiated carcinoma (cSCC). Pembrolizumab was started for the treatment of cSCC. After second cycle of treatment, the cSCC lesion responded dramatically to the use of immune checkpoint inhibitor. Also, the patient experienced significant resolution of pruritus and generalized erythema. During 24 months of follow up after initial treatment with checkpoint inhibition immunotherapy, the patient showed durable response of both cSCC and CTCL, as well as restoration of full donor chimerism, without obvious worsening of graft versus host disease (GVHD).\n\nConclusion\nThis is the first case to our knowledge of rapid and durable response of both cSCC and CTCL to immune checkpoint inhibition after allo-HCT. Although this report highlights the potential for significant response to this class of medication, further studies are required to confirm the efficacy and safety of this approach in patients with CTCL after allo-HCT given the potential concern of GVHD.\n\nKeywords\nCutaneous squamous cell carcinomaCutaneous T-cell lymphomaSézary syndromeImmune checkpoint inhibitorsAllogenic hematopoietic cell transplantPembrolizumabGraft versus host diseaseissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nConventional chemotherapies are considered not to be curative in the majority of cutaneous T-cell lymphomas (CTCL) [1]. Recently, the use of immune checkpoint inhibitors has largely expanded to include hematological malignancies, specifically relapsed/refractory chemoresistant Hodgkin’s Lymphoma (r/r-cHL) and primary mediastinal large B-cell lymphoma [2, 3].The rationale relies on the fact that genetic alterations occurring in the microenvironment of lymphomas specifically in the programmed death ligand receptor (PD-L1/PD-L2) loci can lead to overexpression of PD-L1/2 on malignant cells, which helps tumor cells to evade the effective antitumor immune response [4]. Similarly, CTCL such as Mycosis Fungoides (MF) and Sézary Syndrome (SS) can debilitate the immune response against malignant cells in the tumor microenvironment and thus could be considered a target for therapies that can restore immune surveillance [5]. However, there is a concern for the use of immune checkpoint inhibitors in patients with lymphoma who undergo allogenic hematopoietic cell transplantation due to the possibility of triggering or aggravating graft versus host disease. This has led to lack of literature regarding the safety and efficacy of immune checkpoint inhibitors in this population as patients with prior history of allo-HCT were excluded from clinical trials which examined the efficacy of immunotherapy. Moreover, advanced cutaneous squamous cell carcinoma has been shown to have a high mutational burden which could increase the expression of tumor neoantigens [6]. Also, the association with PD-L1 expression is established with cutaneous squamous cell carcinoma which prompted the study of immune checkpoint inhibitors as a potential therapy [7].\n\nWe describe the first case to our knowledge of a patient with a history of allo-HCT who had a rapid and durable response of both cSCC and CTCL/SS after treatment with immune checkpoint inhibitors.\n\nCase presentation\nA 58-year-old Caucasian male with relapsed/refractory Sézary Syndrome (r/r SS) stage IVA was referred for allogeneic hematopoietic cell transplantation (allo-HCT). The patient had received multiple therapies prior to being assessed for a transplant (Table 1). Positron Emission Tomography/Computed Tomography (PET/CT) with [18F]fluorodeoxyglucose (FDG) prior to transplant (1/17/2017) revealed interval development of a new hypermetabolic soft tissue nodule in the skin of the posterior right shoulder with maximum standard uptake value (SUVmax) of 12.3 and a hypermetabolic right paratracheal lymph node (Fig. 1). Skin biopsy was consistent with residual CTCL/SS, a bone marrow biopsy demonstrated hypocellularity with extensive involvement of mature T-cell lymphoma (79% by flow cytometry), and cytogenetic studies revealed no aberrations. The patient underwent allogeneic hematopoietic cell transplantation (allo-HCT) using a fully matched male sibling donor. The myeloablative conditioning regimen prior to transplant consisted of hyperfractionated total body irradiation combined with high dose cyclophosphamide. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Tacrolimus was subsequently changed to sirolimus due to peri-transplant neurotoxicity. Shortly after transplantation (week 7), the patient developed a diffuse erythematous rash, a biopsy of which was most consistent with skin GVHD (vs CTCL vs drug rash) and received prednisone, mycophenolate mofetil (MMF) with ongoing sirolimus with improvement, and subsequent tapering to low dose prednisone (5 mg daily/ week 23). A bone marrow biopsy 4 months after allo-HCT showed persistent marrow (and peripheral blood) involvement with sézary cells (15% bone marrow involvement by mature T-cell lymphoma with CD4+/CD8+ ratio > 100). There was also mixed chimerism by short tandem repeat (STR) assay with 82% donor cells (Fig. 2). There was incomplete resolution of the skin manifestations of CTCL, which included generalized erythema and pruritus. Repeated skin biopsies were consistent with residual CTCL/SS. Five months after allo-HCT, STR studies again demonstrated persistent mixed chimerism, and donor lymphocyte infusions (DLI) in two separate doses were administered on weeks 26 and 31 (1 and 3 X 10e7 CD3 cells/kg, respectively) without complete resolution of skin symptoms or erythema. Following allo-HCT, there was a gradual worsening of a right shoulder skin lesion noted on PET/CT prior to transplant, and thought to be related to mycosis fungoides secondary to CTCL. The skin mass eventually extended over the superior aspect of the right shoulder with ulceration and hard induration, and 3 months post allo-HCT, the patient underwent subsequent involved-field radiotherapy with a total dose of 50 Gy. The lesion persisted and grew to 17 × 10 cm in maximum dimension with worsening necrosis, ulceration, and spread to the anterior chest wall (Fig. 3), a skin biopsy was performed and histopathology revealed poorly differentiated squamous cell carcinoma. Magnetic Resonance Imaging (MRI) of the shoulder showed a right lesion with no bone or muscular invasion, but there was extensive right axillary lymphadenopathy. FDG-PET/CT revealed worsening of disease with extensive markedly hypermetabolic soft tissue thickening in the right shoulder with SUVmax of 26.7 and interval development of markedly hypermetabolic partially necrotic right axillary lymphadenopathy with SUVmax of 27.3, as well as worsening in FDG uptake of the right paratracheal lymph node. There was interval development of hypermetabolic focal cutaneous lesions, left axillary lymph nodes and pulmonary lesions (T3N2B; Stage IV SCC) (Fig. 1).\nTable 1 Sequence of systemic therapies administered since diagnosis of cutaneous T-cell lymphoma/ Sézary Syndrome\n\nPrior therapy for CTCL/SS\tSequence and Duration\t\nPhotochemotherapy (PUVA)\tFirst Line of Therapy\t8 months (2009)\t\nPhotopheresis\tSecond Line of Therapy\t31 months (2009–2012)\t\nRomidepsin\tThird Line of Therapy\t48 months (2010–2014)\t\nPegylated liposomal doxorubicin\tFourth Line of Therapy\t3 months (2014)\t\nGemcitabine\tFifth Line of Therapy\t1 month (2014)\t\nAlemtuzumab\tSixth Line of Therapy\t2 months (2015)\t\nMogamulizumab\tSeventh Line of Therapy\t1 month (2015)\t\nTotal skin electron beam therapy\tEighth Line of Therapy\t3 months (2016)\t\nBexarotene\tNinth Line of Therapy\t2 months (2016)\t\nPralatrexate\tTenth Line of Therapy\t2 months (2016)\t\nICE (Ifosfamide, Carboplatin, Etoposide)\tEleventh Line of Therapy\t3 months (2016–2017)\t\nSibling allogenic stem cell transplantation\tTwelfth Line of Therapy\t(2017)\t\n\nFig. 1 Anterior and posterior volume-rendered maximum activity-reprojection FDG-PET images showing (a) FDG uptake in the right shoulder (arrow) and a paratracheal lymph node. b markedly hypermetabolic lesion in the right shoulder with SUVmax of 26.7 (arrow), markedly hypermetabolic right axillary and right paratracheal lymphadenopathy with SUVmax of 27.3 with interval development of hypermetabolic focal cutaneous lesions, left axillary lymph node and pulmonary lesions. c near complete response of the right shoulder hypermetabolic lesion (arrow), complete resolution of paratracheal lymph node, left axillary lymph node, pulmonary and cutaneous lesions, with persistent FDG uptake of the right axillary lymph nodes\n\n\nFig. 2 Timeline of bone marrow chimerism performed with STR studies after bone marrow transplantation. * Donor lymphocyte infusion was administered on two separate doses on weeks 26 and 31. Pembrolizumab cycle 1 was at week 36 and last cycle (cycle 14) was at week 78\n\n\nFig. 3 Skin lesions of CTCL and cSCC before and after PD-1 inhibition. a: Generalized eruption of small confluent erythematous macules and papules on the anterior chest wall after stem cell transplant and before pembrolizumab. b: resolution of the previously mentioned erythematous maculopapular eruption after pembrolizumab. c: multiple firm nodules with partial ulceration and keratin deposition on the superior aspect of the right shoulder representing poorly differentiated squamous cell carcinoma (before pembrolizumab), also erythematous eruption can be noted around the cSCC lesion which represents cutaneous lymphoma. d & e: Granular tissue with skin regeneration replacing the nodular ulcerated lesions of cSCC (after pembrolizumab), there is complete resolution of the papular erythematous rash. CTCL: cutaneous T cell lymphoma, cSCC: cutaneous squamous cell carcinoma\n\n\n\nAfter discussion of treatment options with the patient, intravenous pembrolizumab was started at a dose of 200 mg every 3 weeks. The patient had an Eastern Cooperative Oncology Group performance of (ECOG 3) prior to beginning of treatment. After 2nd cycle of pembrolizumab, a macular rash appeared on the lower back. Skin biopsy demonstrated superficial perivascular mixed inflammatory cell infiltrate with normal CD4+/CD8+ ratio and was consistent with grade I skin immune related adverse event (IRAEs) due to pembrolizumab. Prednisone 60 mg was started and tapered over a total of 4 weeks with complete resolution of the skin symptoms secondary to IRAEs. The cutaneous manifestations including generalized erythema and pruritus which were secondary to CTCL resolved completely after the 2nd cycle of immunotherapy. A FDG-PET/CT after the 5th cycle of pembrolizumab showed marked metabolic response and near-complete resolution of the superficial right shoulder mass (SUVmax of 1.9), and complete resolution of right paratracheal and left axillary lymph nodes, as well as pulmonary and cutaneous lesions. There was decreased but persistent FDG uptake in the necrotic right axillary lymph nodes (SUVmax of 18.2) (Fig. 1). Given the rapid and significant response, pembrolizumab was continued for another three cycles and repeated PET/CT showed continued response with decreased FDG avidity in the right axilla. After cycle 14, the patient underwent right axillary lymph node dissection encompassing levels 1–3 nodes for assessment of the residual persistent lymphadenopathy on the right side. Histopathology demonstrated metastatic squamous cell carcinoma in 3 of 17 lymph nodes. His post-operative course was uncomplicated. The complete course of pembrolizumab treatment consisted of 14 cycles, over a course of 9 months. Follow up 24 months after initiation of immune checkpoint blockade therapy (14 months after stopping pembrolizumab) revealed no evidence of recurrence of cSCC. There was no compelling evidence of either progression of CTCL/SS or a flare in GVHD throughout his course of checkpoint inhibition therapy (most recent peripheral blood flow cytometry on week 120 showing no morphologic or immunophenotypic evidence of atypical lymphocytosis or sézary cells and CD4+/CD8+ ration of 0.65).\n\nDiscussion\nSystemic treatment of locally advanced and metastatic cutaneous squamous cell carcinoma has been limited with the exception of recent data supporting the potential role of immune checkpoint blockade specifically cemiplimab [8] among other ongoing trials with other PD-1 and PD-L1 inhibitors (Clinical Trials.gov. Identifiers: NCT02978625, NCT02964559, NCT03284424 and NCT03108131). Also, the data supporting the use of immune checkpoint inhibitors in the treatment of hematological malignancies other than classical Hodgkin’s Lymphoma (cHL) or primary mediastinal large B-cell lymphoma is limited. A new incentive of implementing immune checkpoint blockade in the treatment of T-cell lymphomas is supported by preclinical studies that showed programmed cell death ligand-1 (PD-L1) receptors to be expressed on malignant cells which contribute to suppression of host immunity against the malignant cells. This leads to overgrowth in T-cell clones derived from non-Hodgkin lymphoma [9]. Our case demonstrates a rapid and durable response after treatment with immune checkpoint inhibitors manifested by a resolution of CTCL/SS symptoms within 6 weeks and a remission period of 24 months since initiation of a PD-1 inhibitor. The indication to use pembrolizumab in our patient was for the treatment of poorly differentiated cutaneous squamous cell carcinoma. The theoretical possibility of a derived benefit against CTCL/SS was taken into consideration when starting treatment. Also, the possibility of exacerbating GVHD was also considered. Both poorly differentiated cutaneous squamous cell carcinoma (cSCC) and CTCL/SS responded rapidly within 6 weeks (2 cycles) after initiation of PD-1 inhibitor, without an evidence of GVHD flare.\n\nEarly phase clinical trials using the PD-1 inhibitor (nivolumab) in refractory/relapsed cutaneous T-cell lymphomas demonstrated different objective response rates (ORR) ranging from 15% in mycosis fungoides (MF) to 40% in peripheral T-cell lymphoma/Sézary Syndrome (SS) in phase I studies (number of evaluable patients = 18) [10]. However, the previous study excluded patients with prior allogenic hematopoietic cell transplant. A different study using pembrolizumab demonstrated an ORR of 38% in 24 evaluable patients with MF/SS stages Ib-IV with the longest duration of response reported to be 46 weeks [11]. Interestingly, there were higher response rates in retrospective studies examining the role of PD-1 inhibition after allo-HCT compared to patients who received immunotherapy prior to transplant for r/r-cHL [12, 13]. These two previous retrospective studies showed ORR of 95 and 77% with 1 –year progression free survival (PFS) of 85.2% compared to ORR of 75 and 87% respectively in patients who received immune checkpoint inhibitors prior to transplant [2, 12–14]. This raises the hypothesis that immune checkpoint blockade could have a synergistic role after allo-HCT or a role in homing of donor T-cells leading to an enhanced graft versus tumor effect. Some data support the previous hypothesis as immune escape is one of the mechanisms considered to cause relapse after transplant in hematological malignancies, and T-cell exhaustion is a potential mechanism of relapse after allo-HCT due to overexpression of PD-1/PD-L1 receptors, which leads to inactivation of effective T-cells in the tumor microenvironment [15]. Norde et al. found that relapsed myeloid leukemia after allo-HCT had higher expression and upregulation of PD-L1 receptors on progenitor malignant clones. It was also observed in the same study the suppressive effect on allogenic CD3+ T-cells when there was high expression of PD-L1 on malignant leukemic cells. Interestingly, blockade of the PD-1/PD-L1 interaction can augment the expansion of effector CD8+ T-cells and reactivate unresponsive T-memory cells in the microenvironment required for graft versus leukemia effect [15]. Moreover, there is a small body of evidence supporting a role of immune checkpoint inhibitors in the bone marrow microenvironment in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myelopthisis due to melanoma [16, 17].\n\nThe concern with the use of immune checkpoint inhibitors after allo-HCT is the development of graft versus host disease (GVHD). Conflicting data exist regarding the occurrence of this adverse event, with some studies reporting increased incidence and worsening of preexisting GVHD with 30% (6 of 20 patients), and 26% deaths in patients who received immune checkpoint blockade after allo-HCT [12, 13]. In the previous two retrospective studies there were 10 deaths related to GVHD in 51 patients (23 of whom developed GVHD) [12, 13]. However, another retrospective study assessing patients who were treated with immune checkpoint inhibitors after allo-HCT did not report GVHD development in any of the 7 evaluable patients [18].\n\nThe largest systematic review assessing the risk of GVHD with immune checkpoint inhibitors after allo-HCT showed that 49% of patients who developed GVHD had a prior history of the disease [19]. Some of the predictive factors of GVHD development in this patient population were higher doses of immune checkpoint inhibitors, shorter intervals between transplant and start of immunotherapy, and previous history of GVHD. This systematic review also supports other observations of higher response rates when immune checkpoint inhibitors were administered after transplant compared to those who received immunotherapy before they underwent allo-HCT [12, 13, 19].\n\nIn our case, we did not observe GVHD after treatment with PD-1 inhibitors. In fact, the patient’s erythema and pruritus which were manifestations of patient’s CTCL improved significantly after starting pembrolizumab. Moreover, there was a dermatological immune related adverse event observed in the patient during treatment (after 2nd cycle of pembrolizumab) which correlated with the response of both cSCC and CTCL. The previous observation is supported by a retrospective study showing robust immune response to PD-1/PD-L1 inhibitors when lichenoid and spongiotic IRAEs develop during treatment with PD-1/PD-L1 inhibitors [20].\n\nIt should be noted that donor lymphocyte infusion (DLI) which was performed in our patient on weeks 26 and 31 could have potentially led to full engraftment of allo-HCT resulting in the response observed in CTCL. The median response from administration of DLI to full engraftment is estimated to be 8–12 weeks [21]. However, the response of cSCC and CTCL in our case was observed to occur only after the administration of pembrolizumab (first cycle was at week 36) and the substantial deep response was observed after the second cycle which was at week 39.\n\nIn conclusion, our case is the first to describe a rapid and sustained clinical response of both CTCL/SS and cSCC to immune checkpoint inhibition after allo-HCT, without development of GVHD. However, this observation should be interpreted with caution given the non-trivial concern of GVHD. Further larger studies are needed to confirm the efficacy of immune checkpoint inhibitors and their safety profile in this patient population.\n\nAbbreviations\nAllo-HCTallogenic hematopoietic stem cell transplant\n\nCTCLCutaneous T cell lymphoma\n\nGVHDGraft versus host disease\n\nIRAEsImmune related adverse events\n\nPD-1Programmed death receptor 1\n\nPET/CTPositron emission tomography- computed tomography\n\nr/r-cHLRelapsed/refractory classical Hodgkin’s lymphoma\n\ncSCCCutaneous squamous cell carcinoma\n\nSSSézary syndrome\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNot applicable.\n\nAuthors’ contributions\nK.K performed the chart, literature review to support conclusions of this report, prepared Fig. 2 and wrote the manuscript with consultation with the other authors. F.D prepared Fig. 1 with supervision on the manuscript. R.C.F operated on the case and supervised the surgical peri-operative course. L.A.C & A.M prepared Fig. 3 and supervised the work. G.A & P.W supervised the entire work. All authors contributed to the final version of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNo funding provided for this study.\n\nAvailability of data and materials\nData was acquired through patient chart review using Washington University in Saint Louis medical records.\n\nEthics approval and consent to participate\nNot Applicable.\n\nConsent for publication\nWritten and verbal consent were obtained from the patient prior to submission for publication. A copy of the written consent form is available at the editorial office for this journal.\n\nCompeting interests\nKK reports no conflict of interest. AM reports: kyowa kirin- advisory board, Helsinn- Advisory board, Elorac, Sologenix MiRagen (investigator), investigator in CITN study “embrolizymab and IFN-gamma in MF/SS and synovial sarcoma”. LC reports no conflict of interest. FD reports no conflict of interest. PW reports no conflict of interest. RF reports no conflict of interest. GA speaker bureau for Merck.\n==== Refs\nReferences\n1. Hughes CF Khot A McCormack C Lade S Westerman DA Twigger R Buelens O Lack of durable disease control with chemotherapy for mycosis fungoides and Sezary syndrome: a comparative study of systemic therapy Blood. 2015 125 71 81 10.1182/blood-2014-07-588236 25336628 \n2. Chen R Zinzani PL Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic Hodgkin lymphoma J Clin Oncol 2017 35 19 2125 2132 10.1200/JCO.2016.72.1316 28441111 \n3. Zinzani PL Ribrag V Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma Blood. 2017 130 3 267 270 10.1182/blood-2016-12-758383 28490569 \n4. Roemer MG Advani RH Ligon AH PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome J Clin Oncol 2016 34 23 2690 2697 10.1200/JCO.2016.66.4482 27069084 \n5. Sivanand A Surmanowicz P Alhusayen R Hull P Litvinov IV Zhou Y Gniadecki R Immunotherapy for Cutaneous T-Cell Lymphoma: Current Landscape and Future Developments J Cutan Med Surg 2019 23 5 537 544 10.1177/1203475419867610 31353944 \n6. Pickering CR Mutational landscape of aggressive cutaneous squamous cell carcinoma Clin Cancer Res 2014 20 24 6582 6592 10.1158/1078-0432.CCR-14-1768 25303977 \n7. Slater NA PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis J Cutan Pathol 2016 43 8 663 670 10.1111/cup.12728 27153517 \n8. Migden MR PD-1 blockade with Cemiplimab in advanced cutaneous squamous-cell carcinoma N Engl J Med 2018 379 4 341 351 10.1056/NEJMoa1805131 29863979 \n9. Wilcox RA Feldman AL B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders Blood. 2009 114 10 2149 2158 10.1182/blood-2009-04-216671 19597183 \n10. Lesokhin AM Ansell SM Armand P Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study J Clin Oncol 2016 34 23 2698 2704 10.1200/JCO.2015.65.9789 27269947 \n11. Khodadoust M, Rook AH, Porcu P, et al. Pembrolizumab for treatment of relapsed/refractory mycosis Fungoides and Sezary syndrome: clinical efficacy in a Citn multicenter phase 2 study. Blood. 2016;128.\n12. Herbaux C Gauthier J Brice P Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma Blood. 2017 129 18 2471 2478 10.1182/blood-2016-11-749556 28270452 \n13. Haverkos BM Abbott D Hamadani M PD-1 blockade for relapsed lymphoma postallogeneic hematopoietic cell transplant: high response rate but frequent GVHD Blood. 2017 130 2 221 228 10.1182/blood-2017-01-761346 28468799 \n14. Ansell SM Lesokhin AM Borrello I PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma N Engl J Med 2015 372 4 311 319 10.1056/NEJMoa1411087 25482239 \n15. Norde WJ Maas F PD-1/PD-L1 interaction contribute to functional T-cell impairment in patients who relapse with cancer after allogenic stem cell transplantation Cancer Res 2011 71 15 5111 5122 10.1158/0008-5472.CAN-11-0108 21659460 \n16. Boddu P Kantarjian H The emerging role of immune checkpoint based approaches in AML and MDS Leuk Lymphoma 2018 59 4 790 802 10.1080/10428194.2017.1344905 28679300 \n17. Rosner S Sen F Postow M Response after treatment with pembrolizumab in a patient with myelophthisis due to melanoma: the role of checkpoint inhibition in the bone J Immunother Cancer 2017 5 34 10.1186/s40425-017-0236-3 28428883 \n18. Schoch LK Borrello I Fuchs EJ Checkpoint inhibitor therapy and graft versus host disease in allogeneic bone marrow transplant recipients of haploidentical and matched products with post-transplant cyclophosphamide [abstract] Blood 2016 128 22 Abstract 4571 10.1182/blood.V128.22.4571.4571 \n19. Ijaz A Khan AY Malik SU Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation Biol Blood Marrow Transplant 2019 25 1 94 99 10.1016/j.bbmt.2018.08.028 30195074 \n20. Min Lee CK Li S Tran DC Zhu GA Kim J Kwong BY Chang ALS Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study J Am Acad Dermatol 2018 79 6 1047 1052 10.1016/j.jaad.2018.05.035 29857011 \n21. Deol A Lum LG Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited Cancer Treat Rev 2010 36 7 528 538 10.1016/j.ctrv.2010.03.004 20381970\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "7(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "Allogenic hematopoietic cell transplant; Cutaneous T-cell lymphoma; Cutaneous squamous cell carcinoma; Graft versus host disease; Immune checkpoint inhibitors; Pembrolizumab; Sézary syndrome",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D002294:Carcinoma, Squamous Cell; D003131:Combined Modality Therapy; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D000072078:Positron Emission Tomography Computed Tomography; D011182:Postoperative Care; D012751:Sezary Syndrome; D012867:Skin; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": "338",
"pmc": null,
"pmid": "31801591",
"pubdate": "2019-12-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31353944;27269947;28270452;30195074;28468799;29857011;21659460;28679300;20381970;28441111;28428883;27153517;25303977;27069084;28490569;19597183;29863979;25336628;25482239",
"title": "Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for sézary syndrome.",
"title_normalized": "rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for s zary syndrome"
} | [
{
"companynumb": "NVSC2020US021633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
{
"abstract": "This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B-cell non-Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti-CD20 radioimmunotherapy. Patients received InO 1·8 mg/m(2) intravenously on a 28-d cycle for a planned 4-8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty-one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression-free survival was 12·7 (8·9-26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity.",
"affiliations": "John Theurer Cancer Center, HUMC, Hackensack, NJ, USA.;University of Alabama at Birmingham, Birmingham, AL, USA.;Washington University School of Medicine, St. Louis, MO, USA.;Penn State Hershey Cancer Institute, Hershey, PA, USA.;Minnesota Oncology, Minneapolis, MN, USA.;Cancer Institute Hospital, Tokyo, Japan.;Inventiv Health, Cambridge, MA, USA.;Pfizer Inc, New York, NY, USA.;Pfizer Inc, Cambridge, MA, USA.;Nagoya Daini Red Cross Hospital, Nagoya, Japan.",
"authors": "Goy|Andre|A|;Forero|Andres|A|;Wagner-Johnston|Nina|N|;Christopher Ehmann|W|W|;Tsai|Michaela|M|;Hatake|Kiyohiko|K|;Ananthakrishnan|Revathi|R|;Volkert|Angela|A|;Vandendries|Erik|E|;Ogura|Michinori|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000080045:Inotuzumab Ozogamicin",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "174(4)",
"journal": "British journal of haematology",
"keywords": "chemotherapy; inotuzumab ozogamicin; non-Hodgkin lymphoma; radioimmunotherapy; rituximab",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000080045:Inotuzumab Ozogamicin; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D016499:Radioimmunotherapy; D012074:Remission Induction; D016879:Salvage Therapy; D015996:Survival Rate; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "571-81",
"pmc": null,
"pmid": "27101934",
"pubdate": "2016-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy.",
"title_normalized": "a phase 2 study of inotuzumab ozogamicin in patients with indolent b cell non hodgkin lymphoma refractory to rituximab alone rituximab and chemotherapy or radioimmunotherapy"
} | [
{
"companynumb": "JP-ROCHE-1219441",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND Rituximab is a chimeric monoclonal antibody to CD20 that is used to treat vasculitis, B-cell lymphoproliferative disorders, and B-cell non-Hodgkin lymphoma (NHL). A report is presented of a case of rituximab-induced acute thrombocytopenia (RIAT) in a woman with splenic marginal zone lymphoma (SMZL) and chronic hepatitis C virus (HCV) infection. CASE REPORT A 46-year-old woman with SMZL complicated by chronic HCV infection presented with worsening B symptoms of fever, night sweats, and loss of weight. The patient had a history of recreational drug use. Intravenous treatment with rituximab (dose, 375 mg/m²) commenced with close monitoring in hospital. On the following day, the complete blood count (CBC) showed that her platelet count had dropped from her admission level of 167,000/μl to 7,000/μl, with no change in hemoglobin or white blood cell (WBC) levels. A diagnosis of RIAT was made. The patient was managed conservatively and monitored for the development of potential clinical complications. CONCLUSIONS RIAT is a rare complication of treatment with rituximab and may be poorly recognized. Further studies are needed to determine the incidence and causes of thrombocytopenia in patients treated with rituximab and the possible association with chronic viral infections, including HCV.",
"affiliations": "Department of Internal Medicine, University of Missouri School of Medicine, Kansas City, MO, USA.;Department of Internal Medicine, University of Missouri School of Medicine, Kansas City, MO, USA.;Department of Hematology and Oncology, University of Missouri School of Medicine, Kansas City, MO, USA.;Department of Hematology and Oncology, University of Missouri School of Medicine, Kansas City, MO, USA.",
"authors": "Qureini|Aref|A|;Asif|Samia|S|;Harry|Stephanie|S|;Madhusudhana|Sheshadri|S|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.917644",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3154107110.12659/AJCR.917644917644ArticlesA Case of Rituximab-Induced Acute Thrombocytopenia in a Patient with Splenic Marginal Zone Lymphoma and Chronic Hepatitis C Virus Infection Qureini Aref EF1Asif Samia EF1Harry Stephanie EF2Madhusudhana Sheshadri EF2\n1 Department of Internal Medicine, University of Missouri School of Medicine, Kansas City, MO, U.S.A.\n2 Department of Hematology and Oncology, University of Missouri School of Medicine, Kansas City, MO, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Aref Qureini, e-mail: qureinia@umkc.edu2019 21 9 2019 20 1394 1397 20 5 2019 03 7 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 46\n\nFinal Diagnosis: Rituximab induced acute thrombocytopenia\n\nSymptoms: Abdominal discomfort\n\nMedication:\n—\n\nClinical Procedure: —\n\nSpecialty: Hematology\n\nObjective:\nAdverse events of drug therapy\n\nBackground:\nRituximab is a chimeric monoclonal antibody to CD20 that is used to treat vasculitis, B-cell lymphoproliferative disorders, and B-cell non-Hodgkin lymphoma (NHL). A report is presented of a case of rituximab-induced acute thrombocytopenia (RIAT) in a woman with splenic marginal zone lymphoma (SMZL) and chronic hepatitis C virus (HCV) infection.\n\nCase Report:\nA 46-year-old woman with SMZL complicated by chronic HCV infection presented with worsening B symptoms of fever, night sweats, and loss of weight. The patient had a history of recreational drug use. Intravenous treatment with rituximab (dose, 375 mg/m2) commenced with close monitoring in hospital. On the following day, the complete blood count (CBC) showed that her platelet count had dropped from her admission level of 167,000/μl to 7,000/μl, with no change in hemoglobin or white blood cell (WBC) levels. A diagnosis of RIAT was made. The patient was managed conservatively and monitored for the development of potential clinical complications.\n\nConclusions:\nRIAT is a rare complication of treatment with rituximab and may be poorly recognized. Further studies are needed to determine the incidence and causes of thrombocytopenia in patients treated with rituximab and the possible association with chronic viral infections, including HCV.\n\nMeSH Keywords:\nAntibodies, Monoclonal, Murine-DerivedDrug-Related Side Effects and Adverse ReactionsHepatitis C, ChronicLymphoma, B-Cell, Marginal ZoneThrombocytopenia\n==== Body\nBackground\nRituximab is a chimeric monoclonal antibody to CD20 that has been widely used since its approval by the US Food and Drug Administration (FDA) in 1997 to treat vasculitis, B-cell lymphoproliferative disorders, and B-cell non-Hodgkin lymphoma (NHL) [1–3] The use of rituximab has been reported to result in reactivation of hepatitis B virus (HBV) in a patient with carrier status, resulting in hepatic failure [4]. A previously reported multicenter study identified a significant risk of severe hepatotoxicity with rituximab infusion in patients with chronic hepatitis C virus (HCV) infection [5]. Rituximab-induced acute thrombocytopenia (RIAT) has been previously described as the occurrence of thrombocytopenia following rituximab infusion [6–8]. A report is presented of a case of RIAT in a woman with splenic marginal zone lymphoma (SMZL) and chronic HCV infection.\n\nCase Report\nA 46-year-old woman with a diagnosis of splenic marginal zone lymphoma (SMZL) presented with a one-week history of drenching night sweats, abdominal pain, myalgia, fatigue, and flu-like symptoms. The patient had a history of recreational drug use. She reported significant unintentional weight loss over several months. She had been diagnosed with SMLZ four months previously and was diagnosed with chronic hepatitis C virus (HCV) infection. Initially, the plan was to treat the patient for chronic HCV infection, followed by an assessment of the status of her SMZL before considering rituximab and chemotherapy. Because of the known risk associated with the use of rituximab in patients with chronic HCV infection, the initiation of therapy with rituximab was a cause for concern. The gastroenterology service was consulted to provide the patient with HCV treatment plan. However, the patient continued to use illicit drugs and was found to have positive urine drug screen results for methamphetamine and marijuana, which disqualified her for a chronic HCV treatment plan.\n\nOn physical examination, she was found to have hepatosplenomegaly without palpable lymphadenopathy. A complete blood count (CBC) showed a platelet count of 179,000/μl, hemoglobin of 7.9 g/L, and white blood cell (WBC) count of 4,200/μl, which were similar to previous values. A screen for human immunodeficiency virus (HIV) infection was negative, and her liver function tests were normal. Computed tomography (CT) imaging of the abdomen showed an enlarged spleen (craniocaudal diameter, 27 cm) and liver (craniocaudal diameter, 20 cm), and the liver was homogenous in appearance. Mesenteric and retroperitoneal lymphadenopathy was present. Given the severity of her symptoms, the imaging findings, and anticipated delays for HCV treatment, the decision was made to begin treatment with rituximab, without chemotherapy, and with inpatient monitoring. Treatment began with intravenous rituximab at a dose of 375 mg/m2, with pre-treatment that included dexamethasone 10 mg and oral diphenhydramine 50 mg once daily. She was treated with oral naproxen 500 mg bd for generalized pain.\n\nOn the day following the start of rituximab infusion, a repeat CBC showed that the platelet count had dropped from her admission level of 167,000/μl to 7,000/μl, with no change in hemoglobin or WBC levels. Peripheral blood smears were also examined before and after transfusion with rituximab (Figures 1, 2).\n\nDuring the next 12 hours, the patient was transfused with 1 unit of platelets, which raised her platelet count to 24,000/μl. No site of bleeding was identified, and the patient was hemodynamically stable. No heparin had been given during the previous 30 days, which excluded a diagnosis of heparin-induced thrombocytopenia (HIT). An antinuclear antibody panel test was negative.\n\nDuring the week following platelet transfusion, her platelet counts increased, returning to 139,000/μl at the end of one week. Acute severe thrombocytopenia was suspected to be drug-induced, and the drugs considered included naproxen, diphenhydramine, acetaminophen, and rituximab. The pharmacy records showed that the patient had been previously treated with diphenhydramine, acetaminophen, and naproxen, but this was the patient’s first exposure to rituximab. Laboratory tests using flow cytometry were performed to identify drug-associated anti-platelet antibodies. In the flow cytometry method, the patient’s serum was incubated with normal group O target platelets in the presence and absence of drug-bound immunoglobulins, and the fluorescence values obtained in the presence and absence of drug were compared. A fluorescence ratio of ≤2.0 was the cutoff for the detection of drug-dependent antiplatelet antibodies. IgM and IgG antiplatelet antibodies for diphenhydramine, acetaminophen, naproxen, and rituximab were negative.\n\nA diagnosis of rituximab-induced acute thrombocytopenia (RIAT) was made. The patient was managed conservatively and monitored for the development of potential clinical complications.\n\nDiscussion\nThis report presented a case of rituximab-induced acute thrombocytopenia (RIAT) in a 46-year-old woman with splenic marginal zone lymphoma (SMZL) who had a history of chronic hepatitis C virus (HCV) infection. A previously reported cohort study on the mechanisms involved in RIAT showed an incidence of 3% in clinical trials, but in a post-marketing drug study, the incidence was higher, at 20% with a platelet count of <49,000/μl within the 30 days following rituximab infusion [6,7]. Giezen et al. showed that most cases of RIAT occurred within the first ten days after rituximab administration [7]. In 2018, a case report of RIAT and review of the literature published by Omura et al. found that acute thrombocytopenia could occur with rituximab reinfusion, but the incidence and the factors involved in recurrence remain unknown [8]. Ram et al. reported that most cases of RIAT developed on average at 19 hours after rituximab infusion and spontaneous resolution of thrombocytopenia occurred at an average of four days [9].\n\nThe mechanisms involved in the development of RIAT remain to be elucidated. Proposed mechanisms include the presence of CD20 antigen (FcγRIIa) on the platelet surface [8,10], the presence of soluble anti-CD20 antigen in the plasma [11], leading to immune complex formation followed by complement activation and binding of rituximab to Cq1, resulting in the release of cytokines, including tumor necrosis factor-a (TNF-a) [9,12]. Although a previous case report identified the presence of antibodies to rituximab [9], none were detected in the serum of the patient described in the present case report. This finding suggests that a variety of possible mechanisms may lead to RIAT in individual cases. Although the effects of rituximab in our patient were self-limited, there have been previously reported significant adverse effects associated with RIAT, including epistaxis and gastrointestinal bleeding [13,14].\n\nConclusions\nThis report presented a case of rituximab-induced acute thrombocytopenia (RIAT) in a woman with splenic marginal zone lymphoma (SMZL) who had a history of chronic hepatitis C virus (HCV) infection. RIAT is a rare complication of treatment with rituximab and may be poorly recognized. Further studies are needed to determine the incidence and causes of thrombocytopenia in patients treated with rituximab and the possible association with chronic viral infections, including HCV. Because rituximab treatment is often given as an outpatient, blood counts are not routinely examined after rituximab infusion but are usually obtained at weekly or monthly intervals, which means that RIAT may be under-diagnosed. Also, the remaining uncertainties about the incidence and risk factors for RIAT have significant clinical implications, including reluctance to use rituximab and to continue to treat patients with drugs that may have a worse toxicity profile.\n\nConflict of interest\n\nNone.\n\nFigure 1. Peripheral blood smear before rituximab infusion.\n\nFigure 2. Peripheral blood smear after rituximab infusion.\n==== Refs\nReferences:\n1. Pierpont TM Limper CB Richards KL Past, present, and future of rituximab – the world’s first oncology monoclonal antibody therapy Front Oncol 2018 8 163 29915719 \n2. Ramos-Casals M Garcia-Hernandez FJ de Ramon E Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases Clin Exp Rheumatol 2010 28 4 468 76 20525449 \n3. Storz U Rituximab: How approval history is reflected by a corresponding patent filing strategy MAbs 2014 6 4 820 37 24866199 \n4. Tsutsumi Y Yamamoto Y Ito S Hepatitis B virus reactivation with a rituximab-containing regimen World J Hepatol 2015 7 21 2344 51 26413224 \n5. Ennishi D Maeda Y Niitsu N Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: A Japanese multi-center analysis Blood 2010 116 24 5119 25 20823454 \n6. Giezen TJ Mantel-Teeuwisse AK ten Berg MJ Rituximab-induced thrombocytopenia: A cohort study Eur J Haematol 2012 89 3 256 66 22639923 \n7. McLaughlin P Grillo-Lopez AJ Link BK Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program J Clin Oncol 1998 16 8 2825 33 9704735 \n8. Omura Y Shimazu H Takahashi T Rituximab-induced acute thrombocytopenia in a patient with follicular lymphoma: A case report and review of the literature Intern Med 2018 57 8 1151 54 29269668 \n9. Ram R Bonstein L Gafter-Gvili A Rituximab-associated acute thrombocytopenia: an under-diagnosed phenomenon Am J Hematol 2009 84 4 247 50 19260124 \n10. Qiao J Al-Tamimi M Baker RI The platelet Fc receptor, Fcgamma RIIa Immunol Rev 2015 268 1 241 52 26497525 \n11. Manshouri T Do KA Wang X Circulating CD20 is detectable in the plasma of patients with chronic lymphocytic leukemia and is of prognostic significance Blood 2003 101 7 2507 13 12446458 \n12. Michelmann I Bockmann D Nurnberger W Thrombocytopenia and complement activation under recombinant TNF alpha/IFN gamma therapy in man Ann Hematol 1997 74 4 179 84 9174546 \n13. Rigamonti C Volta C Colombi S Severe thrombocytopenia and clinical bleeding associated with rituximab infusion in a lymphoma patient with massive splenomegaly without leukemic invasion Leukemia 2001 15 1 186 87 11243389 \n14. Thachil J Mukherje K Woodcock B Rituximab-induced haemorrhagic thrombocytopenia in a patient with hairy cell leukaemia Br J Haematol 2006 135 2 273 74 16965386\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone; D008875:Middle Aged; D000069283:Rituximab; D013160:Splenic Neoplasms; D013921:Thrombocytopenia",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "1394-1397",
"pmc": null,
"pmid": "31541071",
"pubdate": "2019-09-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16965386;26413224;11243389;29269668;22639923;12446458;29915719;26497525;20525449;19260124;9174546;24866199;20823454;9704735",
"title": "A Case of Rituximab-Induced Acute Thrombocytopenia in a Patient with Splenic Marginal Zone Lymphoma and Chronic Hepatitis C Virus Infection.",
"title_normalized": "a case of rituximab induced acute thrombocytopenia in a patient with splenic marginal zone lymphoma and chronic hepatitis c virus infection"
} | [
{
"companynumb": "US-CELLTRION INC.-2019US027502",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies against inhibitory receptors on T cells resulting in anticancer activity. In kidney transplant (KT) recipients, ICPI use has been associated with acute allograft rejection. In failed allografts, however, the effects of ICPIs are unknown. We present a case of a 66-year-old man with a history of diabetes, renal cell cancer, left native nephrectomy, and end-stage kidney disease. He received a deceased donor KT which failed after 6 years due to biopsy-proven recurrent diabetic nephrosclerosis. He was started on hemodialysis and his immunosuppression was gradually weaned off. A year later, he was diagnosed with renal cell cancer in his right native kidney requiring nephrectomy. He later developed metastasis and was started on combination ICPIs. He developed hematuria, allograft pain, and malaise consistent with graft intolerance syndrome 28 days after starting ICPIs. Urine culture and cystoscopy were normal. A computed tomography scan of his abdomen revealed an enlarged allograft with patchy enhancement. After a multidisciplinary discussion, he underwent transplant nephrectomy. Histopathology showed chronic active T cell-mediated rejection. As ICPI use becomes prevalent, practitioners need to be aware of its potential complications among KT recipients both with functioning and failed allografts.",
"affiliations": "Division of Nephrology and Hypertension, Sidney-Kimmel College of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Division of Surgery, Sidney-Kimmel College of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Division of Nephrology and Hypertension, Sidney-Kimmel College of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Division of Nephrology and Hypertension, Sidney-Kimmel College of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.",
"authors": "Mejia|Christina D|CD|0000-0002-2914-1232;Frank|Adam M|AM|;Singh|Pooja|P|0000-0002-0253-2970;Yadav|Anju|A|0000-0003-0785-8467",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16326",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(3)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "cancer/malignancy/neoplasia; clinical research/practice; immune regulation; immunosuppression/immune modulation; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; rejection",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000368:Aged; D064591:Allografts; D006084:Graft Rejection; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D016030:Kidney Transplantation; D008297:Male; D009392:Nephrectomy; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1322-1325",
"pmc": null,
"pmid": "32976688",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Immune checkpoint inhibitor therapy-associated graft intolerance syndrome in a failed kidney transplant recipient.",
"title_normalized": "immune checkpoint inhibitor therapy associated graft intolerance syndrome in a failed kidney transplant recipient"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-089017",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND\nProton pump inhibitors (PPIs) are among the most widely used drugs around the globe. A growing body of literature, however, has reported numerous side effects, such as hypomagnesemia. Symptoms associated with hypomagnesaemia range from nausea, tetany and cardiac arrhythmias. Treatment of PPI-induced hypomagnesaemia involves discontinuation of the PPI and magnesium supplementation if needed.\n\n\nMETHODS\nA 72-year-old female was admitted to the ICU with omeprazole-induced severe hypomagnesaemia twice during a one-year timespan, clinically manifested by tetany and respiratory failure due to acute decompensated heart failure following new onset atrial fibrillation. After discontinuation of the PPI and intravenous magnesium supplementation she recovered fully.\n\n\nCONCLUSIONS\nHypomagnesaemia is a potentially serious adverse effect of PPIs. Serum magnesium levels should be monitored in chronic PPI-users with any neuromuscular, cardiovascular or non-specific symptoms, especially in the presence of known risk factors (alcohol use, malnutrition, malabsorption, hypertension and concomitant use of diuretics).",
"affiliations": "Martini Ziekenhuis, afd. Intensive Care, Groningen.;Martini Ziekenhuis, afd. Intensive Care, Groningen.;Martini Ziekenhuis, afd. Intensive Care, Groningen.",
"authors": "van den Berg|Sjoerd|S|;Scheer|Margot L J|MLJ|;Holman|Nicole D|ND|",
"chemical_list": "D054328:Proton Pump Inhibitors; D009853:Omeprazole",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "162()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008275:Magnesium Deficiency; D009853:Omeprazole; D054328:Proton Pump Inhibitors",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30182626",
"pubdate": "2018-08-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe hypomagnesaemia due to proton pump inhibitor use.",
"title_normalized": "severe hypomagnesaemia due to proton pump inhibitor use"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-225141",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TORSEMIDE"
},
"drug... |
{
"abstract": "In cancer patients, impairment of kidney function is not uncommon. Recently, the efficacy of the combination of gemcitabine and nab-paclitaxel for pancreatic ductal adenocarcinoma (PDAC) patients has been reported, however, there is no recommendation for dose and administration to patients undergoing hemodialysis (HD). A 66-year-old man began receiving HD for chronic renal failure 4 years previously. He suffered from diarrhea, back pain, and loss of appetite, and his weight gradually decreased. Abdominal dynamic computed tomography showed a 45-mm hypodense mass in the pancreatic body and a 30-mm hypodense mass in the liver. The patient was diagnosed with metastatic PDAC. He started combination chemotherapy of gemcitabine and nab-paclitaxel without dose modification. He developed pneumonia and neutropenia in the first and second courses, so we modified to a 60% dose of gemcitabine and nab-paclitaxel on day 1 every 2 weeks. After dose modification, he continued combination chemotherapy for over 7 months without severe adverse events or tumor progression. Combination chemotherapy using gemcitabine and nab-paclitaxel was effective in a PDAC patient undergoing HD. While it is possible to originally administer these drugs with no dose modification, early dose modification was needed for our patient because of severe adverse events.",
"affiliations": "Department of Gastroenterology, Yokohama Minami Kyosai Hospital, 1-21-1 Mutsuurahigasi, Kanazawa-ku, Yokohama, 2360037, Japan. taku47@yokoham-cu.ac.jp.;Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.;Department of Gastroenterology, Yokohama Minami Kyosai Hospital, 1-21-1 Mutsuurahigasi, Kanazawa-ku, Yokohama, 2360037, Japan.;Department of Gastroenterology, Yokohama Minami Kyosai Hospital, 1-21-1 Mutsuurahigasi, Kanazawa-ku, Yokohama, 2360037, Japan.;Department of Nephrology/Hypertension, Yokohama Minami Kyosai Hospital, Yokohama, Japan.;Department of Gastroenterology, Yokohama Minami Kyosai Hospital, 1-21-1 Mutsuurahigasi, Kanazawa-ku, Yokohama, 2360037, Japan.;Department of Gastroenterology, Yokohama Minami Kyosai Hospital, 1-21-1 Mutsuurahigasi, Kanazawa-ku, Yokohama, 2360037, Japan.;Gastroenterology Division, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.",
"authors": "Kaneko|Takashi|T|http://orcid.org/0000-0001-9368-1658;Sugimori|Kazuya|K|;Tozuka|Yuichiro|Y|;Fukushima|Taito|T|;Okada|Kazuya|K|;Oka|Hiroyuki|H|;Okazaki|Hiroshi|H|;Maeda|Shin|S|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-00976-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "12(5)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Combination chemotherapy; Gemcitabine; Hemodialysis; Nab-paclitaxel; Pancreatic cancer",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D021441:Carcinoma, Pancreatic Ductal; D003841:Deoxycytidine; D017809:Fatal Outcome; D006801:Humans; D007676:Kidney Failure, Chronic; D008113:Liver Neoplasms; D008297:Male; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D010530:Peritoneal Dialysis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "484-489",
"pmc": null,
"pmid": "30993653",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12655447;17009648;17826617;18270381;18476951;18723487;19406977;20118214;20349418;21561347;21709400;21969517;22585996;24131140;24621160;24882381;25648269;25874862;26199247;26842789;27247222;27284481;28123593",
"title": "Combination chemotherapy with gemcitabine and nab-paclitaxel for a metastatic pancreatic ductal adenocarcinoma patient undergoing hemodialysis.",
"title_normalized": "combination chemotherapy with gemcitabine and nab paclitaxel for a metastatic pancreatic ductal adenocarcinoma patient undergoing hemodialysis"
} | [
{
"companynumb": "JP-ACCORD-125221",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Cancers of the colon are commonly treated with fluoropyrimidines, which often cause severe toxicities in patients with certain variants in DPYD. Y186C (rs115232898) and a variant in the 3' untranslated region (rs12132152) are uncommon alleles previously observed in African-Americans. An African-American female underwent 5-fluorouracil-based therapy (400 mg/m2 bolus, 1200 mg/m2/day over 46 h). The patient experienced severe pancytopenia after the first cycle. After 5-fluorouracil (5-FU) dose reduction (600 mg/m2/day), the steady-state 5-FU plasma concentration became 474 ng/ml (range 301-619 ng/ml) and increased following a subsequence dose increase (800 mg/m2/day; 1248 ng/ml). After a 1000 mg/m2/day dose resulted in myelosuppression, 5-FU was again de-escalated for the remaining cycles (600 mg/m2). The observed complications are likely a function of uncommon genetic variants that affect DPYD metabolism.",
"affiliations": "Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.;Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.;Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.;Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.;Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.;Laboratory of Tumor Immunology & Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.;Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.",
"authors": "Sissung|Tristan M|TM|0000-0002-3684-5377;Cordes|Lisa|L|0000-0003-3833-4084;Peer|Cody J|CJ|0000-0001-9395-3473;Gandhy|Shruti|S|;Redman|Jason|J|0000-0001-8200-0167;Strauss|Julius|J|0000-0002-7550-4938;Figg|William D|WD|0000-0003-2428-5613",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2020-0120",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "22(2)",
"journal": "Pharmacogenomics",
"keywords": null,
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D001741:African Americans; D000483:Alleles; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil; D006579:Heterozygote; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged; D011110:Polymorphism, Genetic",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "81-85",
"pmc": null,
"pmid": "33305610",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "24388031;26894782;28850174;23695028;24647007;20217574;23588312;26432245;29152729;27569869;29545919;18085512;31653159;26716401",
"title": "Case report: severe toxicity in an African-American patient receiving FOLFOX carrying uncommon allelic variants in DPYD.",
"title_normalized": "case report severe toxicity in an african american patient receiving folfox carrying uncommon allelic variants in dpyd"
} | [
{
"companynumb": "US-TEVA-2021-US-1887731",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "Intravenous lipid rescue therapy (LRT) may be implemented to attenuate drug toxicity. Little is known about LRT interference with laboratory tests in overdose settings. A 54-year-old man with a history of depression consumed unknown amounts of diphenhydramine, amitriptyline, and acetaminophen (APAP). Initial workup showed aspartate aminotransferase (AST) of 138 U/L, APAP of 177 μg/mL, and a QRS interval of 136 milliseconds. N-acetylcysteine, sodium bicarbonate, and 20% intravenous LRT were initiated. Laboratory test results drawn less than 6 hours later showed an APAP level of 44 μg/mL and an undetectable AST (Siemens Vista 1500 analyzer, lower limit of detection: alanine aminotransferase, 6 U/L; AST, 3 U/L). N-acetylcysteine and LRT infusions were stopped. Eight hours later, serum AST was measured at 488 U/L and increased over the next 2 days to a peak of 1600 U/L before recovery. Given a gradually rising course of AST following APAP ingestion, a single undetectable measurement is highly unlikely and probably erroneous. For this Siemens analyzer, serum lipid concentrations greater than 400 mg/dL cause interference with the AST measurement. Because lipid levels greater than 400 mg/dL with other similar analyzers are known to falsely decrease the AST, it is possible that extreme lipemia caused this laboratory result; a triglyceride level of 3648 mg/dL has been reported after LRT infusion. This conclusion is limited by the lack of repeat measurement of liver enzymes or measurement of serum lipid levels. Lipid rescue therapy may cause lipemia that interferes with the assay for liver enzymes. Suspected abnormal laboratory values should be repeated, or other techniques can be used to remove lipemic interference.",
"affiliations": "Georgia Poison Center, Atlanta, GA 30303, USA; Emergency Medicine, Emory University, Atlanta, GA, USA. Electronic address: mpunja2@emory.edu.",
"authors": "Punja|Mohan|M|;Neill|Stewart G|SG|;Wong|Stella|S|",
"chemical_list": "D005217:Fat Emulsions, Intravenous; D000639:Amitriptyline; D000082:Acetaminophen; D004155:Diphenhydramine; D001219:Aspartate Aminotransferases",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "31(10)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000082:Acetaminophen; D000639:Amitriptyline; D001219:Aspartate Aminotransferases; D004155:Diphenhydramine; D062787:Drug Overdose; D005188:False Negative Reactions; D005217:Fat Emulsions, Intravenous; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1536.e1-2",
"pmc": null,
"pmid": "23932123",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Caution with interpreting laboratory results after lipid rescue therapy.",
"title_normalized": "caution with interpreting laboratory results after lipid rescue therapy"
} | [
{
"companynumb": "US-MYLANLABS-2019M1062355",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "Permanent chemotherapy-induced alopecia (PCIA) has been described following high-dose chemotherapy regimens for allogeneic bone marrow transplants; however, reports of PCIA in breast cancer patients are increasing. Many prior reports involve treatment with taxanes, but the role of endocrine therapies has not been well defined. Permanent alopecia in breast cancer patients appears to be a potential adverse effect of taxanes and endocrine therapies. Although the cytotoxic effects of taxanes may lead to permanent hair loss, the influence of endocrine therapies on the remaining follicles may affect the pattern of hair loss. Further characterization of these cases may elucidate risk factors for developing permanent alopecia, allowing for more appropriate risk stratification and counseling. We describe 3 patients with breast cancer who experienced PCIA following chemotherapy with taxanes.",
"affiliations": "Dr. Slaught is from the Department of Dermatology, Oregon Health and Science University, Portland. Dr. Roman is from the Department of Psychiatry, University of Pennsylvania, Philadelphia. Dr. Yashar is from the Dermatology Service, Veterans Affairs Greater Los Angeles Healthcare System, California. Drs. Holland and Goh are from the Department of Medicine, Division of Dermatology, UCLA Medical Center, Los Angeles.;Dr. Slaught is from the Department of Dermatology, Oregon Health and Science University, Portland. Dr. Roman is from the Department of Psychiatry, University of Pennsylvania, Philadelphia. Dr. Yashar is from the Dermatology Service, Veterans Affairs Greater Los Angeles Healthcare System, California. Drs. Holland and Goh are from the Department of Medicine, Division of Dermatology, UCLA Medical Center, Los Angeles.;Dr. Slaught is from the Department of Dermatology, Oregon Health and Science University, Portland. Dr. Roman is from the Department of Psychiatry, University of Pennsylvania, Philadelphia. Dr. Yashar is from the Dermatology Service, Veterans Affairs Greater Los Angeles Healthcare System, California. Drs. Holland and Goh are from the Department of Medicine, Division of Dermatology, UCLA Medical Center, Los Angeles.;Dr. Slaught is from the Department of Dermatology, Oregon Health and Science University, Portland. Dr. Roman is from the Department of Psychiatry, University of Pennsylvania, Philadelphia. Dr. Yashar is from the Dermatology Service, Veterans Affairs Greater Los Angeles Healthcare System, California. Drs. Holland and Goh are from the Department of Medicine, Division of Dermatology, UCLA Medical Center, Los Angeles.;Dr. Slaught is from the Department of Dermatology, Oregon Health and Science University, Portland. Dr. Roman is from the Department of Psychiatry, University of Pennsylvania, Philadelphia. Dr. Yashar is from the Dermatology Service, Veterans Affairs Greater Los Angeles Healthcare System, California. Drs. Holland and Goh are from the Department of Medicine, Division of Dermatology, UCLA Medical Center, Los Angeles.",
"authors": "Slaught|Christa|C|;Roman|Michael|M|;Yashar|Sharona|S|;Holland|Vanessa|V|;Goh|Carolyn|C|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids",
"country": "United States",
"delete": false,
"doi": "10.12788/cutis.0215",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "107(3)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000505:Alopecia; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D043823:Taxoids",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "E17-E22",
"pmc": null,
"pmid": "33956617",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Permanent Alopecia in Breast Cancer Patients: Role of Taxanes and Endocrine Therapies.",
"title_normalized": "permanent alopecia in breast cancer patients role of taxanes and endocrine therapies"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-22884",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOCINONIDE"
},
"drugaddition... |
{
"abstract": "Infection with nontuberculous mycobacteria (NTM) is uncommon in the head and neck; therefore there is no clear consensus on treating these infections. Our objective was to report our experience with a unique case of NTM infection of the parotid in an immunocompetent patient, in order to determine appropriate management through our experience with this pathology. A 57-year-old man, known for numerous comorbid diseases, presented to our institution complaining of right parotid swelling and pain. A computed tomography (CT) of the neck showed a multiloculated collection in the inferior portion of the right parotid gland, compatible with abscess formation. This abscess was drained by interventional radiology (IR) but required repeat drainage twice due to lack of initial improvement. He was treated with several antibiotics as culture results initially indicated Gram-positive bacilli and then Mycobacterium species, with final identification by a reference laboratory as Mycobacterium abscessus. Imipenem was initiated with amikacin and clarithromycin. His infection clinically and radiologically resolved after 5 months of antibiotherapy. In our case, the patient improved following intravenous antibiotic therapy. Our experience demonstrates that appropriate antibiotherapy can lead to resolution of Mycobacterium abscessus infection in the parotid without the risks associated with surgical intervention.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2.;Department of Otolaryngology-Head and Neck Surgery, Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2.;Department of Medicine, Division of Infectious Diseases, Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2.;Department of Otolaryngology-Head and Neck Surgery, Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2.",
"authors": "Kay-Rivest|Emily|E|0000-0002-4085-4532;Bouhabel|Sarah|S|;Oughton|Matthew Thomas|MT|;Hier|Michael Peter|MP|0000-0001-8352-1917",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/4324525",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2016/4324525Case ReportMedical Management for the Treatment of Nontuberculous Mycobacteria Infection of the Parotid Gland: Avoiding Surgery May Be Possible http://orcid.org/0000-0002-4085-4532Kay-Rivest Emily \n1\nBouhabel Sarah \n1\nOughton Matthew Thomas \n2\nhttp://orcid.org/0000-0001-8352-1917Hier Michael Peter \n1\n\n*\n1Department of Otolaryngology-Head and Neck Surgery, Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E22Department of Medicine, Division of Infectious Diseases, Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2*Michael Peter Hier: mhier@ent.jgh.mcgill.caAcademic Editor: Florian Thalhammer\n\n2016 1 6 2016 2016 432452528 3 2016 21 4 2016 Copyright © 2016 Emily Kay-Rivest et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Infection with nontuberculous mycobacteria (NTM) is uncommon in the head and neck; therefore there is no clear consensus on treating these infections. Our objective was to report our experience with a unique case of NTM infection of the parotid in an immunocompetent patient, in order to determine appropriate management through our experience with this pathology. A 57-year-old man, known for numerous comorbid diseases, presented to our institution complaining of right parotid swelling and pain. A computed tomography (CT) of the neck showed a multiloculated collection in the inferior portion of the right parotid gland, compatible with abscess formation. This abscess was drained by interventional radiology (IR) but required repeat drainage twice due to lack of initial improvement. He was treated with several antibiotics as culture results initially indicated Gram-positive bacilli and then Mycobacterium species, with final identification by a reference laboratory as Mycobacterium abscessus. Imipenem was initiated with amikacin and clarithromycin. His infection clinically and radiologically resolved after 5 months of antibiotherapy. In our case, the patient improved following intravenous antibiotic therapy. Our experience demonstrates that appropriate antibiotherapy can lead to resolution of Mycobacterium abscessus infection in the parotid without the risks associated with surgical intervention.\n==== Body\n1. Introduction\nAlthough infection with nontuberculous mycobacteria (NTM) is uncommon in the head and neck region, isolating these organisms in the parotid gland is even less common. The parotid gland in particular, unlike other salivary glands, has lymph nodes that are within the parenchyma of the gland itself, making treatment with antibiotherapy more challenging. Parotid gland infections are usually caused by pathogens such as Staphylococcus aureus and anaerobic bacteria [1] and only in rare cases are secondary to a mycobacterial infection. Mycobacteria can be classified into three main groups: the bacteria that cause tuberculosis (M. tuberculosis), the bacteria causing leprosy (M. leprae), and finally all the others, collectively known as nontuberculous mycobacteria. In general, these organisms most commonly lead to pulmonary disease. It is reported that over 150 different species of NTM exist, and the most commonly discussed ones are the members of the Mycobacterium avium complex (MAC) [2]. A rarer species, Mycobacterium abscessus, is a Gram-positive, acid-fast rod that belongs to the group of rapid-growing NTM. In this report, we describe a case of a Mycobacterium abscessus parotid gland abscess in an immunocompetent, adult patient. We also review previous literature describing NTM infections of the parotid gland in order to attempt identification of appropriate management for this pathology. At this time, it is unclear whether surgical intervention or medical management is the preferred treatment modality.\n\n2. Case Presentation\nOn June 5, 2014, a 57-year-old man presented to the emergency department of our institution, complaining of right parotid swelling and pain for the past two weeks. His past medical history consisted of type II diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, and severe peripheral vascular disease requiring several surgical interventions and long-term anticoagulation on warfarin. He was not taking immunosuppressant medication. He reported having woken up with a large, swollen, and nonprogressive mass on the right cheek. It was described as tender and caused dysphagia (to solids more than liquids). The week prior to arrival in hospital, the patient had been treated with a seven-day course of oral penicillin following a dental procedure. It remains unclear why the patient was placed on prophylactic antibiotics following the dental procedure, as he had no history of artificial heart valves, no history of infective endocarditis, and no other congenital heart conditions. On presentation, his vital signs were normal and he was afebrile. His physical exam showed a 4 cm × 3 cm tender, nonfluctuant right neck mass just below the angle of the mandible. The rest of the physical exam was unremarkable. His white blood cell count (WBC) was slightly elevated at 12.7. HIV testing was negative. A computed tomography (CT) of the neck showed a multiloculated collection in the inferior portion of the right parotid gland, with rim and septal enhancement, compatible with an abscess formation. It showed direct involvement of the right sternocleidomastoid muscle with edematous changes and thickening. The infectious disease (ID) service was contacted and the patient was empirically started on piperacillin-tazobactam 4.5 g IV q8h, which he received until day 5 after admission. Given the CT findings, the decision was made to proceed to drainage of the abscess by interventional radiology on day 1 of admission; three milliliters (cc) of pus was drained and sent for culture, with initial results demonstrating aerobic Gram-positive bacilli. The patient did not improve following this intervention; in fact, his condition worsened and the abscess increased in size. At this time, piperacillin-tazobactam was changed to meropenem 1 g IV q8h. Vancomycin 1.25 g IV q12h was also started but stopped on day 6 after admission when screening swabs and abscess cultures were negative for methicillin-resistant Staphylococcus aureus (MRSA). The patient's clinical status did not improve despite the antibiotic changes and he was brought back for a second ultrasound-guided aspiration and pigtail insertion on day 5 after admission, with further 10 cc of purulent fluid being drained. Following this second intervention, the swelling improved and the patient was discharged home on meropenem IV. Blood cultures remained negative throughout. When the patient was seen in the outpatient Otolaryngology-Head and Neck Surgery (OTL-HNS) clinic on June 19, 2014 (20 days after initial presentation), a dramatic clinical improvement was noted. Although complete resolution had not yet been achieved, a major decrease in the swelling was described. There was a slight yellow-coloured ooze noted from the area. The patient was otherwise afebrile and well. The decision was made to drain the remaining fluid once again. Based on cultures staining positive for acid-fast bacilli and initial MALDI-TOF analysis consistent with Mycobacterium species (possibly M. tuberculosis or M. bovis), quadruple therapy for M. tuberculosis (isoniazid, rifampin, pyrazinamide, and ethambutol) was initiated, and the meropenem was continued pending final results. By July 7 (day 38 after initial presentation), the provincial reference laboratory identified the organism as Mycobacterium abscessus, and antibiotherapy was changed to imipenem 500 mg IV q6h plus amikacin 900 mg (10 mg/kg for a 90 kg patient) IV q24h. On the July 17, 2014, during a follow-up visit to the ID clinic, clarithromycin 500 mg PO BID was added to the patient's treatment regimen. This represented the standard therapy for mycobacterial infections: induction with imipenem and amikacin followed by clarithromycin treatment.\n\nOn July 27, 2014, the patient was admitted to hospital for a gastrointestinal bleed, with a supratherapeutic INR of 6.0. Infectious diseases were consulted to follow the neck mass. The ID team attributed the increase in INR to the concomitant use of broad-spectrum antibiotics along with warfarin. They suggested continuing the imipenem and amikacin, restarting clarithromycin after bleeding was controlled, and daily monitoring of his INR. Furthermore, a work-up was done for immunodeficiencies but all tests came back as normal. All serologies were also found to be negative. Amikacin was subsequently stopped after one month due to ototoxicity (mild loss of ultrahigh frequency range hearing) detected on serial audiometry. However, imipenem and clarithromycin were continued for an additional four months. Serial CT imaging of his neck in November and December showed complete resolution of the fluid components of the abscess.\n\n3. Discussion\nAs noted in the few other existing case reports, nontuberculous mycobacterial infection of the parotid gland is quite rare, especially in adults who are immunocompetent. Most of the literature describing this pathology is within the field of pediatrics or among adults with HIV infection. Very few case reports describe immunocompetent adults with NTM infection of the parotid.\n\nIn our case, despite the fact that our patient was not immunocompromised, the diagnosis of diabetes mellitus is significant, as it is a well-known risk factor for developing parotitis [3]. It is thought that diabetes may lead to “changes in the composition of saliva, duct obstruction, and reduced immunity,” making the patient more susceptible to infections of the parotid gland [4].\n\nIt remains difficult to assess what may have led to this unusual infection in this immunocompetent patient. Some reports suggest that the most likely cause of infection is by direct ingestion of the pathogen [5]. NTM are found throughout the environment, in water, food, and soil. As ingestion is a possible mechanism of infection, this may explain why children are more at risk of contracting these types of infections. Interestingly, in April 2016 the Centers for Disease Control and Prevention published a review of M. abscessus infections among patients of a pediatric dentistry practice in Georgia, USA. They describe a cluster of 9 cases of confirmed or suspected infections related to common source exposure: water rinse in the dentist's office [6]. Nonetheless, despite this isolated event, no other reported contemporaneous cases are present in the literature. We do not believe that the dental procedure that he underwent prior to developing this infection was the cause. It is also unclear why MALDI-TOF analysis identified this organism as possible M. tuberculosis or M. bovis, as these slow-growing mycobacteria are significantly different from the rapid-growing M. abscessus; an error in sample processing or preparation may have occurred.\n\nMany different treatment modalities for NTM infection of the parotid gland lymph nodes are described in the few existing reports. Shah and Haddad Jr. report that surgical excision of the parotid gland is considered more effective than antibiotic treatment [7]. In their experience, they describe three patients with NTM parotid adenitis (all children between 15 and 30 months of age). In two of their patients, disease improvement was not seen with prolonged antibiotherapy and only resolved after surgical intervention. In the third patient, surgical excision was planned from the start, with a preoperative course of clarithromycin and good postoperative resolution. In another case series performed by Lindeboom et al. (done in children and encompassing all cervicofacial NTM infections), surgical removal of tissues infected with NTM was successful in 96% of patients, compared to a 66% rate of complete regression when the infection was treated with antibiotics alone [8]. Furthermore, only one report published showed successful results with a combination of abscess drainage and antibiotic treatment [9]. In our case, initial drainage by interventional radiology along with antibiotic treatment resulted in slow resolution. The patient required repeated drainage in interventional radiology and resolved with long-term intravenous antibiotic therapy. The patient did achieve complete resolution, despite the delay in pathogen identification and proper treatment. Although several case reports describe better outcomes with surgical intervention preceded by antibiotherapy, complete surgical excision of a parotid gland is not without risks, particularly in an abscessed gland. There always exists the chance of injury to the facial nerve, which can leave the patient with permanent hemifacial paralysis. There is also the risk of Frey syndrome, numbness along the distribution of the greater auricular nerve, bleeding and hematoma, and seroma formation. On the other hand, certain antibiotics given in the long term can be associated with side-effects such as ototoxicity (amikacin). Overall, it is necessary to weigh the risks of surgery compared to its benefits, but combined antimicrobial therapy appears to be a reasonable alternative to surgery.\n\n4. Conclusion\nAs mentioned above, NTM infection of the parotid gland is a rare entity. To our knowledge, a total of five case reports exist describing this type of infection in adults, with only two in an immunocompetent individual ([4, 10–13], summarized in Table 1). Given the rarity of the disease, there is no established “gold standard” at this time for treatment. The literature proposes that a combined surgical and medical approach with close follow-up may be the preferred method for management of NTM infections of the parotid gland. However, our experience demonstrates that using appropriate antibiotherapy can also lead to resolution without the risks associated with surgery.\n\nAcknowledgments\nThe authors acknowledge the Department of Medicine, Division of Infectious Diseases, for their help.\n\nConsent\nFull patient consent was received prior to preparation of this paper.\n\nCompeting Interests\nNone of the authors have any competing interests in the paper.\n\nAuthors' Contributions\nEmily Kay-Rivest carried out the data collection and drafting of the paper. All authors contributed to the redaction of the paper and approved its final form.\n\nTable 1 Summary of case reports of NTM parotid infection in adults.\n\nStudy\tNumber of cases\tBacteria\tComorbid disease\tTreatment modality\t\n Benharrats et al. 1998 [11]\t1 case\t\nM. xenopi\n\tHIV positive\tAntibiotics alone\t\nLawn et al. 2005 [10]\t1 case\t\nM. scrofulaceum\n\tHIV positive\tAntibiotics alone\t\nGittinger et al. 2008 [4]\t1 case\t\nM. avium\n\tRheumatoid arthritis, DMII secondary to steroids\tSurgical excision and then antibiotics\t\nPadovani et al. 2007 [13]\t1 case\tNTM\tNone cited\tSurgical excision\t\n Yamanaka et al. 2013 [12]\t1 case\t\nM. fortuitum or M. chelonae (suspected)\n\tNone\tAntibiotics alone\n==== Refs\n1 Brook I. The bacteriology of salivary gland infections Oral and Maxillofacial Surgery Clinics of North America 2009 21 3 269 274 10.1016/j.coms.2009.05.001 2-s2.0-67650150847 19608044 \n2 Johnson M. M. Odell J. A. Nontuberculous mycobacterial pulmonary infections Journal of Thoracic Disease 2014 6 3 210 220 10.3978/j.issn.2072-1439.2013.12.24 2-s2.0-84896028580 24624285 \n3 Thiede O. Stoll W. Schmal F. Clinical aspects of abscess development in parotitis HNO 2001 50 332 338 12063691 \n4 Gittinger F. S. Raible A. Kempf V. A. J. Non-tuberculous mycobacterial infection of the parotid gland in an immunosuppressed adult Journal of Medical Microbiology 2008 57 4 536 539 10.1099/jmm.0.47698-0 2-s2.0-42149164256 18349380 \n5 Green P. A. von Reyn C. F. Smith R. P. Mycobacterium avium complex parotid lymphadenitis: successful therapy with clarithromycin and ethambutol Pediatric Infectious Disease Journal 1993 12 7 615 617 10.1097/00006454-199307000-00015 2-s2.0-0027158440 8346008 \n6 Peralta G. Tobin-D’Angelo M. Parham A. Notes from the field: Mycobacterium abscessus infections among patients of a pediatric dentistry practice—Georgia, 2015 Morbidity and Mortality Weekly Report 2016 65 355 356 10.15585/mmwr.mm6513a5 27054966 \n7 Shah M. B. Haddad J. Jr. Nontuberculous mycobacteria-induced parotid lymphadenitis successfully limited with clarithromycin and rifabutin Laryngoscope 2004 114 8 1435 1437 10.1097/00005537-200408000-00023 2-s2.0-3843051434 15280723 \n8 Lindeboom J. A. Kuijper E. J. Van Coppenraet E. S. B. Lindeboom R. Prins J. M. Surgical excision versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children: a multicenter, randomized, controlled trial Clinical Infectious Diseases 2007 44 8 1057 1064 10.1086/512675 2-s2.0-33947525207 17366449 \n9 Losurdo G. Castagnola E. Cristina E. Cervical lymphadenitis caused by nontuberculous mycobacteria in immunocompetent children: clinical and therapeutic experience Head & Neck 1998 20 3 245 249 10.1002/(sici)1097-0347(199805)20:3<245::aid-hed10>3.0.co;2-j 2-s2.0-0031895228 9570631 \n10 Lawn S. D. Checkley A. Wansbrough-Jones M. H. Acute bilateral parotitis caused by Mycobacterium scrofulaceum : immune reconstitution disease in a patient with AIDS Sexually Transmitted Infections 2005 81 6 517 518 10.1136/sti.2005.014993 2-s2.0-29144499334 16326858 \n11 Benharrats I. Jacob L. Taulera O. Paroditis due to mycobacterium and HIV infection Revue de Medecine Interne 1998 19 9 676 677 10.1016/s0248-8663(99)80052-6 2-s2.0-0031659338 9793160 \n12 Yamanaka T. Okamoto H. Hosoi H. Non-tuberculous mycobacterial infection of the parotid gland in an immunocompetent elderly patient BMJ Case Reports 2013 10.1136/bcr-2013-200990 2-s2.0-84886711823 \n13 Padovani D. Aimoni C. Grasso D. L. Pastore A. Non tuberculous mycobacteria infection of the parotid region: two familiar cases Auris Nasus Larynx 2007 34 4 577 579 10.1016/j.anl.2007.07.012 2-s2.0-35348997324 17919868\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2016()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "4324525",
"pmc": null,
"pmid": "27340407",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "12063691;15280723;16326858;17366449;19608044;9793160;24624285;24132446;17919868;9570631;8346008;18349380;27054966",
"title": "Medical Management for the Treatment of Nontuberculous Mycobacteria Infection of the Parotid Gland: Avoiding Surgery May Be Possible.",
"title_normalized": "medical management for the treatment of nontuberculous mycobacteria infection of the parotid gland avoiding surgery may be possible"
} | [
{
"companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2016-03913",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMIPENEM"
},
"drugadditional"... |
{
"abstract": "A trisomy 21 neonate presented with congenital chylous pleural effusion and ascites that was refractory to conventional pharmacotherapy. Midodrine, an oral alpha-1-adrenoreceptor agonist, achieved remission of chylous effusion without any adverse effects. To the best of our knowledge, this is the first neonatal case of successful management of congenital chylous pleural effusion and ascites with midodrine.",
"affiliations": "Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. Electronic address: rainbow09tama21@yahoo.co.jp.;Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.;Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.;Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.;Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.",
"authors": "Tamaoka|Satoshi|S|;Osada|Asami|A|;Kin|Takane|T|;Arimitsu|Takeshi|T|;Hida|Mariko|M|",
"chemical_list": "D058646:Adrenergic alpha-1 Receptor Agonists; D008879:Midodrine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2020.10.071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "159(4)",
"journal": "Chest",
"keywords": "congenital chylothorax; congenital chylous ascites; midodrine; neonate; trisomy 21",
"medline_ta": "Chest",
"mesh_terms": "D058646:Adrenergic alpha-1 Receptor Agonists; D000328:Adult; D002916:Chylothorax; D002915:Chylous Ascites; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008879:Midodrine; D010996:Pleural Effusion; D011247:Pregnancy",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e189-e191",
"pmc": null,
"pmid": "34022016",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Midodrine, an Oral Alpha-1 Adrenoreceptor Agonist, Successfully Treated Refractory Congenital Chylous Pleural Effusion and Ascites in a Neonate.",
"title_normalized": "midodrine an oral alpha 1 adrenoreceptor agonist successfully treated refractory congenital chylous pleural effusion and ascites in a neonate"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1027005",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
},
"drugadditional": null,
... |
{
"abstract": "Treatment with antiseizure medications (ASMs) confers a risk of drug-induced liver injury (DILI), especially for older ASMs. We sought to quantify recent reports of DILI attributed to both older and newer generation ASMs and survey newly marketed ASMs for hepatotoxicity in a large post-marketing database.\n\n\n\nWe queried over 2.6 million adverse event reports made to the FDA Adverse Event Reporting System (FAERS) database between July 1, 2018 and March 31, 2020 for DILI due to ASMs commonly used in clinical practice. Patient characteristics and outcomes were assessed. We calculated the reporting odds ratio (ROR) of DILI for each individual ASM versus all non-ASM reports.\n\n\n\nA total of 2175 DILI cases were attributed to an ASM during the study period. 97.2% of these were designated as serious reactions, which include death, hospitalization, disability, and other life-threatening outcomes. A number of older and newer generation ASMs were associated with DILI, specifically: carbamazepine (ROR 2.92), phenobarbital (ROR 2.91), oxcarbazepine (ROR 2.58), phenytoin (ROR 2.40), valproate (ROR 2.22), lamotrigine (ROR 2.06), clobazam (ROR 1.67), levetiracetam (ROR 1.56), and diazepam (ROR 1.53). However, increased odds of DILI were not seen with zonisamide, perampanel, stiripentol, lacosamide, clonazepam, pregabalin, felbamate, eslicarbazepine, cannabidiol, topiramate, gabapentin, ethosuximide, brivaracetam, or primidone. Vigabatrin, tiagabine, and rufinamide all had zero reports of DILI.\n\n\n\nThe majority of newer generation ASMs were not significantly associated with DILI. Future studies utilizing FAERS in conjunction with other data sources will be critical for the ongoing surveillance of DILI, particularly as newly marketed ASMs continue to enter into widespread clinical use.",
"affiliations": "Rutgers-Robert Wood Johnson Medical School, Department of Neurology, 125 Paterson Street Suite 6200, New Brunswick, NJ 08901, United States. Electronic address: brad.kamitaki@rutgers.edu.;Rutgers-Robert Wood Johnson Medical School, Department of Medicine, Division of Gastroenterology and Hepatology, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States; Center for Liver Diseases and Liver Masses, Rutgers-Robert Wood Johnson Medical School, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States.;Rutgers-Robert Wood Johnson Medical School, Department of Neurology, 125 Paterson Street Suite 6200, New Brunswick, NJ 08901, United States.;Rutgers-Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08901, United States.;Rutgers-Robert Wood Johnson Medical School, Department of Medicine, Division of Gastroenterology and Hepatology, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States; Center for Liver Diseases and Liver Masses, Rutgers-Robert Wood Johnson Medical School, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States.;Rutgers-Robert Wood Johnson Medical School, Department of Medicine, Division of Gastroenterology and Hepatology, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States; Center for Liver Diseases and Liver Masses, Rutgers-Robert Wood Johnson Medical School, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States.;Rutgers-Robert Wood Johnson Medical School, Department of Medicine, Division of Gastroenterology and Hepatology, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States; Center for Liver Diseases and Liver Masses, Rutgers-Robert Wood Johnson Medical School, 125 Paterson Street Suite 5100B, New Brunswick, NJ 08901, United States.",
"authors": "Kamitaki|Brad K|BK|;Minacapelli|Carlos D|CD|;Zhang|Pengfei|P|;Wachuku|Christopher|C|;Gupta|Kapil|K|;Catalano|Carolyn|C|;Rustgi|Vinod|V|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2021.107832",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "117()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "ASM; Anticonvulsant; DILI; Hepatotoxicity; Pharmacovigilance",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000927:Anticonvulsants; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D010672:Phenytoin; D014481:United States",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "107832",
"pmc": null,
"pmid": "33626490",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug-induced liver injury associated with antiseizure medications from the FDA Adverse Event Reporting System (FAERS).",
"title_normalized": "drug induced liver injury associated with antiseizure medications from the fda adverse event reporting system faers"
} | [
{
"companynumb": "US-UCBSA-2021013413",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Data on ocular manifestations of inflammatory bowel disease (IBD) in children are limited. Some authors have reported a high prevalence of asymptomatic uveitis, yet the significance of these observations is unknown and there are no recommendations on which ophthalmologic follow-up should be offered.\n\n\n\nChildren with IBD seen at a single referral center for pediatric gastroenterology were offered ophthalmologic evaluation as part of routine care for their disease. Ophthalmologic evaluation included review of ocular history as well as slit-lamp and fundoscopic examination. Medical records were also reviewed for previous ophthalmologic diagnoses or complaints.\n\n\n\nData from 94 children were included (52 boys; median age 13.4 yr). Forty-six patients had a diagnosis of Crohn's disease, 46 ulcerative colitis, and 2 IBD unclassified. Intestinal disease was in clinical remission in 70% of the patients; fecal calprotectin was elevated in 64%. One patient with Crohn's disease had a previous diagnosis of clinically manifest uveitis (overall uveitis prevalence: 1.06%; incidence rate: 0.3 per 100 patient-years). This patient was also the only one who was found to have asymptomatic uveitis at slit-lamp examination. A second patient had posterior subcapsular cataract associated with corticosteroid treatment. No signs of intraocular complications from previous unrecognized uveitis were observed in any patient.\n\n\n\nChildren with IBD may have asymptomatic uveitis, yet its prevalence seems lower than previously reported, and it was not found in children without a previous diagnosis of clinically manifest uveitis. No ocular complications from prior unrecognized uveitis were observed.",
"affiliations": "*Department of Medicine, Surgery, and Health Sciences, University of Trieste, Trieste, Italy; and †Institute for Maternal and Child Health IRCCS \"Burlo Garofolo,\" Trieste, Italy.",
"authors": "Naviglio|Samuele|S|;Parentin|Fulvio|F|;Nider|Silvia|S|;Rassu|Nicolò|N|;Martelossi|Stefano|S|;Ventura|Alessandro|A|",
"chemical_list": "D039841:Leukocyte L1 Antigen Complex",
"country": "England",
"delete": false,
"doi": "10.1097/MIB.0000000000001079",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "23(6)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005243:Feces; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases; D007558:Italy; D039841:Leukocyte L1 Antigen Complex; D008297:Male; D012074:Remission Induction; D014605:Uveitis",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "986-990",
"pmc": null,
"pmid": "28328621",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ocular Involvement in Children with Inflammatory Bowel Disease.",
"title_normalized": "ocular involvement in children with inflammatory bowel disease"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1044798",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
... |
{
"abstract": "Leukopenia is a known hematological side effect of atypical antipsychotics. We report a case of an antipsychotic-naive patient with schizophrenia who developed leukopenia after a single dose of olanzapine, which worsened during subsequent treatment with risperidone. Normalization of the white blood cell counts occurred within 24 hours of risperidone discontinuation. Possible synergistic mechanisms underlying olanzapine-induced and risperidone-induced leukopenia are discussed. This case highlights the challenges in identifying and managing nonclozapine antipsychotic-induced leukopenia in a susceptible patient.",
"affiliations": "WOON, TEE, DEANG, and CHAN: Department of Psychiatry, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia GAN: Department of Pharmacy, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia.",
"authors": "Woon|Luke Sy-Cherng|LS|;Tee|Chun Keat|CK|;Gan|Lydia Lay Yen|LLY|;Deang|Kanit Tha|KT|;Chan|Lai Fong|LF|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "24(2)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D014150:Antipsychotic Agents; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007970:Leukopenia; D008875:Middle Aged; D000077152:Olanzapine; D018967:Risperidone; D012559:Schizophrenia",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "121-124",
"pmc": null,
"pmid": "29509183",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Olanzapine-induced and Risperidone-induced Leukopenia: A Case of Synergistic Adverse Reaction?",
"title_normalized": "olanzapine induced and risperidone induced leukopenia a case of synergistic adverse reaction"
} | [
{
"companynumb": "MY-MANKIND-000053",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "BACKGROUND\nThis study not only evaluated the clinical effects of treatment using haploidentical hematopoietic stem cells (haplo-HSCs) combined with human umbilical cord mesenchymal stem cells (UC-MSCs) in patients with severe aplastic anemia (SAA), but also investigated the factors related to graft versus host disease (GVHD).\n\n\nMETHODS\nCotransplantation of haplo-HSCs and UC-MSCs was performed in 24 SAA patients. The conditioning regimens consisted of rabbit anti-human T-lymphocyte immunoglobulin (ATG), cyclophosphamide, and fludarabine with or without busulfan. GVHD was prevented using cyclosporine A, ATG, anti-CD25 monoclonal antibody, and mycophenolate material.\n\n\nRESULTS\nThe incidence of acute GVHD was 50%. The incidence of severe acute GVHD was not related to gender, age, donor-recipient relations, and patient/donor pair, while patient/donor pair (r = 0.541, P = 0.022) was significantly correlated with incidence of chronic GVHD. Upon follow-up for a median of 13 months, 5 of the 24 patients (20.8%) were dead. The survival rates at 3 and 6 months in all patients were 87.5% (21/24) and 83.3% (20/24), respectively.\n\n\nCONCLUSIONS\nCotransplantation of haplo-HSCs combined with UC-MSCs was an effective and safe approach for the treatment of patients with SAA. The appropriate conditioning regimen and early treatment for infection also played a critical role in the success of HSCT.",
"affiliations": "Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.;Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China. xiongwuxiao@suhu.com.",
"authors": "Xu|Lixin|L|;Liu|Zhouyang|Z|;Wu|Yamei|Y|;Yang|Xueliang|X|;Cao|Yongbin|Y|;Li|Xiaohong|X|;Yan|Bei|B|;Li|Songwei|S|;Da|Wanming|W|;Wu|Xiaoxiong|X|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40001-018-0311-3",
"fulltext": "\n==== Front\nEur J Med ResEur. J. Med. ResEuropean Journal of Medical Research0949-23212047-783XBioMed Central London 31110.1186/s40001-018-0311-3ResearchClinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia Xu Lixin Honeysister22@163.com 1Liu Zhouyang liu11979@sina.com 1Wu Yamei rippleya@126.com 1Yang Xueliang xueliangwuhan@126.com 1Cao Yongbin yongbincao@hotmail.com 1Li Xiaohong lily.lxh@163.com 1Yan Bei sunny790422@163.com 1Li Songwei 382538893@qq.com 1Da Wanming dawanming@medmail.com.cn 2Wu Xiaoxiong +86-010-66848181xiongwuxiao@suhu.com 11 grid.414889.8Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048 China 2 0000 0004 1761 8894grid.414252.4Department of Hematology, Chinese PLA General Hospital, Beijing, 100853 China 1 3 2018 1 3 2018 2018 23 1228 2 2017 20 2 2018 © The Author(s) 2018Open 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\nThis study not only evaluated the clinical effects of treatment using haploidentical hematopoietic stem cells (haplo-HSCs) combined with human umbilical cord mesenchymal stem cells (UC-MSCs) in patients with severe aplastic anemia (SAA), but also investigated the factors related to graft versus host disease (GVHD).\n\nMethods\nCotransplantation of haplo-HSCs and UC-MSCs was performed in 24 SAA patients. The conditioning regimens consisted of rabbit anti-human T-lymphocyte immunoglobulin (ATG), cyclophosphamide, and fludarabine with or without busulfan. GVHD was prevented using cyclosporine A, ATG, anti-CD25 monoclonal antibody, and mycophenolate material.\n\nResults\nThe incidence of acute GVHD was 50%. The incidence of severe acute GVHD was not related to gender, age, donor-recipient relations, and patient/donor pair, while patient/donor pair (r = 0.541, P = 0.022) was significantly correlated with incidence of chronic GVHD. Upon follow-up for a median of 13 months, 5 of the 24 patients (20.8%) were dead. The survival rates at 3 and 6 months in all patients were 87.5% (21/24) and 83.3% (20/24), respectively.\n\nConclusion\nCotransplantation of haplo-HSCs combined with UC-MSCs was an effective and safe approach for the treatment of patients with SAA. The appropriate conditioning regimen and early treatment for infection also played a critical role in the success of HSCT.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s40001-018-0311-3) contains supplementary material, which is available to authorized users.\n\nKeywords\nSevere aplastic anemiaHaploidentical hematopoietic stem cells transplantationUmbilical cord-derived mesenchymal stem cellsGraft versus host diseaseThe PLA general hospital clinical research support funds2012FC-TSYS-4007issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nSevere aplastic anemia (SAA) is a life-threatening disease characterized by hypoplastic bone marrow and pancytopenia [1]. Although allogeneic hematopoietic stem cell transplantation (HSCT) is the first choice for the treatment of SAA [2], it is difficult to search for the human leukocyte antigen (HLA)-compatible donors in China [3]. Recent studies have investigated the effect of haploidentical HSCT (haplo-HSCT) in SAA patients, and it has been considered as an optional treatment [4–7]. Nevertheless, the high incidence of graft versus host disease (GVHD) limited the clinical application of haplo-HSCT in patients with SAA.\n\nIt has been demonstrated that mesenchymal stem cells (MSCs) can reduce the risks of both acute GVHD (aGVHD) and chronic GVHD (cGVHD) [8]. Notably, human umbilical cord-derived mesenchymal stem cells (UC-MSCs) have higher activities of proliferation and differentiation in comparison with the bone marrow MSCs [9]. Recent study has revealed that UC-MSCs can not only reduce the risk of GVHD, but also increase the transplantation rate of allogeneic HSCs [10]. A previous study by Wu et al. [11] and another research by Zhang et al. [12] have preliminarily shown that the cotransplantation of haplo-HSCs and third-party donor-derived UC-MSCs achieved favorable outcomes for patients with aplastic anemia. However, several problems remain to be further resolved, such as the correlation factors affecting GVHD and lack of optimal sources of donors.\n\nIn this study, we reviewed 24 patients with SAA who received the cotransplantation of haplo-HSCs and UC-MSCs with modified conditioning, and evaluated the safety and efficacy of the cotransplantation of UC-MSCs and donor HSCs in SAA patients and investigated the factors related to GVHD.\n\nMethods\nPatients\nThe whole protocol was approved by the Institutional Review Board of our hospital, and informed written consents were obtained from all patients. All donors were eligible for donating HSCs, and they also signed the informed consent forms for donation before transplantation.\n\nThis study recruited 24 patients with SAA (14 males and 10 females) who underwent cotransplantation of human UC-MSCs and HSCs from June 2010 to August 2013. The inclusion criteria were as follows: patients presenting with SAA or very severe aplastic anemia (VSAA) were defined according to the International Aplastic Anemia Study Group [13]; patients who underwent previous therapy regimens, including cyclosporine A (CSA), stanozole/andriol, granulocyte colony stimulating factor (G-CSF), anti-human T-lymphocyte immunoglobulin (ATG), Erythropoietin (EPO), glucocorticoid—however, they failed to respond to this therapy regimen; patients who received multiple transfusions and whose transfusion dependence was confirmed when the transplantation was performed; patients who agreed to participate in HSCT; and all donors who were relatives to the patients. Patients who had uncontrolled infections and severe liver, renal, lung, or heart diseases before transplantation were excluded in this study. The detailed information about patients and preparation of donors is listed in Additional file 1: Table S1.\n\nPreparation of UC-MSCs and HSCs\nUC-MSCs were purchased from the National Engineering Research Center of Cell Products. HSCs were isolated from peripheral blood of the donors who were injected subcutaneously with recombinant human G-CSF (rhG-CSF, 5 µg/kg day) for 5–6 consecutive days. In brief, peripheral blood (200–600 mL) was collected on day 5, and red cells were removed to avoid the incompatibility of major cross-match. Then, HSCs were separated using Fenwal CS-3000 plus blood cell separator (Baxter International Inc., Deerfield, IL, USA) on days 6 and 7. Finally, mononuclear cells [(4–6) × 108/kg] and CD34+ cells [(2–4) × 108/kg] were obtained.\n\nHSCs and UC-MSCs transplantation\nAnti-inflammatory, hepatoprotective and gastric mucosa-protecting treatments were performed on patients with sodium bicarbonate, dexamethasone and promethazine before transplantation. The conditioning regimens included rabbit ATG (Fresenius AG, Oberursel, Germany), cyclophosphamide (Cy), and fludarabine (Flu) treatment. For the patients with acute SAA (SAA-I), intravenous administration of 30 mg/(m2 day) of Flu and 500–800 mg/(m2 day) of Cy was performed from days − 5 to − 2, and 5 μg/(kg day) of ATG was administered from days − 4 to − 1 (Fig. 1a). For the patients with chronic SAA (SAA-II), the same treatment of ATG and Cy was applied as above with the supplement of 0.6 mg/(kg 6 h) of busulfan (BU) from days − 8 to − 5 prior to transplantation (Fig. 1b) [3]. On day 0, HSCs were infused intravenously. Then, a total of 5 × 105/kg UC-MSCs was transfused at 4 h before infusion with HSCs.Fig. 1 The schematic diagram of conditioning regimen and prophylaxis and management of GVHD. Conditioning included 1 of 2 regimens: for patients with SAA-I (a), intravenous administration of fludarabine (Flu) 30 mg/(m2 day) and cyclophosphamide (Cy) 500–800 mg/(m2 day) from day − 5 to − 2, anti-human T-lymphocyte immunoglobulin (ATG) 5 μg/(kg day) from day − 4 to − 1; or for SAA-II (b), the same treatment of ATG and Cy with busulfan (Bu) 0.6 mg/(kg 6 h) from day − 7 to − 6. Prophylaxis and management of GVHD included: intravenous administration of cyclosporine A (CSA) 3 mg/kg from day − 5, followed by gradual decrease in concentration after reaching a target trough blood concentration of 250–450 ng/mL and then withdrawal in the next 2–3 months, oral mycophenolate mofetil (MMF) administration (20 mg/kg/day) from day − 1 to + 100, and intravenous anti-CD25 antibody (CD25Ab) monoclonal antibody (0.5 mg/kg/day) on day + 4 after HSCT. SAA-I: acute severe aplastic anemia, SAA-II: chronic severe aplastic anemia\n\n\n\n\nManagement of GVHD\nProphylaxis of GVHD was carried out by the administration of immunosuppressive agents, such as CSA, mycophenolate mofetil (MMF), and anti-CD25 antibody (CD25Ab; Basiliximab, Novartis Pharma Stein AG, Stein, Switzerland). To achieve a target trough with blood concentration of 250–450 ng/mL at 12 months after HSCT, CSA (3 mg/kg) was conducted by intravenous injection from day − 5 (Fig. 1); then, CSA concentration was gradually decreased and withdrawn in the next 2–3 months. Oral MMF administration (20 mg/kg/day) was conducted from days − 1 to day + 100, and intravenous injection of CD25Ab monoclonal antibody (0.5 mg/kg/day) was performed only on day + 4 after HSCT (Fig. 1). Glucksberg-Seattle criteria (GSC) [14] were used for the diagnosis and grading of GVHD, and those with grade III-IV acute GVHD (aGVHD) were served as severe aGVHD.\n\nSupportive care\nPatients were housed in the laminar flow clean ward. They were asked to take a medicated bath, and treated with acyclovir, ornidazole, sulfamethoxazole trimethoprim, and sulfadiazine 1 or 2 days before conditioning. On day + 3 after HSCT, G-CSF and thrombopoietin (TPO) were administered subcutaneously until the achievement of hematopoietic reconstitution. Prostaglandin E1 (PGE1; 20 μg/day; Beijing Tide Pharmaceutical Co., LTD, Beijing, China) and compound Danshen (20 mg/day; Shanghai No. 1 Biochemical & Pharmaceutical Co., LTD, Shanghai, China) were administered from day − 5 to day + 14 as hepatic veno-occlusive disease (VOD) prophylaxis. Mesna injection (Baxter, Shanghai, China) was used to prevent the hemorrhagic cystitis (HC).\n\nEngraftment\nNeutrophil engraftment was defined as the first of three consecutive days with an absolute neutrophil count (ANC) above 0.5 × 109/L, and platelet engraftment was defined as the first day of a week with the platelet count exceeding 20 × 109/L in the absence of transfusion. Hematopoietic chimerism was assessed using peripheral blood samples of the donor and recipient via short-tandem repeated sequence-PCR (STR-PCR) DNA fingerprinting [15] for sex-matched pairs and karyotype analysis for sex-mismatched pairs. The bone marrow of the recipient was analyzed for hematopoietic chimerism every 30 days until 90 days after HSCT. For blood-type incompatible pairs, the measurement of blood-type titer was processed weekly after hematopoietic reconstitution.\n\nStatistical analysis\nPatients were followed up for 3–44 months. Kaplan–Meier analysis was calculated as survival in the absence of death. The relationships between the incidence of GVHD and gender, age, blood type, donor–recipient relations, and patient/donor pair were evaluated using Chi-square test. All statistical analyses were performed using the standard statistical package of SPSS 19.0 (IBM, Armonk, New York, USA). A two-sided P value of 0.05 or less was considered statistically significant.\n\nResults\nEngraftment and chimerism\nClinical features of patients and their donors, and the subsequent outcomes in 24 case are shown in Table 1. The median scores of infusion numbers of MNCs and CD34+ cells were 10.6 × 108/kg and 4.55 × 106/kg for all the patients, respectively. The median times to achieve neutrophil and platelet engraftment were 11 and 13 days, respectively. All the patients achieved 70–100% donor chimerism within 1 month after haplo-HSCT.Table 1 Clinical features of patients and their donors as well as the outcomes of 24 cases\n\nCase\tSex/age\tDonor/age\tHLA -matched\tABO pairs D/R\tMNC 108/kg\tCD34+ 106/kg\tANC > 2 × 109/L (D)\tPLT > 20 × 109/L (D)\taGVHD grade/cGVHD grade\tOutcome (M)\t\n1\tF/25\tMother/47\t3/6\tB/AB\t9.43\t1.9\t12\t15\t–/–\tDead 3\t\n2\tM/14\tMother/39\t3/6\tO/B\t10.96\t12.83\t12\t13\t–/–\tDead 3\t\n3\tM/5\tMother/30\t4/6\tAB/B\t10.2\t2.79\t12\t13\tIII/Ext\tDead 12\t\n4\tM/9\tSister/22\t5/6\tO/O\t10.37\t3.24\t10\t12\tIV/Ext\tAlive 12\t\n5\tM/23\tMother/51\t4/6\tB/B\t8.1\t2.97\t10\t14\t–/Ext\tAlive 10\t\n6\tF/18\tBrother/22\t3/6\tO/O\t10.56\t4.546\t10\t14\tII/Lim\tAlive 13\t\n7\tM/16\tFather/43\t3/6\tB/B\t8.82\t3.25\t10\t14\tIII/–\tAlive 13\t\n8\tM/13\tMother/33\t3/6\t0/A\t10.97\t3.47\t9\t10\tIII/–\tAlive 11\t\n9\tM/22\tFather/41\t4/6\tO/A\t10.06\t3.79\t8\t14\tIV/–\tDead 4\t\n10\tF/9\tMother/31\t3/6\tA/A\t9.62\t4.71\t10\t12\t–/–\tAlive 10\t\n11\tM/21\tFather/45\t3/6\tA/A\t10.83\t4.02\t11\t13\t–/–\tAlive 11\t\n12\tM/25\tMother/48\t3/6\tA/AB\t8.05\t3.45\t13\t13\tII/–\tAlive 19\t\n13\tF/25\tMother/47\t3/6\tA/A\t12.47\t18.65\t11\t15\tIII/–\tAlive 17\t\n14\tF/8\tMother/32\t3/6\tA/A\t10.03\t5.33\t12\t15\tI/–\tAlive 16\t\n15\tM/16\tFather/43\t3/6\tB/B\t13.18\t7.96\t13\t15\t–/–\tAlive 15\t\n16\tF/17\tSister/27\t3/6\tB/B\t6.3\t3.75\t21\t25\t–/–\tAlive 20\t\n17\tF/13\tMother/46\t4/6\tO/AB\t9.96\t10.2\t12\t12\tI/–\tAlive 27\t\n18\tM/17\tFather/37\t3/6\tO/O\t9.36\t7.52\t11\t13\tI/Lim\tAlive 41\t\n19\tF/24\tSister/21\t4/6\tA/A\t9.66\t6.94\t11\t13\t–/–\tAlive 41\t\n20\tM/20\tSister/23\t3/6\tB/AB\t9.28\t5.08\t16\t18\tI/Lim\tAlive 44\t\n21\tM/15\tMother/37\t4/6\tO/O\t7.93\t3.76\t8\t10\t–/–\tDead 3\t\n22\tF/13\tSister/18\t5/6\tB/B\t11.2\t12.56\t10\t10\t–/–\tAlive 4\t\n23\tM/8\tMother/32\t3/6\tA/A\t8.1\t3.94\t10\t12\t–/–\tAlive 5\t\n24\tF/55\tBrother/49\t3/6\tO/B\t9.24\t4.72\t10\t11\t–/–\tAlive 12\t\nF female, M male, HLA human leukocyte antigen, D donor, R recipient, MNC mononuclear cells, ANC absolute neutrophil count, PLT platelets, aGVHD acute graft-versus-host disease, cGVHD chronic graft-versus-host disease, Ext extensive, Lim limited, D day, M months\n\n\n\n\nGVHD\nThe GVHD incidences of all patients after HSCT are shown in Table 2. Of the 24 patients, 12 cases (50%) developed aGVHD, including 4 (16.7%) with grade I, 2 (8.35%) with grade II, 4 (16.7%) with grade III, and 2 (8.35%) with grade IV. Meanwhile, 3 of the 24 (12.5%) patients developed extensive cGVHD, and 2 cases among them also experienced III–IV aGVHD. In addition, 3 of the 24 (12.5%) patients who experienced I–II aGVHD also developed limited cGVHD. The other 11 patients had no GVHD. As shown in Table 3, the incidence of severe aGVHD was not related to gender, age, donor–recipient relations and patient/donor pair, while patient/donor pair was significantly correlated with extensive cGVHD (r = 0.541, P = 0.022). The postoperative incidences of extensive cGVHD were 2/15 of patients with blood-type compatibility, 1/1 of major cross-match mismatch and 0 of minor cross-match mismatch. The rise in GVHD incidence paralleled the increase in HLA loci (χ2 = 7.764, P = 0.022). Extensive cGVHD trended to occur in male and patients who also suffered from severe aGVHD (P = 0.060 and P = 0.099, respectively).Table 2 GVHD incidences in allogeneic HSCT recipients\n\nParameters\tN = 24, (%)\t\nAcute GVHD\t\n I\t4 (16.7%)\t\n II\t2 (8.35%)\t\n III\t4 (16.7%)\t\n IV\t2 (8.35%)\t\nChronic GVHD\t\n Lim\t3 (12.5%)\t\n Ext\t3 (12.5%)\t\nHSCT hematopoietic stem cell transplantation, aGVHD acute graft-versus-host disease, cGVHD chronic graft-versus-host disease, Ext extensive, Lim limited\n\n\nTable 3 The correlation of variables with GVHD incidence in allogeneic HSCT recipients\n\nVariables\tSevere aGVHD\tExtensive cGVHD\t\nIncidence (%)\t\nr\n\tP value\tIncidence (%)\t\nr\n\tP value\t\nGender\t\t0.293\t0.134\t\t0.319\t0.060\t\n Male\t5/14 (35.7%)\t\t\t3/14 (21.4%)\t\t\t\n Female\t1/10 (10%)\t\t\t0/10\t\t\t\nAge, years\t\t0.05\t0.807\t\t0.033\t0.872\t\n ≥ 20\t2/9 (22.2%)\t\t\t1/9 (11.1%)\t\t\t\n < 20\t4/15 (26.7%)\t\t\t2/15 (13.3%)\t\t\t\nDonor-recipient relationship\t\t0.083\t0.599\t\t0.055\t0.465\t\n Mother–child\t3/12 (25%)\t\t\t2/12 (16.7%)\t\t\t\n Father–child\t2/5 (25%)\t\t\t0/5\t\t\t\n Siblings\t1/7 (14.3%)\t\t\t1/7 (14.3%)\t\t\t\nPatient/donor pair\t\t0.225\t0.566\t\t0.541\t0.022\t\n 3 HLA loci\t3/16 (18.8%)\t\t\t0/16\t\t\t\n 2 HLA loci\t2/6 (33.3%)\t\t\t2/6 (33.3%)\t\t\t\n 1 HLA loci\t1/2 (50%)\t\t\t1/2 (50%)\t\t\t\nSevere aGVHD\t\t\t\t\t0.364\t0.099\t\n Yes\t\t\t\t2/6 (33.3%)\t\t\t\n No\t\t\t\t1/18 (5.6%)\t\t\t\nHSCT hematopoietic stem cell transplantation, aGVHD acute graft-versus-host disease, cGVHD chronic graft-versus-host disease, HLA human leukocyte antigen\n\n\n\n\nOther complications\nDuring HSCT period, all patients suffered from nausea, vomiting, and various degrees of anepithymia, and then these symptoms regressed after symptomatic and supportive therapies. Nineteen patients (19/24, 79.2%) who developed stomatitis also showed improvement after mouth care and the topical application of epithelium growth factor. At the stage of bone marrow suppression, various degrees of fevers occurred in patients, and then fevers were controlled by the administrations of imipenem, vancomycin, and antifungals. The incidence of pulmonary infection was 16.7% (4/24). Two cases with pulmonary infection developed into severe pneumonia, and one of them finally died. There were two patients with septicemia and two cases with engraftment syndrome. Fifteen patients (15/24, 62.5%) had viral infections, including Cytomegalovirus (CMV) or Epstein Barr Virus (EBV)-emia in eight cases, and two or more viruses infection in five cases. Three patients (3/24, 12.5%) developed HC. Sixteen patients suffered from diarrhea, and they all responded well to antidiarrheal treatment and regulation of intestinal microecology. The incidences of infectious diarrhea, fungal enteritis, and viral enteritis were 29.2% (7/24), 4.2% (1/24), 16.7% (6/24), respectively, and all of these cases developed into grade III-IV intestinal GVHD. Besides, three patients developed epilepsy. Among them, seizure was resolved in one patient since day + 28 via the replacement of CSA by FK506, and this patient was in stable condition in 2 years after being discharged. The second patient with refractory seizures since day + 60 was diagnosed as positive EBV in his cerebrospinal fluid, and then the patient’s condition improved after antiviral therapy. However, drop of blood cells and infection occurred in the third patient with seizures on day + 90 of haplo-HSCT, and he refused further treatment and finally died.\n\nFollow-up\nUpon follow-up for a median of 13 months, 5 of the 24 patients (20.8%) were dead. The survival rates at 3 and 6 months in all patients were 87.5% (21/24) and 83.3% (20/24), respectively (Fig. 2). Among the five dead patients, two died as a result of early graft rejection; one died because of rejecting further treatment for reduced blood cell counts and pulmonary infection; the other two patients died due to the uncontrollable grade IV aGVHD, among whom one also suffered from serious pulmonary infection 1 year after haplo-HSCT.Fig. 2 Survival curves of patients with SAA after cotransplantation of haploidentical HSCs and human UC-MSCs. This curve was generated using Kaplan–Meier analysis. The survival rate at 44 months in all the patients was 79.2%\n\n\n\n\nDiscussion\nRecent studies suggested that immunosuppressants improved the efficacy of HSCT in patients with SAA [16, 17]. In HLA-matched transplantation for treatment of aplastic anemia, the conditioning regimen consisting of Cy, ATG, and Flu could remarkably decrease the failure rate of transplantation [18, 19]. Similarly, our study also selected this conditioning regimen in patients with SAA-I; however, we adjusted Cy at the concentration of 500–800 mg/m2 day according to the demographic data of the patients. For patients with SAA-II, reduced doses of BU was supplemented into the conditioning regimen to enhance immune ablation. Our results demonstrated that all patients with modified conditioning regimen achieved a high engraftment without serious toxic reactions or deaths.\n\nGVHD, as a common complication following allogeneic HSCT, was the principal cause of morbidity and nonrelapse mortality in long-term survivors [20, 21]. Our study showed that the incidence of aGVHD after haplo-HSCT was 50% (six cases of grade I–II aGVHD and six cases of grade III–IV aGVHD), which was consistent with Wu’s study showing 57.1% incidence of aGVHD [3]. However, previous studies showed the incidence ranged of 44–64% for II–IV aGVHD and 12–26% for extensive cGVHD [22, 23]. Therefore, it seemed that the infusion of third-party donor-derived UC-MSCs might play a considerable role in reducing the incidence of severe GVHD. Furthermore, our study found that gender, age, donor-recipient relationship, and patient/donor pair were not associated with the incidence of the severe aGVHD, while the incidences of extensive cGVHD were increased in patients with major cross-match mismatch and less HLA loci. Besides, cGVHD incidences were also more likely to occur in males or patients who had developed aGVHD. All these results suggested that it might be an optional prevention route for cGVHD to effectively control severe aGVHD and avoid major cross-match mismatch.\n\nThis study showed that the mortality for the entire group of patients was 20.8%, suggesting that cotransplantation of haplo-HSCs and human UC-MSCs might be an effective treatment modality for patients with SAA. However, despite infusions of human UC-MSC after allogeneic HSCT, Si et al. [24] reported that the 3-year overall survival rate was 74.2%, which was lower than our results (87.5%). The differences in the survival rate might be attributable to the pediatric patients enrolled in Si et al.’s study. Besides, the deaths reported in five patients in this study all occurred due to different complications, such as early graft rejection, reduced blood cell counts, pulmonary infection, and aGVHD, which indicated that preoperative prophylaxis and care also played essential role in a successful HSCT.\n\nThis study has some limitations. First, because cotransplantation of human UC-MSCs and HSCs is not a conventional treatment for patients with SAA, it was difficult to recruit the patients who underwent cotransplantation of human UC-MSCs and HSCs for this study. Due to the small sample size of this study, a prospective study with larger sample size will be performed to confirm our results. Second, a thorough evaluation of the patients to determine the correlation factors affecting GVHD was still required to conduct the cotransplantation. Third, no control group to compare the efficacy and safety of cotransplantation of UC-MSCs and haplo-HSCs was available. Thus, a case–control group comparison of evaluations of treatments with HSCs or UC-MSCs alone is necessary to strengthen the integrity and statistical power of this study and to validate our present results in the future study. Despite these limitations, this study has preliminarily demonstrated the safety and effectiveness of cotransplantation of haplo-HSCs and UC-MSCs for the treatment of patients with SAA.\n\nConclusion\nThis study suggested that the combined application of UC-MSCs in HSCT was a safe and efficacious method for the treatment of SAA. The appropriate conditioning regimen and early treatment for infections and other complications also played a critical role in the success of HSCT.\n\nAdditional file\n\nAdditional file 1: Table S1. Pre-transplant characteristics of patients and their donors.\n\n \n\n\nAbbreviations\nUC-MSCsumbilical cord mesenchymal stem cells\n\nSAAsevere aplastic anemia\n\nGVHDgraft versus host disease\n\nHSCThematopoietic stem cell transplantation\n\nHLAthe human leukocyte antigen\n\naGVHDacute GVHD\n\ncGVHDchronic GVHD\n\nVSAAvery severe aplastic anemia\n\nCSAcyclosporine A\n\nG-CSFgranulocyte colony stimulating factor\n\nATGanti-human T-lymphocyte immunoglobulin\n\nEPOerythropoietin\n\nCycyclophosphamide\n\nFlufludarabine\n\nMMFmycophenolate mofetil\n\nTPOthrombopoietin\n\nPGE1prostaglandin E1\n\nVODveno-occlusive disease\n\nANCabsolute neutrophil count\n\nSTR-PCRshort-tandem repeated sequence-PCR\n\nCMVcytomegalovirus\n\nEBVEpstein Barr Virus\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s40001-018-0311-3) contains supplementary material, which is available to authorized users.\n\nLixin Xu and Zhouyang Liu are joint first authors\n\nAuthors’ contributions\nYW, XY, and YC participated in the design of this study. XL and BY performed the statistical analysis. LX carried out the study, together with ZL, and collected important background information. SL and WD helped to draft the manuscript. XW conceived of this study, and participated in the design, and helped to draft the manuscript. All the authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors thank everyone in the team for their support.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nConsent for publication\nInformed written consents were obtained from all patients.\n\nEthics approval and consent to participate\nThe whole protocol was approved by the Institutional Review Board of our hospital and the consents to participate were obtained from all patients.\n\nFunding\nThis work was supported by The PLA general hospital clinical research support funds (2012FC-TSYS-4007).\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Scheinberg P Young NS How I treat acquired aplastic anemia Blood 2012 120 6 1185 1196 10.1182/blood-2011-12-274019 22517900 \n2. Wang H Yan H Wang Z Zhu L Liu J Guo Z Cotransplantation of allogeneic mesenchymal and hematopoietic stem cells in children with aplastic anemia Pediatrics 2012 129 6 e1612 e1615 10.1542/peds.2011-2091 22566416 \n3. Wu Y Cao Y Li X Xu L Wang Z Liu P Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD Stem Cell Res 2014 12 1 132 138 10.1016/j.scr.2013.10.001 24185180 \n4. Martelli MF Di Ianni M Ruggeri L Pierini A Falzetti F Carotti A “Designed” grafts for HLA-haploidentical stem cell transplantation Blood 2014 123 7 967 973 10.1182/blood-2013-10-531764 24363403 \n5. Zhu H Luo RM Luan Z Lee V Zhu YP Luo CJ Unmanipulated haploidentical haematopoietic stem cell transplantation for children with severe aplastic anaemia Br J Haematol 2016 174 5 799 805 10.1111/bjh.14110 27263533 \n6. Jaiswal SR Chatterjee S Mukherjee S Ray K Chakrabarti S Pre-transplant sirolimus might improve the outcome of haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide for patients with severe aplastic anemia Bone Marrow Transplant 2015 50 6 873 875 10.1038/bmt.2015.50 25798678 \n7. Gupta N Choudhary D Sharma SK Khandelwal V Dhamija M Haploidentical hematopoietic SCT for acquired severe aplastic anemia using post-transplant high-dose CY Bone Marrow Transplant 2014 50 1 155 156 10.1038/bmt.2014.222 25285802 \n8. Yanez R Lamana ML García-Castro J Colmenero I Ramirez M Bueren JA Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease Stem cells 2006 24 11 2582 2591 10.1634/stemcells.2006-0228 16873762 \n9. Wang HS Hung SC Peng ST Huang CC Wei HM Guo YJ Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord Stem Cells 2004 22 7 1330 1337 10.1634/stemcells.2004-0013 15579650 \n10. Wu KH Chan CK Tsai C Chang YH Sieber M Chiu TH Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells Transplantation 2011 91 12 1412 1416 10.1097/TP.0b013e31821aba18 21494176 \n11. Wu Y Wang Z Cao Y Xu L Li X Liu P Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells with a myeloablative regimen for refractory/relapsed hematologic malignancy Ann Hematol 2013 92 12 1675 1684 10.1007/s00277-013-1831-0 23842707 \n12. Zhang X Li JY Cao K Lu H Hong M Qian S Cotransplantation of HLA-identical mesenchymal stem cells and hematopoietic stem cells in Chinese patients with hematologic diseases Int J Lab Hematol 2010 32 2 256 264 10.1111/j.1751-553X.2009.01181.x 19656235 \n13. Camitta BM Thomas ED Nathan DG Gale RP Kopecky KJ Rappeport JM A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia Blood 1979 53 3 504 514 32941 \n14. Glucksberg H Storb R Fefer A Buckner C Neiman P Clift R Clinical manifestations of graft-versus-host disease in human recipients of marrow from Hl-A-matched sibling donor S Transplantation 1974 18 4 295 304 10.1097/00007890-197410000-00001 4153799 \n15. Xu LX Cao YB Wang ZH Liu ZY Liu B Zhao DD Efficacy of haploidentical allogeneic bone marrow hematopoietic stem cell transplantation combined with umbilical cord blood derived mesenchymal stem cells for severe aplastic anemia Zhongguo Shi Yan Xue Ye Xue Za Zhi 2011 19 5 1241 1245 22040980 \n16. Shin SH Yoon JH Yahng SA Lee SE Cho BS Eom KS The efficacy of rabbit antithymocyte globulin with cyclosporine in comparison to horse antithymocyte globulin as a first-line treatment in adult patients with severe aplastic anemia: a single-center retrospective study Ann Hematol 2013 92 6 817 824 10.1007/s00277-013-1674-8 23318980 \n17. Maury S Aljurf M Management of adult patients older than 40 years refractory to at least one immunosuppressive course: HLA-identical sibling HSCT using fludarabine-based conditioning Bone Marrow Transplant 2013 48 2 196 197 10.1038/bmt.2012.251 23222386 \n18. George B Mathews V Viswabandya A Kavitha M Srivastava A Chandy M Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC) regimens reduce rejection and improve outcome in Indian patients undergoing allogeneic stem cell transplantation for severe aplastic anemia Bone Marrow Transplant 2007 40 1 13 18 10.1038/sj.bmt.1705669 17450183 \n19. Maury S Bacigalupo A Anderlini P Aljurf M Marsh J Socié G Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen Haematologica 2009 94 9 1312 1315 10.3324/haematol.2009.006916 19734425 \n20. Hale G Jacobs P Wood L Fibbe W Barge R Novitzky N CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells Bone Marrow Transplant 2000 26 1 69 76 10.1038/sj.bmt.1702477 10918407 \n21. Okamoto M Okano A Akamatsu S Ashihara E Inaba T Takenaka H Rituximab is effective for steroid-refractory sclerodermatous chronic graft-versus-host disease Leukemia 2005 20 1 172 173 10.1038/sj.leu.2403996 \n22. Bensinger WI Martin PJ Storer B Clift R Forman SJ Negrin R Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers N Engl J Med 2001 344 3 175 181 10.1056/NEJM200101183440303 11172139 \n23. Couban S Simpson DR Barnett MJ Bredeson C Hubesch L Howson-Jan K A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies Blood 2002 100 5 1525 1531 10.1182/blood-2002-01-0048 12176866 \n24. Si Y Yang K Qin M Zhang C Du Z Zhang X Efficacy and safety of human umbilical cord derived mesenchymal stem cell therapy in children with severe aplastic anemia following allogeneic hematopoietic stem cell transplantation: a retrospective case series of 37 patients Pediatr Hematol Oncol 2014 31 1 39 49 10.3109/08880018.2013.867556 24383400\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0949-2321",
"issue": "23(1)",
"journal": "European journal of medical research",
"keywords": "Graft versus host disease; Haploidentical hematopoietic stem cells transplantation; Severe aplastic anemia; Umbilical cord-derived mesenchymal stem cells",
"medline_ta": "Eur J Med Res",
"mesh_terms": "D000328:Adult; D000741:Anemia, Aplastic; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D008875:Middle Aged; D014019:Tissue Donors; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical",
"nlm_unique_id": "9517857",
"other_id": null,
"pages": "12",
"pmc": null,
"pmid": "29490698",
"pubdate": "2018-03-01",
"publication_types": "D016428:Journal Article",
"references": "15579650;21494176;16239908;32941;22040980;17450183;24383400;19734425;23842707;25285802;23318980;10918407;4153799;16873762;25798678;24363403;22566416;19656235;22517900;23222386;27263533;12176866;11172139;24185180",
"title": "Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia.",
"title_normalized": "clinical evaluation of haploidentical hematopoietic combined with human umbilical cord derived mesenchymal stem cells in severe aplastic anemia"
} | [
{
"companynumb": "CN-ACCORD-064417",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to evaluate the demographic characteristics of patients with bilateral bisphosphonate-related low-energy femoral shaft fractures.\n\n\nMETHODS\nThe clinical registry was reviewed for patients with bisphosphonate-related low-energy fractures localized at femoral shaft between January 2008 and January 2012. Patients with a diagnosis of postmenopausal osteoporosis, bisphosphonate usage of at least 5 years and prodromal pain prior to fracture were included the study.\n\n\nRESULTS\nFive women met the inclusion criteria. All patients had bilateral low-energy sequential femoral shaft fractures. Fracture patterns were similar and atypical (transverse-short oblique fractures with lateral cortical thickening). Mean period of bisphosphonate treatment was 8.6 years. Mean patient age was 76.2 years. Union time of three patients was between 20 and 28 weeks. The remaining two fractures were revised for delayed union or nonunion.\n\n\nCONCLUSIONS\nLong-term (over 5 years) use of bisphosphonates may cause insufficiency fractures due to increased fragility and brittleness which have a close relationship with depressed bone remodeling. While there is still no causal relationship between bisphosphonates and atypical, low-energy femoral shaft fractures, we have some concerns about the optimal usage time and long-term safety of bisphosphonate drugs.",
"affiliations": "Department of Orthopaedics and Traumatology, GATA Haydarpaşa Training Hospital, İstanbul, Turkey. selamicakmak@gmail.com",
"authors": "Çakmak|Selami|S|;Mahiroğulları|Mahir|M|;Keklikçi|Kenan|K|;Sarı|Enes|E|;Erdik|Baran|B|;Rodop|Osman|O|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "Turkey",
"delete": false,
"doi": "10.3944/aott.2013.2934",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1017-995X",
"issue": "47(3)",
"journal": "Acta orthopaedica et traumatologica turcica",
"keywords": null,
"medline_ta": "Acta Orthop Traumatol Turc",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019386:Alendronate; D050071:Bone Density Conservation Agents; D016723:Bone Remodeling; D042241:Early Diagnosis; D005260:Female; D005264:Femoral Fractures; D006801:Humans; D015663:Osteoporosis, Postmenopausal; D010146:Pain; D011859:Radiography; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "9424806",
"other_id": null,
"pages": "162-72",
"pmc": null,
"pmid": "23748615",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bilateral low-energy sequential femoral shaft fractures in patients on long-term bisphosphonate therapy.",
"title_normalized": "bilateral low energy sequential femoral shaft fractures in patients on long term bisphosphonate therapy"
} | [
{
"companynumb": "TR-ACTAVIS-2014-15092",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Methotrexate (MTX)-associated classical Hodgkin lymphoma (CHL) is unlikely to regress following discontinuation of MTX, and its treatment usually requires chemotherapy. Standard chemotherapy for CHL is the ABVD regimen, which contains pneumotoxic bleomycin. This can be problematic in MTX-CHL patients suffering from an autoimmune disease (AID), such as rheumatoid arthritis (RA), as they frequently have pulmonary complications. However, brentuximab vedotin (BV)-containing chemotherapy without bleomycin (A + AVD regimen) was recently reported to show favorable efficacy for CHL, and could therefore be beneficial in MTX-CHL. We treated three cases of MTX-CHL using the A + AVD regimen. All were female and had received MTX for more than 15 years. Underlying AIDs in these patients were RA in two patients, and overlap syndrome with systemic lupus erythematosus and dermatomyositis in one patient. The A + AVD regimen resulted in a complete response in all patients. Peripheral neuropathy developed in two patients, necessitating reduction of the BV dose. All three patients experienced hematological toxicity necessitating dose reduction; however, no severe adverse effects, including infection or pulmonary complication, were documented. RA was well-controlled without additional immunosuppressants. The A + AVD regimen is a promising chemotherapy for MTX-CHL with favorable efficacy and tolerable toxicity profiles.",
"affiliations": "Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan. satoshi.ichikawa.b4@tohoku.ac.jp.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematopathology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-cho, Sendai, 980-8574, Japan.",
"authors": "Ichikawa|Satoshi|S|http://orcid.org/0000-0003-3163-7197;Fukuhara|Noriko|N|;Saito|Kei|K|;Onodera|Koichi|K|;Shirai|Tsuyoshi|T|;Onishi|Yasushi|Y|;Yokoyama|Hisayuki|H|;Fujii|Hiroshi|H|;Ichinohasama|Ryo|R|;Harigae|Hideo|H|",
"chemical_list": "D001761:Bleomycin; D000079963:Brentuximab Vedotin; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-020-02822-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "111(5)",
"journal": "International journal of hematology",
"keywords": "A + AVD; Bleomycin-induced lung injury; Brentuximab vedotin; Classical Hodgkin lymphoma; Methotrexate-associated lymphoproliferative disease; Rheumatoid arthritis",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D000079963:Brentuximab Vedotin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008727:Methotrexate; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "667-672",
"pmc": null,
"pmid": "31955346",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31257348;29224502;2472035;16186594;25593236;26980727;10706507;29455236;9819449;23560463;31784937;8648387;31116708;28504035;29738359;28877615;28552544;28380678",
"title": "Successful treatment of methotrexate-associated classical Hodgkin lymphoma with brentuximab vedotin-combined chemotherapy: a case series.",
"title_normalized": "successful treatment of methotrexate associated classical hodgkin lymphoma with brentuximab vedotin combined chemotherapy a case series"
} | [
{
"companynumb": "JP-PFIZER INC-2020044327",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Leptospirosis is a zoonosis transmitted through urine of infected animals. Symptoms range from mild influenza-like symptoms to severe pulmonary hemorrhagic syndrome (SPHS); the latter are often fatal. The serogroup distribution in Denmark has changed from 1988 to 2012, with Icterohaemorrhagiae and Sejroe now being predominant. CASE REPORT A 45-year-old Danish woman living in an area endemic for Hanta virus, without prior medical history, was admitted because of lower back pain radiating to the left hip, fever, headache, nausea, and malaise. Two weeks before admission she had been bitten by a mouse or a rat. Blood tests revealed raised white cells and CRP, electrolyte imbalances, raised creatinine, low thrombocytes, and a slightly decreased clotting factor (II, VII, and X). Treatment with broad-spectrum intravenous antibiotics and supporting therapy was initiated very quickly. Eight hours after admission she died from respiratory failure where severe hemoptysis was observed. Leptospiral DNA was later detected in a urine sample. CONCLUSIONS This case represents leptospirosis with severe pulmonary hemorrhagic syndrome. In spite of immediate treatment with broad-spectrum antibiotics, the patient died a few hours after hospital admission.",
"affiliations": "Department of Rheumatology, Odense University Hospital, Svendborg Hospital, Svendborg, Denmark.;Department of Cardiology, Odense University Hospital, Svendborg Hospital, Svendborg, Denmark.;Diagnostic Center, Odense University Hospital, Svendborg Hospital, Svendborg, Denmark.;Department of Radiology, Odense University Hospital, Svendborg Hospital, Svendborg, Czech Republic.;Department of Rheumatology, Odense University Hospital, Svendborg Hospital, Svendborg, Denmark.",
"authors": "Søndergaard|Mads Madsen|MM|;Tursunovic|Amela|A|;Thye-Rønn|Peter|P|;Bang|Jacob Christian|JC|;Hansen|Inger Marie Jensen|IM|",
"chemical_list": "D004269:DNA, Bacterial",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.900477",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D004269:DNA, Bacterial; D003937:Diagnosis, Differential; D005260:Female; D006469:Hemoptysis; D006801:Humans; D007919:Leptospira; D007922:Leptospirosis; D017116:Low Back Pain; D008875:Middle Aged; D013902:Radiography, Thoracic; D012720:Severity of Illness Index; D013577:Syndrome",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "883-886",
"pmc": null,
"pmid": "27881835",
"pubdate": "2016-11-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23862041;16954459;18325275;23951234;21106802;12092040;25655055;11292640;22744922",
"title": "Leptospirosis-Associated Severe Pulmonary Hemorrhagic Syndrome with Lower Back Pain as an Initial Symptom.",
"title_normalized": "leptospirosis associated severe pulmonary hemorrhagic syndrome with lower back pain as an initial symptom"
} | [
{
"companynumb": "DK-PFIZER INC-2017006319",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.