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{
"abstract": "We present a rare case of a neonate with PHACES syndrome (posterior fossa malformations, large facial hemangiomas, cerebral arterial anomalies, cardiovascular anomalies, eye anomalies and sternal clefting or supraumbilical raphe) and diffuse hemangiomatosis of the ileum, presenting with multiple intestinal perforations and peritonitis. The infant was successfully treated with propranolol and methylprednisolone as well as octreotide, tranexamic acid, and supportive therapy for massive intestinal bleeding.",
"affiliations": "Professor Vjekoslav Krželj, MD, PhD, University of Split, School of Medicine , Department of Health Studies, Ruđera Boškovića 35, 21000 Split, Croatia; vkrzelj@ozs.unist.hr.",
"authors": "Vrkić Boban|Ivona|I|;Lozić|Bernarda|B|;Stričević|Luka|L|;Čulo Čagalj|Ivana|I|;Skelin Glavaš|Ana|A|;Krželj|Vjekoslav|V|",
"chemical_list": null,
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "27(4)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D001017:Aortic Coarctation; D005124:Eye Abnormalities; D005260:Female; D006391:Hemangioma; D006801:Humans; D007231:Infant, Newborn; D007414:Intestinal Neoplasms; D020752:Neurocutaneous Syndromes; D013577:Syndrome",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "265-269",
"pmc": null,
"pmid": "31969240",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "PHACES Syndrome with Intestinal Hemangiomatosis.",
"title_normalized": "phaces syndrome with intestinal hemangiomatosis"
} | [
{
"companynumb": "HR-PFM-2020-00827",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Gaining vascular access in a neonate during cardiopulmonary resuscitation is crucial and challenging. Intraosseous (IO) access can offer a fast and reliable method for achieving emergency access for fluids and drugs when venous access fails in a critically ill child. IO access can however result in rare, but serious adverse events including compartment syndrome and amputation. We describe a case resulting in leg amputation due to IO infusion in a neonate after resuscitation and therapeutic hypothermia. We compared 10 tibia X-rays in three age groups. The mean medullary diameter of the proximal tibia at the recommended site for IO access was 7 mm in neonate, 10 mm in 1- to 12-month-old infants, and 12 mm in 3- to 4-year-old children. This provides a narrow margin of safety for the correct positioning and the avoidance of dislodgement of the IO needle. The correct position of the IO needle should be confirmed by bone marrow aspiration and fluid bolus. Unnecessary touching of the IO needle after fixing it in place should be avoided by inserting a luer-lock catheter with a three-way stop-cock for IO drug and fluid administration. Regular observation of the circulation and possible swelling of the leg should be performed. The IO administration of inotropic infusions should also be avoided after the initial resuscitation phase. When treating with therapeutic hypothermia, it may be wise to remove the IO needle much earlier than the currently recommended 24 h because of the problems in peripheral circulation and its monitoring.",
"affiliations": "Department of Anaesthesia and Intensive Care, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;Department of Anaesthesia and Intensive Care, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.;HUS Medical Imaging Center, Radiology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.",
"authors": "Suominen|P K|PK|;Nurmi|E|E|;Lauerma|K|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/aas.12602",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5172",
"issue": "59(10)",
"journal": "Acta anaesthesiologica Scandinavica",
"keywords": null,
"medline_ta": "Acta Anaesthesiol Scand",
"mesh_terms": "D000328:Adult; D016887:Cardiopulmonary Resuscitation; D002675:Child, Preschool; D003161:Compartment Syndromes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017148:Infusions, Intraosseous; D008297:Male; D012306:Risk; D013977:Tibia",
"nlm_unique_id": "0370270",
"other_id": null,
"pages": "1389-93",
"pmc": null,
"pmid": "26300243",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intraosseous access in neonates and infants: risk of severe complications - a case report.",
"title_normalized": "intraosseous access in neonates and infants risk of severe complications a case report"
} | [
{
"companynumb": "FI-MYLANLABS-2015M1038742",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "Nivolumab is commonly used as monotherapy or in combination therapy for management of locally advanced or metastatic melanoma; however, it is also associated with immunotherapy-related adverse events concerning for disease progression or tumor flare reaction. This report presents a case of a non-neoplastic pseudotumor of the lung initially mistaken for malignancy that occurred in a patient receiving adjuvant nivolumab therapy following complete resection of stage IIIB melanoma. The diagnosis was made by lung biopsy and confirmed by a wedge resection, with findings consistent with organizing pneumonia type of pulmonary inflammatory pseudotumor rather than malignancy.",
"affiliations": "Department of Hematology & Oncology, University of Texas Medical Branch, Galveston, Texas, USA.;School of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.;Department of Cardiothoracic Surgery, University of Texas Medical Branch, Galveston, Texas, USA.;Department of Hematology & Oncology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Hematology & Oncology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.;Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.",
"authors": "Nelson|Blessie Elizabeth|BE|https://orcid.org/0000-0002-8227-638X;Hong|Angelina|A|;Okereke|Ike|I|;Markowitz|Avi|A|;Willis|Maurice|M|;Muthukumarana|Palawinnage V|PV|;Nawgiri|Ranjana|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/dc.24846",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1097-0339",
"issue": "49(10)",
"journal": "Diagnostic cytopathology",
"keywords": "immunotherapy; melanoma; pseudotumor",
"medline_ta": "Diagn Cytopathol",
"mesh_terms": null,
"nlm_unique_id": "8506895",
"other_id": null,
"pages": "1150-1154",
"pmc": null,
"pmid": "34331523",
"pubdate": "2021-10",
"publication_types": "D016422:Letter",
"references": null,
"title": "Non-neoplastic inflammatory pseudotumor of the lung after immunotherapy for melanoma: A diagnostic pitfall on fine needle aspiration biopsy of lung.",
"title_normalized": "non neoplastic inflammatory pseudotumor of the lung after immunotherapy for melanoma a diagnostic pitfall on fine needle aspiration biopsy of lung"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-2022-022975",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nCancer in the elderly is becoming a complex and frequent issue. At least 30% of lung carcinomas are expected to arise each year in elderly patients, who often have significant comorbidity. The most appropriate treatment for this large portion of cancer patients remains unknown. The purpose of this Phase II trial was to make a comprehensive evaluation of the activity, toxicity, and tolerability of single-agent vinorelbine in elderly and relatively poorly performing patients with inoperable nonsmall cell lung carcinoma (NSCLC).\n\n\nMETHODS\nPatients age 70 years or older were eligible to participate in this trial if they had a pathologic diagnosis, a performance status lower than 4 (Eastern Cooperative Oncology Group [ECOG] scale), and gave informed consent. Vinorelbine was given intravenously (i.v.) at a dose of 25 mg/m(2) every week until progression, persistent toxicity, or refusal.\n\n\nRESULTS\nForty-six patients entered the study; their median age was 75 years (range, 70-83 years). Five patients never started on vinorelbine; 27 others had early treatment suspensions. The median number of weekly infusions was 5 (range, 0-28); the median dose intensity was 70% of projected. Toxicity was generally mild, mainly hematologic, and never life-threatening. ECOG performance status, body weight, and almost all the scores from the quality-of-life questionnaires remained constant during the first 6 weeks of treatment. Two patients obtained partial response, 10 patients had some tumor regression, and 26 had tumor stabilization. The estimated median time to progression was 19 weeks (quartile range, 11-23 weeks), and the median survival 34 weeks (quartile range, 16-63 weeks).\n\n\nCONCLUSIONS\nIn our group of patients who had poor prognoses, vinorelbine was well tolerated, moderately active, and capable of ensuring relatively long survival. It may represent a valuable therapeutic option for the treatment of nonresectable NSCLC in elderly patients.",
"affiliations": "Divisione di Pneumologia, Ospedale S. Croce e Carle, Cuneo, Italy.",
"authors": "Buccheri|G|G|;Ferrigno|D|D|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D000077235:Vinorelbine",
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(20000615)88:12<2677::aid-cncr5>3.0.co;2-b",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "88(12)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D016019:Survival Analysis; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2677-85",
"pmc": null,
"pmid": "10870049",
"pubdate": "2000-06-15",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Vinorelbine in elderly patients with inoperable nonsmall cell lung carcinoma: a phase II study.",
"title_normalized": "vinorelbine in elderly patients with inoperable nonsmall cell lung carcinoma a phase ii study"
} | [
{
"companynumb": "TR-PFM-2020-02707",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINORELBINE TARTRATE"
},
"drugadditional": null,
... |
{
"abstract": "The objective of this study is to explore whether the use of medications that antagonize mediators of inflammatory responses reduces the risk of delirium in older adults.\n\n\n\nA nested case-control study was conducted using data from a prospective study of delirium in older long-term care residents from 7 long-term care facilities in Montreal and Quebec City, Canada. The Confusion Assessment Method was used to diagnose incident delirium. The use of medications that antagonize mediators of inflammatory responses was determined by examining facility pharmacy databases and coding medications received daily by each resident. Risk sets were built using incidence density sampling: each risk set consisted of a case with incident delirium and all controls without incident delirium at the same date and facility. Conditional logistic regression was used to assess the association of exposure to inflammation antagonist medications with the incidence of delirium.\n\n\n\nOf 254 residents, 95 developed incident delirium during 24 weeks (cases); each case was matched with up to 35 controls. Unadjusted and adjusted odds ratios (95% CI) of delirium for residents exposed to at least one inflammation antagonist medication were 0.53 (0.34, 0.81) and 0.60 (0.38, 0.92), respectively. Estimates of the risk of incident delirium associated with specific medications and medication classes were mostly protective but not statistically significant.\n\n\n\nThe use of medications that antagonize mediators of inflammatory responses may reduce the risk of delirium in older adults. Despite study limitations, the findings merit further investigation using larger patient samples, more precise measures of exposure and better control of potential confounding variables. Copyright © 2016 John Wiley & Sons, Ltd.",
"affiliations": "Department of Psychiatry, St. Mary's Hospital Center and McGill University, Montreal, Quebec.;St. Mary's Research Centre, St Mary's Hospital Center, Montreal, Quebec.;Division of Geriatric Medicine, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec.;Faculty of Nursing Sciences, Laval University, Montreal, Quebec.;Division of Geriatric Medicine, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec.;Institut Universitaire de Gériatrie de Montréal; Département de médecine familiale, Université de Montréal, Montreal, Quebec.;Division of Geriatric Medicine, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec.;St. Mary's Research Centre, St Mary's Hospital Center, Montreal, Quebec.;St. Mary's Research Centre, St Mary's Hospital Center, Montreal, Quebec.",
"authors": "Cole|Martin G|MG|;McCusker|Jane|J|;Wilchesky|Machelle|M|;Voyer|Philippe|P|;Monette|Johanne|J|;Champoux|Nathalie|N|;Vu|Minh|M|;Ciampi|Antonio|A|;Belzile|Eric|E|",
"chemical_list": "D014150:Antipsychotic Agents; D006633:Histamine Antagonists",
"country": "England",
"delete": false,
"doi": "10.1002/gps.4468",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-6230",
"issue": "32(2)",
"journal": "International journal of geriatric psychiatry",
"keywords": "delirium; nested case-control study; neuroinflammation; older; prevention",
"medline_ta": "Int J Geriatr Psychiatry",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D016022:Case-Control Studies; D003693:Delirium; D005260:Female; D006633:Histamine Antagonists; D006801:Humans; D015994:Incidence; D016015:Logistic Models; D008134:Long-Term Care; D008297:Male; D011446:Prospective Studies; D011792:Quebec; D012307:Risk Factors",
"nlm_unique_id": "8710629",
"other_id": null,
"pages": "208-213",
"pmc": null,
"pmid": "27001903",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of medications that antagonize mediators of inflammatory responses may reduce the risk of delirium in older adults: a nested case-control study.",
"title_normalized": "use of medications that antagonize mediators of inflammatory responses may reduce the risk of delirium in older adults a nested case control study"
} | [
{
"companynumb": "CA-JNJFOC-20180903227",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugadditional": "3... |
{
"abstract": "Internationally, overdose is the primary cause of death among people injecting drugs. However, since 2001, heroin-related overdose deaths in the United States (US) have risen sixfold, paralleled by a rise in the death rate attributed to synthetic opioids, particularly the fentanyls. This paper considers the adaptations some US heroin injectors are making to protect themselves from these risks.\n\n\n\nBetween 2015 and 2016, a team of ethnographers collected data through semi-structured interviews and observation captured in field notes and video recording of heroin preparation/consumption. Ninety-one current heroin injectors were interviewed (Baltimore, n = 22; Chicago, n = 24; Massachusetts and New Hampshire, n = 36; San Francisco, n = 9). Experience injecting heroin ranged from < 1-47 years. Eight participants, who were exclusively heroin snorters, were also interviewed. Data were analyzed thematically.\n\n\n\nAcross the study sites, multiple methods of sampling \"heroin\" were identified, sometimes used in combination, ranging from non-injecting routes (snorting, smoking or tasting a small amount prior to injection) to injecting a partial dose and waiting. Partial injection took different forms: a \"slow shot\" where the user injected a portion of the solution in the syringe, keeping the needle in the injection site, and continuing or withdrawing the syringe or a \"tester shot\" where the solution was divided into separate injections. Other techniques included getting feedback from others using heroin of the same batch or observing those with higher tolerance injecting heroin from the same batch before judging how much to inject themselves. Although a minority of those interviewed described using these drug sampling techniques, there is clearly receptivity among some users to protecting themselves by using a variety of methods.\n\n\n\nThe use of drug sampling as a means of preventing an overdose from injection drug use reduces the quantity absorbed at any one time allowing users to monitor drug strength and titrate their dose accordingly. Given the highly unpredictable potency of the drugs currently being sold as heroin in the US, universal precautions should be adopted more widely. Further research is needed into facilitators and barriers to the uptake of these drug sampling methods.",
"affiliations": "Heroin in Transition Study, Department of Family and Community Medicine, UCSF, 500 Parnassus Avenue, Milberry Union East, 3rd Floor, San Francisco, CA, 94143, USA. Sarah.Mars@ucsf.edu.;Heroin in Transition Study, Department of Family and Community Medicine, UCSF, 500 Parnassus Avenue, Milberry Union East, 3rd Floor, San Francisco, CA, 94143, USA.;Heroin in Transition Study, Department of Family and Community Medicine, UCSF, 500 Parnassus Avenue, Milberry Union East, 3rd Floor, San Francisco, CA, 94143, USA.",
"authors": "Mars|Sarah G|SG|;Ondocsin|Jeff|J|;Ciccarone|Daniel|D|",
"chemical_list": "D009294:Narcotics; D003932:Heroin",
"country": "England",
"delete": false,
"doi": "10.1186/s12954-018-0232-z",
"fulltext": "\n==== Front\nHarm Reduct JHarm Reduct JHarm Reduction Journal1477-7517BioMed Central London 23210.1186/s12954-018-0232-zResearchToots, tastes and tester shots: user accounts of drug sampling methods for gauging heroin potency Mars Sarah G. Sarah.Mars@ucsf.edu 12Ondocsin Jeff jeffondocsin@gmail.com 1Ciccarone Daniel Daniel.Ciccarone@ucsf.edu 121 0000 0001 2297 6811grid.266102.1Heroin in Transition Study, Department of Family and Community Medicine, UCSF, 500 Parnassus Avenue, Milberry Union East, 3rd Floor, San Francisco, CA 94143 USA 2 0000 0001 2297 6811grid.266102.1Department of Family and Community Medicine, University of California, San Francisco, CA USA 16 5 2018 16 5 2018 2018 15 268 3 2018 29 4 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\nInternationally, overdose is the primary cause of death among people injecting drugs. However, since 2001, heroin-related overdose deaths in the United States (US) have risen sixfold, paralleled by a rise in the death rate attributed to synthetic opioids, particularly the fentanyls. This paper considers the adaptations some US heroin injectors are making to protect themselves from these risks.\n\nMethods\nBetween 2015 and 2016, a team of ethnographers collected data through semi-structured interviews and observation captured in field notes and video recording of heroin preparation/consumption. Ninety-one current heroin injectors were interviewed (Baltimore, n = 22; Chicago, n = 24; Massachusetts and New Hampshire, n = 36; San Francisco, n = 9). Experience injecting heroin ranged from < 1–47 years. Eight participants, who were exclusively heroin snorters, were also interviewed. Data were analyzed thematically.\n\nResults\nAcross the study sites, multiple methods of sampling “heroin” were identified, sometimes used in combination, ranging from non-injecting routes (snorting, smoking or tasting a small amount prior to injection) to injecting a partial dose and waiting. Partial injection took different forms: a “slow shot” where the user injected a portion of the solution in the syringe, keeping the needle in the injection site, and continuing or withdrawing the syringe or a “tester shot” where the solution was divided into separate injections. Other techniques included getting feedback from others using heroin of the same batch or observing those with higher tolerance injecting heroin from the same batch before judging how much to inject themselves. Although a minority of those interviewed described using these drug sampling techniques, there is clearly receptivity among some users to protecting themselves by using a variety of methods.\n\nConclusions\nThe use of drug sampling as a means of preventing an overdose from injection drug use reduces the quantity absorbed at any one time allowing users to monitor drug strength and titrate their dose accordingly. Given the highly unpredictable potency of the drugs currently being sold as heroin in the US, universal precautions should be adopted more widely. Further research is needed into facilitators and barriers to the uptake of these drug sampling methods.\n\nKeywords\nOverdoseHeroinFentanylTest shotTester shotInjectionInsufflationInhalationHarm reductionUnited Stateshttp://dx.doi.org/10.13039/100000026National Institute on Drug AbuseDA037820Ciccarone Daniel issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nHeroin can be taken into the human body in a wide variety of ways, including snorting or sniffing powder or heroin solution (intranasal use), inhalation of the heated vapors (“chasing”), orally and as anal suppositories (“plugging”). Injecting, whether intravenous, subcutaneous or intramuscular, is the method of administration carrying the highest risk for multiple types of infections, overdoses and their complications [1–15]. However, despite these risks, injection appeals to users because it is the most efficient, cost-effective method of use, and intravenous injection in particular has the most intense onset of effect (“rush”). These can be important considerations when users face rising tolerance to heroin’s effects [16, 17].\n\nHeroin “source form”—its chemical characteristics based on country of origin—also influences its mode of use [18, 19]. Bioavailability, or the measure of a drug dose that achieves circulation in the bloodstream, in turn reflects the mode of use. The three main source forms of heroin in the US—Colombian-sourced powdered heroin and both Mexican-sourced black tar heroin and powdered heroin—are all hydrochloride salts in contrast with the Afghanistan-sourced base heroin, aka “smoking heroin,” found in Europe [20]. The hydrochloride (HCL) form has relatively low bioavailability when smoked compared with base heroin [21]. Heroin HCL may be potentiated when smoked by the addition of caffeine [22], but research indicates no significant culture of heroin smoking in the US [23, 24] likely due to available source forms. Use outside of controlled conditions [25] as well as poor chasing technique [26] may also negatively affect the bioavailability of smoked heroin.\n\nAnother non-injection option to chasing/smoking is intranasal use. Intranasal heroin administration has been found to be an effective drug delivery route. It has been theorized that the lower price of US heroin in the early 1990s rather than its higher purity—as well as fears of contracting HIV—may have led to increased usage of intranasal administration [27]. US data on hospitalizations in the 1990s suggests an increase in heroin inhalation and smoking, primarily in the northeast during this period [28].\n\nFor many decades, overdose has been the primary cause of deaths among people injecting drugs [6, 9, 29–32], but since 2001, heroin-related overdose deaths have risen sixfold in the United States [33]. Heroin-related overdose intensified after 2010, with overdose mortality rates tripling between 2010 and 2014 from 1.0 to 3.4 per 100,000 [34]. The increase in heroin-related deaths has been paralleled by a rise in the death rate attributed to synthetic opioids other than methadone. The age-adjusted rate of overdose deaths attributed to synthetic opioids other than methadone, which includes fentanyl and its analogs, doubled between 2015 and 2016, rising to 6.2 per 100,000 [35]. Evidence from the US Drug Enforcement Agency indicates this increase is being primarily driven by illicitly manufactured fentanyl rather than diverted pharmaceutical fentanyl [36, 37]. While some have focused on the potency of fentanyl [38, 39] in increasing the risk for overdose, others have highlighted the risk of vicissitudes in the purity of fentanyl and its analogs in combination with heroin [40, 41].\n\nIn the face of overdose-related morbidity and mortality, numerous public health interventions have tried to address the risks of overdose over the last 20 years. These strategies include overdose education and peer naloxone distribution [42–44]. Promoting what has been termed “reverse transition” from injecting to a non-injecting route of administration constitutes another approach to reducing overdose risk [45].\n\nOne study of UK-based “chasers” and injectors found that while preferred administration routes were likely to persist for years and multiple route transitions were uncommon, 16% of their sample had reverse transitioned [46]. Another study of reverse transitions among heroin and cocaine users in New York City found that transition from injection to non-injection use appeared to be a relatively stable, long-term behavior change [47]. Among other transitions, several harm reduction organizations in the UK advocated for switching to rectal administration (\"plugging\"), the so-called “up your bum” campaign, but it is unclear how widespread this practice actually is [48, 49].\n\nGiven the low rate of “chasing” among US heroin users, one practice some injectors have adopted to reduce the risk of overdose is the use of “tester shots” or “test shots.” This entails injecting a small quantity of a drug sample in order to assess its potency qualitatively before deciding whether to inject the remainder of the dose [50–52]. A tester shot requires practitioners to perform two injections, a factor that may act as a barrier to the widespread adoption of this behavior, as venous access can become challenging for long-term injectors and higher injection frequency increases the risk of injection-related complications including viral transmission [2, 53].\n\nCircumventing the multiple injection problem of the tester shot, “slow shots” allow the injector to insert the needle, release the tourniquet, and very slowly inject while assessing the embodied effect with the needle still in the vein [54]. A further refinement of this is the “graduated” or “controlled” shot where the needle remains in the vein, but the dose is divided into three with a pause for assessment of its effects between each third [55]. The term “tester shot” is used in this paper to encompass all forms of partial dose injection, while “drug sampling” refers to any method of administration involving a partial dose.\n\nThere is a dearth of qualitative research on behavioral adaptions that current heroin injectors are making with respect to the ongoing fentanyl adulteration crisis in the US. In this paper, we present findings from ethnographic fieldwork trips in 2015 and 2016 to Baltimore, Maryland; Worcester, Lowell, and Lawrence, Massachusetts; Nashua, New Hampshire; San Francisco, California; and Chicago, Illinois on embodied methods of gauging opioid strength that injection drug users in these areas are taking to prevent overdose. With the exception of California, where solid black tar heroin dominates, all these states have powder sourced from Mexico or Colombia and are suffering rising heroin- and fentanyl-related deaths.\n\nIn 2016, Baltimore lost 454 people to heroin-related overdoses, up from 260 the previous year, and 419 people to fentanyl-related overdoses, up from 120 in 2015 [56, 57]. The figures available for Massachusetts do not distinguish between heroin and prescription opioids. In 2016, among the 1374 individuals whose deaths were opioid-related (including heroin) and a toxicology screen was also available, 1031 of them (75%) had a positive screen result for fentanyl, an increase from 754 (57%) in 2015, although this may depend on the frequency of toxicological screening [58, 59]. Drug overdose deaths in New Hampshire increased by 1629% between 2010 and 2015, largely as a result of fentanyl. Hillsborough County, the location of Nashua, where 43.6% of the fentanyl deaths occurred, was most affected by these overdose deaths. The rate of death caused by fentanyl, heroin, and other opioids rose sharply between 2015 and 2016 [60]. In Chicago in 2016, there were 487 overdose deaths involving heroin and 420 involving fentanyl, both rising from the previous year [61]. In San Francisco in 2016, 41 deaths were attributed to heroin overdose and 22 attributed to fentanyl, doubling from the previous year [62, 63]. Data for 2017 are not available for all sites, but Baltimore showed a small decline in heroin-related deaths (from 334 in January to September 2016 to 305 in the same period of 2017) but a much larger increase in fentanyl-related deaths (from 276 January to September 2016 to 427 in the same period in 2017) [64]. Massachusetts experienced a modest decline in overall opioid deaths in 2017 but an increase in the proportion screening positive for fentanyl (to 83%) [65].\n\nMethods\nThe “Heroin in Transition” (HIT) study is conducting “hotspot” research where ethnographers are dispatched to locations around the country upon receiving reports of unusual or dangerous heroin or high levels of overdose [40]. HIT’s approach is adapted from “rapid assessment,” a short-term multidisciplinary research model aimed at gaining an insider perspective of social, economic or health problems and their possible solutions [66]. Originally developed in the 1970s, rapid assessment has enabled researchers to gain knowledge about emerging health problems in a short time period and has been used effectively in investigating health concerns related to drug use [67–69].\n\nHIT uses highly focused ethnography to investigate new and evolving heroin forms and users’ responses, their methods and contexts of use [17]. The paucity of data regarding the risks associated with novel heroin forms of unknown purity and modes of use, along with contamination of the heroin supply with fentanyl [41] and the urgent need for knowledge acquisition to develop interventions, makes rapid ethnography highly appropriate to this time sensitive problem.\n\nUnlike most rapid assessment, the HIT model is chiefly qualitative, with quantitative questions explored by the Heroin in Transition study outside the rapid assessment to inform the overall picture. Our research model aims to represent “from below” the experiences and perceptions of users in the current opioid epidemic. These data are placed alongside observations by the ethnographers based on their own experience of observing heroin and its use in other locations. Data are not formally triangulated, but we hope that a composite picture emerges from the multiple perspectives of users and ethnographers. Further, rapid ethnography allows us to generate hypotheses to be tested by quantitative research methods. Between 2015 and 2016, the ethnographic team visited Baltimore, Maryland (November 2015 and March 2016); San Francisco, California (February 2016); the Massachusetts cities of Lawrence, Lowell, Worcester and Nashua, New Hampshire (June 2016); and Chicago, Illinois (September 2016).\n\nRecruitment and data collection\nFollowing information about fentanyl-laced and fentanyl-substituted heroin in Baltimore, New Hampshire and Massachusetts and high levels of overdose in Chicago, contact was made with harm reduction service providers in these locations. In San Francisco, the ethnographic team used personal contacts to arrange interviews with users and also carried out recruitment on the street. The study protocol was also approved by the University of California, San Francisco Institutional Review Board. The data and its collection are protected by a US Federal Certificate of Confidentiality issued by the National Institutes of Health/National Institute on Drug Abuse.\n\nData were collected through semi-structured interviews, ethnographic observation captured in collaborative field notes and video recording of heroin preparation and consumption. With its observation in the field and long established “ground-up” approach to data collection, ethnography is a method well suited for examining the experiences and phenomena of everyday life—and has been used widely in research among drug users [3, 70]. Rapid ethnography uses a more directed and condensed approach than traditional ethnography, collecting data with a particular set of questions in mind.\n\nTo be eligible for the study, participants had to be at least 18 years of age and self-reported current injectors whose primary drug was heroin. Exclusion criteria covered individuals who were intoxicated or otherwise unable to give informed consent or answer questions reliably. Researchers approached users attending needle and syringe program sites, explained the study to them, and obtained their consent. Some snowball sampling was also conducted [71]. Only verbal consent is sought to avoid the collection of participants’ full names or signatures. Pamphlets approved by UCSF IRB explaining the study and respondents’ rights were also provided. Interviews are conducted in as private a setting as possible. Before the interview begins, the research participants are reminded that they are free to decline to answer any question or to leave or stop talking to the researcher at any time. The team carries mobile phones for emergencies. Respondents received a small cash sum in compensation for their interview (approximately 0.5–1 h), aiming to balance respect for participants’ time while not acting as an inducement for users to participate [72]. All participants were interviewed once while some provided neighborhood tours or permitted the ethnographers to observe and film heroin injections.\n\nThe semi-structured interviews were carried out by the ethnographers (JO, EW, FMC and MH), project director (SM), and PI (DC) immediately upon recruitment at the needle and syringe program locations, in rental cars, cafés, users’ homes or drug-using locations. An interview guide provided a general structure to the conversation, including questions on the respondents’ life course of drug use, a typical day in their life involving drug acquisition and use, perceived changes in the heroin supply, knowledge of fentanyl, preferences for heroin vs. fentanyl, methods of use, perceived physiological effects and experiences of overdose.\n\nAfter our initial visit to Baltimore indicated some tester shot usage among the population, focused questioning on drug sampling was incorporated into the interview guide for subsequent sites. All interviews were audio-recorded and transcribed in their totality and verified (by JO) against the audio recording. Field notes were drafted collaboratively each research day and finalized after the trips. The PI (DC) is a physician and can address participants’ medical concerns or questions or that arise during the flow of this research. As data is analyzed, findings are fed back to local service providers to assist in the development of tailored harm reduction responses.\n\nSample characteristics\nThis was a non-random convenience sample. Across all sites, 91 current heroin injectors were interviewed (Baltimore, n = 22; Chicago, n = 24; Massachusetts and New Hampshire, n = 36; San Francisco, n = 9), of whom 62 were male and 29 were female. The experience injecting heroin ranged from less than a year to 47 years. Eight participants, who were dedicated heroin snorters, were also interviewed. Names have been changed to protect confidentiality.\n\nAnalysis\nTranscripts were read in their entirety, and text relating to tester shots/snorting and other harm reduction methods were extracted by JO and discussed by JO, DC, and SM, who then clarified categories of activity, motivation, provenance and other themes arising from the data. Observations from the field notes and video recording were also incorporated in the analysis. The analysis gave priority to the ways in which people experience heroin but also included the reflections of the ethnographers observing the drugs and their administration.\n\nSome degree of subjectivity and contextual influence are present in all data interpretation, but the ethnographers maintained an awareness of this, discussing and examining their own positionality and preexisting ideas at multiple points during the research process. Data analysis was conducted by three multidisciplinary researchers with diverse life experiences, disciplinary backgrounds, age, and mixed genders. Where discrepancies in the interpretation of the findings arose, these were discussed until agreement was reached.\n\nResults\nMotives\nThe unpredictability of heroin potency is a long-established problem of its illicit supply, particularly for injectors whose dose is delivered in a single “bolus,” putting them at increased risk of overdose relative to those who insufflate (toot, snort or sniff) or smoke heroin. Users become aware of these risks in a number of ways, including personally experiencing or witnessing overdoses or losing friends or partners. The research study’s first encounter with drug sampling was with a young man in San Francisco who, after experiencing an overdose, had started smoking the strong black tar heroin known locally as “point dope” before judging how much to inject:I’ll smoke it just to see how I feel from taking a couple of hits and then I’ll only do a point [0.1g] or if I’m really spooked, like, even less, just try it out. […] Yeah, you know what’s funny though, I didn’t always do that until I had OD’ed and then I was like “Oh fuck! Now I’m playing with my life here.” (Riley, in his 20s, using for 7 years)\n\n\n\nLike Riley, some interviewees mentioned adopting drug sampling as a result of experiencing overdose firsthand, but others did so after observing others. Liz from Lawrence, MA, a woman in her 20s who had been injecting for 1 year and had never personally overdosed, explained that she had adapted her behavior with fentanyl-laced heroin, “Because you learn from everybody else being stupid”:[…]when I get stuff I don’t know what it is, I do a little bit before I do something that I feel. Like I want to kind of scale out how much I want to do. Because I don’t want to die. But these people are just doing a gram shot and just… my friend just died two days ago.\n\n\n\nWhile some referred to these methods as their regular practice, others sampled in particular circumstances such as after periods of abstinence or when the heroin or its source were unfamiliar. In Chicago, David, who was in his 30s and had been using for 7 years, generally relied upon a regular dealer to regulate the quality and strength of his heroin, as well as keeping his doses small, but he snorted heroin prior to injecting when buying from an unfamiliar source:Q: Do you ever taste a new bag?\n\nA: No, because I’ve been going through the same guy and it’s just always consistent. His is always, you know, straightforward. You know what you’re going to get. So I trust it. But if I were to go to somebody else that I hadn’t gone to before I would definitely taste it, snort a little bit, or you know if I were to shoot it, I would shoot a small amount. Because you can always shoot more, you can never shoot less.\n\n\n\nDrug sampling methods\nUsers described a wide variety of methods for drug sampling, sometimes creatively combining them together, from using non-injecting routes of administration such as snorting, smoking or tasting a small amount prior to injection to injecting a partial dose and waiting. Partial injection could take different forms: either a “slow shot” where the user injected a portion of the solution in the syringe, keeping the needle in the injection site, and then either continuing or withdrawing the syringe or a “tester shot” where the solution was divided between two or more separate injections. Other techniques included getting feedback from other users who were using heroin of the same batch or observing other users with higher tolerance injecting heroin from the same batch before judging how much to inject themselves.\n\nDrug sampling by snorting and tasting\nIn Chicago, where the powder heroin can be snorted rather than smoked, several injectors described snorting their heroin before injecting. Ray, in his 50s and using for 25 years, explained that this not only gave an indication of its strength but also a taste at the back of the throat which, he believed, was indicative of its ingredients:\n\n\nA: […] I’m not the only one that do this. There’s a lot of my buddies that do heroin too, will toot [snort] it first before we even start cooking it up to see what’s it about. […]See, when you toot dope it’s supposed to go down your nose and it’s supposed to go down smooth without no burn or none of that… Now, once you get that drain, it’s the taste. It tastes like dope. Because see, some dope that tastes like aspirin ain’t dope…. So you get familiar with the taste of dope too once you do it, once you had done it so long with me…. So once you get all that in perspective, […] the taste, the smoothness going down, the drain, you’ll start feeling a nice, warm sensation. So now I know it’s straight [heroin] so it’s time for me to party now.\n\n\n\n\nTester shot\nSeveral of our research participants indicated that they had begun injecting a smaller amount of heroin to assess qualitatively its embodied effects before injecting a larger dose. Johnny in Chicago, in his 20s and using for 6 years, was among those who endorsed this method:A: […] I’m very cautious on my heroin intake. I like to know how much I’m doing. And if anything, I always do a little bit less and sometimes I get pissed off because I don’t get high from the little shot.\n\nQ: So you take care of yourself, testing a little bit.\n\nA: I always test the waters before. You don’t just jump in with heroin.\n\n\n\nGlen, in his 20s, using for approximately 1 year in Baltimore, described his method of tester shot:Q: How long are you waiting to judge how strong it is?\n\nA: I’d say anywhere from 5 to 15 minutes.\n\nQ: 5 to 15 minutes. You’re a patient guy. I imagine a lot of other people aren’t so patient.\n\nA; Well, it’s… pays off in the end, I guess.\n\n\n\nHalf-dose slow shot\nSome of those interviewed had managed to avoid overdose entirely, perhaps as a result of using drug sampling methods. Larry, a Baltimore man in his 60s who had survived over 40 years of heroin use without overdosing, explained how he injected half his shot of heroin, waited a short time, and then decided whether to inject the rest. If he decided to inject the rest of the shot after waiting, he registered to check whether he was still accessing the vein first. We asked him about how he managed the decision not to use the whole shot:Q: So what happens if you’re feeling like that half shot is really good, do you have enough self-control to take the rest of it out and not do it?\n\nA: Yeah, I can. And I also like to have it where I can put the rest of it in me, because I feel as though my intake can allow me to take the rest of that there.\n\n\n\nCombined tester and slow shots\nJames, a Baltimore man in his 50s who had been injecting for half his life and never overdosed, had recently experienced a number of friends dying from overdoses. His method involved loading the syringe with half the dose and then further dividing the half doses for a slow shot:A: […] I don’t, what they call, slam it and put the whole thing in me. I do it little by little just to see what the effects is and stuff.\n\nQ: So do you like have one syringe and you use a little bit of it or do you like have several syringes?\n\nA: No, just one syringe and one syringe I put what we say 80 on the height. So once I cook it up and do what I’m going to do with it, and most of the time I’ll speedball, you know, cocaine and heroin. And I will take 40 of it and I’ll take the other 40 and put it to the side and then when I hit myself I’ll just put 20 in it just to see, you know, what the effects is …\n\n\n\nCombined user report and slow shot\nJanice, also a long-term user in Baltimore, in her 50s, who had also never overdosed, used a combination of approaches to regulate her intake. This involved getting an oral report from a friend, gauging how much to dilute the heroin depending on her friend’s reaction, and then taking a half-dose slow shot, keeping the needle in place before deciding whether to use more.Q: … Since you don’t know whether it’s going to be weak or strong how do you manage that?\n\nA: What I do is I get a reading from someone else because I know myself.\n\nQ: A reading?\n\nA: Meaning they tell me how it is for them. And that determines how much water I’ll put on mine. Like my girlfriend might say, 'Girl, that dope is good as a motherfucker.' I might put 40 on it and I’ll put a 60. […]\n\nQ: You dilute it if the strength is good?\n\nA: Yes.\n\nQ: All right. Then how do you inject that 60? […]\n\nA: 30.\n\nQ: You’ll do 30?\n\nA: I’ll do 30, wait for it to hit me and see if I can handle it or do I need to come out.\n\nQ: How long you waiting for?\n\nA: As soon as it hit me. Which usually takes I’d say 20 seconds.\n\nQ: 20 seconds, okay. And then you just decide to pull out or --?\n\nA: Or go ahead with it.\n\n\n\nMixed heroin-tolerance partners\nRelying on friends’ experiences of a single batch was also something we observed in Baltimore. Glen and Scott are running buddies sharing resources including heroin [3]. Glen had only started injecting in the last year after a brief period snorting heroin following his transition from opioid pills. Scott, in his 40s, had a higher opiate tolerance after using heroin for many years and acted as “taster.” In this case, Glen heated a speedball in a single cooker, dividing the solution equally between two syringes. After Glen had injected Scott in his neck, Scott reported on its strength and advised Glen to go ahead and inject his own dose. Although Glen’s tolerance was lower, they shared equal doses, perhaps an equity demanded by their friendship, but took care to keep each other safe.\n\nUsers’ reflections on drug sampling\nHowever, there are limits to the drug sampling strategies just described, especially in the age of fentanyl. Harry, a user in his 40s from Lowell, MA, using for 20 years, explained that even with a tester shot, he had almost overdosed from heroin he later believed to contain fentanyl:I almost overdosed, I almost died. I almost went out. And I didn’t do much, it was kind of like a tester shot and it was really powerful. I just thought it was really good dope, you know? I didn’t know it was fentanyl until it started getting around that the fentanyl was floating around…\n\n\n\nWhether users developed these methods themselves, learnt them from peers, publicity campaigns or harm reduction workers was often unclear. However, an awareness of the irreversibility of injection was a recurring theme.I’m taking my time because if I’m gonna mix it with 65 [units of water], I’m gonna put 10 or 15 in me to see the quality of what I’m putting in me, because you can always put more in, but can’t take it out. I’m a firm believer in that.—Doug, Baltimore, in his 40s, using for 32 years\n\n\n\n\nI’ll do a little bit at a time just to make sure I’m not – that I’m cool. And then you can always give yourself more but you can’t take back.—Joanie, Chicago, in her 30s, using for 14 years\n\n\n\n\n\nQ: Do you ever do a tester shot or do you use the whole thing in one shot?\n\nA: It depends on the drug, sometimes I don’t do it all at once. You have to respect dope; if you know it’s strong, you have to use it carefully.—Gonzalo, Nashua, NH, in his 50s, using for 20 years\n\n\n\n\n\nQ: And you were saying a bit about how you avoid ODing yourself?\n\nA: Oh yeah, because I don’t, you know, push the whole thing in me at one time, because like I said, there is no pulling it back […] once you push it in you, ain’t no trying to pull it back […]—James, Baltimore\n\n\n\n\nThe presence of overdose as an imminent danger was especially pervasive among users in Baltimore and Massachusetts, many of whom had lost friends, relatives or acquaintances. Although a minority of those interviewed described using these drug sampling techniques, there is clearly receptivity among some users to protecting themselves by using a variety of methods.\n\nDiscussion\nOur ethnographic research shows that in the five states visited for this study, some people using heroin have incorporated tester shots and other drug sampling strategies into their injection practices. These included a wide range of approaches, sometimes in combination, in which people used their own or others’ embodied experiences to judge the strength of the drug qualitatively before deciding on their dose. While these methods do not guarantee safety from an overdose, particularly in the cases of some of the more powerful fentanyls, it would be valuable to test epidemiologically whether those using drug sampling methods report experiencing fewer overdoses.\n\nPeer advocacy for tester shots and drug sampling may be the most effective means of expanding the use of these methods. A number of research studies conducted in the US and internationally have demonstrated the connection between social norms, peer adoption, self-efficacy and perceived acceptability in the successful adoption of harm reduction strategies [73–77]. Other research has demonstrated how social norms within drug-using groups influence the perception of risks and acceptable practices [78]. The promotion of drug sampling methods between peers as a form of harm reduction therefore needs to be done in a way that reflects the structural risks of the regional drug economy and an awareness of local norms among users. For instance, to advise users to sample their heroin by smoking before injecting might be suitable where a base form of the drug, such as Afghanistan-sourced heroin, is dominant, but in the case of US powder heroin, much of the drug would be lost before absorption and snorting prior to injection would be a better option. Alternatively, where heroin prices are high and/or availability is low, tester shots may be more appealing than snorting. Aside from these market considerations, further research into facilitators and barriers to the uptake of drug sampling is needed. Barriers suggested to date are a loss of intensity from spreading the dose over time and “wasting” heroin through less effective delivery methods such as snorting [26, 79].\n\nPsychologically informed approaches may also shed some light on how best to encourage the use of drug sampling. One survey of the self-efficacy of harm reduction practices, including tester shots, found that adherence to all harm reduction strategies surveyed was markedly lower when respondents were asked to imagine being in withdrawal [80]. A later study identified being in a hurry to use (24%) and purchasing drugs from a known dealer (20%) as the most significant barriers to the adoption of tester shots [81]. Health beliefs about perceived susceptibility to and severity of overdose may influence the adoption of overdose-related harm reduction methods such as tester shots [82]. Many of those we spoke with reported the recent deaths of friends, family and acquaintances [17, 41], as well as experiencing their own overdoses. We do not know whether decisions to use drug sampling strategies are shaped more by psychological or situational factors.\n\nIn order for tester shots and other drug sampling strategies to be effective at preventing overdose, people who inject heroin must be willing to use them consistently, since risk is difficult to determine at the point of use. Other interventions that may be effective aids in assessing overdose risk include point-of-use testing, also known as drug checking, and qualitative user discernment of street heroin. Recent research has shown a high willingness among younger, US-based injection drug users to utilize fentanyl test strips [83], but the hypersensitivity of on-the-market fentanyl test strips raises questions about their efficacy in helping injectors to quantify risk. Harm reduction interventions focusing on “universal precautions,” i.e., consistent use of drug sampling, may be more effective than point-of-use fentanyl testing. This and the utility of combined interventions need to be evaluated. User discernment of fentanyl-adulterated and -substituted heroin may also be a useful supplement to both drug sampling and point of use testing [40].\n\nThis study is explorative qualitative research based on a convenience sample of heroin injectors in five US states. Due to the non-random sampling methods and semi-structured interview format, quantitative comparisons of drug sampling patterns across the research locations or by sample characteristics should not be made. The data comprise a snapshot of drug consumption behavior that can generate hypotheses but not conclusive findings. Interviews carried out at needle and syringe programs and other public health settings may be influenced by social desirability bias. Some interviewees were recruited outside of these environments, however, in an effort to mitigate this bias.\n\nConclusions\nHarm reduction services are central in the promotion of safer drug use techniques. Bearing in mind the non-random study sample, we found heroin sampling methods to be most common in Baltimore and Chicago, where robust harm reduction services have been established for more than two decades (Baltimore’s in 1994 and Chicago’s in 1991). In Massachusetts, two of the three cities visited had no official needle and syringe programs, while Worcester’s had only started in 2016, and few users mentioned using tester shots or other drug sampling methods. In Chicago, where most of those using tester shots and snorting were interviewed, the local harm reduction service, Chicago Recovery Alliance [84], has been teaching these methods for two decades. Snorting, for those willing to do so, was considered a particularly informative method for evaluating the drug as it included other sensations, allowing users to detect pH balance, additives, and other drug characteristics.\n\nThe use of tester shots and other drug sampling methods as a means of preventing an overdose from injection drug use reduces the quantity absorbed at any one time, allowing users to monitor for drug strength and titrate their dose accordingly. In the face of greater perceived susceptibility to and severity of opioid-related overdose due to the rising presence of fentanyl-adulterated and -substituted heroin [40], this could be a useful strategy to reduce both morbidity and mortality.\n\nAbbreviations\nHCLHydrochloride\n\nHITHeroin in Transition\n\nUSUnited States\n\nAcknowledgements\nThe authors would like to thank first and foremost the research participants for their willingness to share their knowledge and experiences with us. We would also like to thank the litany of harm reduction workers across all field sites who have enabled us to perform our research. Thanks to Mary Howe, Fernando Montero Castrillo, and Eliza Wheeler for their hardwork collecting data on the ground as part of the ethnographic field staff. Thank you to our colleagues on the Heroin in Transition study, Jay Unick, Georgiy Bobashev, Daniel Rosenblum and Philippe Bourgois. The authors would also like to thank their partners—Jason Fessel, Margaret Smith and Kimberly Koester—for their support of the project and helpful contributions to our research. Finally, we thank the funders, the National Institutes of Health and National Institute on Drug Abuse (Grant number DA037820).\n\nFunding\nThis work was supported by the National Institutes of Health and National Institute on Drug Abuse (Grant No. DA037820).\n\nAvailability of data and materials\nThe datasets generated and analyzed during the current study are not publicly available for reasons of confidentiality. The qualitative data collected in this study could be used to identify individuals involved in illicit and/or illegal activities and is therefore only available to the research team. It is protected by a Federal Certificate of Confidentiality.\n\nAuthors’ contributions\nSGM and JO conducted the initial analysis and drafted the preliminary manuscript collaboratively. They discussed the analysis regularly with DC. All authors helped revise the manuscript and assisted with the classification of findings. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe University of California, San Francisco IRB approved this research study. All participants provided oral consent at the time of the interview.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ciccarone D, Unick GJ, Cohen JK, Mars SG, Rosenblum D. Nationwide increase in hospitalizations for heroin-related soft tissue infections: associations with structural market conditions. Drug Alcohol Depend. 2016;163:126–33.\n2. 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National Institute on Drug Abuse Overdose death rates: number of deaths from heroin 2015 \n34. Rudd RA Aleshire N Zibbell JE Matthew GR Increases in drug and opioid overdose deaths—United States, 2000–2014 Am J Transplant 2016 16 1323 1327 10.1111/ajt.13776 \n35. Hedegaard H, Warner M, Miniño A. Drug overdose deaths in the United States, 1999–2016: NCHS Data Brief; 2017. https://www.cdc.gov/nchs/products/databriefs/db294.htm. Accessed 4 Mar 2018\n36. Drug Enforcement Administration National heroin threat assessment summary—updated 2016 Washington DC Department of Justice \n37. Drug Enforcement Administration DEA issues nationwide alert on fentanyl as threat to health and public safety 2015 Washington DC US Department of Justice, Drug Enforcement Administration \n38. Gladden RM, Martinez P, Seth P. Fentanyl law enforcement submissions and increases in synthetic opioid–involved overdose deaths—27 states, 2013–2014. MMWR Morb Mortal Wkly Rep. 2016;65:837–843.\n39. Peterson AB, Gladden R, Delcher C, et al. Increases in fentanyl-related overdose deaths—Florida and Ohio, 2013–2015. MMWR Morb Mortal Wkly Rep. 2016;65:844–849.\n40. Ciccarone D Ondocsin J Mars SG Heroin uncertainties: exploring users’ perceptions of fentanyl-adulterated and-substituted ‘heroin’ Int J Drug Policy. 2017 46 146 155 10.1016/j.drugpo.2017.06.004 28735775 \n41. Ciccarone D Fentanyl in the US heroin supply: a rapidly changing risk environment Int J Drug Policy. 2017 46 107 111 10.1016/j.drugpo.2017.06.010 28735776 \n42. Walley AY Xuan Z Hackman HH Quinn E Doe-Simkins M Sorensen-Alawad A Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis BMJ 2013 346 f174 10.1136/bmj.f174 23372174 \n43. Doe-Simkins M Walley AY Epstein A Moyer P Saved by the nose: bystander-administered intranasal naloxone hydrochloride for opioid overdose Am J Public Health 2009 99 788 791 10.2105/AJPH.2008.146647 19363214 \n44. Seal KH Thawley R Gee L Bamberger J Kral AH Ciccarone D Naloxone distribution and cardiopulmonary resuscitation training for injection drug users to prevent heroin overdose death: a pilot intervention study J Urban Health. 2005 82 303 311 10.1093/jurban/jti053 15872192 \n45. Strang J Bearn J Farrell M Finch E Gossop M Griffiths P Route of drug use and its implications for drug effect, risk of dependence and health consequences Drug Alcohol Rev 1998 17 197 211 10.1080/09595239800187001 16203485 \n46. Griffiths P Gossop M Powis B Strang J Transitions in patterns of heroin administration: a study of heroin chasers and heroin injectors Addiction 1994 89 301 309 10.1111/j.1360-0443.1994.tb00896.x 8173499 \n47. Des Jarlais DC Arasteh K Perlis T Hagan H Heckathorn DD Mcknight C The transition from injection to non-injection drug use: long-term outcomes among heroin and cocaine users in New York City Addiction 2007 102 778 785 10.1111/j.1360-0443.2007.01764.x 17506155 \n48. Hit.org.uk. Up your bum--an alternative to injecting. https://www.hit.org.uk/index.php/publications/leaflets/item/92-up-your-bum-an-alternative-to-injecting.\n49. Merchants Quay Ireland. Safer injecting guide. 2007. http://www.drugs.ie/resourcesfiles/guides/mqi_safer_injecting_guide.pdf.\n50. Harm Reduction Coalition. Getting off right: a safety manual for injection drug users. New York: Harm Reduction Coalition; 2012. http://harmreduction.org/wp-content/uploads/2011/12/getting-off-right.pdf.\n51. Curtis M Guterman L Overdose prevention and response a guide for people who use drugs and harm reduction staff in Eastern Europe and Central Asia 2009 \n52. Harm Reduction Coalition. H is for heroin. New York: Harm Reduction Coalition; 2000. http://harmreduction.org/wp-content/uploads/2011/12/HisforHeroin.pdf.\n53. Harris M Rhodes T Venous access and care: harnessing pragmatics in harm reduction for people who inject drugs Addiction 2012 107 1090 1096 10.1111/j.1360-0443.2011.03749.x 22151433 \n54. Matthews W Fentanyl and harm reduction strategies 2017 \n55. Chicago Recovery Alliance. Controlling your shot. http://www.anypositivechange.org/bvcsi_20.html. Accessed 28 Feb 2018.\n56. Maryland Department of Health and Mental Hygiene Drug and alcohol related intoxication deaths in Maryland, 2016 2017 \n57. Maryland Department of Health and Mental Hygiene Drug- and alcohol-related intoxication deaths in Maryland, 2015 2016 \n58. Massachusetts Department of Public Health Data brief: opioid-related overdose deaths among Massachusetts residents 2017 Massachusetts Department of Public Health \n59. Massachusetts Department of Public Health Data brief: opioid-related overdose deaths among Massachusetts residents 2016 \n60. Sorg MH, Wren JA, Center MCSP, Stewart K, Cao Y. Unintentional fentanyl overdoses in New Hampshire: an NDEWS HotSpot analysis. 2017. https://ndews.umd.edu/sites/ndews.umd.edu/files/ndews-hotspot-unintentional-fentanyl-overdoses-in-new-hampshire-final-09-11-17.pdf.\n61. Chicago Department of Public Health. Epidemiology report: increase in overdose deaths involving opioids—Chicago 2015–2016. Chicago; 2017. https://www.cityofchicago.org/content/dam/city/depts/cdph/tobacco_alchohol_and_drug_abuse/2016ChicagoOpioidReport.pdf. Accessed 24 Apr 2018\n62. San Francisco Department of Public Health Death of three men overnight likely drug related: health officials concerned about possible fentanyl poisoning: urge safety and precautions for drug users 2018 \n63. San Francisco Department of Public Health San Francisco safe injection services task force: final report 2017 2017 \n64. Maryland Department of Health Unintentional drug- and alcohol-related intoxication deaths in Maryland: data update through 3rd quarter 2017 \n65. Massachusetts Department of Public Health Data brief: opioid-related overdose deaths among Massachusetts residents. Data brief 2018 Massachusetts Department of Public Health \n66. Beebe J. Rapid assessment process: an introduction. Walnut Creek: AltaMira Press; 2001.\n67. Harris K Jerome N Fawcett S Rapid assessment procedures: a review and critique Hum Organ 1997 56 375 378 10.17730/humo.56.3.w525025611458003 \n68. Trotter RT Needle RH Goosby E Bates C Singer M A methodological model for rapid assessment, response, and evaluation: the RARE program in public health Field Methods 2001 13 137 159 10.1177/1525822X0101300202 \n69. Page JB, Singer M. Comprehending drug use: ethnographic research at the social margins. New Brunswick: Rutgers University Press; 2010.\n70. Raikhel E, Garriott W. Addiction trajectories. Durham: Duke University Press; 2013.\n71. Barendregt C van der Poel A van de Mheen D Tracing selection effects in three non-probability samples Eur Addict Res 2005 11 124 131 10.1159/000085547 15990429 \n72. Ritter AJ Fry CL Swan A The ethics of reimbursing injecting drug users for public health research interviews: what price are we prepared to pay? Int J Drug Policy. 2003 14 1 3 10.1016/S0955-3959(02)00094-4 \n73. Gyarmathy VA Li N Tobin KE Hoffman IF Sokolov N Levchenko J Correlates of unsafe equipment sharing among injecting drug users in St. Petersburg, Russia Eur Addict Res 2009 15 163 170 10.1159/000220344 19506377 \n74. Andía JF Deren S Robles RR Kang S-Y Colón HM Peer norms and sharing of injection paraphernalia among Puerto Rican injection drug users in New York and Puerto Rico AIDS Educ Prev 2008 20 249 257 10.1521/aeap.2008.20.3.249 18558821 \n75. Shaw SY Shah L Jolly AM Wylie JL Determinants of injection drug user (IDU) syringe sharing: the relationship between availability of syringes and risk network member characteristics in Winnipeg Canada Addiction 2007 102 1626 1635 10.1111/j.1360-0443.2007.01940.x 17854339 \n76. Hawkins WE Latkin C Mandel W Oziemkowska M Do actions speak louder than words? Perceived peer influences on needle sharing and cleaning in a simple of injection drug users AIDS Educ Prev 1999 11 122 10214496 \n77. Jamner MS Corby NH Wolitski RJ Bleaching injection equipment: influencing factors among IDUs who share Subst Use Misuse. 1996 31 1973 1993 10.3109/10826089609066447 8969019 \n78. Rhodes T Singer M Bourgois P Friedman SR Strathdee SA The social structural production of HIV risk among injecting drug users Soc Sci Med 2005 61 1026 1044 10.1016/j.socscimed.2004.12.024 15955404 \n79. Carruthers S Loxley W Attitudes of novice heroin injectors towards non-injecting routes of administration to prevent the transmission of blood borne viruses Int J Drug Policy. 2002 13 69 74 10.1016/S0955-3959(02)00005-1 \n80. Phillips KT Rosenberg H The development and evaluation of the harm reduction self-efficacy questionnaire Psychol Addict Behav 2008 22 36 10.1037/0893-164X.22.1.36 18298229 \n81. Bonar EE Rosenberg H Injection drug users’ perceived barriers to using self-initiated harm reduction strategies Addict Res Theory 2014 22 271 278 10.3109/16066359.2013.838225 25419201 \n82. Bonar EE Bohnert AS Perceived severity of and susceptibility to overdose among injection drug users: relationships with overdose history Subst Use Misuse 2016 51 1379 1383 10.3109/10826084.2016.1168447 27245115 \n83. Krieger MS Yedinak JL Buxton JA Lysyshyn M Bernstein E Rich JD High willingness to use rapid fentanyl test strips among young adults who use drugs Harm Reduct J 2018 15 7 10.1186/s12954-018-0213-2 29422052 \n84. The Chicago Recovery Alliance. http://www.anypositivechange.org/menu.html. Accessed 5 Mar 2018.\n\n",
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"title": "Toots, tastes and tester shots: user accounts of drug sampling methods for gauging heroin potency.",
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"abstract": "BACKGROUND\nEosinophilic pleural effusion (EPE) is an eosinophil count ≥10% in pleural effusion, which is a rare condition in drug therapy.\nWe describe the case of a 70-year-old Alzheimer patient who was taking olanzapine for 2 months for the treatment of depression, and developed peripheral eosinophilia and bilateral EPE.\nOlanzapine-induced peripheral eosinophilia and eosinophilic pleural effusion was diagnosed.\n\n\nMETHODS\nOlanzapine was discontinued, and repeated drainage of fluid from the pleural cavity was performed.\n\n\nRESULTS\nAll symptoms-as well as the EPE-were resolved 6 months later.\n\n\nCONCLUSIONS\nThis case is a reminder that olanzapine may be a potential agent for EPE, and that this should be considered in clinical practice.",
"affiliations": "Department of Pharmacy, The Affiliated Hospital of Medical School of Ningbo University Department of Respiratory Medicine, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China.",
"authors": "Huang|Jing|J|;Yu|Yiming|Y|;Lin|Wei|W|;Zhang|Dandan|D|;Deng|Zaichun|Z|;Ding|Qunli|Q|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29443793MD-D-17-0575310.1097/MD.0000000000009996099964200Research ArticleClinical Case ReportOlanzapine-induced peripheral eosinophilia and eosinophilic pleural effusion A case reportHuang Jing MSaYu Yiming MDbLin Wei MSaZhang Dandan BSaDeng Zaichun MDbDing Qunli MSb∗Manchia. Mirko a Department of Pharmacy, The Affiliated Hospital of Medical School of Ningbo Universityb Department of Respiratory Medicine, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China.∗ Correspondence: Qunli Ding, Department of Respiratory Medicine, The Affiliated Hospital of Medical School of Ningbo University, No. 247, Renmin Road, Jiangbei, Ningbo, Zhejiang, China (e-mail: ccding2005@163.com)2 2018 16 2 2018 97 7 e999615 9 2017 31 1 2018 1 2 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0Abstract\nRationale:\nEosinophilic pleural effusion (EPE) is an eosinophil count ≥10% in pleural effusion, which is a rare condition in drug therapy.\n\nPatient concerns:\nWe describe the case of a 70-year-old Alzheimer patient who was taking olanzapine for 2 months for the treatment of depression, and developed peripheral eosinophilia and bilateral EPE.\n\nDiagnoses:\nOlanzapine-induced peripheral eosinophilia and eosinophilic pleural effusion was diagnosed.\n\nInterventions:\nOlanzapine was discontinued, and repeated drainage of fluid from the pleural cavity was performed.\n\nOutcomes:\nAll symptoms—as well as the EPE—were resolved 6 months later.\n\nLessons:\nThis case is a reminder that olanzapine may be a potential agent for EPE, and that this should be considered in clinical practice.\n\nKeywords\nadverse drug reactioneosinophilic pleural effusionEPEolanzapineOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nEosinophilic pleural effusion (EPE) is defined as an eosinophil count ≥ 10% in the pleural effusion. EPE occurs most commonly during conditions associated with the presence of blood or air in the pleural space, infections, inflammatory disorders, malignancy, and pulmonary embolism.[1] However, EPE due to drug reaction is a less common occurrence. Certain drugs, including dantrolene, valproic acid, diltiazem, and simvastatin, are known to induce EPE.[2] Our knowledge of drug-induced EPE comes almost exclusively from case reports. Publication of such cases can help identify drug-induced EPE. Here, we report a case of peripheral eosinophilia and bilateral EPE associated with olanzapine use in an Alzheimer patient.\n\n2 Case report\nTwo months prior to admission, a 70-year-old Chinese man was admitted to a rehabilitation unit and received medical treatment for the diagnosis of Alzheimer disease. His medications included memantine (20 mg daily PO), olanzapine (10 mg daily PO), paroxetine (20 mg daily PO), and piracetam (1.2 g 3 times daily PO). Two months later he presented with shortness of breath and chest pain. He was found to have a massive bilateral pleural effusion on the left side, which was detected by a chest computed tomography (CT) scan (Fig. 1), and was transferred to our respiratory department. On admission, the patient presented with no obvious dyspnea, cough, sputum, or other respiratory symptoms. He was fully conscious, and his vital signs were normal: temperature 36.8°C, pulse 96 bpm, respiratory rate 20 bpm, blood pressure 112/70 mm Hg, and blood oxygen saturation 98%. Pulmonary examination found dullness to percussion and diminished breath sounds on the right lower base with no pulmonary rales, confirmed as a pleural effusion by chest CT scan and B-scan ultrasonography. A chest CT scan showed no pleural thromboembolism. The remainder of the examination was unremarkable except for mild edema found in the lower limbs.\n\nFigure 1 Chest computed tomography scan at presentation, showing a bilateral and massive left-side pleural effusion.\n\nLaboratory tests showed a normal white cell count of 9500/μL (reference range 3500–10,000/μL) with significant eosinophilia of 1040/μL (10.9% of blood eosinophils), revealing a peripheral eosinophilia. Other laboratory test values showed a lactate deaminase level of 218 U/L (106–211 U/L), a C-reactive protein level of 11.9 mg/L (0–10 mg/L), and normal levels of hemoglobin and platelets. Liver function, renal function, blood coagulation function, serum rheumatologic work-up, tumor markers, antituberculosis antibody test, Schistosoma Japonium antibody test, and stool studies for parasite ova were all unremarkable/negative. No fever or rash was observed.\n\nA thoracentesis yielded an exudate serosanguinous pleural effusion that contained 6000/μL white blood cells with an excess of 43% of eosinophilia, 40,000/μL red blood cells, 454 U/L lactate deaminase (106–211 U/L), and 7.07 mmol/L glucose (2.5–4.5 mmol/L). A thinprep cytologic test of pleural fluid showed no evidence of malignant cells, but significant eosinophilic infiltration was observed (Fig. 2). Fluid bacterial cultures were negative. These examinations were repeated and similar results were obtained.\n\nFigure 2 Thinprep cytologic test of pleural fluid, showing a significant eosinophilic infiltration.\n\nExamination results failed to yield any probable etiology of EPE, such as malignancy, infection, tuberculosis, pulmonary embolism, or autoimmune diseases. The suspicion of an iatrogenic pleural effusion due to drug reaction was considered given that the patient had taken several neurological agents for 2 months. Based on the above consideration, as well as suggestions from case reports in the literature, olanzapine was the only drug that was discontinued. This was combined with repeated drainage of the fluid from the pleural cavity (almost 1200 mL EPE was removed), resulting in a progressive improvement of our patient's condition and transference back to the rehabilitation unit. Six months later, reinspection results revealed that the peripheral eosinophilia and EPE had been resolved (Fig. 3).\n\nFigure 3 Chest computed tomography scan 6 months after olanzapine withdrawal, showing the resolution of the eosinophilic pleural effusion.\n\n3 Discussion\nIdiopathic EPE due to drug reaction is rarely encountered in clinical practice. As a comprehensive review of drug-induced pleural effusion suggests, drugs such as valproic acid, propylthiouracil, isotretinoin, nitrofurantoin, bromocriptine, dantrolene, gliclazide, and mesalamine could be potential medications for EPE.[2] To date, the list of the drugs implicated as potential causes of EPE has expanded, and (to the best of our knowledge) now also includes clozapine, olanzapine, tizanidine, trimipramine, fluoxetine, warfarin, vitamins B6/H, diltiazem, simvastatin, lisinopril, imidapril, daptomycin, and tosufloxacin.[3–5] Most of these drugs are neurological agents, cardiovascular agents, or chemotherapeutic agents.\n\nOlanzapine is an atypical antipsychotic medication approved by the US Food and Drug Administration (US FDA) and European Medicines Agency to treat schizophrenia and bipolar disorder. The most commonly reported adverse effects include weight gain, somnolence, dry mouth, dizziness, peripheral edema, orthostatic hypotension, tardive dyskinesia, seizures, and rash after sunlight exposure.[6] However, olanzapine-induced EPE is rarely reported.\n\nIn the literature, we found 2 cases of olanzapine-associated EPE. Alagha et al[7] reported a case of a 53-year-old male who had been treated with 10 mg olanzapine once daily for depression without other comorbidities for nearly 1 month. This patient began to experience a progressive and worsening left chest pain, as well as exertional dyspnea and dry cough, and had experienced these symptoms for 3 weeks before medical consultation. A left pleural effusion containing 75% eosinophils in the pleural cavity was detected, along with a small pericardial effusion. After withdrawal of olanzapine, the pleural effusion and other symptoms disappeared within 1 month. Another case report described an elderly patient with a history of depression with psychosis. This patient presented a right eosinophil-rich pleural effusion and peripheral eosinophilia after 12 months of olanzapine therapy. A diagnosis of olanzapine-induced EPE was suspected and 6 months later the pleural fluid resolved after olanzapine was discontinued.[8] Finally, there was a case reporting a pericardial and bilateral pleural effusion associated with clozapine treatment in a patient who was also taking with olanzapine.[9]\n\nIn our case, olanzapine was used off-label for the treatment of depression in an Alzheimer patient, despite the fact that the US FDA has issued a black box warning about a higher mortality rate in elderly patients with dementia treated with olanzapine.[6] The inference of olanzapine-induced EPE in our case was made with a causal relationship between medication intake and symptom onset, a lack of alternative explanations, and suggestions from case reports in the literature. This diagnosis was further supported by clinical improvement during the first several days after discontinuing olanzapine, as well as the complete resolution of EPE 6 months later. Utilizing the Naranjo Probability Scale,[10] our patient had a score of 6, indicating that the EPE was “probably” caused by olanzapine (Table 1). Thus, our case may be the first case reported of EPE-induced by olanzapine in patient with Alzheimer disease.\n\nTable 1 Naranjo Adverse Drug Reaction (ADR) Probability Scale.\n\nThe pathogenic mechanisms of drug-induced pleural effusions are to date not entirely understood. The proposed mechanisms include hypersensitivity or allergic reaction, direct toxic effect, increased oxygen free-radical production, suppression of antioxidant defense mechanism, and chemical-induced inflammation.[2] The pathogenesis for olanzapine-induced EPE in our case remains speculative. An allergic reaction is strongly suspected because of the peripheral eosinophilia.\n\nAccording to reports, the clinical symptoms of drug-induced EPE consist of chest pain, dyspnea, dry cough, and sometimes low-grade fever. The latency of EPE appearance can vary from hours to months, and potentially even years.[11] In the 3 olanzapine-associated EPE cases, patients’ symptoms were seen varying from 1 month to 1 year of the initiation of olanzapine treatment and manifested as progressive breathlessness and chest pain. There was no-inclination of the lateral manifestation observed in these cases: 1 EPE was right-sided, 1 left-sided, and 1 bilateral with a mass in the left lobe. The complete resolution of the EPE takes 1 to 6 months.\n\nIn summary, the case we reported and those reviewed support that olanzapine may be a causative agent of EPE, and prompt discontinuation is suggested when it is strongly suspected.\n\nAbbreviations: CT = computed tomography, EPE = eosinophilic pleural effusion, US FDA = The US Food and Drug Administration.\n\nThis study was approved by the Affiliated Hospital of Medical School of Ningbo University Ethics Committee.\n\nThis work was supported by a grant from the Natural Science Foundation of Zhejiang (No. LY15H010004, Qunli Ding) and a grant from the Natural Science Foundation of Ningbo (No. 2014A610279, Qunli Ding).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Oba Y Abu-Salah T \nThe prevalence and diagnostic significance of eosinophilic pleural effusions: a meta-analysis and systematic review . Respiration \n2012 ;83 :198 –208 .21576924 \n[2] Huggins JT Sahn SA \nDrug-induced pleural disease . Clin Chest Med \n2004 ;25 :141 –53 .15062606 \n[3] Krenke R Light RW \nDrug-induced eosinophilic pleural effusion . Eur Respir Rev \n2011 ;20 :300 –1 .22130825 \n[4] Broaddus VC Light RW \nDisorders of the Pleura. Murray and Nadel's Textbook of Respiratory Medicine . 6th ed Amsterdam : Elsevier Inc ; 2016 .\n[5] Zouak A Bongrain É Launois C \nEosinophilic pleuritic: an unusual complication of treatment with an angiotensin converting enzyme inhibitor . Rev Mal Respir \n2015 ;32 :737 –41 .26370487 \n[6] Orsolini L Tomasetti C Valchera A \nAn update of safety of clinically used atypical antipsychotics . Expert Opin Drug Saf \n2016 ;15 :1329 –47 .27347638 \n[7] Alagha K Tummino C Sofalvi T \nIatrogenic eosinophilic pleural effusion . Eur Respir Rev \n2011 ;20 :118 –20 .21632800 \n[8] Evison M Holme J Alaloul M \nOlanzapine-induced eosinophilic pleuritis . Respir Med Case Rep \n2015 ;14 :24 –6 .26029571 \n[9] Boot E de Haan L Guzelcan Y \nPericardial and bilateral pleural effusion associated with clozapine treatment . Eur Psychiatry \n2004 ;19 :65 .14969785 \n[10] Naranjo CA Busto U Sellers EM \nA method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther \n1981 ;30 :239 –45 .7249508 \n[11] Kalomenidis I Light RW \nEosinophilic pleural effusions . Curr Opin Pulm Med \n2003 ;9 :254 –60 .12806236\n\n",
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"abstract": "FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet.\n\n\n\nThis study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety.\n\n\n\nA total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004).\n\n\n\nFOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered.",
"affiliations": "Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan. Electronic address: ken-kato@momo.so-net.ne.jp.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan.;Department of Colorectal Surgery, Kansai Rosai Hospital, Hyogo, Japan.;Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Kagawa University Hospital, Kagawa, Japan.;Cancer Center, Aichi Medical University, Aichi, Japan.;Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan.;Department of Surgery, Nakagami Hospital, Okinawa, Japan.;Aizawa Comprehensive Cancer Center, Aizawa Hospital, Nagano, Japan.;Gastrointestinal Cancer Center, Sano Hospital, Hyogo, Japan.;Department of Surgery, Kawanishi City Hospital, Hyogo, Japan.;Department of Biostatistics, Yokohama City University School of Medicine, Kanagawa, Japan.;Department of Surgery, Shimane Prefectural Central Hospital, Shimane, Japan.",
"authors": "Oki|Eiji|E|;Kato|Takeshi|T|;Bando|Hideaki|H|;Yoshino|Takayuki|T|;Muro|Kei|K|;Taniguchi|Hiroya|H|;Kagawa|Yoshinori|Y|;Yamazaki|Kentaro|K|;Yamaguchi|Tatsuro|T|;Tsuji|Akihito|A|;Iwamoto|Shigeyoshi|S|;Nakayama|Goro|G|;Emi|Yasunori|Y|;Touyama|Tetsuo|T|;Nakamura|Masato|M|;Kotaka|Masahito|M|;Sakisaka|Hideki|H|;Yamanaka|Takeharu|T|;Kanazawa|Akiyoshi|A|",
"chemical_list": "D009944:Organoplatinum Compounds; D000068258:Bevacizumab; C418331:UGT1A1 enzyme; D014453:Glucuronosyltransferase; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clcc.2018.01.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-0028",
"issue": "17(2)",
"journal": "Clinical colorectal cancer",
"keywords": "Bevacizumab; Colorectal cancer; FOLFOXIRI; UGT1A1",
"medline_ta": "Clin Colorectal Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D000068258:Bevacizumab; D002166:Camptothecin; D064146:Chemotherapy-Induced Febrile Neutropenia; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077982:Progression-Free Survival",
"nlm_unique_id": "101120693",
"other_id": null,
"pages": "147-155",
"pmc": null,
"pmid": "29530335",
"pubdate": "2018-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study.",
"title_normalized": "a multicenter clinical phase ii study of folfoxiri plus bevacizumab as first line therapy in patients with metastatic colorectal cancer quattro study"
} | [
{
"companynumb": "JP-PFIZER INC-2020289280",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Intramedullary spinal cord metastasis is an increasingly common diagnosis in patients with cancer largely owing to new imaging techniques and the increase lifespan of patients with malignant tumors. The diagnosis confers significant morbidity and a poor prognosis. Mainstay palliative treatment options include corticosteroids, fractionated radiotherapy and surgery in select cases. In the modern era of immunotherapy for the treatment of several tumor types, the efficacy of these agents against parenchymal CNS tumors remains unanswered. Here, we report a case of regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor.",
"affiliations": "Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, VA 22908 USA.;Department of Medicine (Hematology-Oncology), University of Virginia, Charlottesville, VA 22908 USA.;Department of Pathology, University of Virginia, Charlottesville, VA 22908 USA.;Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, VA 22908 USA.",
"authors": "Phillips|Kester A|KA|;Gaughan|Elizabeth|E|;Gru|Alejandro|A|;Schiff|David|D|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.2217/cns-2017-0007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-0907",
"issue": "6(4)",
"journal": "CNS oncology",
"keywords": "anti-programmed cell death-1; checkpoint inhibitors; intramedullary spinal cord metastasis; nivolumab; pembrolizumab",
"medline_ta": "CNS Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D000077594:Nivolumab; D013120:Spinal Cord Neoplasms",
"nlm_unique_id": "101594668",
"other_id": null,
"pages": "275-280",
"pmc": null,
"pmid": "29034739",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "4052974;6325758;22658127;27267608;16215815;3968561;22810899;8857717;27393516;9368732;11165413;26372703;8402479;24217091;24714771;3579664;17310265",
"title": "Regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor: a case report.",
"title_normalized": "regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor a case report"
} | [
{
"companynumb": "US-TEVA-2018-US-844080",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": "3",
... |
{
"abstract": "68Ga-PSMA PET/CT is a commonly performed procedure in the staging of intermediate- and high-risk prostate cancer after biochemical recurrence. Uptake of 68Ga-PSMA in benign conditions is also reported in the literature. Docetaxel is the mainstay of treatment in high-volume hormone-sensitive prostate cancer and castration-resistant prostate cancer. The major treatment-emergent adverse drug reactions attributed to docetaxel include myelosuppression, alopecia, and asthenia. Interstitial pneumonitis is seen in less than 2% of docetaxel-treated patients. We present a case of metastatic castration-resistant prostate cancer, wherein docetaxel-induced interstitial pneumonitis was detected on 68Ga-PSMA PET/CT, after docetaxel treatment.",
"affiliations": "From the Departments of Nuclear Medicine and PET.;From the Departments of Nuclear Medicine and PET.;Medical Oncology, Regional Cancer Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;From the Departments of Nuclear Medicine and PET.;From the Departments of Nuclear Medicine and PET.",
"authors": "Kumar|Sunil|S|;Singh|Harmandeep|H|;Das|Chandan K|CK|;Kumar|Rajender|R|;Mittal|Bhagwant Rai|BR|",
"chemical_list": "D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D009842:Oligopeptides; C000718244:gallium 68 PSMA-11; D000077143:Docetaxel; D004492:Edetic Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000003445",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "46(5)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000368:Aged; D000077143:Docetaxel; D004492:Edetic Acid; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D009842:Oligopeptides; D000072078:Positron Emission Tomography Computed Tomography; D011471:Prostatic Neoplasms",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "e268-e269",
"pmc": null,
"pmid": "33315676",
"pubdate": "2021-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Docetaxel-Induced Interstitial Pneumonitis Detected on 68Ga-PSMA PET/CT.",
"title_normalized": "docetaxel induced interstitial pneumonitis detected on 68ga psma pet ct"
} | [
{
"companynumb": "IN-SHILPA MEDICARE LIMITED-SML-IN-2021-00086",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nThe prognosis of anaplastic thyroid cancer (ATC) is poor with a mean survival time of six months following diagnosis. Despite various attempts to modify common treatment modalities including surgery, external beam radiation and chemotherapy, an effective treatment is not available yet. We report, here, a patient who achieved long-term survival based on multimodal treatment, including in vitro evaluation of drug response of his tumor cells.\n\n\nMETHODS\nA 42 years old male patient underwent total thyroidectomy with central and lateral neck dissection for ATC (pT4b, pN0 (0/36), L0, V0, Pn1, R0 cM0 - UICC-Stage: IV b). From the tumor tissue a primary cell culture was established. While the patient received a combined radio-chemotherapy cell viability assays were performed using Sorafenib, Vandetanib und MLN8054 (Aurora kinase inhibitor) as inhibitors. Cell viability was determined by MTT-assay after 72 and 144h of treatment.\n\n\nCONCLUSIONS\nAll the three compounds affected cell viability in a time- and dose dependent manner. These effects were most pronounced by Sorafenib. Based on in vitro findings, the patient was treated daily with 400mg Sorafenib for 75days. 43 months after initial diagnosis, the patient had no evidence of disease as shown by MRI, CT and FDG-PET-CT imaging.\n\n\nCONCLUSIONS\nIn the setting of multimodal treatment, in vitro drug evaluation of individual tumor cells of patients might be a promising tool to ameliorate the fatal prognosis of selected ATC patients.",
"affiliations": "Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Electronic address: seckhard@med.uni-marburg.de.;Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.;Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.;Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.;Department of Nuclear Medicine, Philipps-University, Baldingerstraße, 35043 Marburg, Germany.;Department of Nuclear Medicine, Philipps-University, Baldingerstraße, 35043 Marburg, Germany.;Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.;Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.",
"authors": "Eckhardt|S|S|;Hoffmann|S|S|;Damanakis|A I|AI|;Di Fazio|P|P|;Pfestroff|A|A|;Luster|M|M|;Wunderlich|A|A|;Bartsch|D K|DK|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(16)30197-310.1016/j.ijscr.2016.06.013Case ReportIndividualized multimodal treatment strategy for anaplastic thyroid carcinoma—Case report of long-term remission and review of literature Eckhardt S. seckhard@med.uni-marburg.dea⁎Hoffmann S. aDamanakis A.I. aDi Fazio P. aPfestroff A. bLuster M. bWunderlich A. aBartsch D.K. aa Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germanyb Department of Nuclear Medicine, Philipps-University, Baldingerstraße, 35043 Marburg, Germany⁎ Corresponding author at: Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.Department of Visceral, Thoracic and Vascular SurgeryPhilipps University MarburgBaldingerstrasseMarburgD-35043Germany seckhard@med.uni-marburg.de16 6 2016 2016 16 6 2016 25 174 178 25 3 2016 7 6 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• The prognosis of anaplastic thyroid cancer (ATC) is poor with a mean survival time of six months following diagnosis.\n\n• A generally accepted and effective treatment strategy for ATC has not been established yet.\n\n• Pre-therapeutic in vitro investigation of novel drugs could succeed for a personalized antitumor therapy in patients affected by ATC.\n\n• Individualized tumor therapy gives explanation concerning the mechanisms regulating the biology of ATC.\n\n• In vitro drug evaluation of individual tumor cells might be a promising tool to ameliorate the prognosis of ATC patients.\n\n\n\nIntroduction\nThe prognosis of anaplastic thyroid cancer (ATC) is poor with a mean survival time of six months following diagnosis. Despite various attempts to modify common treatment modalities including surgery, external beam radiation and chemotherapy, an effective treatment is not available yet. We report, here, a patient who achieved long-term survival based on multimodal treatment, including in vitro evaluation of drug response of his tumor cells.\n\nPresentation of case\nA 42 years old male patient underwent total thyroidectomy with central and lateral neck dissection for ATC (pT4b, pN0 (0/36), L0, V0, Pn1, R0 cM0 – UICC-Stage: IV b). From the tumor tissue a primary cell culture was established. While the patient received a combined radio-chemotherapy cell viability assays were performed using Sorafenib, Vandetanib und MLN8054 (Aurora kinase inhibitor) as inhibitors. Cell viability was determined by MTT-assay after 72 and 144 h of treatment.\n\nDiscussion\nAll the three compounds affected cell viability in a time- and dose dependent manner. These effects were most pronounced by Sorafenib. Based on in vitro findings, the patient was treated daily with 400 mg Sorafenib for 75 days. 43 months after initial diagnosis, the patient had no evidence of disease as shown by MRI, CT and FDG-PET-CT imaging.\n\nConclusion\nIn the setting of multimodal treatment, in vitro drug evaluation of individual tumor cells of patients might be a promising tool to ameliorate the fatal prognosis of selected ATC patients.\n\nKeywords\nAnaplastic thyroid carcinomaCase reportIndividualized therapyTyrosine kinase inhibitorsMultimodal treatment strategy\n==== Body\n1 Introduction\nAlthough anaplastic thyroid carcinoma (ATC) accounts only for 2% of thyroid carcinomas, it is one of the most aggressive diseases with a median survival time of 6 months after the diagnosis and a mortality rate higher than 90% [1]. Effective treatment strategies to overcome this fatal prognosis are still lacking. Multimodality treatment consisting of surgical resection, if possible, in combination with radio- and/or chemotherapy is generally recommended [2]. Nevertheless new therapeutic strategies are urgently required to overcome the poor prognosis of ATC [3].\n\nNew insights into the biological behavior, the genetic and molecular pathogenesis of ATC might offer the possibility of novel targeted therapies [4].\n\nBut as more new systemic agents become available, it is important to get information on the drug response of different compounds on individual ATC tumor cells.\n\nBased on the current literature and on the results of our own investigations, three compounds (Aurora kinase inhibitor MLN8054, multikinase inhibitors Vandetanib and Sorafenib) were selected to be evaluated in this setting.\n\nThe BRAF- and multikinase inhibitor Sorafenib (Nexavar®, BAY49-3006) has proven to inhibit multiple intracellular signaling pathways leading to cell cycle arrest and initiation of apoptosis in thyroid carcinoma cell lines regardless of their tumor subtype origin or the BRAF-status [5]. Several studies evaluated the effect of Sorafenib in thyroid cancer and reported positive effects [6], [7]. Based on these results, Sorafenib got granted marketing authorization since 2014 for the treatment of patients with progressive, locally advanced or metastatic, differentiated thyroid carcinoma in Europe.\n\nVandetanib (AstraZeneca, Macclesfield, UK) is an oral multikinase inhibitor that selectively targets RET, VEGFR and EGFR tyrosine kinases [8], [9]. Its efficacy was determined in a phase II-trial enrolling patients with poorly differentiated thyroid carcinoma (PDTC). It was shown that patients receiving Vandetanib had longer progression free survival (PFS 11 months) compared to the placebo group (5 months) [10].\n\nAurora kinases (A–C) are serine/threonine kinases that play a crucial role in cell division. They are overexpressed in many human tumors including ATC, where they account for aberrant cell proliferation. MLN8054 has shown profound antitumor activity in ATC cells in vitro and in vivo\n[11], [12].\n\nHere we report a patient suffering from ATC, who was free of disease 43 months after multimodal treatment with surgery, radio-chemotherapy and individualized targeted therapy with Sorafenib based on in vitro testing of drug efficacy in his tumor cells. This approach might represent an effective strategy for an optimized, tailored treatment of ATC.\n\n2 Presentation of case\nA 42-year-old man was referred to our institution in September 2012, two weeks after he underwent a subtotal thyroidectomy in an external hospital for a rapidly growing scintigraphically cold nodule in the right thyroid lobe. Histopathological examination stated an ATC in the right lobe showing a negative staining for thyroid transcription factor 1 (TTF-1) and thyroglobulin (Tg). Postoperative laryngoscopy demonstrated paresis of the laryngeal nerve on the right side.\n\nAt this time, CT scan of the thorax, MRI scan of the neck, thyroid scintigraphy and ultrasonography demonstrated a persisting lesion of 21 × 18 mm on the right side of the neck without evidence of distant metastatic disease, but with some enlarged suspicious lymph nodes (max. 26 × 20 mm). Fine needle aspiration biopsy confirmed remnants of an ATC. Bronchoscopy and gastroscopy showed no evidence of infiltration of the esophagus or the trachea.\n\nAfter multidisciplinary tumor board decision, the patient underwent a multimodal therapeutic strategy, including an individualized targeted therapy.\n\nThe patient first underwent completion thyroidectomy with a bilateral cervicocentral and cervicolateral lymphadenectomy in September 2012. The tumor was classified as ATC pT4b, pN0 (0/36), L0, V0, Pn1, R0 cM0 – UICC-Stage: IV b. A second expert confirmed the diagnosis of an ATC, immunonegative for TTF1 and TG and without a BRAFV600E mutation. Ki-67 index was 60–70%. Four weeks after surgical resection, a combined radio-chemotherapy was started for four weeks with four cycles of Cisplatin 25 mg/m2 and Docetaxel 20 mg/m2 combined with an external radiation beam therapy for a total dose of 64.8 Gy. A MRI-scan, performed after receiving the combined therapy, was negative for metastases or tumor recurrence.\n\nFrom fresh tumor tissue a primary cell culture was established and in vitro analysis of three different drugs demonstrated Sorafenib as the most effective one (Fig. 1A–C). Thus, Sorafenib was administered as an individual treatment strategy in off-label use to the patient, with 400 mg twice a day starting in January 2013. Because of adverse events (polyneuropathy, pain in muscles and bones) the initial dose was reduced to 400 mg once a day. Sorafenib was given in three cycles over a period of 75 days.\n\nAfter completion of multimodal treatment, the patient staging, evaluated by CT scan of the thorax and MRI scan of the neck, showed neither recurrent disease nor metastases.\n\nIn June 2013, a complete re-staging, including MRI of the neck, CT of the thorax and FDG-PET-CT, was performed. Imaging detected a new solitary lesion of 10 × 7 mm size in the right upper lobe of the lung that was suspicious for a metastasis (Fig. 2). According to the recommendation of our tumor board, based on the absence of additional lesions, the patient underwent a video-assisted thoracoscopic wedge resection of this lesion. Histopathology of the collected fresh tissue confirmed the metastatic lesion originated from the primary ATC. Collected tissue was once again transferred to the laboratory and established as a primary cell culture. The case was discussed again in our interdisciplinary tumor board, where an additional adjuvant therapy with taxans and platin was considered, but the patient refused this therapy and preferred to undergo close surveillance with CT imaging of the thorax and MRI of the neck in 6 months intervals. At the last staging, in January 2016, 43 months after his initial operation, the patient was without evidence of recurrent or metastatic disease.\n\n2.1 Methods and experiments for individualized in-vitro testing of drug efficacy\n2.1.1 Preparation of patient-derived human tumor tissue\nTumor cells were attained by mechanical dissociation of tumor tissue, obtained from the completion thyroidectomy and the pulmonary lesion and successfully established as primary cell culture.\n\n2.1.2 Compounds\nSorafenib, Vandetanib and MLN8054 were used as inhibtors. Stock solutions (10 mM each) were prepared in dimethylsulfoxid (DMSO) and stored at −20 °C.\n\n2.1.3 In vitro experiments\nPrimary cell culture was maintained by propagating the cells in DMEM-h21/Ham's F12 1:1 (v/v) supplemented with 10% FCS and 10U/ml penicillin and 100 μg/ml streptomycin (all: Biochrom, Berlin, Germany) under standard conditions (37 °C, 5% CO2). Before use in experiments, cell viability was assessed by Trypan blue exclusion.\n\nTo test the sensitivity of the tumor cells towards the various inhibitors, cells were seeded in 96 well plates (1 × 104 cells/well) and treated with increasing concentrations (0.1–10 μM) of Sorafenib, Vandetanib und MLN8054 for up to 144 h. Cell viability was determined by MTT-assay and dose-response curves were created.\n\n2.2 Results\nEffects on cell viability of the individual tumor cells caused by treatment with Sorafenib, Vandetanib and MLN8054\n\n2.2.1 Cells established from the primary tumor\nCell viability of the individual tumor cells was considerably affected by all the three compounds. As documented here for Sorafenib, each compound induced a dose- and time-dependent decrease in cell viability (Fig. 1B and C). This effect was most pronounced by Sorafenib (Fig. 1B and C). Here cytoviability was reduced to about 50% at a drug concentration about 2 μM after 72 h, whereas for Vandetanib and MLN8054 IC50 values were calculated as ≈7 μM and ≈5 μM (Fig. 1B and C).\n\nProlonged treatment with 5 μM Sorafenib and Vandetanib resulted in 100% reduction of cell viability, MLN8054 showed a lower effect, here cell viability was decreased only to about 30% at 10 μM (Data not shown). Further, the effect of combined therapy with Sorafenib and Vandetanib was evaluated in vitro. In comparison with the single treatment, no synergistic effect or increase of efficacy could be measured (Data not shown).\n\n2.2.2 Cells established from the pulmonary metastasis\nTumor cells originated from the pulmonary metastasis where established as primary culture as well and treated with Sorafenib and Vandetanib similarly. As assessed by MTT-assay, comparable results were revealed. Once again after 72 h about 50% of the cells were killed at concentrations about 3 μM (Sorafenib) and 7 μM (Vandetanib), documenting a similar behaviour of the cells from the primary tumor and the metastasis (Fig. 3A and B).\n\n3 Discussion\nA generally accepted treatment strategy for ATC has not been established yet [13], [14]. By analyzing 2742 cases Haymart et al. showed that the median survival of patients with stage IVb ATC is quite poor with just 6 months. Despite of a prolonged overall survival (median survival of 9.9 month) obtained by a combined multidisciplinary therapy consisting of surgery, radiation and chemotherapy, there is still a desperate need to support and accelerate clinical research [15].\n\nIn previous publications several authors pointed out the benefit of an initial complete and radical resection of the ATC [16], [17]. Passler et al. showed that patients without tumor residues (R0) had a significantly better prognosis with a median survival of 6.1 months than patients with tumor residues (R1/R2) with a median survival of 2.2 months and a 3-year survival of 50% vs. 4%. Therefore, in our case we performed a radical completion thyroidectomy with bilateral neck dissection to achieve a R0 situation.\n\nAlthough several reports pointed out the inefficacy of single chemotherapy in patients with ATC [18], [19], some combined therapies improved survival [20]. That is why our patient received – corresponding to the American Thyroid Association Guidelines for Patients with Anaplastic Thyroid Carcinoma – a combined chemotherapy with docetaxel and cisplatin [4]. Both agents are known to have a great clinical activity in metastatic ATC, but it is not confirmed that they really prolonged survival or quality of life [4]. So, to complete the multimodal treatment strategy in the presented patient, surgical resection and chemotherapy were followed by radiation therapy. Retrospective analysis of the SEER data of 516 patients revealed that only the combined use of surgical resection and external beam radiotherapy were identified as independent predictors of survival in ATC patients [1].\n\nOur patient first received a combined radio-chemotherapy. Meanwhile a primary cell culture was established and the effects of two multi-kinase inhibitors (Sorafenib, Vandetanib) and of one aurora kinase inhibitor (MLN8054) were evaluated in vitro. From these the mostly effective one was Sorafenib. Further, similar effects were shown for cells of the primary tumor and the metastasis. These results point out the feasibility of preclinical in vitro evaluation, especially, since it is well known, that the biological behavior of ATC – like other tumors – is inconsistent. Therefore a successful therapy may be more common, if the patient receives – corresponding to the individual evaluated ATC – the most effective treatment.\n\nAs younger age is associated with improved survival in patients affected by ATC [15], it must be pointed out that the positive clinical course in the presented case might have been also promoted by the limited disease at the time of diagnosis and the young age of the patient.\n\n4 Conclusion\nOur case report demonstrates – to our best knowledge – for the first time that pre-therapeutic in vitro investigation of novel drugs could succeed for a personalized antitumor therapy in a patient affected by ATC. By availability of vital tumor cells, this approach might offer the possibility for reflection of the individual tumor cell characteristics and optimize therapeutic options for patients suffering from ATC.\n\nConflict of interest\nNone.\n\nFunding\nNone.\n\nEthical approval\nThis is not a research study.\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\nAuthors’ contributions\nS. Eckhardt: analysis and interpretation of data, acquisition of data, drafting the article.\n\nS. Hoffmann: conception and design of the study, acquisition of data.\n\nA.I. Damanakis: final approval of the version to be submitted.\n\nP. Di Fazio: revising the article for important intellectual content.\n\nA. Pfestroff: analysis and interpretation of data.\n\nM. Luster: conception and design of the study.\n\nA. Wunderlich: analysis and interpretation of data, acquisition of data.\n\nD.K. Bartsch: conception and design of the study, revising the article for important intellectual content.\n\nGuarantor\nThis is not a research study. All authors read and approved the final manuscript. Therefore, all authors are responsible for this report.\n\nAppendix A Supplementary data\nThe following is Supplementary data to this article: \n\nAppendix A Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijscr.2016.06.013.\n\nFig. 1 (A) Individual tumor cells established as primary culture. (B) Dose-response curve of the tumor cells established as primary culture and treated with Sorafenib for up to 144 h. Concentrations as indicated. Data reported present the mean ± SD of experiment performed in triplicates. Control: DMSO treated cells. (C) Dose-response curve of the tumor cells established as primary culture and treated with Sorafenib, Vandetanib and MLN8054 for 72 h. Concentrations as indicated. Data reported present the mean ± SD of experiment performed in triplicates. Control: DMSO treated cells.\n\nFig. 1Fig. 2 FDG-PET-CT screen of a pulmonary metastasis of ATC nine months after diagnosis.\n\nFig. 2Fig. 3 (A) Dose-response curves of tumor cells originated from the PT1 and the Met2 and treated with Sorafenib for 72 h. Concentrations as indicated. Data reported present the mean ± SD of experiment performed in triplicates. Control: DMSO treated cells. (B) Dose-response curves of tumor cells originated from the PT1 and the Met2 and treated with Vandetanib for 72 h. Concentrations as indicated. Data reported present the mean ± SD of experiment performed in triplicates. Control: DMSO treated cells.\n\n1PT = primary tumor.\n\n2Met = pulmonary metastasis.\n\nFig. 3\n==== Refs\nReferences\n1 Kebebew E. Greenspan F.S. Clark O.H. Woeber K.A. McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors Cancer 103 2005 1330 1335 15739211 \n2 Nagaiah G. Hossain A. Mooney C.J. Parmentier J. Remick S.C. Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment J. Oncol. 2011 2011 542358 21772843 \n3 Dean D.S. Gharib H. Epidemiology of thyroid nodules Best Pract. Res. Clin. Endocrinol. Metab. 22 2008 901 911 19041821 \n4 Smallridge R.C. Ain K.B. Asa S.L. Bible K.C. Brierley J.D. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer Thyroid 22 2012 1104 1139 23130564 \n5 Broecker-Preuss M. Müller S. Britten M. Worm K. Kurt Werner S. Sorafenib inhibits intracellular signaling pathways and induces cell cycle arrest and cell death in thyroid carcinoma cells irrespective of histological origin or BRAF mutational status BMC Cancer 15 2015 184 25879531 \n6 Thomas L. Lai S.Y. Dong W. Feng L. Dadu R. Sorafenib in metastatic thyroid cancer: a systematic review Oncologist 19 2014 251 258 24563075 \n7 Savvides P. Nagaiah G. Lavertu P. Fu P. Wright J.J. Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid Thyroid 23 2013 600 604 23113752 \n8 Carlomagno F. Vitagliano D. Guida T. Ciardiello F. Tortora G. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases Cancer Res. 62 2002 7284 7290 12499271 \n9 Hoffmann S. Gläser S. Wunderlich A. Lingelbach S. Dietrich C. Targeting the EGF/VEGF-R system by tyrosine-kinase inhibitors—a novel antiproliferative/antiangiogenic strategy in thyroid cancer Langenbecks Arch. Surg. 391 2006 589 596 17053904 \n10 Leboulleux S. Bastholt L. Krause T. de la Fouchardiere C. Tennvall J. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial Lancet Oncol. 13 2012 897 905 22898678 \n11 Wunderlich A. Fischer M. Schlosshauer T. Ramaswamy A. Greene B.H. Evaluation of Aurora kinase inhibition as a new therapeutic strategy in anaplastic and poorly differentiated follicular thyroid cancer Cancer Sci. 102 2011 762 768 21214672 \n12 Manfredi M.G. Ecsedy J.A. Meetze K.A. Balani S.K. Burenkova O. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase Proc. Natl. Acad. Sci. U. S. A. 104 2007 4106 4111 17360485 \n13 Smallridge R.C. Copland J.A. Anaplastic thyroid carcinoma: pathogenesis and emerging therapies Clin. Oncol. (R. Coll. Radiol.) 22 2010 486 497 20418080 \n14 Granata R. Locati L. Licitra L. Therapeutic strategies in the management of patients with metastatic anaplastic thyroid cancer: review of the current literature Curr. Opin. Oncol. 25 2013 224 228 23493194 \n15 Haymart M.R. Banerjee M. Yin H. Worden F. Griggs J.J. Marginal treatment benefit in anaplastic thyroid cancer Cancer 119 2013 3133 3139 23839797 \n16 Schlumberger M. Parmentier C. Delisle M.J. Couette J.E. Droz J.P. Combination therapy for anaplastic giant cell thyroid carcinoma Cancer 67 1991 564 566 1985750 \n17 Voutilainen P.E. Multanen M. Haapiainen R.K. Leppäniemi A.K. Sivula A.H. Anaplastic thyroid carcinoma survival World J. Surg. 23 1999 975 978 discussion 978–979 10449831 \n18 Tennvall J. Tallroth E. el Hassan A. Lundell G. Akerman M. Anaplastic thyroid carcinoma. Doxorubicin, hyperfractionated radiotherapy and surgery Acta Oncol. 29 1990 1025 1028 2278722 \n19 Levendag P.C. De Porre P.M. van Putten W.L. Anaplastic carcinoma of the thyroid gland treated by radiation therapy Int. J. Radiat. Oncol. Biol. Phys. 26 1993 125 128 8482618 \n20 Seto A. Sugitani I. Toda K. Kawabata K. Takahashi S. Chemotherapy for anaplastic thyroid cancer using docetaxel and cisplatin: report of eight cases Surg. Today 45 2015 221 226 25734195\n\n",
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"issue": "25()",
"journal": "International journal of surgery case reports",
"keywords": "Anaplastic thyroid carcinoma; Case report; Individualized therapy; Multimodal treatment strategy; Tyrosine kinase inhibitors",
"medline_ta": "Int J Surg Case Rep",
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"title": "Individualized multimodal treatment strategy for anaplastic thyroid carcinoma-Case report of long-term remission and review of literature.",
"title_normalized": "individualized multimodal treatment strategy for anaplastic thyroid carcinoma case report of long term remission and review of literature"
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"abstract": "BACKGROUND\nLyme disease is not uncommon and can sometimes progress to neurological complications. We report here an unusual case of bilateral diaphragmatic paralysis secondary to Lyme neuroborreliosis.\n\n\nMETHODS\nA 79-year-old man was admitted to the intensive care unit for acute respiratory distress requiring intubation and the long-term use of nocturnal non-invasive ventilation. Three months beforehand he had been bitten by a tick and developed erythema migrans which was treated with Doxycycline for 10 days. This clinical presentation became complicated a few days later by the progressive onset of severe dyspnoea. At admission, chest radiography revealed bilateral elevation of the diaphragm. Pulmonary function tests revealed a severe restrictive disorder aggravated by decubitus. A diaphragmatic electromyogram showed bilateral axonal polyneuropathy of the phrenic nerves. IgG and IgM antibodies to Borrelia burgdorferi were detectable in serum and cerebrospinal fluid, leading to the diagnosis of Lyme disease. He was treated with intravenous ceftriaxone 2g per day for 21 days, leading to a substantial improvement in symptoms.\n\n\nCONCLUSIONS\nIn the presence of unilateral or bilateral diaphragmatic paralysis of undetermined aetiology, it seems relevant to perform Lyme serology in the blood and, in positive cases, to follow up with a lumbar puncture in order to detect intrathecal IgG synthesis.",
"affiliations": "Service des maladies respiratoires, hôpital Haut-Lévêque, centre hospitalier universitaire de Bordeaux, 33600 Pessac, France. Electronic address: claire_bon38@yahoo.fr.;Service de neurologie, hôpital F. Mitterrand, 4, boulevard Hauterive, 64046 Pau, France.;Service de pneumologie, hôpital F. Mitterrand, 4, boulevard Hauterive, 64046 Pau, France.;Service de réanimation, hôpital F. Mitterrand, 4, boulevard Hauterive, 64046 Pau, France.;Service de médecine interne et maladies infectieuses, hôpital F. Mitterrand, 4, boulevard Hauterive, 64046 Pau, France.;Service de pneumologie, hôpital F. Mitterrand, 4, boulevard Hauterive, 64046 Pau, France.;Service des maladies respiratoires, hôpital Haut-Lévêque, centre hospitalier universitaire de Bordeaux, 33600 Pessac, France.",
"authors": "Bon|C|C|;Krim|E|E|;Colin|G|G|;Picard|W|W|;Gaborieau|V|V|;Gourcerol|D|D|;Raherison|C|C|",
"chemical_list": "D002443:Ceftriaxone; D004318:Doxycycline",
"country": "France",
"delete": false,
"doi": "10.1016/j.rmr.2018.07.008",
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"issue": "36(2)",
"journal": "Revue des maladies respiratoires",
"keywords": "Ceftriaxone; Dyspnoea; Dyspnée; Lyme disease; Maladie de Lyme; Nerf phrénique; Paralysie diaphragmatique; Phrenic nerve; Respiratory paralysis",
"medline_ta": "Rev Mal Respir",
"mesh_terms": "D000368:Aged; D015748:Borrelia burgdorferi Group; D002443:Ceftriaxone; D004318:Doxycycline; D006801:Humans; D020852:Lyme Neuroborreliosis; D008297:Male; D012128:Respiratory Distress Syndrome; D012133:Respiratory Paralysis",
"nlm_unique_id": "8408032",
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"pages": "197-203",
"pmc": null,
"pmid": "30711345",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral diaphragmatic palsy due to Lyme neuroborreliosis.",
"title_normalized": "bilateral diaphragmatic palsy due to lyme neuroborreliosis"
} | [
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"abstract": "Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.",
"affiliations": "Lake Erie College of Osteopathic Medicine, 1858 W Grandview Blvd, Erie, PA 16509, USA.;St. John's Episcopal Hospital, Department of Family Medicine, Queens 327 Beach 19th St., NY 11691, USA.;St. John's Episcopal Hospital, Department of Family Medicine, Queens 327 Beach 19th St., NY 11691, USA.;St. John's Episcopal Hospital, Department of Family Medicine, Queens 327 Beach 19th St., NY 11691, USA.;Lake Erie College of Osteopathic Medicine, 1858 W Grandview Blvd, Erie, PA 16509, USA.",
"authors": "Sussman|Melissa|M|https://orcid.org/0000-0001-7649-0753;Epifania|Michael|M|;Eng|Derrick|D|;Cho|Jae|J|;Steward|Richard|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/8816390",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X\n2090-6838\nHindawi\n\n10.1155/2021/8816390\nCase Report\nConsiderations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis\nhttps://orcid.org/0000-0001-7649-0753\nSussman Melissa melissa.sussman@gmail.com\n1\nEpifania Michael 2\nEng Derrick 2\nCho Jae 2\nSteward Richard 1 2\n1Lake Erie College of Osteopathic Medicine, 1858 W Grandview Blvd, Erie, PA 16509, USA\n2St. John's Episcopal Hospital, Department of Family Medicine, Queens 327 Beach 19th St., NY 11691, USA\nAcademic Editor: Michael Kluge\n\n2021\n20 2 2021\n2021 881639031 8 2020\n15 1 2021\n4 2 2021\nCopyright © 2021 Melissa Sussman et al.\n2021\nThis 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.\nClozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.\n==== Body\n1. Introduction\n\nClozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].\n\nA benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].\n\nAs more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.\n\n2. Case Presentation\n\nA 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).\n\nPast medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).\n\n2.1. Treatment Course\n\nOn the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.\n\nOn Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.\n\nGentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.\n\nPatient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.\n\n3. Discussion\n\nAs CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.\n\n3.1. Screening: Renal Failure and HLA\n\nThough CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.\n\nAssociations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.\n\n3.2. Management Protocol for Clozapine-Induced Agranulocytosis\n\nWhile standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].\n\nIn our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.\n\nThere also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].\n\n3.3. Valproic Acid and CYP Effects\n\nFinally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.\n\n4. Conclusion\n\nThrough this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.\n\nAcknowledgments\n\nThe authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.\n\nAbbreviations\n\nCIA: Clozapine-induced agranulocytosis\n\nANC: Absolute neutrophil count\n\nDVT: Deep vein thrombosis\n\nCKD: Chronic kidney disease\n\nAKI: Acute kidney injury\n\nCYP: Cytochrome P450\n\nEMS: Emergency medical services\n\nED: Emergency department\n\nHLA: Human leukocyte antigen\n\nG-CSF: Granulocyte-colony stimulating factor.\n\nData Availability\n\nThe subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].\n\nConsent\n\nWritten informed consent was obtained and is on the file.\n\nConflicts of Interest\n\nThe authors declare that there that there is no conflict of interest regarding the publication of this article.\n\nTable 1 Treatment course lab table.\n\nTreatment day\tTreatment day 0\tTreatment day 1\tTreatment day 2\tTreatment day 3\tTreatment day 4\tTreatment day 5\tTreatment day 6\tTreatment day 7\tTreatment day 8\tTreatment day 9\tTreatment day 10\tTreatment day 11\tTreatment day 12\t\nLab value\t\n ANC level (μL)\t0.05\t0\t0.01\t0.01\t0.01\t0.01\t0\t0.02\t0.04\t0.57\t3.97\t11.51\t10.38\t\n WBC (L)\tN/A\t0.4\t0.4\t0.3\t0.2\t0.3\t0.2\t0.3\t0.4\t1.8\t7\t18.7\tN/A\t\n Temperature max\t98.8\t98.6\t100.7\t103.1\t101\t98.5\t99.3\t97.3\t98.1\t98.6\t97.8\t97.7\t98.1\t\n BP\t\t127/79\t144/77\t110/59\t113/48\t131/59\t101/53\t129/61\t127/65\t119/64\t130/75\t117/65\t130/70\t\n Hgb (G/DL)\t10.4\t9.9\t11\t10.5\t9.8\t8.9\t8.5\t8\t8\t8.6\t9.6\t9.3\t8.4\t\n Hematocrit (%)\t33.8\t31.8\t36.4\t33.6\t31.6\t29.3\t27.2\t26.3\t26.1\t28.1\t32.2\t30.6\t28.6\t\n H&H\t10.4/33.8\t9.9/31.8\t11.0/36.4\t10.5/33.6\t9.8/31.6\t8.9/29.3\t8.5/27.2\t8.0/26.3\t8.0/26.1\t8.6/28.1\t9.6/32.2\t9.3/30.6\t8.4/28.6\t\n BUN\tN/A\tN/A\t38\t36\t46\t55\t77\t70\t57\t43\t33\t29\t25\t\n CR\tN/A\tN/A\t1.57\t1.93\t2.3\t2.8\t3.2\t2.45\t1.98\t1.69\t1.75\t1.55\t1.59\t\n eGFR\tN/A\tN/A\t33.61\t26.48\t21.63\t17.24\t14.78\t20.11\t25.71\t30.87\t29.65\t34.11\t33.12\t\n Valproate level\t36.5 L\t\t\t50.9 L\t\t\t\t\t\t\t\t\t\t\n Amlodipine dose\t10 mg\t10 mg\t10 mg\tNot given\tNot given\t10 mg\t10 mg\t10 mg\tRefused\t10 mg\t10 mg\t10 mg\t10 mg\t\n Docusate dose\tRefused\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t200 mg\t\n PEG dose\t17 grams\t17 grams\t\t\t\t\t\t\t\t\t\t\t\t\n Valproate dose\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t500 mg t.i.d\t\n Filgrastim dose\tN/A\t300 mcg\t300 mcg\t800 mcg\t800 mcg\t800 mcg\tN/A\tN/A\t800 mcg\tN/A\tN/A\tN/A\tN/A\n==== Refs\n1 Schneck C. D. Miklowitz D. J. Miyahara S. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD American Journal of Psychiatry 2008 165 3 370 377 10.1176/appi.ajp.2007.05081484 2-s2.0-42449123123\n2 Fitton A. Heel R. C. Clozapine. A review of its pharmacological properties, and therapeutic use in schizophrenia Drugs 1990 40 5 722 747 10.2165/00003495-199040050-00007 2-s2.0-0025599851 2292234\n3 Ciapparelli A. Dell'Osso L. di Poggio A. B. Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study The Journal of Clinical Psychiatry 2003 64 4 451 458 10.4088/JCP.v64n0416 2-s2.0-10744231096 12716249\n4 Perlis R. Ostacher M. J. Patel J. K. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) The American Journal of Psychiatry 2006 163 2 217 224 10.1176/appi.ajp.163.2.217 2-s2.0-33645004244 16449474\n5 Rosenheck R. Dunn L. Peszke M. Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia The American Journal of Psychiatry 1999 156 1 88 93 10.1176/ajp.156.1.88 2-s2.0-0032897189 9892302\n6 Sheshamani M. Is clozapine cost-effective? The European Journal of Health Economics 2002 3 S104 S113 10.1007/s10198-002-0115-8 2-s2.0-0036961111 15609156\n7 Ojong M. Allen S. N. Management and prevention of agranulocytosis in patients receiving clozapine Mental Health Clinician 2013 3 3 139 143 10.9740/mhc.n166825\n8 Alvir J. M. J. Lieberman J. A. Safferman A. Z. Schwimmer J. L. Schaaf J. A. Clozapine-induced agranulocytosis: incidence and risk factors in the United States New England Journal of Medicine 1993 329 3 162 167 10.1056/nejm199307153290303 2-s2.0-0027238608\n9 Newburger P. E. Autoimmune and other acquired neutropenias Hematology. American Society of Hematology. Education Program 2016 2016 1 38 42 10.1182/asheducation-2016.1.38https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380382/ 27913460\n10 Coates T. Newburger P. Rosmarin A. Drug-Induced Neutrapenia and Agranulocytosis 2020 https://www.uptodate.com/contents/drug-induced-neutropenia-and-agranulocytosis?search=clozapine%20induced%20agranulocytosis%20managment&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H8\n11 Flanagan R. J. Dunk L. Haematological toxicity of drugs used in psychiatry Human Psychopharmacology 2008 23 S1 S27 S41 10.1002/hup.917 2-s2.0-38649101300\n12 Schulte P. Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring The Annals of Pharmacotherapy 2016 40 4 683 688 10.1345/aph.1G396 2-s2.0-33646243828\n13 Kar N. Barreto S. Chandavarkar R. Clozapine monitoring in clinical practice: beyond the mandatory requirement Clinical Psychopharmacology and Neuroscience 2016 14 4 323 329 10.9758/cpn.2016.14.4.323 2-s2.0-84992476765 27776383\n14 Freudenreich O. McEnvoy J. Guidelines for prescribing clozapine in schizophrenia. Marder S, Solomon D, eds. Uptodate 2018 https://www.uptodate.com/contents/guidelines-for-prescribing-clozapine-in-schizophrenia\n15 Girardin F. R. Poncet A. Perrier A. Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine The Pharmacogenomics Journal 2019 19 2 211 218 10.1038/s41397-017-0004-2 2-s2.0-85039999648 29298994\n16 Kanofsky J. D. Woesner M. E. Harris A. Z. Kelleher J. P. Gittens K. Jerschow E. A case of acute renal failure in a patient recently treated with clozapine and a review of previously reported cases The Primary Care Companion For CNS Disorders 2011 13 3 10.4088/PCC.10br01091 2-s2.0-79960269097\n17 Estébanez C. Fernández Reyes M. J. Sánchez Hernández R. Acute interstitial nephritis caused by clozapine Nefrologia 2002 22 3 277 281 12123128\n18 Hunter R. Gaughan T. Queirazza F. McMillan D. Shankie S. Clozapine-induced interstitial nephritis - a rare but important complication: a case report J Med Case Rep 2009 3 1 p. 8574 10.4076/1752-1947-3-8574 2-s2.0-73449133373\n19 Davis E. A. K. Kelly D. L. Clozapine-associated renal failure: A case report and literature review Mental Health Clinician 2019 9 3 124 127 10.9740/mhc.2019.05.124 31123659\n20 Opgen-Rhein C. Dettling M. Clozapine-induced agranulocytosis and its genetic determinants Pharmacogenomics 2008 9 8 1101 1111 10.2217/14622416.9.8.1101 2-s2.0-50149096834 18681784\n21 Goldstein J. I. Fredrik Jarskog L. Hilliard C. Clozapine-induced agranulocytosis is associated with rare _HLA-DQB1_ and _HLA-B_ alleles Nature Communications 2014 5 1 10.1038/ncomms5757 2-s2.0-84923091172\n22 Amgen Inc. Neupogen (filgrastim) [package insert]. U.S. Food and Drug Administration website 2021 https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/103353s5196lbl.pdf/\n23 Diaz F. J. Eap C. B. Ansermot N. Crettol S. Spina E. de Leon J. Can valproic acid be an inducer of clozapine metabolism? Pharmacopsychiatry 2014 47 3 89 96 10.1055/s-0034-1371866 2-s2.0-84901341793 24764199\n24 Wen X. Wang J. S. Kivistö K. T. Neuvonen P. J. Backman J. T. In vitroevaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9) British Journal of Clinical Pharmacology 2001 52 5 547 553 10.1046/j.0306-5251.2001.01474.x 11736863\n25 Facciolà G. Avenoso A. Scordo M. G. Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders Therapeutic Drug Monitoring 1999 21 3 341 345 10.1097/00007691-199906000-00017 2-s2.0-0033045133 10365650\n26 Gunes A. Bilir E. Zengil H. Babaoglu M. O. Bozkurt A. Yasar U. Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients Basic & Clinical Pharmacology & Toxicology 2007 100 6 383 386 10.1111/j.1742-7843.2007.00061.x 2-s2.0-34248657974 17516991\n27 Kiang T. K. Ping C. H. Anari M. R. Tong V. Abbott F. S. Chang T. K. Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9∗1/∗1 genotype Toxicological Sciences 2006 94 2 261 271 10.1093/toxsci/kfl096 2-s2.0-33751423375 16945988\n28 Malik S. Lally J. Ajnakina O. Sodium valproate and clozapine induced neutropenia: a case control study using register data Schizophrenia Research 2018 195 267 273 10.1016/j.schres.2017.08.041 2-s2.0-85028654032 28882687\n29 Aydin M. Ilhan B. C. Calisir S. Yildirim S. Eren I. Continuing clozapine treatment with lithium in schizophrenic patients with neutropenia or leukopenia: brief review of literature with case reports Therapeutic Advances in Psychopharmacology 2016 6 1 33 38 10.1177/2045125315624063 26913176\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6838",
"issue": "2021()",
"journal": "Case reports in psychiatry",
"keywords": null,
"medline_ta": "Case Rep Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101583308",
"other_id": null,
"pages": "8816390",
"pmc": null,
"pmid": "33688445",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "12716249;20126316;27776383;15609156;16945988;17516991;9892302;18198271;18681784;26913176;21977363;10365650;11736863;8515788;12123128;31123659;16449474;27913460;28882687;16595571;2292234;29298994;24764199;18098216;25187353",
"title": "Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.",
"title_normalized": "considerations of hla renal failure valproic acid use and current treatment guidelines in clozapine induced agranulocytosis"
} | [
{
"companynumb": "US-MYLANLABS-2021M1019781",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "1",
... |
{
"abstract": "Anagrelide, a phospholipase A2 inhibitor, is widely used in the management of essential thrombocythemia. To date, anagrelide has only rarely been reported to be associated with the development of drug-induced interstitial pneumonitis. We herein report two cases of anagrelide-associated interstitial pneumonitis. The patients were a 67-year-old woman and a 75-year-old man, both with essential thrombocythemia. Both cases developed interstitial pneumonitis at 8 weeks after administration of anagrelide. Because anagrelide-induced interstitial pneumonitis was suspected from CT scan and bronchoalveolar lavage fluid findings, anagrelide-therapy was discontinued and corticosteroid administration was initiated. Anagrelide withdrawal and corticosteroid administration resulted in marked symptom amelioration. A lymphocyte stimulation test using anagrelide was positive in both cases. As interstitial pneumonitis is a rare adverse event during anagrelide-therapy administration, physicians must be vigilant in identifying drug-induced interstitial pneumonitis in patients treated with anagrelide because early detection can decrease the severity and prevent mortality.",
"affiliations": "Department of Hematology and Oncology, Tosei General Hospital.",
"authors": "Kajiguchi|Tomohiro|T|;Kamoshita|Sonoko|S|;Ito|Takayasu|T|;Yagi|Mitsuaki|M|;Kimura|Tomoki|T|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; C021139:anagrelide",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.119",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D010975:Platelet Aggregation Inhibitors; D011014:Pneumonia; D011799:Quinazolines; D013920:Thrombocythemia, Essential; D016896:Treatment Outcome",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "119-125",
"pmc": null,
"pmid": "28321088",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced interstitial pneumonitis in essential thrombocythemia treated with anagrelide.",
"title_normalized": "drug induced interstitial pneumonitis in essential thrombocythemia treated with anagrelide"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-NB-001490",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "As a result of the ever widening disparity between organ supply and demand, a resurgence of interest has occurred in kidney recovery from donation after cardiac death (DCD) donors. New techniques of in situ extracorporeal support offer the potential to reduce warm ischemic injury and optimize donor management prior to organ recovery. In addition, preliminary outcomes using kidneys from selected deceased donors with rising serum creatinine levels have been promising. However, contraindications to successful organ donation and transplantation may include the presence of abdominal compartment syndrome, generalized bowel infarction, refractory shock with profound metabolic and lactic acidosis, and acute anuric renal failure, particularly in the setting of DCD. We report herein the successful recovery and transplantation of kidneys from an unstable donor with the above constellation of conditions in the setting of extracorporeal support after declaration of death by asystole.",
"affiliations": "Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA.",
"authors": "Zuckerman|Jack M|JM|;Singh|Rajinder P|RP|;Farney|Alan C|AC|;Rogers|Jeffrey|J|;Hines|Michael H|MH|;Stratta|Robert J|RJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/j.1432-2277.2009.00860.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "22(8)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Transpl Int",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D001237:Asphyxia; D003161:Compartment Syndromes; D000075202:Contraindications; D003643:Death; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005922:Glomerulonephritis, IGA; D006085:Graft Survival; D006801:Humans; D007238:Infarction; D007422:Intestines; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D013405:Suicide; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting; D009927:Tissue and Organ Procurement",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "798-804",
"pmc": null,
"pmid": "19298251",
"pubdate": "2009-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful kidney transplantation from a donation after cardiac death donor with acute renal failure and bowel infarction using extracorporeal support.",
"title_normalized": "successful kidney transplantation from a donation after cardiac death donor with acute renal failure and bowel infarction using extracorporeal support"
} | [
{
"companynumb": "US-ROCHE-656220",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3",
... |
{
"abstract": "Mediastinal B-cell lymphomas present in the mediastinum and are most frequent in young patients. Nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL) are the common types, whereas mediastinal gray-zone lymphoma (MGZL) is extremely rare and has pathological features intermediate between NSHL and PMBL. The indeterminate pathobiology of MGZL has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized. We conducted a prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim in untreated MGZL. We analyzed biomarkers of outcome and compared their clinical and biological characteristics to PMBL. Twenty-four MGZL patients had a median age of 33 years (range, 14 to 59 years), and 46% had mediastinal masses ≥10 cm. At 59 months median follow-up, the event-free survival and overall survival were 62% and 74%, respectively. The serum absolute lymphocyte count, the presence of tumor-infiltrating dendritic cells, CD15 expression on the malignant cells, and tumor morphology were biomarkers of outcome in MGZL. Compared with PMBL, MGZL patients were more likely to be male, express CD15, have lower expression of CD20, and have a worse outcome. DA-EPOCH-R alone is effective in MGZL. The trial was registered at ClinicalTrials.gov (NCT00001337).",
"affiliations": "Lymphoid Malignancy Branch.;Laboratory of Pathology.;Laboratory of Pathology.;Radiation Oncology Branch, and.;Lymphoid Malignancy Branch.;Center for Cancer Research, National Cancer Institute, Bethesda, MD.;Lymphoid Malignancy Branch.;Lymphoid Malignancy Branch.;Laboratory of Pathology.;Lymphoid Malignancy Branch.",
"authors": "Wilson|Wyndham H|WH|;Pittaluga|Stefania|S|;Nicolae|Alina|A|;Camphausen|Kevin|K|;Shovlin|Margaret|M|;Steinberg|Seth M|SM|;Roschewski|Mark|M|;Staudt|Louis M|LM|;Jaffe|Elaine S|ES|;Dunleavy|Kieron|K|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2014-03-564906",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "124(10)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016393:Lymphoma, B-Cell; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "1563-9",
"pmc": null,
"pmid": "25024303",
"pubdate": "2014-09-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "7519036;23763460;19544140;10561314;16224207;20309430;11807147;9680346;9363863;12393731;9819449;21590365;22133772;21822207;23574119;18378569;17242396;12933571;17242397;20220182;8141877;11017109;12975453",
"title": "A prospective study of mediastinal gray-zone lymphoma.",
"title_normalized": "a prospective study of mediastinal gray zone lymphoma"
} | [
{
"companynumb": "US-JNJFOC-20141001237",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RADIATION THERAPY"
},
"drugadditional": null,
... |
{
"abstract": "Two patients experienced amnesia after taking zolpidem 5 and 10 mg. Neither patient could recall telephone conversations that took place within an hour of taking the drug. The first patient placed a call shortly after ingestion; the second took the dose, fell asleep, and was awakened by the call. Health care providers should be aware of the possibility that in some patients, sedative-hypnotic agents such as zolpidem may produce amnesia that begins a short time after ingestion and may persist into the sleep cycle. This may be particularly important in individuals who, after taking a hypnotic agent, may have to make significant decisions that they must be able to remember.",
"affiliations": "Department of Pharmacotherapy, Coastal AHEC, Wilmington, NC 28402-9025, USA.",
"authors": "Canaday|B R|BR|",
"chemical_list": "D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "16(4)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D000647:Amnesia; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008875:Middle Aged; D011725:Pyridines; D000077334:Zolpidem",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "687-9",
"pmc": null,
"pmid": "8840378",
"pubdate": "1996",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amnesia possibly associated with zolpidem administration.",
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"abstract": "Nitrofurantoin is a commonly used treatment for urinary tract infections with a risk for pulmonary toxicity. We report a case of a 48-year-old woman on a prophylactic regimen of nitrofurantoin who exhibited classic signs of bacterial sepsis including elevated procalcitonin (PCL) and C-reactive protein (CRP) levels two days post-nephrolithotripsy. The microbial analysis did not reveal an infectious cause for the initial symptoms and, subsequently, the patient developed a dry cough, fever, chills, and transient hypoxemia requiring supplemental oxygen. Pulmonary imaging revealed significant abnormal features inconsistent with the patient's symptoms which indicated an inflammatory/immune reaction to nitrofurantoin. Treatment discontinuation improved the patient's symptoms and reduced PCL and CRP levels to within normal limits. A high index of suspicion for nitrofurantoin-associated pulmonary toxicity is warranted for patients on a regimen of nitrofurantoin who exhibit severe pulmonary symptoms and elevated PCL and CRP levels with no corresponding infection.",
"affiliations": "Internal Medicine, Marshfield Medical Center, Marshfield, USA.;Internal Medicine, Rawalpindi Medical College, Rawalpindi, PAK.;Pulmonary and Critical Care Medicine, Staten Island University Hospital / Northwell Health, Staten Island, USA.;Infectious Disease, Marshfield Medical Center, Marshfield, USA.;Pulmonary and Critical Care Medicine, Robert Packer Hospital, Sayre, USA.",
"authors": "Khan|Tahir Muhammad Abdullah|TMA|;Ansari|Yusra|Y|;Siddiqui|Abdul Hasan|AH|;Matthew|Hall|H|;Siddiqui|Faraz|F|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5516Infectious DiseaseInternal MedicinePulmonologyNitrofurantoin-associated Acute Pulmonary Toxicity Mimicking Severe Sepsis with Significantly Elevated Procalcitonin Muacevic Alexander Adler John R Khan Tahir Muhammad Abdullah 1Ansari Yusra 2Siddiqui Abdul Hasan 3Matthew Hall 4Siddiqui Faraz 5\n1 \nInternal Medicine, Marshfield Medical Center, Marshfield, USA \n2 \nInternal Medicine, Rawalpindi Medical College, Rawalpindi, PAK \n3 \nPulmonary and Critical Care Medicine, Staten Island University Hospital / Northwell Health, Staten Island, USA \n4 \nInfectious Disease, Marshfield Medical Center, Marshfield, USA \n5 \nPulmonary and Critical Care Medicine, Robert Packer Hospital, Sayre, USA \nTahir Muhammad Abdullah Khan doctmabdullah@gmail.com29 8 2019 8 2019 11 8 e551612 7 2019 28 8 2019 Copyright © 2019, Khan et al.2019Khan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/21460-nitrofurantoin-associated-acute-pulmonary-toxicity-mimicking-severe-sepsis-with-significantly-elevated-procalcitoninNitrofurantoin is a commonly used treatment for urinary tract infections with a risk for pulmonary toxicity. We report a case of a 48-year-old woman on a prophylactic regimen of nitrofurantoin who exhibited classic signs of bacterial sepsis including elevated procalcitonin (PCL) and C-reactive protein (CRP) levels two days post-nephrolithotripsy. The microbial analysis did not reveal an infectious cause for the initial symptoms and, subsequently, the patient developed a dry cough, fever, chills, and transient hypoxemia requiring supplemental oxygen. Pulmonary imaging revealed significant abnormal features inconsistent with the patient’s symptoms which indicated an inflammatory/immune reaction to nitrofurantoin. Treatment discontinuation improved the patient’s symptoms and reduced PCL and CRP levels to within normal limits. A high index of suspicion for nitrofurantoin-associated pulmonary toxicity is warranted for patients on a regimen of nitrofurantoin who exhibit severe pulmonary symptoms and elevated PCL and CRP levels with no corresponding infection.\n\nnitrofurantoinpulmonary toxicitysepsisprocalcitoninThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nNitrofurantoin is used to treat uncomplicated urinary tract infection, and its use can lead to acute, subacute, or chronic pulmonary toxicity [1]. Nitrofurantoin-associated pulmonary toxicity can manifest as cough, mild fever, shortness of breath, and pulmonary infiltrates on clinical imaging [2-7]. We report a hyperacute presentation of nitrofurantoin-induced toxicity initiated within two days of nitrofurantoin use manifesting as a severe systemic inflammatory response with fever, shaking, chills, lethargy, leukocytosis, significantly elevated C-reactive protein (CRP) and procalcitonin (PCL) levels mimicking severe sepsis of bacterial origin though no infective cause for these symptoms was found. The patient further developed mild transient hypoxemic respiratory failure with dry cough that was associated with bilateral multifocal pulmonary infiltrates and bilateral small pleural effusions with basilar atelectasis. The clinical condition of the patient spontaneously improved by cessation of nitrofurantoin use, and inflammatory markers rapidly trended downward with no additional complications post-nitrofurantoin discontinuation. This case report highlights a unique hyperacute presentation of nitrofurantoin-induced pulmonary toxicity characterized by a severe inflammatory response with significantly elevated PCL level (25.5 ng/mL), a marker which is generally indicative of bacterial sepsis [8,9].\n\nCase presentation\nA 48-year-old female with history of hypertension, obesity, polycystic ovarian syndrome, and right-sided nephrolithiasis experienced right-flank severe colicky pain with nausea and non-bloody vomiting within 24 hours post-urology intervention of right ureteroscopy with laser lithotripsy, stone extraction, and double-J stent placement. The patient’s symptoms were secondary to the displacement of a ureteral stent that resulted in spontaneous expulsion of the stent with subsequent mild improvement of symptoms. However, the patient then developed shaking, chills, and a fever of 39.1°C (102.4°F) associated with lethargy and weakness. The patient denied urinary, respiratory, or other symptoms, and a chart review indicated the patient had been discharged home post-surgery on a prophylactic regimen of 100 mg nitrofurantoin administered twice daily.\n\nOn examination, the patient appeared lethargic and had dry oral mucous membranes. Abdominal exam revealed a soft, non-distended abdomen with mild right flank discomfort. Chest auscultation was clear except for bibasilar mild crackles. Vitals were normal except for mild tachycardia. Lab work showed leukocytosis of 19,000 cells/µL (normal: 4,000-11,000/µL) with elevated lactic acid of 2.5 mmol/L (normal lactic acid: <2.0 mmol/L), serum creatinine (SCr) of 1.3 mg/dL (baseline SCr: 1.0 mg/dL), and elevated blood urea nitrogen (BUN) of 26 mg/dL. In addition, PCL and CRP levels were elevated to 25.5 ng/mL and 39.3 mg/dL, respectively, indicating a bacterial infection. Urinalysis was unremarkable for infection or hematuria. To evaluate flank pain, a computed tomography (CT scan) of the abdomen and pelvis without contrast was performed which revealed multiple small calculi in both kidneys with mild right hydronephrosis, ureteral edema, and stranding of the right kidney and collecting system suggesting reactionary changes due to recent instrumentation versus possible infection (Figure 1). Since the patient was on a prophylactic nitrofurantoin regimen, we presumed that urinalysis with no pyuria was secondary to the use of nitrofurantoin, and due to recent urinary tract intervention, right kidney and ureteral inflammation on CT scan, a urinary source of infection was highly suspected as contributing to the clinical condition. After taking urine cultures and blood cultures, the patient was initiated on an empiric regimen of intravenous piperacillin-tazobactam at 3.375 gm every 8 hours, and nitrofurantoin was discontinued.\n\nFigure 1 Computed tomography imaging of the abdomen and pelvis without contrast\nComputed tomography imaging of the abdomen and pelvis. Note the multiple small calculi in both kidneys with mild hydronephrosis, ureteral edema, and stranding of the right kidney and collecting system (arrow).\n\nWithin 24 hours of admission, the patient developed mild dry cough, a fever of 38.89°C (102°F), and chills associated with transient hypoxia with a pulse oximetry desaturation to 86% requiring 1 L nasal cannula oxygen to maintain normal oxygenation. A chest radiograph revealed an asymmetric left suprahilar density and right infrahilar density consistent with atelectasis, aspiration, or multifocal pneumonia (Figure 2).\n\nFigure 2 Chest X-ray\nChest X-ray to identify pulmonary abnormalities. Note the asymmetric left suprahilar density and right infrahilar density in this image (arrows).\n\nComprehensive respiratory viral panel, urine Legionella, and streptococcal pneumonia antigen were negative. Sputum cultures could not be taken because of nonproductive cough. Preliminary urine cultures and blood cultures revealed no growth. Due to atypical presentation of pulmonary symptoms, follow-up CT angiography of the chest revealed no evidence of pulmonary emboli. The ground glass opacities were present throughout both lungs with small bilateral pleural effusions and adjacent bibasilar atelectasis (Figure 3).\n\nFigure 3 Computed tomography of chest with contrast\nComputed tomographic imaging of the chest revealed no pulmonary embolism, but multifocal ground-glass opacities were observed (arrows).\n\nPulmonary imaging findings were out of proportion to the clinical condition of the patient. Urology and infectious disease physicians evaluated the patient, and it was considered that nitrofurantoin use was contributing to acute onset of bilateral multifocal pulmonary infiltrates leading to mild transient cough and transient pulse oximetry desaturation associated with physiological systemic inflammatory stress response as evidenced by fever, leukocytosis, and significantly elevated PCL and CRP. After the third day of hospitalization, the piperacillin-tazobactam regimen was discontinued, and the patient was observed off all antibiotics. The patient continued to improve without antibiotics and did not require supplemental oxygen with resolution of symptoms within the next three days. We determined that inflammatory findings present in imaging of the right kidney and collecting system were likely secondary to recent urological instrumentation with laser lithotripsy while the transient right-sided flank pain was probably secondary to displacement of the ureteral stent leading to ureteral colic. Serum inflammatory markers continued to improve without antibiotics after cessation of nitrofurantoin use with decreases in serum PCL and CRP levels from admission to discharge day specifically 25.5 ng/mL to 2.1 ng/mL and 39.3 mg/dL to 14.5 mg/dL, respectively. The patient was discharged after six days of hospitalization, and it was strongly recommended the patient avoid use of nitrofurantoin in the future to prevent recurrence of pulmonary toxicity. The patient continues to have a stable clinical condition after discharge and no complications have been reported since then.\n\nDiscussion\nNitrofurantoin is used to treat acute uncomplicated cystitis and as a prophylaxis for recurrent uncomplicated urinary tract infections [1]. Beers criteria recommend against the use of nitrofurantoin in patients 65 years and older due to its potential side effects of pulmonary toxicity, hepatotoxicity, and peripheral neuropathy [10]. Nitrofurantoin toxicity can present as acute, subacute, or chronic pulmonary reaction with a variety of clinical manifestations, but in our patient, it presented as severe sepsis with pulmonary infiltrates [2,4,6,7]. Sovijärvi et al. reported that acute pulmonary toxicity is more common than subacute or chronic toxicity with onset of acute pulmonary reaction usually noticed after a mean of 8.7 days after the initiation of nitrofurantoin though onset can be as early as within 24 to 48 hours of nitrofurantoin use as seen in our patient [2]. Subacute pulmonary reactions usually occur after one month of nitrofurantoin use; however, chronic nitrofurantoin-induced pulmonary toxicity usually manifests after a median interval of six to 23 months when nitrofurantoin was used as prophylaxis for recurrent urinary tract infection [2,5-7].\n\nNitrofurantoin pulmonary toxicity is more commonly observed in women compared to men though the high prevalence observed in women is probably secondary to a greater susceptibility of women to recurrent urinary tract infections requiring antibiotic therapy [2,3,5,6,11]. According to the Swedish Adverse Drug Reaction Committee Registry, 85% of patients diagnosed with nitrofurantoin-induced acute or chronic pulmonary toxicity were the women with a median age of 59 years for acute reaction versus 68 years of age for chronic pulmonary toxicity [3,12].\n\nPatients with nitrofurantoin-induced pulmonary toxicity usually present with fever, cough, dyspnea, eosinophilia in blood, and bilateral lung infiltrates seen on chest images [2,4-7]. The most common imaging findings are bilateral infiltrates seen on chest radiography and bilateral ground-glass opacities detected on CT scans of the chest, but in some cases, subpleural irregular linear opacities and patchy consolidations can be observed [2,3,5-7].\n\nA majority of patients with nitrofurantoin-associated pulmonary toxicity show rapid improvement with the cessation of nitrofurantoin [2]. However, in patients with no improvement with cessation of nitrofurantoin or with questionable diagnosis, a bronchoalveolar lavage (BAL) analysis may be considered to evaluate for infection, lymphangitic carcinomatosis, or alveolar hemorrhage. BAL in patients with nitrofurantoin-induced toxicity usually have eosinophilia, neutrophilia, and lymphocytosis [13,14]. It is important to note that acute eosinophilic pneumonia associated with acute respiratory distress syndrome due to nitrofurantoin use has been reported in the literature and should be considered a possible diagnosis for patients with a recent history of nitrofurantoin use, as these patients respond well to the cessation of culprit drug and with corticosteroid therapy [13].\n\nThe pulmonary biopsy is usually not needed in patients with nitrofurantoin-induced toxicity though it may be considered when the patient does not show improvement after discontinuation of nitrofurantoin, and there is a high index of suspicion for alternative diagnoses. In an acute reaction, a pulmonary biopsy usually reveals an acute reaction with eosinophils, interstitial inflammation, vasculitis, and alveolar exudates [2]. However, in cases of subacute and chronic pulmonary reaction that usually develop after at least one and six months of treatment, respectively, lung biopsy reveals nonspecific lung tissue inflammation, interstitial fibrosis, and capillary sclerosis [2,5].\n\nMost patients with acute, subacute, and chronic lung injury respond well to cessation of nitrofurantoin therapy resulting in spontaneous clinical recovery; however, those with severe pulmonary toxicity may need systemic corticosteroid therapy [2,5,7,13]. Patients with acute pulmonary toxicity usually recover within 15 days of discontinuing nitrofurantoin use, but in patients with chronic pulmonary toxicity, recovery may take longer, and the signs of pulmonary fibrosis may persist for a longer time in more than 50% of patients [2,3]. Patients with both acute and chronic nitrofurantoin-induced pulmonary toxicity generally have a good prognosis including those patients with lung biopsy or radiographic evidence of chronic interstitial lung disease [2,5,15]. Patients with nitrofurantoin-induced interstitial lung disease with severely distorted bronchial architecture and honeycombing observed on imaging may benefit from a transbronchial biopsy to assess the reversibility of pulmonary lesions [16]. Findings of acute or subacute interstitial pneumonitis on lung biopsy usually suggest a good prognosis, and these patients usually respond well to prednisone therapy in addition to discontinuation of nitrofurantoin [16].\n\nDespite a generally good prognosis, fatalities have been reported in the literature. According to the medicine and healthcare products regulatory authority report, from 1963 until 2010, 11 out of 392 patients affected with nitrofurantoin-associated lung injury were reported to have a fatal outcome [6]. Therefore, caution should be exercised when prescribing a nitrofurantoin regimen, and patients with severe symptoms of hypoxia and multifocal lung infiltrates on radiography should be hospitalized for close monitoring and symptom management.\n\nOur patient’s presentation of nitrofurantoin-induced toxicity was unique in that it mimicked severe bacterial sepsis including tachycardia, lethargy, high-grade fever, chills, mild nonproductive cough with dyspnea, and hypoxia associated with elevated PCL and CRP levels in addition to leukocytosis without eosinophilia. PCL is considered a more specific marker for bacterial infection compared to other inflammatory markers such as serum leukocyte count, CRP, and erythrocyte sedimentation rate though recent work indicates comparable diagnostic performance with PCL and CRP as sepsis markers [8,9]. However, this is the first reported case of acute pulmonary toxicity due to nitrofurantoin mimicking bacterial infection with significant elevations in PCL. Nevertheless, such a diagnosis warrants a careful evaluation of the patient including infectious disease work-up to exclude the possibility of infectious cause as a contributing factor to the patient's symptomatology, and it is important to note that absence of eosinophilia usually observed in nitrofurantoin-induced pulmonary injury does not rule out a diagnosis of nitrofurantoin-induced pulmonary toxicity.\n\nConclusions\nNitrofurantoin-induced pulmonary toxicity can occur as early as within 24 to 48 hours of initiation of drug exposure, and recent medications use by the patient should be explored at the time of presentation for all patients exhibiting respiratory symptoms and sepsis with no identifiable infectious cause. Though elevated PCL is a marker for bacterial sepsis, it can be elevated in nitrofurantoin-pulmonary toxicity without bacterial infection. Early cessation of nitrofurantoin therapy in patients with hyperacute pulmonary toxicity carries a good prognosis and results in early resolution of symptoms without the need for systemic steroids; patients should be recommended to not use nitrofurantoin in the future to avoid toxicity recurrence.\n\nDue to the higher prevalence of nitrofurantoin-induced pulmonary toxicity, physicians should be cautious in prescribing nitrofurantoin, and patients should be informed about the possibility of pulmonary toxicity along with other adverse effects at the time of prescription. Providers should also continue long-term surveillance of patients on a long-term nitrofurantoin regimen to ensure early detection of toxicity and to discontinue nitrofurantoin promptly.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nThe authors acknowledge Emily Andreae, PhD, for manuscript editing assistance.\n==== Refs\nReferences\n1 International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases Clin Infect Dis Gupta K Hooton TM Naber KG 103 120 52 2011 \n2 Nitrofurantoin-induced acute, subacute and chronic pulmonary reactions Scand J Respir Dis Sovijärvi AR Lemola M Stenius B Idänpään-Heikkilä J 41 50 58 1977 https://www.ncbi.nlm.nih.gov/pubmed/841294 841294 \n3 Adverse reactions to nitrofurantoin. Analysis of 921 reports Am J Med Holmberg L Boman G Böttiger LE Eriksson B Spross R Wessling A 733 738 69 1980 https://www.ncbi.nlm.nih.gov/pubmed/7435512 7435512 \n4 Hospitalizations for pulmonary reactions following nitrofurantoin use Chest Jick SS Jick H Walker AM Hunter JR 512 515 96 1989 2766810 \n5 Chronic nitrofurantoin-induced lung disease Mayo Clin Proc Mendez JL Nadrous HF Hartman TE Ryu JH 1298 1302 80 2005 16212142 \n6 Lung toxicity and nitrofurantoin: the tip of the iceberg? QJM Weir M Daly GJ 271 272 106 2013 22836192 \n7 Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature J Infect Public Health Kabbara WK Kordahi MC 309 313 8 2015 25747822 \n8 Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit Crit Care BalcI C Sungurtekin H Gürses E Sungurtekin U Kaptanoglu B 85 90 7 2002 12617745 \n9 Clinical usefulness of procalcitonin and C-reactive protein as outcome predictors in critically ill patients with severe sepsis and septic shock PLoS One Ryu JA Yang JH Lee D 138150 10 2015 \n10 American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults J Am Geriatr Soc American Geriatrics Society Beers Criteria Update Expert Panel 674 694 67 2019 30693946 \n11 How common are pulmonary and hepatic adverse effects in older adults prescribed nitrofurantoin? J Am Geriatr Soc Claussen K Stocks E Bhat D Fish J Rubin CD 1316 1320 65 2017 28306135 \n12 Pulmonary reactions to nitrofurantoin. 447 cases reported to the Swedish Adverse Drug Reaction Committee 1966-1976 Eur J Respir Dis Holmberg L Boman G 180 189 62 1981 https://www.ncbi.nlm.nih.gov/pubmed/?term=Pulmonary+reactions+to+nitrofurantoin.+447+cases+reported+to+the+Swedish+Adverse+Drug+Reaction+Committee+1966-1976 7308333 \n13 Acute eosinophilic pneumonia associated with acute respiratory distress syndrome: case report. (Article in Portuguese) Rev Port Pneumol Baptista JP Casanova PC Sousa JP 355 364 10 2004 15492880 \n14 Chronic nitrofurantoin reaction associated with T-lymphocyte alveolitis Chest Brutinel WM Martin WJ 2nd 150 152 89 1986 3484445 \n15 Nitrofurantoin-induced lung disease: about two cases. (Article in French) Rev Med Interne Mrozek N Delèvaux I Legendre M André M Trouillier S Voinchet H Aumaitre O 149 151 29 2008 17655981 \n16 Rapid resolution of nitrofurantoin-induced interstitial lung disease. (Article in Spanish) Arch Bronconeumol Viejo MA Fernández Montes A Montes JV Gómez-Román JJ Ibarbia CG Hernández JL 352 355 45 2009 19339098\n\n",
"fulltext_license": "CC BY",
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"issue": "11(8)",
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"keywords": "nitrofurantoin; procalcitonin; pulmonary toxicity; sepsis",
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"pubdate": "2019-08-29",
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"title": "Nitrofurantoin-associated Acute Pulmonary Toxicity Mimicking Severe Sepsis with Significantly Elevated Procalcitonin.",
"title_normalized": "nitrofurantoin associated acute pulmonary toxicity mimicking severe sepsis with significantly elevated procalcitonin"
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"abstract": "Lidocaine and prilocaine are local anesthetics, a class of medications which are frequently used in clinical medicine to minimize pain in a variety of procedures. They are commonly found in over-the-counter products such as topical anesthetic creams advertised to relieve localized muscle and joint pain. While safe and well-tolerated when used appropriately, an overdose of these anesthetics increases the risk for local anesthetic systemic toxicity (LAST), which in severe cases can present with seizures, cardiac dysrhythmias, and ultimately cardiovascular collapse. The reduced muscle mass of pediatric patients puts them at an increased risk of LAST due to the depot effect of the systemically absorbed anesthetic. Methemoglobinemia may also be associated with local anesthetic toxicity. Our case involves a previously healthy 15-month-old female who presented to one of our networks' emergency departments in status epilepticus following an accidental ingestion of a tube of 2.5% lidocaine/2.5% prilocaine cream. Her seizure activity was initially resistant to intraosseous benzodiazepine administration, but ultimately resolved following administration of lipid emulsion and sodium bicarbonate. Additionally, the patient had refractory hypoxia on the monitor which resolved shortly after administration of methylene blue. After stabilization, the patient was transferred to the Pediatric ICU and ultimately made a complete recovery. LAST is a life-threatening presentation which requires early recognition by clinicians, as well as an understanding of the appropriate treatment modalities. We review the assessment and management of LAST, with special focus on the pediatric patient.",
"affiliations": "Department of Emergency Medicine, St. Luke's University Health Network, Bethlehem, PA, USA.;Department of Emergency Medicine, St. Luke's University Health Network, Bethlehem, PA, USA.;Section of Medical Toxicology, Department of Emergency Medicine, St. Luke's University Health Network, Bethlehem, PA, USA. Electronic address: keith.baker@sluhn.org.",
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"abstract": "The occurrence of de novo hepatocellular carcinoma (HCC) after liver transplantation (LT) for advanced HCCs has been extremely limited. In this article, a case of de novo HCC in a liver graft with sustained hepatitis C virus clearance after living donor liver transplantation (LDLT) for multiple HCCs and hepatitis C cirrhosis is reported. The recipient was a 58-year-old female, and the left lobe living donor was the 30-year-old healthy daughter of the recipient. Three years after LDLT, the patient received 48 weeks of interferon treatment for recurrent hepatitis C with advanced fibrosis. The patient has shown successful viral clearance since then. However, an HCC was recognized in the liver graft during a follow-up computed tomography scan performed 6 years after LDLT, and it was surgically resected. To analyze its origin [either from the patient (metastatic) or from the living donor (de novo)], genotyping by microsatellite analysis of tissue and blood samples from the donor and recipient was performed, and it revealed that the HCC originated from the donor. To the best of our knowledge, this is the first report of de novo HCC in a liver graft with sustained hepatitis C virus clearance after LT for advanced HCCs and hepatitis C cirrhosis.",
"affiliations": "Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Morita|Kazutoyo|K|;Taketomi|Akinobu|A|;Soejima|Yuji|Y|;Ikegami|Toru|T|;Fukuhara|Takasuke|T|;Iguchi|Tomohiro|T|;Nagata|Shigeyuki|S|;Sugimachi|Keishi|K|;Gion|Tomonobu|T|;Shirabe|Ken|K|;Maehara|Yoshihiko|Y|",
"chemical_list": "D004273:DNA, Neoplasm",
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"mesh_terms": "D000328:Adult; D006528:Carcinoma, Hepatocellular; D004273:DNA, Neoplasm; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D016031:Liver Transplantation; D019520:Living Donors; D018895:Microsatellite Repeats; D008875:Middle Aged; D011183:Postoperative Complications",
"nlm_unique_id": "100909185",
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"title": "De novo hepatocellular carcinoma in a liver graft with sustained hepatitis C virus clearance after living donor liver transplantation.",
"title_normalized": "de novo hepatocellular carcinoma in a liver graft with sustained hepatitis c virus clearance after living donor liver transplantation"
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{
"abstract": "A potential therapeutic role for immune transformation in Parkinson's disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson's disease patients. Both Parkinson's disease patients and controls were monitored for 2 months for baseline profiling. Parkinson's disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson's disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson's disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson's disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.",
"affiliations": "Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Neurology Consultants of Nebraska, PC and Nebraska Medicine, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Great Plains Center for Clinical and Translational Research, University of Nebraska Medical Center, Omaha, NE USA.;Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Scripps Center for Metabolomics, Scripps Research Institute, La Jolla, CA USA.;Departments of Chemistry, Cell and Molecular Biology, and Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.;Great Plains Center for Clinical and Translational Research, University of Nebraska Medical Center, Omaha, NE USA.;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.",
"authors": "Gendelman|Howard E|HE|;Zhang|Yuning|Y|;Santamaria|Pamela|P|;Olson|Katherine E|KE|;Schutt|Charles R|CR|;Bhatti|Danish|D|;Shetty|Bhagya Laxmi Dyavar|BLD|;Lu|Yaman|Y|;Estes|Katherine A|KA|;Standaert|David G|DG|0000-0003-2921-8348;Heinrichs-Graham|Elizabeth|E|0000-0002-7914-5258;Larson|LuAnn|L|;Meza|Jane L|JL|;Follett|Matthew|M|;Forsberg|Erica|E|;Siuzdak|Gary|G|;Wilson|Tony W|TW|;Peterson|Carolyn|C|;Mosley|R Lee|RL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1038/s41531-017-0013-5",
"fulltext": "\n==== Front\nNPJ Parkinsons DisNPJ Parkinsons DisNPJ Parkinson's Disease2373-8057Nature Publishing Group UK London 1310.1038/s41531-017-0013-5ArticleEvaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial Gendelman Howard E. +1 402 559 8920hegendel@unmc.edu 1Zhang Yuning 1Santamaria Pamela 2Olson Katherine E. 1Schutt Charles R. 1Bhatti Danish 3Shetty Bhagya Laxmi Dyavar 1Lu Yaman 1Estes Katherine A. 1http://orcid.org/0000-0003-2921-8348Standaert David G. 4http://orcid.org/0000-0002-7914-5258Heinrichs-Graham Elizabeth 1Larson LuAnn 5Meza Jane L. 6Follett Matthew 1Forsberg Erica 7Siuzdak Gary 8Wilson Tony W. 13Peterson Carolyn 5Mosley R. Lee 11 0000 0001 0666 4105grid.266813.8Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA 2 0000 0000 9827 4675grid.429696.6Neurology Consultants of Nebraska, PC and Nebraska Medicine, Omaha, NE USA 3 0000 0001 0666 4105grid.266813.8Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE USA 4 0000000106344187grid.265892.2Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL USA 5 0000 0001 0666 4105grid.266813.8Great Plains Center for Clinical and Translational Research, University of Nebraska Medical Center, Omaha, NE USA 6 0000 0001 0666 4105grid.266813.8Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE USA 7 0000000122199231grid.214007.0Scripps Center for Metabolomics, Scripps Research Institute, La Jolla, CA USA 8 0000000122199231grid.214007.0Departments of Chemistry, Cell and Molecular Biology, and Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA USA 23 3 2017 23 3 2017 2017 3 101 12 2016 17 2 2017 23 2 2017 © The Author(s) 2017This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/\nA potential therapeutic role for immune transformation in Parkinson’s disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson’s disease patients. Both Parkinson’s disease patients and controls were monitored for 2 months for baseline profiling. Parkinson’s disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson’s disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson’s disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson’s disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.\n\nImmune modulation: translating the benefits\nThe immune system modulating drug sargramostim shows promising results in a small clinical trial with Parkinson’s disease (PD) patients. Previous studies have shown that sargramostim increases the number of regulatory T cells, attenuates immune responses, and confers neuroprotection in animal models of neurodegenerative disease. To determine whether these findings translate to humans, Howard E. Gendelman at the University of Nebraska Medical Center, USA, and colleagues examined the effects of sargramostim in 20 patients with PD. Despite the high number of mild to moderate reported adverse events, the drug was generally well tolerated and led to an increase in regulatory T cell number and activity. Moreover, preliminary assessments after 6 and 8 weeks of treatment suggested an overall improvement in the motor skills of patients that received the drug compared with those that received a placebo.\n\nSubject terms\nParkinson's diseaseNeuroimmunologyChronic inflammationImmunotherapyissue-copyright-statement© The Author(s) 2017\n==== Body\nIntroduction\nPD, the most common neurodegenerative movement disorder, is a progressive and debilitating disease that affects up to 5 million people worldwide.1 Characteristic movement deficits parallel reductions in striatal dopamine and progressive loss of substantia nigra pars compacta dopaminergic neurons and their striatal connections. To date, therapy is nearly exclusively devoted to symptomatic control of disease manifestations.1 Considerable research efforts are underway to define disease mechanisms and as such develop novel therapies to affect disease outcomes. Indeed, despite knowledge of disease mechanisms, therapeutic modalities remain palliative.1 Considerable evidence supports the notion that immune alterations exist in PD. Such alterations can be modulated for “potential” therapeutic benefit.2 Mechanisms that could be harnessed for therapeutic gain rest in transforming neurotoxic innate and adaptive immune responses. Indeed, work performed by a number of laboratories have shown that Lewy bodies, containing aggregated and nitrated α-synuclein (N-α-syn), released into the extraneuronal environment induce activated macrophages and microglia and affect the emergence of effector T cell (Teff) populations.2–4 In animal models of PD, brain-infiltrating macrophages and microglia produce pro-inflammatory neurotoxins that damage surrounding nigral neurons. Such neurotoxin-producing cells can exacerbate disease outcomes as mediated by peripheral N-α-syn-induced Teff.5, 6 In contrast, regulatory T cells (Treg) maintain immunological tolerance, attenuate inflammation, and can positively modify disease at least in PD animal models.7, 8 As neurodestructive Th1 and Th17 cells can be transformed by pharmacological interventions into neuroprotective Treg, a platform has recently come operative to harness immunological responses for therapeutic gain.3\n\n\nSargramostim (Sanofi US, Bridgewater, NJ) is an Food and Drug Administration-approved human recombinant granulocyte-macrophage colony-stimulating factor known to affect myeloid recovery in patients receiving bone marrow transplantation or cancer therapy along with induction of Treg immune responses.9, 10 The latter was shown to protect against nigrostriatal neurodegeneration in rodent PD models.11, 12 However, sargramostim administered under regimens to counter myeloablative intervention or as adjunctive neoplastic therapy has mild adverse effects that include increased white blood cell (WBC) counts, injection site reactions, and bone or sternal pain, which may be self-limiting for some within aged populations.13 Despite mild adverse effects of sargramostim, we evaluated an immune-mediated neuroprotective compound as a potential therapy for PD. We found that on the whole sargramostim was well-tolerated, and the adverse effects observed were similar to the effects of this treatment in other patient populations. Our results demonstrated that sargramostim produced the expected immune transformation with the emergence of increased numbers and improved function of Treg. These desired immunological endpoints were confirmed by metabolomic and transcriptomic tests, showing engagement of the serum tryptophan metabolites that included L-kynurenine, quinolinic acid, and serotonin. Although the study was not powered for motor activity efficacy, nor was it long-term, positive effects on some patients' motor skill sets were seen. The results are of potential importance and warrant the consideration of larger-scale investigations. The clinical efficacy endpoints examined remain exploratory in nature and are also dependent on larger-scale monitoring.\n\nResults\nDemographics and baseline hematologic and immune profiles\nIn all, 22 PD patients and 17 non-Parkinsonian subjects were enrolled and assessed for eligibility. No significant differences in demographics were discernible between the PD patients and 17 non-PD subjects (Table 1). PD patients ranged from 53 to 76 years of age with a median and mean age of 64 with symptoms for 3–14 years (median 6 years and mean 7 years). Compared with non-PD subjects who exhibited a mean age of 65 years of age, the immune and WBC differential profiles for PD patients at entry exhibited increased frequencies of neutrophils and α4β7 integrin-expressing Teffs and Tregs, but decreased levels of CD39+ Tregs and basophils confirmed previously reported immune profiles.14\nTable 1 Demographics and entry study profiles for non-Parkinsonian subjects and PD patients\n\n\tNon-Parkinsonian subjects\tPD patients\t\n\nDemographics\na\n\t\nN\n\tMean (SD)\t\nN\n\tMean (SD)\t\nAge (years)\t17\t65 (7)\t20\t64 (7)\t\nTime since first symptoms (years)\tn/a\tn/a\t20\t7 (3)\t\nTime since diagnosis (years)\tn/a\tn/a\t19\t6 (3)\t\nUPDRS III score\tn/a\tn/a\t20\t22 (8)\t\n\t\nN (Percentage)\t\nN (Percentage)\t\nMale sex\t9 (53)\t16 (80)\t\nCaucasian race\t17 (100)\t20 (100)\t\nJob with pesticides\t1 (5)\t2 (10)\t\nExposure to pesticides\t4 (24)\t10 (50)\t\nJob with chemical solvents\t4 (24)\t8 (40)\t\nJob with other chemical fumes\t4 (24)\t8 (40)\t\nJob with heavy metals\t2 (12)\t2 (10)\t\nHematological parameter\tMean (SD)\tMean (SD)\t\nWBC × 103/μL\t6.3 (1.4)\t6.8 (1.6)\t\nRBC × 106/μL\t4.7 (0.4)\t4.7 (0.3)\t\nHemoglobin, g/dL\t14.4 (1.1)\t14.4 (0.8)\t\nHematocrit, %\t43.2 (6.6)\t43.1 (2.2)\t\nMean corpuscular volume (MCV), fL\t91.6 (3.8)\t91.3 (4.1)\t\nMean corpuscular hemoglobin concentration (MCHC), %\t33.2 (0.9)\t33.4 (0.7)\t\nRed cell distribution width (RDW), %\t13.2 (0.7)\t13.0 (1.1)\t\nPlatelet count × 103/μL\t225.6 (37.9)\t233.0 (57.6)\t\nNeutrophils, %\t61.7 (5.6)\t66.0 (6.9)b\n\t\nLymphocytes, %\t25.4 (6.0)\t23.2 (5.7)\t\nMonocytes, %\t8.5 (1.9)\t7.4 (1.3)\t\nEosinophils, %\t2.9 (1.5)\t2.5 (1.4)\t\nBasophils, %\t1.0 (0.2)\t0.7 (0.4)b\n\t\nNeutrophil × 103/μL\t3.9 (1.0)\t4.6 (1.2)\t\nLymphocytes × 103/μL\t1.6 (0.5)\t1.6 (0.5)\t\nMonocytes × 103/μL\t0.5 (0.1)\t0.5 (0.1)\t\nEosinophils × 103/μL\t0.2 (0.1)\t0.2 (0.1)\t\nBasophils × 103/μL\t0.1 (0.0)\t0.0 (0.0)\t\nT cell panel\tMean (SD)\tMean (SD)\t\nCD3+, %\t70.5 (7.1)\t71.3 (8.5)\t\nCD3+/μL\t1162.7 (456.9)\t1123.2 (360.6)\t\nCD4+, %\t50.9 (7.2)\t49.2 (11.0)\t\nCD4+/μL\t835.9 (320.9)\t769.4 (263.6)\t\nCD8+, %\t18.9 (6.4)\t21.3 (8.1)\t\nCD8+/μL\t316.3 (183.2)\t342.6 (195.6)\t\nCD4+/CD8+ Ratio\t3.1 (1.0)\t2.9 (1.1)\t\n% Teff/CD4+\t1.1 (0.4)\t1.1 (0.4)\t\n% α4β7 Integrin+/Teff\t8.3 (3.5)\t14.5 (10.6)b\n\t\n% Treg/CD4+\t5.4 (1.2)\t5.4 (1.3)\t\n% FOXP3+/CD4+\t8.9 (2.8)\t8.7 (2.6)\t\n% CD39+/Treg\t55.8 (15.8)\t41.6 (23.8)c\n\t\n% α4β7 Integrin+/Treg\t6.2 (2.1)\t8.6 (3.0)b\n\t\n\nn/a not applicable\n\n\na Demographic information obtained from controls and patients at the time of enrollment were used\n\n\nb\nP < 0.05\n\n\nc\nP ≤ 0.10 by Mann–Whitney U test\n\n\n\n\nSargramostim effects on primary safety endpoints and adverse events\nTwenty PD patients randomized to receive sargramostim (N = 10) or placebo (N = 10) (Supplementary Fig. S1) showed similar demographics and pesticide/heavy metal exposure histories (Table 2). Seventy percent of the PD patients completed the study. All patients treated with sargramostim and 80% of placebo-treated patients reported at least one adverse event; the difference between the sargramostim group (10/10, 100%, 95% CI 72–100) and placebo group (8/10, 80%, 95% CI 49–94) was non-significant (hazard ratio 1.25, 95% CI 0.92–1.70). The most frequently reported adverse events among sargramostim-treated and placebo-treated patients, respectively, were injection site reactions (10/10, 100% vs. 4/10, 40%, P = 0.01), abnormal laboratory/WBC counts (10/10, 100% vs. 3/10, 30%, P = 0.003) and pain at sites other than injection sites included bone extremities, torso, pain, and chest-tightening (7/10, 70% vs. 3/10, 30%, P = 0.179) are all well-known associations with sargramostim administration and were considered mild adverse reactions.15 Eosinophil frequencies increased by 8-fold to 16-fold during sargramostim treatment (P < 0.0001), and all hematological values returned to baseline by 4 weeks after drug cessation. Physical examination and blood metabolic values were unremarkable during treatment.Table 2 Demographics and adverse events for PD patients\n\n\nDemographics\n\tPlacebo\tSargramostim\t\n\t\nN\n\tMean (SD)\t\nN\n\tMean (SD)\t\nAge (years)\t10\t67 (6)\t10\t62 (7)\t\nTime since first symptoms (years)\t9\t7 (3)\t10\t7 (2)\t\nTime since diagnosis (years)\t10\t5 (4)\t10\t6 (3)\t\nUPDRS III score\t10\t24 (10)\t10\t20 (5)\t\n\t\nN (Percentage)\t\nN (Percentage)\t\nMale sex\t8 (80)\t8 (80)\t\nCaucasian race\t10 (100)\t10 (100)\t\nJobs with pesticides\t3 (30)\t0 (0)\t\nExposure to pesticides\t7 (70)\t3 (30)\t\nJobs with chemical solvents\t4 (40)\t4 (40)\t\nJobs with other chemical fumes\t5 (40)\t4 (40)\t\nJobs with heavy metals\t1 (10)\t1 (10)\t\nAdverse eventsa\n\t\t\t\nAny adverse event\t8 (80)\t10 (100)\t\nAny severe adverse events\t0 (0)\t3 (30)\t\nAny serious adverse events\t0 (0)\t1 (10)\t\nAdverse event leading to withdrawal\t0 (0)\t4 (40)\t\nPossible relationship to drug\t7 (70)\t10 (100)\t\nDefinitive relationship to drug\t2 (20)\t7 (70)\t\nCategorya\n\t\t\t\nInjection site reaction\t4 (40)\t10 (100)b\n\t\nAbnormal laboratory values\t3 (30)\t10 (100)b\n\t\nPain, other than injection site\t3 (30)\t7 (70)\t\nPain, upper torso and extremities\t0 (0)\t7 (70)b,g\n\t\nPain, lower torso and extremities\t3 (30)\t3 (30)\t\nChest pain or discomfort\t0 (0)\t4 (40)\t\nMuscle, soreness, weakness\t4 (40)\t3 (30)\t\nRash, other than injection site\t2 (20)\t4 (40)\t\nShortness of breath, wheezing\t0 (0)\t3 (30)\t\nGI tract, nausea, vomiting\t0 (0)\t3 (30)\t\nInjury\t3 (30)\t2 (20)\t\nHeadache\t2 (20)\t2 (20)\t\nFatigue\t2 (20)\t2 (20)\t\nInfection, any\t2 (20)\t2 (20)\t\nNeurological, psychological, dyskinesia\t2 (20)\t2 (20)\t\nChills, fever\t1 (10)\t2 (20)\t\nItching, other than injection site\t0 (0)\t2 (20)\t\nCardiovascular, hematological\t0 (0)\t2 (20)\t\nSkin, not infection\t3 (30)\t1 (10)\t\nEquilibrium\t1 (10)\t1 (10)\t\nSleep anomalies\t1 (10)\t1 (10)\t\nEdema, other than injection site\t0 (0)\t1 (10)\t\nOphthalmological\t0 (0)\t1 (10)\t\n\tMedian (IQR)\tMean (SD)\tMedian (IQR)\tMean (SD)\t\nSeverity of combined adverse eventsc\n\t1.2 (1.1–1.4)\t1.2 (0.1)\t1.7 (1.4–1.8)e\n\t1.6 (0.3)\t\nLikelihood of events being drug-relatedd\n\t2.4 (1.9–2.7)\t2.2 (0.6)\t3.8 (3.1–3.9)e\n\t3.6 (0.6)\t\nSeverity of injection site reactionc\n\t1.5 (1.0–2.0)\t1.5 (0.6)\t1.0 (1.0–2.0)\t1.3 (0.5)\t\nSeverity of pain, other than injection sitec,g\n\t1.0 (1.0–1.8)\t1.2 (0.5)\t2.0 (2.0–3.0)\t2.0 (0.7)\t\nSeverity of pain, upper torso and extremitiesc,g\n\tndf\n\tnd\t2.0 (1.8–2.0)\t2.0 (0.6)\t\nSeverity of pain, lower torso and extremitiesc,g\n\t1.0 (1.0–1.8)\t1.2 (0.5)\t2.0 (1.5–3.0)\t2.1 (0.8)\t\n\na Adverse events reported since the initiation of placebo/drug. More than two adverse advents per patient may have been reported; however, patients are only counted once within each category. The same patient may be counted in different categories\n\n\nb\nP ≤ 0.01 by Fisher’s exact test\n\n\nc Scored by attending physician; 1 = mild, 2 = moderate, 3 = severe\n\n\nd Scored by attending physician; 1 = Unrelated, 2 = Unlikely, 3 = Possibly, 4 = Probably, 5 = Definite\n\n\ne\nP ≤ 0.004 by Mann–Whitney U test\n\n\nf\nnd no data\n\n\ng The incidence of upper torso bone and musculoskeletal chest pain were higher in patients treated with sargramostim compared with placebo and was distinct from that associated with PD19–22\n\n\n\n\n\nMean (±standard deviation [SD]) severity scores for all adverse events were greater in the sargramostim group (1.6 ± 0.3) than in placebo group (1.2 ± 0.1) (P = 0.004). Event-associated severities for all pain sites between groups were not significantly different and ranged from mild and moderate (Table 2). Frequencies of patients with pain at sites other than injection sites that included upper and lower torso and extremities were not significantly different between treatment groups (P = 0.179). Pain severities as scored by the attending physician at injection sites and at sites other than injection sites including the extremities, the lower torso, and the upper torso and included “chest-tightening”, ranged from mild to moderate and were not significantly different between treatment groups (Table 2). Notably, during the 2 months of pre-treatment baseline observations in our study (visits 1–3), three patients reported pre-treatment pain (2/10, 20% in the sargramostim group vs. 1/10, 10% in the placebo group) (data not shown), suggesting that reported pain experienced during treatment was distinguishable from those attributable to PD. However, in the context of staggered enrollment and non-significant event frequencies among treatment groups, adverse events were not considered significant enough to break the study blind. The likelihood of a treatment-associated adverse event was greatest in the sargramostim group (P = 0.002) with likelihood scores ranging from possible to probable, while those in the placebo group ranged from unlikely to possible.\n\nSevere events included a generalized hypersensitivity reaction, a leukocytoclastic vasculitis, and a thrombotic stroke; the latter two were deemed unlikely associated with drug. Notably, for the first patient enrolled, sargramostim was formulated with benzyl alcohol as a preservative. Administration of this formulation for 48 days led to the vasculitis, which responded successfully to formulation cessation and steroid treatment with complete symptom resolution. As benzyl alcohol was deemed vasculitis-associated, the preservative was removed from all subsequent preparations without further incidents of vasculitis. The subject who experienced stroke presented a previous history of hypertension and parallel co-morbid vascular events and were confirmed by magnetic resonance imaging examination. As there were no contraindications of sargramostim for cerebrovascular disease the subject remained in and completed the study. The four sargramostim-treated patients who withdrew from study included the two subjects with upper torso, bone pain, or chest-tightening (Supplementary Fig. S1, Table 2). Extensive work up demonstrated that none of these symptoms were linked to cardiac disease that was the precipitating concern that led to drug cessation decisions. Complete data sets for analysis were obtained for 66 visits by sargramostim-treated patients compared with 77 visits for placebo group. Serum anti-sargramostim antibodies were detected in the drug group by week 4 of treatment (visit 5), but diminished by week 8 (visit 7). Antibody levels were marginal at 4 weeks after drug cessation (Supplementary Fig. S2).\n\nSargramostim increases CD4+ Treg subsets and Treg-mediated suppression\nThe study yielded expected Treg induction outcomes. This provides clear evidence that sargramostim treatment can achieve the desired immunological endpoint. Sargramostim treatment resulted in higher numbers of CD3+ and CD4+ T cells (Supplementary Fig. S3b, d) with increasing, though not significant, frequencies when compared with placebo (Supplementary Fig. S3a, c). Frequencies and numbers of CD8+ T cells (Supplementary Fig. S3e, f) and ratios of CD4+ and CD8+ cells (Supplementary Fig. S3g) were unaffected. Frequencies of CD4+ Teffs remained unchanged regardless of whether sargramostim or placebo was administered (Fig. 1a). In contrast, sargramostim treatment increased frequencies of CD4+CD127loCD25hi Tregs as early as 2 weeks, which remained elevated thereafter (Fig. 1b, c). Tregs exhibited higher frequencies of subsets that express CD39 and FAS (CD95), or intracellular CTLA4 (iCTLA4) (Fig. 1d–f). Treg function was assessed as the ability to suppress CD3/CD28-stimulated proliferation of CD4+CD25− Tresps. Baseline Treg function in PD patients was diminished (P = 0.07) compared with non-PD subjects (Table 1, Fig. 1g, Entry), thus confirming results from our previous study.14 Prior to treatment, Treg function was similar among both randomized PD patient groups (Fig. 1h, Pre-Treatment). In contrast, treatment with sargramostim increased Treg activity compared with pre-treatment (differences in slopes, P = 0.04) and to placebo group (differences in slope, P = 0.06 and elevation, P = 0.07) (Fig. 1i).Fig. 1 Peripheral blood lymphocytes from PD patients treated with placebo or sargramostim were assessed for the expression of Treg phenotype and function over a 3-month mean baseline (visits 1–3), every 2 weeks after the initiation of treatment (visits 4–7), and 4 weeks after discontinuation of treatment (visit 8). Flow cytometric analyses for percentage of a CD4+ Teffs (CD4+CD127hiCD25hi), b CD4+ Tregs (CD4+CD127loCD25hi), c FOXP3+CD4+ Tregs, d iCTLA4+CD4+ Tregs, e CD39+CD4+ Tregs, and f FAS+CD4+ Tregs. Plots represent the medians, interquartile ranges (IQRs) (boxes), and non-outlier ranges (whiskers) for T cells from PD patients. Levels of T cell subsets from PD patients treated with placebo (n = 6–10) (blue) or sargramostim (n = 5–9) (red) were compared by Mann–Whitney U test with P ≤ a0.10, b0.05, or c0.01. g–i Enriched Treg isolates were assessed for the capacity to suppress CD3/CD28-stimulated CD4+CD25− Tresps from a healthy donor. Tregs were serially diluted two-fold and co-stimulated with a constant number of CFSE-stained Tresps to yield decreasing Treg:Tresp ratios. Treg activity as percentage inhibition of proliferation was determined for g non-Parkinsonian controls (n = 17) and non-allocated PD patients (n = 20) at 8, 4, and 0 weeks before treatment initiation (Entry, visits 1–3); h for randomized PD patients prior to initiation of treatment (Pre-Treatment, visits 1–3); and i at 2, 4, 6, and 8 weeks after initiation (Treatment, visits 4–7). Comparison of differences in slope or elevation as an indicator of Treg activity was determined by linear regression analyses for baseline paired controls and PD patients (P\nslope = 0.49, P\nelevation = 0.065, n = 17) (Entry); for baseline of placebo (n = 10) or sargramostim (n = 10) randomized PD patients (P\nslope = 0.59, P\nelevation = 0.17) (Pre-Treatment); and for PD patients during treatment with sargramostim (n = 5–9) compared with placebo (n = 9–10) (P\nslope = 0.063, P\nelevation = 0.058) (Treatment). Comparison of Treg activity from pre-treated and treated patients randomized to sargramostim group (P\nslope = 0.039) or placebo group (P\nslope = 0.88, P\nelevation = 0.04)\n\n\n\n\nSargramostim induces immune-linked metabolites and augments suppressor activity\nSargramostim-mediated increases in Treg frequency and function suggested the possible prevalence of systemic conditions conducive for Treg development. To assess that possibility, serum from PD patients prior to, during, and after treatment with sargramostim or placebo were assessed by global untargeted metabolomic analyses. Six-hundred metabolites were dysregulated following sargramostim treatment compared with controls (Fig. 2a). Using the mummichog algorithm,16 significant alterations in the tryptophan pathway (P < 0.002) were found with links to inflammation, immunological tolerance, and Treg function (Fig. 2b). To delineate those alterations, targeted metabolomics for the tryptophan pathway yielded levels of three key metabolites from sargramostim-treated patients that differed significantly from pre-treatment or post-treatment levels and levels from placebo-treated patients (Fig. 2c, d). L-Kynurenine concentration from the sargramostim group was 2.3-fold and 3.0-fold higher than those from pre-treated or placebo-treated patients, respectively; and quinolinic acid concentration was 2.4-fold higher than those from either pre-treated or placebo-treated patients. Both metabolites returned to baseline levels by 4 weeks after treatment. In contrast, serotonin levels from sargramostim-treated patients diminished 2.5-fold (P = 0.03) and 2.2-fold (P = 0.054) from levels of pre-treated and placebo-treated patients.Fig. 2 Metabolomic analyses from serum from sargramostim-treated or placebo-treated PD patients. a Global metabolomic analysis was performed on serum samples from the entire PD patient cohort. Comparisons of metabolic features were performed between sample groups specifically focusing on pre-treatment groups (visits 1 and 2) vs. on treatment groups (visits 5 and 7), and between treatment groups either on placebo or on sargramostim. A cloud plot illustrating the dysregulated features between pre-treatment and on-treatment are overlaid on the chromatographic runs. Each circle represents a dysregulated feature at a specific retention time (x-axis) and mass-to-charge ratio (y-axis). The diameter of each feature represents the fold change and the color intensity represents the significance (P-value). Six-hundred metabolites were found to be upregulated or downregulated in PD patients treated with sargramostim compared with their respective pre-treated controls. b The 600 dysregulated metabolites were cross-referenced with known metabolic pathways, analyzed by Welch’s t-test to identify dysregulated features, and altered metabolic pathways were determined by using the mummichog algorithm which maps possible metabolite matches and targets local enrichments that reflect true pathway activity opposed to false matches that otherwise are randomly distributed.16 The plot shows the statistical relevance of dysregulated metabolic pathways for sargramostim-treated patients compared with pre-treated controls as the −log10\nP-value as the function of the weighted mean percentage overlap of metabolite pathway identifying the tryptophan metabolism as a key pathway affected by treatment with sargramostim. The greater color intensity represents a more significant P-value and the diameter represents the percent coverage of metabolites found to be dysregulated in a given pathway. c Targeted metabolomic analyses of serum from PD patients at pretreatment (Pre, visits 1 and 2), at weeks 4 and 8 during treatment (On, visits 5 and 7), and at 4 weeks after treatment cessation (Post, visit 8). When available, results from the same patient, but at different visits were averaged and binned into pre-treatment or on-treatment. Medians and IQRs of tryptophan metabolite concentrations were determined from patients randomized into placebo group (blue bars) (n\nPre = 8, n\nOn = 9, n\nPost = 8) or sargramostim group (red bars) (n\nPre = 9, n\nOn = 7, n\nPost = 5). Comparison of median metabolite concentrations between pre-treatment, on-treatment, and post-treatment samples and between samples from placebo-treated and sargramostim-treated groups were determined by Mann–Whitney U tests. Of the 18 targeted metabolites from the tryptophan pathway, many were below the calibration curve or detection limits, or were unchanged. d Metabolomic analysis showed concentrations of kynurenine and quinolinic acid upregulated, whereas serotonin was downregulated within the tryptophan pathway. Enzymes in the tryptophan pathway include TPH2, tryptophan hydroxylase-2; 5HTD, 5-hydroxytryptophan decarboxylase; TDO, tryptophan 2,3-dioxygenase; IDO, indoleamine 2,3-dioxygenase; AFMID, arylformamidase; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; and HAO, 3-hydroxyanthranilate 3,4-dioxygenase\n\n\n\n\nSargramostim induces a complex pattern of immune activation in CD4+CD25− T cells\nThe presence of both pro-inflammatory and anti-inflammatory mediators in sargramostim-treated patients posed putative mechanisms for relationships between immunity and clinical outcomes. Thus, the effects of sargramostim on T cell gene expression were examined in a random subset of patients. Five placebo-treated and four sargramostim-treated PD patients were evaluated. CD4+ T cells were isolated from whole blood and depleted of CD25+ Tregs and Teffs. RNA from CD4+CD25− T cells was isolated and cDNA made for quantitative real-time Polymerase Chain Reaction (PCR) to determine expressed genes linked to Th1, Th2, Th17, and Treg. Expectedly, sargramostim induced a significant upregulation of mRNAs associated with T cell proliferation (GATA4, IL2, HOXA10, and KIF2C) (Fig. 3a). Moreover, with increased Treg numbers and function induced by sargramostim, anti-inflammatory PPARG, LRRC32, FOSL1, IL1R2, IL13RA1, NR4A3, and GFI1 gene expression was increased. Sargramostim upregulated expression of genes associated with pro-inflammatory Th1 and Th17 effectors (IL17RE, IL17A, RORC, IL18, and EOMES), despite a demonstrated lack of increased Teff numbers in sargramostim-treated patients. These data demonstrate a complex pro-inflammatory and anti-inflammatory gene expression and network interaction by T cells poised for Treg or Teff differentiation during sargramostim therapy (Fig. 3b).Fig. 3 T cell gene expression analyses of T cells from sargramostim-treated or placebo-treated PD patients. a Significant increase or decrease in expression of genes by CD4+CD25− T cells from PD patients treated with sargramostim compared with placebo. Genes are divided into those associated with Th1 and Th17 (Pro-inflammatory), Th2 and Tregs (Anti-inflammatory), and general T cell proliferation and differentiation (Non-associated). Significant differences are indicated by a heat map. The map ranged from 40-fold increase (red) to 40-fold decrease (green). b Ingenuity pathway analyses performed on upregulated or downregulated genes to identify putative network associations involved in hematological development and T cell function. Genes and mediators that are upregulated are shaded red with the darker shades indicating more upregulation; shades of green denote downregulation; and nodes in white represent putative-associated function\n\n\n\n\nSargramostim improves motor and cortical motor activities\nThis study was not powered to evaluate clinical outcomes on motor activity, nor was it a long-term study. Thus, the clinical assessments are exploratory in nature. We monitored UPDRS III scores over 2 months (visits 1–3) prior to treatment initiation to establish a pre-treatment baseline. Comparison to baseline, treatment did not appear to worsen motor scores (Fig. 4a). However, while inter-patient variation precluded meaningful statistical analysis of the total UPDRS III scores per visit for each patient, the relative low profiles of scores over visitation from sargramostim-treated patients suggested an overall improvement compared with the placebo group. To confirm that observation, we assessed for each patient, changes from mean baseline score at each visit during pre-treatment (visits 1–3), during treatment (visits 4–7), and after cessation of treatment (visit 8). We showed that compared with placebo treatment, sargramostim showed effects associated with treatment, visit, and treatment-by-visit (Fig. 4b). A transient reduction in score of the placebo group at visit 3 was seen which returned to baseline during the study course. For the sargramostim group, scores diminished over the 8-week treatment period by a mean of 3.1 ± 0.5 (P = 0.004) compared with 0.5 ± 1.3 (P = 0.78) for the placebo group. The greatest changes in UPDRS III scores were found at 6 and 8 weeks (visits 6 and 7) on sargramostim (Fig. 4b). Score changes returned to baseline by 4 weeks (visit 8) after treatment cessation.Fig. 4 PD patients were randomized to receive placebo or sargramostim. a UPDRS III scores of each individual patient were assessed at 0, 4, and 8 weeks (visits 1–3) before treatment (Pre-Treatment); at 2, 4, 6, and 8 weeks (visits 4–7) during treatment (Placebo or Sargramostim); and at 4 weeks (visit 8) after cessation (Placebo or Sargramostim Post-Treatment). Higher scores represent more severe motor symptoms. b Changes from baseline UPDRS III scores were determined at each visit for placebo-treated and sargramostim-treated patients using the mean scores of visits 1–3 for each patient as baseline from which to normalize. Changes in scores from each randomized treatment group were normally distributed and homoscedastic by Levene’s test (P > 0.05). Factorial ANOVA showed an effect of randomized treatment group (P = 0.05) and marginal effects of visit (P = 0.07) and treatment-by-time (P = 0.05). Fisher’s least significant difference post hoc tests were used to determine pairwise differences between placebo and sargramostim treatment at each visit. UPDRS III scores for placebo group diminished at start of treatment, which may reflect a placebo effect, but returned to baseline during the study course. c MEG assessment of beta ERD in PD patients. Paired sample t-test comparison of beta ERD activity at baseline (pre-treatment) and during treatment for the group of PD patients receiving sargramostim. Significant increases in beta ERD amplitudes are noted for the pre-treated patient composite in the left and right precentral gyri, right premotor cortex, and SMA (top panel). Increases in beta ERD activity from pre-treatment to sargramostim-treatment are shown for individual patients. Compared with pre-treatment, the left precentral gyrus showed a significant effect of visit [F(2, 9) = 8.869, P = 0.007] and visit-by-group interaction [F(2, 9) = 6.04, P = 0.022], which was quadratic [F(1, 10) = 10.772, P = 0.008]. The right precentral gyrus also showed a visit-by-group interaction [F(2, 9) = 3.321, P = 0.06], which also was quadratic [F(1, 10) = 5.447, P = 0.04]. The right premotor cortex showed a marginal effect of visit [F(2, 9) = 3.050, P = 0.07] and the effect was quadratic [F(1, 10) = 6.124, P = 0.03]. Quadratic interactions were explained as beta ERD amplitudes that increase from pretreatment baseline while on sargramostim and return to baseline levels after termination of treatment\n\n\n\n\nWe also used magnetoencephalography (MEG) as a biomarker for motor function. Our previous studies showed decreased beta event-related desynchronization (ERD) amplitudes in the motor hand-knob region of the precentral gyrus in PD patients compared with healthy controls.17, 18 In this study, we found no significant differences in beta ERD activity in the placebo group (baseline vs. on-treatment or on-treatment vs. treatment termination) in any motor-related region. In the sargramostim group, beta ERD amplitudes significantly increased from baseline to on-treatment in the left precentral gyrus, right precentral gyrus, right premotor cortex, and supplementary motor area (SMA) (P < 0.005, cluster-corrected; Fig. 4c, top panel). Notably, each patient exhibited increased beta ERD amplitudes on sargramostim when compared with baseline measures (Fig. 4c, bottom panel).\n\nDiscussion\nSargramostim was generally well-tolerated by PD patients. Overall frequencies of patients experiencing adverse events between sargramostim and placebo groups were not significantly different and were confined to increased injection site reactions, increased WBC counts, or upper torso or extremity bone pain; all reported adverse effects to therapy with sargramostim.13 Mild side effects such as extremity or torso pain representing bone marrow replenishment are associated with these types of constitutional symptoms such as bone and muscle ache or minor pain and are helped by nonsteroidal drugs or acetaminophen. Sternal or non-cardiac chest pain or “chest tightening” was rated as moderate to severe symptoms. These torso and extremity pains described for sargramostim are readily distinguishable from the common types of pain experience by patients with PD.19 Meta-analysis of pain in PD for 18 studies and 15,636 cases revealed a mean prevalence of pain in 58.36% of patients that included a relatively wide variation ranging from 11 to 83%.20 The wide variability in prevalence is due, in part, to lack of (1) visibility to the physician, (2) reporting by the patient, (3) treatment priority if reported, and (4) attention to sufficient objective signs that are disregarded.21 Distribution of pain types in PD includes musculoskeletal pain (48%), dystonic pain (26%), neuropathic pain (13%), and non-localized/central pain (8%).20, 22 Musculoskeletal pain originates from rigidity or skeletal deformity due to Parkinsonism. Dystonic pain is related to involuntary muscular contractions and is often associated with anti-Parkinsonian medication. Neuropathic pain is thought to be related to the central dopaminergic deficit. Non-localized/central neuropathic pain is a burning pain with spontaneous onset and periods of exacerbation. It is poorly localized and is more intense on the affected side.\n\nSargramostim treatment was associated with significantly transformed immune function and sera metabolites. Treatment-associated improvements in UPDRS III scores and cortical motor electrical activities paralleled one another as well as the immune biomarker changes. These findings are supported by a number of prior animal and clinical studies for PD2, 3, 5, 11, 14, 23–25 and other neurodegenerative disorders.26–28 Indeed and as in this report, it is now well known that control of pro-inflammatory signals by Tregs is a focus of clinical research activities to develop novel neurotherapeutics for a range of neuroinflammatory and neurodegenerative disorders. By suppression of T cell proliferation and production of a broad range of anti-inflammatory cytokines that includes, for example, interleukin-10 and transforming growth factor-β, Tregs can in fact ameliorate the pathobiology and clinical signs and symptoms of progressive neuronal degeneration. Moreover an imbalance of effector and regulatory immune cells can affect systemic inflammatory and metabolic processes and predict disease progression. This has been previously uncovered for a spectrum of disorders beyond PD that include Alzheimer’s disease, stroke, and amyotrophic lateral sclerosis.26, 27, 29–31 Thus, restoring or increasing Treg frequency and enhancing their suppressive activities by immune modulators such as sargramostim is believed to be a novel yet promising approach for treating these disorders.\n\nFor PD, N-α-syn, the dominant protein in dopaminergic neuronal inclusions, induces potent neurotoxic Teffs that can accelerate nigrostriatal degeneration.5, 32 Transformation of Teff responses by Tregs leads to significant dopaminergic neuronal protection3 and proportional changes in numbers of interferon-γ-producing Th1, IL-4-producing Th2, and CD4+CD25+ T cells are linked to the tempo of disease progression.14, 33 However, whether sargramostim-induced changes in T cell profiles could affect PD pathobiology remained unknown. This possibility is bolstered by drug correction of PD-associated Treg dysfunction and improved motor task outcomes.\n\nParallel observations as shown herein were reported in a spectrum of autoimmune and neurodegenerative diseases.30, 34–37 Thus for Tregs, defining the tempo, phenotype, and functional role in disease is bolstered by their known abilities to attenuate microglial inflammatory responses and ongoing neurodegeneration. Gene array evaluations showed that sargramostim had multiple effects on peripheral T cells, supporting the idea that an established neuroinflammatory environment was required to affect a regulatory cell profile. This unique idea of cooperative pro-inflammatory and anti-inflammatory neuroprotection was supported by our metabolomics studies. Here, tryptophan pathway dominance was associated with flow cytometric Treg activity. While 5-hydroxytryptophan is converted to serotonin,38 tryptophan is, in parallel, converted to kynurenine by indoleamine-pyrrole 2,3-dioxygenase (IDO), and kynurenine is further metabolized to quinolinic acid.39–41 IDO expression and kynurenine production induce Treg formation. Notably, IDO can be increased by both anti-inflammatory and pro-inflammatory cytokines42 as is seen in Parkinsonian patients.43\n\n\nThe clinical observations are exploratory in nature in this study with a relatively small sample size and short duration. It does seem clear, however, that sargramostim does not worsen motor function. The suggestion of improved motor function, along with the apparent biomarker responses measured by MEG, is intriguing and will need to be evaluated more fully in larger studies.\n\nTaken together, our findings show that sargramostim treatment in PD is feasible and reasonably well-tolerated. They support the idea that the effects of sargramostim on T cell polarity change depending on the brain-immune environment. The induction of Tregs, modulation of Teffs, and overall improvement of immune modulatory activities by Tregs is a novel pathway that corrects aberrant immune responses during PD. The therapeutic potential of sargramostim awaits larger confirmatory studies.\n\nMaterials and methods\nParticipants and study design\nThis single-center, randomized, double-blind, phase 1 clinical trial was performed at the University of Nebraska Medical Center (UNMC), Omaha, NE, USA, to test the safety and tolerability of sargramostim for PD. Twenty-two PD patients were recruited from the metropolitan area between 24 September 2013 and 14 August 2015 for an intention to treat design. The final follow-up was 8 January 2016. Inclusion criteria were 35–85 years of age at onset with symptoms of asymmetric bradykinesia and resting tremor or muscle rigidity persisting for ≥3 years, and ≤stage 4 by Hoehn and Yahr disease scale.44 Seventeen age-matched non-Parkinsonian subjects served as non-PD controls. Exclusion criteria included multiple system atrophy, corticobasal degeneration, unilateral Parkinsonism lasting of >3 years, prior head injury, stroke, brain surgery, a PD family history of >1 blood relative with the disease, mental illness, cognitive impairment, and autoimmune, systemic inflammatory or hematologic disease. Patients were excluded if administered lithium, neuroleptics, immune modulatory treatment within 90 days of study onset or had allergies to benzyl alcohol, colony-stimulating factors, yeast-derived products, or ferrous metal body implants. The trial was completed as designed.\n\nStandard protocol approvals, registrations, and patient consents\nThe research protocol (IRB Protocol 487-12) was approved by the UNMC Institutional Review Board. Patients were identified and referred to the Clinical Research Center (CRC) by their primary physician. Written informed consent was obtained from all participants by CRC personnel following the Good Clinical Practice guidelines. This trial is registered at ClinicalTrials.gov, Identifier: NCT01882010.\n\nRandomization and masking\nPD patients were randomized at a 1:1 ratio to receive sargramostim or placebo. Randomization and assignment was performed at the time of accrual since participant enrollment was staggered. Patients were block randomized by the study statistician in randomly chosen blocks of 2 or 4, and the list was given to the trial pharmacist for drug and placebo preparation. The pharmacist prepared identical syringes of sargramostim and placebo to provide doses necessary for 2 weeks. Examining physicians and medical personnel were blinded to treatment assignment. Randomly generated three-letter codes identified patient blood samples and were used throughout the study to monitor processing, analyses, and safety.\n\nProcedures\nThis trial was performed in two parts. In the first part, non-PD subjects and PD patients had three pre-treatment appointments at −8, −4, and 0 weeks (visits 1–3) to determine a comparative baseline; after which, the non-PD subjects were dismissed. In the second part beginning at visit 3, 20 PD patients administered by subcutaneous self-injection either sargramostim at 6 μg/kg/day (10 patients) or a placebo of weight-based volume of saline/day (10 patients) for 56 days.15 PD patients continued with appointments every 2 weeks for 2 months (visits 4–7), and a follow-up visit (visit 8) 4 weeks after treatment cessation. All enrolled patients that received at least one treatment dose were analyzed for primary outcomes. Blood samples, physical examinations, and unified Parkinson’s disease rating scale, part III (UPDRS III) evaluations were performed during each visit. The primary neurologist performed UPDRS III assessments in a double-blinded fashion in the “ON” state. All but one patient maintained their individually prescribed anti-Parkinsonian regimen throughout the study.\n\nStudy drug was withheld for ~24 h prior to each visit. WBC counts with differentials, immunocyte (leukocyte) numbers, and sera metabolites were monitored. Immunocytes obtained from peripheral blood were stained with fluorochrome-conjugated monoclonal antibodies against CD4 (FITC or AF700), CD127 (PerCP-Cy5.5), CD25 (PE), FOXP3/Scurfin (AF647), CD152/CTLA-4 (APC), CD95/FAS/Apo1 (APC), CD39/ENTPD1 (APC), Integrin β7 (APC) (all BD Biosciences, San Jose, CA) and CD49d/Integrin α4 (PE-Cy7) (BioLegend Inc., San Diego, CA). Isotype-matched antibodies were negative controls. For FOXP3 and iCTLA4, cells were permeabilized with BD Cytofix/Cytoperm kit (BD Biosciences). Cell surface and intracellular T cell epitopes were examined with an LSR II flow cytometer (BD Biosciences). For Treg function, CD4+CD127loCD25hi cells were enriched by negative selection using a Complete Kit for Human CD4+CD127loCD25+ and CD4+CD127lo enrichment (Stemcell Technologies, Vancouver, Canada). CD25+ Tregs were 89 ± 8% (mean ± SD) of the enriched CD4+ cell population. Naïve CD4+CD25− responder T cells (Tresps) were isolated from healthy donors for proliferation tests.14 For T cell gene expression, CD4+CD25− T cells were enriched by MACS column negative selection (Miltenyi Biotech, San Diego, CA). mRNA was isolated from Treg-depleted and Teff-depleted CD4+ T cells, reverse transcribed, and cDNA subjected to real-time PCR using the RT2 Profiler Human T Helper Cell Differentiation array (Qiagen, Valencia, CA). Fold-changes were determined using the RT2 Profiler PCR array data analysis software version 3.5.\n\nSerum was submitted for antibody and metabolomic profiling. IgG or IgM anti-sargramostim antibodies were screened by enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation and titers confirmed by endpoint ELISA and by neutralization tests using a luciferase-reported functional assay. For metabolomics, sera was extracted in acetonitrile/methanol, resuspended in acetonitrile/water, sonicated, and analyzed.45 Targeted metabolomic analyses employed reverse phase high-performance liquid chromatograph-mass spectrometry.\n\nRecent reports suggest the utility of MEG in monitoring neurophysiological activity, motor dysfunction, and therapeutic outcomes in PD and other neurodegenerative disorders.17, 18, 46–49 For these studies, cortical neurophysiological activity during a right-hand movement task was recorded using high-density MEG.17, 18 Activity was recorded at 4 weeks (visit 2) before treatment, 8 weeks (visit 7) after initiation of treatment, and 4 weeks (visit 8) after drug cessation. Participants were recorded after 12 h off Parkinsonian medications. MEG data were individually corrected for head motion and noise.50 Artifact-free epochs were transformed into the time-frequency domain, and the movement-related beta ERD response (14–24 Hz, −300 ms to 200 ms, movement onset = 0 ms) was imaged using beamforming.18, 51, 52\n\n\nOutcomes\nThe primary study endpoint was safety as monitored by complete blood counts with differentials, blood metabolic panels, adverse events, and UPDRS III scores. Hematologic panels were performed by the hospital’s clinical laboratory. Regimen-blinded neurologists recorded examinations of blood pressure, pulse, skin, lung, liver, heart, and abdomen. UPDRS III scores were measured in the “ON” state. Physical examinations were unremarkable in all cases. Adverse events were recorded in treatment diaries by patients and by physicians who scored (1–3) events by severity as (1) mild, (2) moderate, or (3) severe, and scored (1–5) whether the event was (1) unrelated, (2) unlikely, (3) possible, (4) probable, or (5) definitely related to the study drug. Mild events cause minimal discomfort or concern, may require minimal or no treatment, and do not interfere with daily activities. Moderate events were defined as discomfort, inconvenience, or concerns ameliorated with simple therapeutic measures. Severe adverse events were defined as discomfort or incapacitation that may require prescription drug therapy, other treatments, or interventions. Secondary outcomes were MEG neurophysiological activities, immune phenotype and function, and serum metabolomics.\n\nStatistical analyses\nSample size estimates of 16 PD and 16 non-PD controls for baseline observations (−8 weeks) were determined to provide 80% power using a two-sided Wilcoxon test assuming normal distribution and a mean percent change from baseline of 0.80. This yielded an overall mean immune response score of 6.32 (SD of 0.97).14 To assess sargramostim effects on immune responses, a sample size of eight in each treatment group was determined to provide a 95% CI equal to the sample mean ± 0.81. All participants that received at least one treatment dose were included. Statistical analyses were conducted using SAS/STAT software (version 9.2 or higher; SAS Institute Inc., Cary, NC) or Statistica (version 9, StatSoft, Tulsa, OK), with tests being two-sided. The frequency of adverse events was compared between groups using the Fisher’s exact test (Prism, v6, GraphPad Software, Inc., La Jolla, CA). CD4+ T cell subsets, function, gene expression, antibody titers, and metabolites were compared between treatment groups using a two independent samples t-test or Mann–Whitney U test. For MEG, a 2 × 3 mixed-model ANOVA statistical evaluation used peak voxels from each significant brain region with treatment as a between-subjects factor and visit as a repeated factor. For Treg function, percentage inhibition of proliferation was determined at each Treg:Tresp ratio as slope and axis-intercepts by linear regression (Prism, v6). A data and safety monitoring board of UNMC physicians and faculty advised study investigators.\n\nElectronic supplementary material\n\nSupplementary Fig. S1\n\n \nSupplementary Fig. S2\n\n \nSupplementary Fig. S3\n\n \n\n\nElectronic supplementary material\nSupplementary Information accompanies the paper on the npj Parkinson’s Disease website (doi:10.1038/s41531-017-0013-5).\n\nAcknowledgements\nThe authors would like to acknowledge and thank the many participants who supported the trial. We are greatly appreciative of Jonathon Beck, Pharm D, Director of Investigational Drug Services, who graciously served as the clinical pharmacist. We are grateful to Amy Hellman, MD, Kenneth A. Follett, MD, PhD, and the nursing and support staff at the Great Plains Center for Clinical and Translational Research who provided outstanding insights and suggestions relevant to the study design and patient care. We thank the Flow Cytometry Research Facility for expert analysis of T cell subsets and proliferation assays. We thank Max J. Kurz, PhD, Director of the Sensorimotor Learning Laboratory, for his supportive work and cross-validating work regarding the objective biomechanical measures of motor skills. We especially thank members of our data safety and monitoring board that included Philip Bierman, MD, Christopher Kratochvil, MD, and R. Gregory Bociek, MD, for their frequent reading, discussion, and advisement for these works. We thank Ms. Robin Taylor for critical reading and advisement of the manuscript. We most graciously thank the many patients and control subjects that participated in this trial and contributed their time, commitment, personal sacrifice, dedication, and tireless efforts to ensure its outcomes. Lastly, we thank the past and present Chancellors of the University of Nebraska Medical Center Harold Maurer, MD, and Jeffrey Gold, MD, for their untiring support and commitment to this work. This study was funded by Sanofi US; by community support received through the Carol Swarts Neuroscience Research Laboratory, the Frances and Louis Blumkin Foundation, and the Nebraska Neuroscience Alliance Endowed Funds; by the Vice-Chancellor’s Office of the UNMC for Core Facility Developments, and by DoD grant uni and NIH grants R01-NS034139 and R01-NS070190.\n\nAuthor contributions\nContributions by listed authors include literature searches (H.E.G., K.E.O., C.R.S., K.A.E., M.F., G.S., T.W.W., and R.L.M.), study design (H.E.G., Y.Z., K.E.O., C.R.S., K.A.E., E.H.-G., L.L., J.L.M., E.F., T.W.W., C.P., and R.L.M.), study execution (H.E.G., Y.Z., P.S., K.E.O., C.R.S., D.H., B.L.D.S., Y.L., K.A.E., E.H.-G., L.L., E.F., G.S., T.W.W., C.P., and R.L.M.), data collection (H.E.G., Y.Z., P.S., K.E.O., C.R.S., D.H., B.L.D.S., Y.L., K.A.E., E.H.-G., L.L., E.F., G.S., T.W.W., C.P., and R.L.M.), analyses of data sets (H.E.G., Y.Z., P.S., K.E.O., C.R.S., B.L.D.S., Y.L., K.A.E., E.H.-G., J.L.M., M.F., E.F., G.S., T.W.W., and R.L.M.), interpretation of data analyses (H.E.G., P.S., K.E.O., C.R.S., D.H., B.L.D.S., Y.L., K.A.E., E.H.-G., J.L.M., M.F., E.F., G.S., T.W.W., and R.L.M.), preparation of figures (H.E.G., K.E.O., C.R.S., E.H.-G., M.F., G.S., T.W.W., and R.L.M.), and writing the manuscript (H.E.G., K.E.O., C.R.S., D.G.S., E.H.-G., J.L.M., M.F., E.F., G.S., T.W.W., and R.L.M.). H.E.G. and R.L.M. serve as guarantors for the manuscript’s data.\n\nCompeting interests\nAll authors indicate no competing interests.\n==== Refs\nReferences\n1. Olanow CW Stern MB Sethi K The scientific and clinical basis for the treatment of Parkinson disease Neurology 2009 72 S1 S136 10.1212/WNL.0b013e3181a1d44c 19470958 \n2. Mosley RL Hutter-Saunders JA Stone DK Gendelman HE Inflammation and adaptive immunity in Parkinson’s disease Cold Spring Harb. Perspect. Med. 2012 2 a009381 10.1101/cshperspect.a009381 22315722 \n3. Reynolds AD Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease J. Immunol. 2010 184 2261 2271 10.4049/jimmunol.0901852 20118279 \n4. Shameli A A critical role for alpha-synuclein in development and function of T lymphocytes Immunobiology 2016 221 333 340 10.1016/j.imbio.2015.10.002 26517968 \n5. 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Lacan G Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease J. Neurosci. Res. 2013 91 1292 1302 10.1002/jnr.23253 23907992 \n25. Chung ES Bee venom phospholipase A2, a novel Foxp3+ regulatory T cell inducer, protects dopaminergic neurons by modulating neuroinflammatory responses in a mouse model of Parkinson’s disease J. Immunol. 2015 195 4853 4860 10.4049/jimmunol.1500386 26453752 \n26. Henkel JS Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival EMBO Mol. Med. 2013 5 64 79 10.1002/emmm.201201544 23143995 \n27. Liesz A Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke J. Neurosci. 2013 33 17350 17362 10.1523/JNEUROSCI.4901-12.2013 24174668 \n28. Raj T Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes Science 2014 344 519 523 10.1126/science.1249547 24786080 \n29. Dansokho C Regulatory T cells delay disease progression in Alzheimer-like pathology Brain 2016 139 1237 1251 10.1093/brain/awv408 26912648 \n30. Ye M Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease J. Neuroinflammation 2016 13 10 10.1186/s12974-016-0476-z 26772975 \n31. Spitz C Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential Cell. Mol. Life Sci. 2016 73 901 922 10.1007/s00018-015-2080-2 26518635 \n32. Brochard V Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease J. Clin. Invest. 2009 119 182 192 19104149 \n33. Baba Y Kuroiwa A Uitti RJ Wszolek ZK Yamada T Alterations of T-lymphocyte populations in Parkinson disease Parkinsonism Relat. 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Hill M IDO expands human CD4+ CD25high regulatory T cells by promoting maturation of LPS-treated dendritic cells Eur. J. Immunol. 2007 37 3054 3062 10.1002/eji.200636704 17948274 \n40. Kwidzinski E Bechmann I IDO expression in the brain: a double-edged sword J. Mol. Med. 2007 85 1351 1359 10.1007/s00109-007-0229-7 17594069 \n41. Heyes MP Chen CY Major EO Saito K Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types Biochem. J. 1997 326 351 356 10.1042/bj3260351 9291104 \n42. Munn DH Mellor AL Indoleamine 2,3 dioxygenase and metabolic control of immune responses Trends Immunol. 2013 34 137 143 10.1016/j.it.2012.10.001 23103127 \n43. Brodacki B Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic Parkinsonism Neurosci. Lett. 2008 441 158 162 10.1016/j.neulet.2008.06.040 18582534 \n44. Goetz CG Movement disorder society task force report on the hoehn and yahr staging scale: status and recommendations Mov. Disord. 2004 19 1020 1028 10.1002/mds.20213 15372591 \n45. Deguchi H Acylcarnitines are anticoagulants that inhibit factor Xa and are reduced in venous thrombosis, based on metabolomics data Blood 2015 126 1595 1600 10.1182/blood-2015-03-636761 26175037 \n46. Wiesman AI Quiet connections: reduced fronto-temporal connectivity in nondemented Parkinson’s disease during working memory encoding Hum. Brain Mapp. 2016 37 3224 3235 10.1002/hbm.23237 27151624 \n47. Oswal A Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson’s disease Brain 2016 139 1482 1496 10.1093/brain/aww048 27017189 \n48. van Wijk BC Subthalamic nucleus phase-amplitude coupling correlates with motor impairment in Parkinson’s disease Clin. Neurophysiol. 2016 127 2010 2019 10.1016/j.clinph.2016.01.015 26971483 \n49. te Woerd ES Oostenveld R Bloem BR de Lange FP Praamstra P Effects of rhythmic stimulus presentation on oscillatory brain activity: the physiology of cueing in Parkinson’s disease Neuroimage Clin. 2015 9 300 309 10.1016/j.nicl.2015.08.018 26509117 \n50. Taulu S Simola J Spatiotemporal signal space separation method for rejecting nearby interference in MEG measurements Phys. Med. Biol. 2006 51 1759 1768 10.1088/0031-9155/51/7/008 16552102 \n51. Van Veen BD van Drongelen W Yuchtman M Suzuki A Localization of brain electrical activity via linearly constrained minimum variance spatial filtering IEEE Trans. Biomed. Eng. 1997 44 867 880 10.1109/10.623056 9282479 \n52. Hillebrand A Singh KD Holliday IE Furlong PL Barnes GR A new approach to neuroimaging with magnetoencephalography Hum. Brain Mapp. 2005 25 199 211 10.1002/hbm.20102 15846771\n\n",
"fulltext_license": "CC BY",
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"journal": "NPJ Parkinson's disease",
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"medline_ta": "NPJ Parkinsons Dis",
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"title": "Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson's disease trial.",
"title_normalized": "evaluation of the safety and immunomodulatory effects of sargramostim in a randomized double blind phase 1 clinical parkinson s disease trial"
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"abstract": "Patients with phospholipase A2 receptor (PLA2R)-associated membranous nephropathy and stage 4 or 5 chronic kidney disease are at high risk of end-stage kidney disease. In recent years, rituximab (RTX) emerged as a safe and efficient treatment for patients with PLA2R-associated membranous nephropathy. Whether its use is also appropriate in patients with an estimated glomerular filtration rate <30 ml/min per 1.73 m2 has not been investigated.\nWe retrospectively reviewed characteristics and outcome of 13 patients with PLA2R-associated membranous nephropathy and stage 4 or 5 chronic kidney disease who received a total of 14 consecutive RTX treatments from January 2012 to March 2018. The treatment regimen consisted of either 2 weekly infusions of 375 mg/m2 or 2 RTX infusions of 1 g/d two weeks apart. When needed, the regimen was repeated to achieve immunological remission.\nThe mean estimated glomerular filtration rate, serum albumin level, and urinary protein level at the first RTX infusion were 18 ± 7 ml/min per 1.73 m2, 25.2 ± 5.4 g/l, and 13.2 ± 7.5 g/d, respectively, with all patients being tested positive for serum PLA2R antibodies. Ten treatment courses led to an increase in estimated glomerular filtration rate and remission of nephrotic syndrome after a median follow-up of 40.8 months (interquartile range, 14.8-46.8). Conversely, 4 RTX treatments were unsuccessful, with patients requiring chronic hemodialysis within 1 year. The urinary albumin-to-protein ratio before treatment was predictive of renal response. Immunological remission occurred after 11 treatment courses and was associated with clinical response in 10 of 11 patients. Three patients experienced severe adverse events.\nRTX seems effective and reasonably safe in PLA2R-associated membranous nephropathy with stage 4 or 5 chronic kidney disease. Immunological remission is associated with a good clinical outcome.",
"affiliations": "Department of Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France.;Department of Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France.;Nephrology Day Hospital, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France.;Department of Immunology, Assistance Publique - Hôpitaux de Paris, Hôpital Saint Antoine, Paris, France.;Department of Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France.;Department of Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France.;Department of Nephrology, Centre Hospitalier Laennec de Creil, Creil, France.;Sorbonne Université, Université Pierre-et-Marie-Curie Paris 06, Paris, France.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Nephrology Day Hospital, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France.;Nephrology Day Hospital, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France.",
"authors": "Hanset|Nicolas|N|;Esteve|Emmanuel|E|;Plaisier|Emmanuelle|E|;Johanet|Catherine|C|;Michel|Pierre-Antoine|PA|;Boffa|Jean-Jacques|JJ|;Fievet|Patrick|P|;Mesnard|Laurent|L|;Morelle|Johann|J|;Ronco|Pierre|P|;Dahan|Karine|K|",
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"doi": "10.1016/j.ekir.2019.12.006",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249 Elsevier \n\nS2468-0249(19)31591-8\n10.1016/j.ekir.2019.12.006\nClinical Research\nRituximab in Patients With Phospholipase A2 Receptor–Associated Membranous Nephropathy and Severe CKD\nHanset Nicolas nicolas.hanset@gmail.com123∗ Esteve Emmanuel 145 Plaisier Emmanuelle 3456 Johanet Catherine 7 Michel Pierre-Antoine 1 Boffa Jean-Jacques 1 Fievet Patrick 8 Mesnard Laurent 459 Morelle Johann 2 Ronco Pierre 3456 Dahan Karine 36 1 Department of Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France\n2 Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium\n3 Nephrology Day Hospital, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France\n4 Sorbonne Université, Université Pierre-et-Marie-Curie Paris 06, Paris, France\n5 Unité Mixte de Recherche_S 1155, Institut National de la Santé Et de la Recherche Médicale, Paris, France\n6 Centre de Référence Maladies Rares “Syndrome Néphrotique Idiopathique de l’Enfant et de l’Adulte,” Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France\n7 Department of Immunology, Assistance Publique - Hôpitaux de Paris, Hôpital Saint Antoine, Paris, France\n8 Department of Nephrology, Centre Hospitalier Laennec de Creil, Creil, France\n9 Department of Intensive Care Nephrology and Kidney Transplantation, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France\n∗ Correspondence: Nicolas Hanset, Department of Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. nicolas.hanset@gmail.com\n20 12 2019 \n3 2020 \n20 12 2019 \n5 3 331 338\n20 9 2019 3 12 2019 9 12 2019 © 2019 International Society of Nephrology. Published by Elsevier Inc.2019International Society of NephrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nPatients with phospholipase A2 receptor (PLA2R)–associated membranous nephropathy and stage 4 or 5 chronic kidney disease are at high risk of end-stage kidney disease. In recent years, rituximab (RTX) emerged as a safe and efficient treatment for patients with PLA2R-associated membranous nephropathy. Whether its use is also appropriate in patients with an estimated glomerular filtration rate <30 ml/min per 1.73 m2 has not been investigated.\n\nMethods\nWe retrospectively reviewed characteristics and outcome of 13 patients with PLA2R-associated membranous nephropathy and stage 4 or 5 chronic kidney disease who received a total of 14 consecutive RTX treatments from January 2012 to March 2018. The treatment regimen consisted of either 2 weekly infusions of 375 mg/m2 or 2 RTX infusions of 1 g/d two weeks apart. When needed, the regimen was repeated to achieve immunological remission.\n\nResults\nThe mean estimated glomerular filtration rate, serum albumin level, and urinary protein level at the first RTX infusion were 18 ± 7 ml/min per 1.73 m2, 25.2 ± 5.4 g/l, and 13.2 ± 7.5 g/d, respectively, with all patients being tested positive for serum PLA2R antibodies. Ten treatment courses led to an increase in estimated glomerular filtration rate and remission of nephrotic syndrome after a median follow-up of 40.8 months (interquartile range, 14.8–46.8). Conversely, 4 RTX treatments were unsuccessful, with patients requiring chronic hemodialysis within 1 year. The urinary albumin-to-protein ratio before treatment was predictive of renal response. Immunological remission occurred after 11 treatment courses and was associated with clinical response in 10 of 11 patients. Three patients experienced severe adverse events.\n\nConclusion\nRTX seems effective and reasonably safe in PLA2R-associated membranous nephropathy with stage 4 or 5 chronic kidney disease. Immunological remission is associated with a good clinical outcome.\n\nGraphical abstract\nKeywords\nCKDESKDimmunosuppressive treatmentmembranous nephropathyPLA2Rrituximab\n==== Body\nMembranous nephropathy (MN) is one of the leading causes of nephrotic syndrome (NS) in adults. Primary MN is associated with a significant risk of developing end-stage kidney disease.1 Until recently, the urinary protein level was the main biomarker to assess severity and guide therapeutic indications to prevent the development of kidney failure, while it remains to date the primary criterion of remission definitions.2,3\n\nA giant leap in the understanding of the pathophysiological mechanisms of primary MN was made in 2009 with the discovery of autoantibodies directed against a podocyte surface antigen, the M-type phospholipase A2 receptor (PLA2R), found in 70% of adult patients with primary MN. After binding to a conformational epitope of PLA2R, those antibodies (Abs) induce characteristic in situ immune complex deposits.4 Accumulating evidence suggests that high titers of anti-PLA2R antibodies (PLA2R Abs) are correlated with clinical evolution, response to treatment, and renal survival.5, 6, 7, 8, 9 Therefore, agents that specifically interfere with B-cell Ab production are the first step toward selective therapy for primary MN. Several retrospective studies and the 2 randomized controlled trials showed that rituximab (RTX) efficiently and safely induced PLA2R Ab depletion and that the decrease in PLA2R Ab titer preceded remission of proteinuria by several months,10,11 suggesting Ab depletion as the first therapeutic target.12\n\nThe use of immunosuppressive therapies, including alkylating agent-corticosteroid combination, calcineurin inhibitors, or RTX, is widely recognized as beneficial in selected patients, that is, high-risk patients with NS and either no improvement over a 6-month period of antiproteinuric therapy, life-threatening symptoms, or progressive kidney failure.3 Nonetheless, latest treatment algorithms, in line with 2012 Kidney Disease: Improving Global Outcomes guidelines, do not suggest using such treatments in patients with an estimated glomerular filtration rate (eGFR) <30 ml/min per 1.73 m2, because of a potential reversal of the risk-benefit balance resulting from both poor efficiency and higher toxicity.12\n\nMoreover, despite the lack of demonstrated impact of the eGFR level on RTX pharmacokinetics and tolerance, patients with an eGFR <30 ml/min per 1.73 m2 were excluded from the 2 RTX-based randomized controlled trials (eGFR ≥ 45 ml/min per 1.73 m2 in the GEMRITUX trial and ≥ 40 ml/min per 1.73 m2 in the MEmbranous Nephropathy Trial Of Rituximab [MENTOR]), and conflicting data exist on whether efficacy could be preserved in altered kidney function.13, 14, 15\n\nIn the present study, we analyzed the efficacy and tolerance of RTX in a cohort of 13 consecutive patients presenting with PLA2R MN and receiving therapy at stage 4 or 5 chronic kidney disease (CKD).\n\nMethods\nPatients and Study Design\nWe retrospectively identified 13 consecutive patients treated with RTX for PLA2R MN and an eGFR <30 ml/min per 1.73 m2 from January 2012 to February 2019. Diagnosis of PLA2R MN was based on histopathological criteria, or positive PLA2R Ab testing when kidney biopsy was contraindicated. Twelve patients were screened at the Nephrology and Dialysis Department of Tenon Hospital, Paris, France, and 1 patient at the Nephrology Department of Saint-Luc Academic Hospital, Brussels, Belgium. Eight patients received RTX for the initial flare, 4 patients were treated for relapse, and 1 for both the initial flare and relapse for a total of 14 treatment courses. Previous treatments, for example, renin-angiotensin system blockade or immunosuppressive therapies, were not regarded as study criteria. The treatment regimen consisted of either 2 weekly RTX doses of 375 mg/m2 or 2 RTX infusions of 1 g/d two weeks apart. Treatment was repeated if needed to achieve PLA2R Ab complete depletion.\n\nPatients’ clinical and biological data at diagnosis, at RTX initiation, and at last follow-up (i.e., last evaluation, last day before hemodialysis, or last follow-up before relapse, as appropriate) were retrospectively recorded. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation as the standardized serum creatinine method was not available for all patients. Serum PLA2R Abs were measured by enzyme-linked immunosorbent assay, using a 14 relative units (RU)/ml positivity threshold, and by indirect immunofluorescence assay (both tests developed by EUROIMMUN AG, Lübeck, Germany). Features suggestive of chronic kidney injury were reviewed from the patient’s records and included histological data (i.e., glomerular sclerosis and tubulointerstitial fibrosis), kidney size, and urinary protein composition (i.e., urinary albumin-to-protein ratio, IgG-to-creatinine ratio, alpha-1 microglobulin-to-creatinine ratio, retinol binding protein-to-creatinine ratio).\n\nOutcomes after RTX treatment were defined as follows: responders referred to patients with partial remission or complete remission according to Kidney Disease: Improving Global Outcomes guidelines (i.e., urinary protein level between 0.3 and 3.5 g/d with a decrease by at least 50% from the initial value and <0.3 g/d, respectively) and stabilization or improvement in eGFR3; nonresponders referred to patients with no complete remission or partial remission and a decline in eGFR. Relapse was defined by the reappearance of proteinuria and circulating PLA2R Abs after partial remission/complete remission and PLA2R Abs negativation. Immunological remission was defined by negative tests for circulating PLA2R Ab detection.\n\nEach patient was fully informed of risks and benefits of the use of RTX at low eGFR.\n\nStatistical Analysis\nNormality was confirmed using the D’Agostino-Pearson and Shapiro-Wilk normality tests, allowing the comparison of means using 2-tailed paired t tests and the comparison of odds ratios using the 2-sided Fisher exact test. All statistics were performed using GraphPad Prism version 5.00 for Windows (GraphPad Software, La Jolla, CA). Normally distributed variables are expressed as means ± SD, and nonnormally distributed variables are expressed as median (interquartile range [IQR]).\n\nResults\nPatients’ Characteristics at Diagnosis and at RTX Infusion\nBaseline characteristics at diagnosis are reported in Table 1. The mean age was 60.7 ± 9.7 years, and the male/female ratio was 2.2. The mean serum creatinine level was 165 ± 90 μmol/l, and the mean eGFR was 48 ± 24 ml/min per 1.73 m2, with 4 patients having an eGFR between 15 and 30 ml/min per 1.73 m2. The mean urinary protein level was 7.9 ± 5.1 g/d and serum albumin level 21.9 ± 6.7 g/l, and the 10 patients tested at diagnosis had circulating PLA2R Abs detected by either enzyme-linked immunosorbent assay, indirect immunofluorescence assay, or both. Three patients were not tested for circulating PLA2R Abs at diagnosis but were serologically positive during follow-up.Table 1 Patients’ characteristics at diagnosis, RTX initiation, and last follow-up\n\nS. no.\tSex\tAge (yr)\tHistology\tMorphology\tsCreat level (μmol/l)\teGFR (ml/min per 1.73 m2)\tuProt level (g/d)\tsAlb level (g/l)\tPLA2R Abs level\tTime (mo)\tPrevious IS treatmenta\tRTX retreatment\t\nS Glom (%)\tIFTA (%)\tTime (mo) : Bx to RTX\tKidney size (left/right; cm)\tTime (mo) : imaging to RTX\tELISA (RU/ml)\tIIFT\tDiagn. to RTX\tRTX to last FU\t\n1b,c\tM\t63\tNA\t40\t104\t11.2/9.4\t2\t103\t996\t1112\t67\t5\t4\t13\t17\t6.8\t16\t24\t34\t718\t85\tNeg\t1/1000\t1/100\tNeg\t104.4 (1.5d)\t5.1\t\t1\t\n2e\tF\t58\t–\t–\t–\tNA\t–\t160\t340\t218\t30\t13\t20\t14\t11\t0.9\t25\t30\t39\tNA\t84\tNeg\tNA\t1/200\tNeg\t35.4\t13.9\t\t1\t\n3c\tF\t66\t0\t33\t18\t11.2/11.2\t1\t128\t202\t603\t47\t27\t7\t7\t12\t11\t20\t26\t30\tNA\t602\tNeg\t1/100\t1/1000\t1/50\t18.4\t11.9\tRTX\t4\t\n4e\tM\t65\t–\t–\t–\tx/13.2\t26\t180\t258\t205\t35\t23\t28\t12\t12\t0.6\t16\t29\t41\tNA\t97\tNeg\t1/1000\t1/500\tNeg\t36.6\t20.6\t\t1\t\n5e\tF\t62\t–\t–\t–\t9.0/x\t1\t370\t408\t201\t11\t10\t21\t6\t25\t0.7\t17\t19\t40\tNA\tNA\tNeg\t1/200\t1/500\tNeg\t2.0\t52.2\t\t0\t\n6\tM\t73\t18\t20\t4\t9.3/9.6\t4\t290\t250\t338\t19\t21\t15\t19\t9\t0.9\t23\t29\t39\t36\t34\tNeg\t1/100\t1/100\tNeg\t3.6\t41.2\t\t0\t\n6b,f\t\t\t18\t20\t51\tNA\t–\t\t310\t300\t\t18\t18\t\t2\t1.7\t\t34\t39\t\t34\tNeg\t\t1/50\tNeg\t47.0 (3.0d)\t15.1\tRTX\t0\t\n7b,g\tM\t59\t0\t10\t46\tNA\t–\t105\t460\t185\t67\t11\t34\t5\t16\t0.5\t26\t19\t38\tNA\t130\tNeg\tNA\t1/500\tNeg\t45.9 (12.0d )\t42.8\tCy-Cs\t0\t\n8b\tM\t34\t0\t10\t128\t10.0/10.0\t1\t130\t321\t140\t56\t18\t47\t2\t7\t0.3\t14\t29\t38\t270\tNA\tNeg\t1/1000\t1/100\tNeg\t128.0 (7.0d )\t40.4\tRTX; C\t0\t\n9b\tM\t58\t9\t10\t45\t10.4/10.8\t30\t100\t230\t146\t71\t27\t43\t4\t14\t0.3\t15\t22\t37\tNA\t81\tNeg\t1/1000\t1/1000\tNeg\t45.0 (8.45d)\t83.1\tRTX; C\t0\t\n10c\tM\t61\t0\t0\t17\t10.9/11.3\t3\t85\t415\t459\t84\t14\t11\t4\t28\t31\t33\t17\t12\tNA\tNA\tNA\t1/1000\t1/1000\t1/500\t17.1\t4.8\tCy-Cs; C\t1\t\n11c\tF\t72\t11\t5\t9\t10.3/11.0\t1\t120\t366\t453\t41\t11\t8\t3\t20\t6\t21\t19\t9\tNA\tNA\tNA\tNA\t1/500\t1/500\t9.0\t8.3\t\t1\t\n12\tM\t64\t23\t20\t6\t10.3/11.0\t6\t273\t270\t231\t20\t22\t26\t8\t8\t0.2\t24\t25\t41\tNA\tNA\tNeg\t1/200\t1/200\tNeg\t6.2\t45.0\t\t0\t\n13b\tM\t54\t23\t10\t348\t10.0/10.3\t2\t97\t186\t155\t74\t29\t35\t6\t4\t0.5\t35\t31\t43\tNA\t52\tNeg\tNA\tNA\tNA\t348.0 (13.0d)\t11.0\t\t0\t\nAbs, antibodies; Bx, biopsy; C, cyclosporine; Cy-Cs, cyclophosphamide-corticosteroid combination therapy; Diagn., diagnosis; eGFR, estimated glomerular filtration rate (according to the Modification of Diet in Renal Disease formula); ELISA, enzyme-linked immunosorbent assay; F, female; FU, follow-up; IFTA, interstitial fibrosis and tubular atrophy; IIFT, indirect immunofluorescence testing; IS, immunosuppressive; M, male; NA, not available; Neg, negative; PLA2R, phospholipase A2 receptor; RTX, rituximab; sAlb, serum albumin; sCreat, serum creatinine; S Glom, sclerotic glomeruli; uProt, urinary protein; x, absent or severely atrophic kidney.\n\nAge is reported at diagnosis; sCreat, eGFR, uProt, sAlb, and PLA2R Ab levels are reported at diagnosis, rituximab, and last follow-up in each parameter column.\n\na A detailed description of previous treatments is provided in Supplementary Figure S1.\n\nb Patients treated for relapse.\n\nc Definitive hemodialysis.\n\nd Delay from relapse.\n\ne Insufficient or no histological data (small sample size in patient 2 and serology-based diagnosis in patients 4 and 5 owing to solitary kidney).\n\nf Patient treated twice with rituximab (see Supplementary Figure S1).\n\ng Transient hemodialysis (started 5 mo after rituximab treatment and discontinued after 4 mo).\n\n\n\nHistological features indicative of chronicity, that is, glomerular sclerosis and tubulointerstitial fibrosis, respectively, involved mean rates of 10% ± 10% and 16% ± 12% of the kidney biopsy sample at diagnosis. The median delay between kidney biopsy and the first RTX infusion was 17.1 months (IQR, 8.45–45.9 months). Renal imaging, performed in a median time of 2.0 months (IQR, 1.0–5.0 months) before RTX therapy, showed a mean kidney size of 10.5 ± 0.9 cm.\n\nAs depicted in Supplementary Figure S1, 6 patients previously received immunosuppressive treatments. In those with previous RTX treatment experience, the time interval since the last dose was at least 16 months.\n\nPatients’ characteristics at RTX initiation are detailed in Table 1. The estimated GFR was below 30 ml/min per 1.73 m2 in all patients, with a mean eGFR of 18 ± 7 ml/min per 1.73 m2. Six RTX courses (43%) were administered in patients who had reached stage 5 CKD. The median serum albumin and urinary protein levels were 25.2 ± 5.4 g/l and 13.2 ± 7.5 g/d, respectively. Serum PLA2R Abs were tested positive in all patients. RTX treatment was administered in a median delay of 12.0 months (IQR, 6.2–18.4 months) after diagnosis and of 7.0 months (IQR, 3.0–8.5 months) after relapse.\n\nOne patient (patient 6) received RTX twice, the first course at diagnosis and the second course at relapse 4 years later. Both episodes occurred with eGFR < 30 ml/min per 1.73 m2 and were separated by a period of complete clinical and immunological remission with eGFR stabilization (up to 22 ml/min per 1.73 m2). Altogether, 14 treatment courses for a total of 13 patients were recorded.\n\nClinical and Immunological Outcomes\nClinical and immunological outcome after RTX infusion is detailed in Table 1 and Figures 1 and 2.Figure 1 Evolution of estimated glomerular filtration rate (eGFR), urinary protein level, serum albumin level, and phospholipase A2 receptor (PLA2R) antibodies at diagnosis (Diagn.), at the first rituximab (RTX) infusion, and at last follow-up (FU). Green lines represent responders (R); and red lines represent nonresponders (NR). +, patient with positive serology; −, patient with negative serology; NA, patient not tested.\n\nFigure 2 Differential evolution of estimated glomerular filtration rate (eGFR), urinary protein level, and serum albumin level at diagnosis (Diagn.), at the first rituximab (RTX) infusion, and at last follow-up (FU) among responders (a) and nonresponders (b). Data presented as mean ± SD. ns, P > 0.03.\n\n\n\nOverall, over a median follow-up period of 17.8 months (IQR, 10.3–43.3 months), the mean eGFR, urinary protein level, and serum albumin level evolved from 18 ± 7 to 23 ± 13 ml/min, from 13 ± 7 to 0.8 ± 8 g/d, and from 25 ± 5 to 34 ± 11 g/l, respectively.\n\nTen treatment courses performed in 9 patients resulted in a renal response (responder group), while 4 (29%) patients had a progression to end-stage kidney disease (nonresponder group) within 1 year.\n\nIn the responder group, the mean eGFR increased from 19 ± 6 to 29 ± 11 ml/min per 1.73 m2 (P = 0.01), the serum albumin level increased from 26.7 ± 5.2 to 39.5 ± 1.8 g/l (P < 0.001), and the urinary protein level decreased from 10.8 ± 6.6 to 0.7 ± 0.4 g/d (P < 0.001) from RTX initiation to last follow-up (median duration, 40.8 months [IQR, 14.8–46.8 months]). Importantly, all the 10 successful treatment courses were associated with complete immunological remission. Two patients received a second course of RTX (administered at 7 and 10 months after the first dose) to reach complete immunological remission.\n\nIn the 4 nonresponders patients, the median time between RTX initiation and the start of hemodialysis was 6.7 months (IQR, 4.9–11.0 months). Three patients never reached immunological remission despite repeated RTX infusions (2 courses in 2 patients and 4 in 1 patient). The fourth patient, treated at an eGFR of 5 ml/min per 1.73 m2, reached immunological remission after RTX treatment but required chronic hemodialysis. All the nonresponders were treated with a high-dose regimen (i.e., 2 RTX infusions of 1 g/d two weeks apart).16\n\nAs shown in Table 2, at RTX initiation, the urinary protein composition was found to be predictive of renal response. Indeed, the mean urinary albumin-to-protein ratio differed significantly between nonresponders and responders (55.2% ± 3.9% and 74.3% ± 8.2%, respectively; P < 0.001) and was predictive of outcome using a 60% threshold (odds ratio, 189.0; 95% confidence interval, 3.2–11110; P = 0.001). Moreover, the urinary IgG level and urinary IgG-to-protein ratio were both significantly higher in nonresponders versus responders (157.6 ± 68.0 mg/mmol vs. 63.3 ± 40.4 mg/mmol; P = 0.01 and 11.3% ± 2.9% vs. 6.7% ± 2.8%; P = 0.02, respectively). By contrast, no significant difference was observed between the 2 groups regarding age, eGFR, serum albumin level, urinary protein level, urinary albumin level, urinary alpha-1 microglobulin level, and urinary retinol binding protein level at RTX initiation.Table 2 Comparison between responders and nonresponders at rituximab initiation\n\nCharacteristic\tResponders\tNonresponders\tP\t\nAge (yr)\t65.6 ± 10.2\t68.6 ± 4.1\t0.58\t\neGFR (ml/min per 1.73 m2)\t19.2 ± 6.5\t14.2 ± 9.3\t0.27\t\nSerum albumin level (g/l)\t26.7 ± 5,2\t21.5 ± 4.2\t0.10\t\nUrinary protein level (g/d)\t10.8 ± 6.6\t19.2 ± 6.7\t0.05\t\nUrinary albumin level (g/d)\t7.1 ± 2.4\t6.9 ± 2.3\t0.88\t\nUrinary albumin-to-protein ratio (%)\t74.3 ± 8.2\t55.2 ± 3.9\t<0.001\t\nUrinary IgG level (mg/mmol)\t63.3 ± 40.4\t157.6 ± 68.0\t0.01\t\nUrinary IgG-to-protein ratio (%)\t6.7 ± 2.8\t11.3 ± 2.9\t0.02\t\nUrinary α1M level (mg/mmol)\t23.0 ± 14.3\t30.6 ± 20.3\t0.46\t\nUrinary α1M-to-protein ratio (%)\t3.1 ± 1.8\t2.3 ± 1.3\t0.48\t\nUrinary RBP level (mg/mmol)\t11.1 ± 7.2\t14.0 ± 5.6\t0.50\t\nUrinary RBP-to-protein ratio (%)\t1.5 ± 1.5\t1.0 ± 0.1\t0.54\t\nα1M, alpha-1 microglobulin; eGFR, estimated glomerular filtration rate (according to the Modification of Diet in Renal Disease formula); RBP, retinol binding protein.\n\nData presented as mean ± SD.\n\n\n\nImmunological remission after RTX treatment was the second parameter associated with renal response (odds ratio, 49.0; 95% confidence interval, 1.6–1502; P = 0.01).\n\nOf the 6 patients with stage 5 CKD before treatment, 3 (50%) had a progression to end-stage kidney disease, including 1 with complete immunological response. The remaining 3 patients reached complete immunological response, had improved kidney function, and were dialysis-free at last follow-up (median, 60 months [IQR, 36–65 months]). One of them required only transient hemodialysis but recovered 5 months after immunological remission.\n\nSafety\nFour severe adverse events requiring hospitalization were reported in 3 patients for a total of 52 RTX infusions. Patient 1 underwent infectious chronic obstructive pulmonary disease exacerbation 1 month after the first RTX infusion. Patient 6 presented with prostatitis 1 month after the first course of RTX and underwent severe laryngospasm and bronchospasm after the first RTX injection of the second course, warranting treatment withdrawal, but achieved immunological remission. Patient 10 presented with Clostridium difficile colitis and giardiasis 1 week after the first RTX administration. No death related to treatment was reported; 1 patient died of status epilepticus of unknown origin 1 year after the last RTX injection.\n\nDiscussion\nManagement of MN has been a source of controversy for decades. The course of the disease is highly heterogeneous and poorly predictable with, on the one side, spontaneous remission occurring in at least one-third of the patients and, on the other side, progression to end-stage kidney disease within 10 years in 35% of the cases.17 Therefore, except when MN is associated with life-threatening complications or rapid decline in kidney function, current international guidelines still recommend the use of conventional antiproteinuric treatments during the first 6 months of the disease to avoid potentially toxic immunosuppressive treatments in patients who may reach spontaneous remission. In the case of persistent NS after this period, guidelines recommend starting immunosuppressive therapy such as corticosteroid-cytotoxic agent combination or calcineurin inhibitors.3,18 For more than a decade, RTX emerged as an effective alternative option to those agents, as suggested in several retrospective studies19, 20, 21, 22 and further confirmed by 2 randomized controlled trials: the French trial GEMRITUX and the North-American trial MENTOR.10,11\n\nFollowing Kidney Disease: Improving Global Outcomes Controversies Conference on glomerular diseases, an international consortium recently proposed that only small kidneys, and not eGFR level, should restrain the use of immunosuppressive agents.23 Indeed, as suggested by previous studies, immunosuppressive therapy, such as alkylating agent-corticosteroid regimen or cyclosporine, could still be efficient in patients with severely deteriorating kidney function, although encumbered by substantial relapse rate and serious treatment-related adverse events in half of cases.24,25\n\nTo date, there is no study evaluating the efficacy of RTX in patients with MN and an eGFR <30 ml/min per 1.73 m2, apart from 2 reported cases with stage 4 CKD.14,15\n\nIn our study, 13 consecutive patients with PLA2R MN and stage 4 or 5 CKD were treated with RTX for a total of 14 treatment courses. The characteristics of patients at diagnosis in this cohort were in accordance with the previously described classical PLA2R MN, that is, predominantly middle-aged men with initial NS and positive PLA2R serology, except that 4 patients had stage 4 CKD at diagnosis.\n\nAfter RTX treatment, renal outcome was favorable in 10 cases. In all these responders, treatment induced remission of the NS, stabilization or improvement in eGFR, and disappearance of circulating PLA2R Abs. By contrast, none of the 4 nonresponders achieved NS remission, with only 1 patient reaching immunological remission. The follow-up duration was markedly shorter in nonresponders (6.7 months) owing to rapid progression to dialysis as compared with the follow-up duration of 40.8 months in responders.\n\nHigh levels of low- and/or high-molecular-weight urinary proteins other than albumin were demonstrated to be predictive of interstitial fibrosis in CKD and renal prognosis in MN.26,27 In our study, the urinary albumin-to-protein ratio and urinary IgG level before RTX initiation were identified as predictive factors of renal response. Although low-molecular-weight protein excretion was found to be markedly increased in both groups, indicating chronic tubulointerstitial damage, higher levels of urinary IgG suggest more severe alterations in the glomerular filtration barrier in nonresponders, presumably indicative of irreversible glomerular scarring in those patients.\n\nPLA2R Abs disappearance after RTX treatment was associated with clinical remission, suggesting that immunological remission (i.e., complete depletion of PLA2R Abs by both enzyme-linked immunosorbent assay and indirect immunofluorescence assay) may be a surrogate for renal survival after RTX treatment in stage 4 or 5 CKD and PLA2R MN.\n\nThe therapeutic protocol consisted of courses of RTX (either two weekly 375 mg/m2 infusion or 2 RTX infusions of 1 g/d 2 weeks apart), repeated as needed to achieve complete immunological remission. In 6 patients, RTX treatment was repeated after 3 to 24 months. We previously showed that RTX was less efficacious at 2 weekly doses of 375 mg/m2 than was cyclophosphamide/steroid combination therapy in inducing immunological remission in patients with high levels of PLA2R Abs.28 In addition, we previously reported that a second course of RTX had a dramatic effect on PLA2R Abs titers, with all but 1 patient reaching complete immunological remission and all retreated patients showing clinical remission.29 The retreatment regimen was stimulated by the GEMRITUX trial where PLA2R Abs levels were markedly decreased as early as 3 months after RTX but not followed by further decrease at 6 months, suggesting an early loss of efficacy of the monoclonal Ab. A previous study showed that RTX blood levels were lower and the B-cell depletion significantly shorter in patients with MN than in patients with rheumatoid arthritis or antineutrophil cytoplasmic antibody vasculitis.21 Urinary loss of the monoclonal Ab in the context of NS likely accounts for those changes in RTX pharmacokinetics and potentially underpowers RTX regimen commonly used in MN.\n\nAfter a total of 52 RTX infusions, severe adverse events (grade 3+) included 3 infections requiring hospitalization (6% of all treatments) and 1 life-threatening infusion reaction (2%), but no death. RTX toxicity does not seem dramatically enhanced by the severity of renal dysfunction as compared to patients with preserved kidney function.10,11 In the GEMRITUX trial, which included younger patients (53 years old vs. 66 years old), 1 severe infection was reported for a total of 74 infusions (1.3%) without an infusion reaction. In the MENTOR trial, a trend toward the lower incidence of severe and serious all-cause adverse events was observed with RTX compared with cyclosporine.11 Even if the rate of severe adverse events appears higher in the population of patients with advanced CKD, RTX remains safer than cyclophosphamide-corticosteroid combination therapy with a 3- to 4-fold lower hazard rate of any kind of adverse events.30\n\nWe acknowledge some limitations due to the retrospective uncontrolled design of our study, the small number of patients, and the heterogeneity of previous therapeutic lines. Clinicopathological correlations could not be analyzed because of the large time intervals between kidney biopsy performed at diagnosis and at RTX therapy.\n\nIn conclusion, RTX therapy in PLA2R MN seems to achieve effective clinical and immunological remission in patients with severely altered kidney function, with acceptable safety. The urinary albumin-to-protein ratio appears to be predictive of renal response to treatment and may represent a valuable and readily available tool to guide therapeutic decision. Given the association of complete immunological remission and clinical remission in our study and the already known association between PLA2R serology, disease progression,5, 6, 7, 8 and posttransplant recurrence,9 we suggest that PLA2R Abs complete depletion should be a therapeutic target in MN. To allow the translation of these findings into routine clinical practice, our observations will need to be confirmed in larger prospective cohorts of patients.\n\nDisclosure\nNH reports travel grants from Fresenius Kabi and Fresenius Medical Care (outside the submitted work). KD reports consulting fees from Alexion, Amicus Therapeutics, and Boehringer Ingelheim (outside the submitted work). J-JB reports research grants from Roche (outside the submitted work). JM reports speaker honoraria from Baxter Healthcare and Fresenius Medical Care, travel grants from Sanofi Genzyme, and research grants from Baxter Healthcare and Alexion (outside the submitted work). All the other authors declared no competing interests.\n\nSupplementary Material\nSupplementary File (PDF)\n \n\nAcknowledgments\nAn abstract of the present work has been presented as a poster at the 56th ERA-EDTA Congress, June 14, 2019, Budapest, Hungary.\n\nAuthor Contributions\nNH and KD contributed to study design and data collection. EE was responsible for statistical analysis. CJ provided phospholipase A2 receptor antibody measurements. NH, KD, and JM drafted the manuscript under the supervision of J-JB, EP, and PR. All authors contributed to the interpretation of the results and approved the final version of the paper.\n\nSupplementary File (PDF)\n\nFigure S1. Detailed description of previous immunosuppressive treatments.\n==== Refs\nReferences\n1 Ponticelli C. Glassock R.J. Glomerular diseases: membranous nephropathy—a modern view Clin J Am Soc Nephrol 9 2014 609 616 23813556 \n2 Schieppati A. Mosconi L. Perna A. Prognosis of untreated patients with idiopathic membranous nephropathy N Engl J Med 8 1993 85 89 \n3 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group KDIGO clinical practice guideline for glomerulonephritis Kidney Int suppl 2 2012 186 197 \n4 Beck L.H. Bonegio R.G. Lambeau G. M-type phospholipase A2 receptor as target antigen in idiopathic MN N Engl Med J 361 2009 11 21 \n5 Ruggenenti P. Debiec H. Ruggiero B. Antiphospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy J Am Soc Nephrol 26 2015 2545 2558 25804280 \n6 Hofstra J.M. Beck L.H. Beck D.M. Anti-phospholipase A2 receptor antibodies correlate with clinical status in primary membranous nephropathy Clin J Am Soc Nephrol 6 2011 1286 1291 21474589 \n7 Hoxha E. Thiele I. Zahner G. Phospholipase A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy J Am Soc Nephrol 25 2014 1357 1366 24610926 \n8 Bech A.P. Hofstra J.M. Brenchley P.E. Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy Clin J Am Soc Nephrol 7 2014 1386 1392 \n9 Gupta G. Fattah H. Ayalon R. Pre-transplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post-kidney transplantation Clin Transplant 30 2016 461 469 26854647 \n10 Dahan K. Debiec H. Plaisier E. Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up J Am Soc Nephrol 28 2017 348 358 27352623 \n11 Fervenza F.C. Appel G.B. Barbour S.J. Rituximab or cyclosporine in the treatment of membranous nephropathy N Engl J Med 381 2019 36 46 31269364 \n12 De Vriese A.S. Glassock R.J. Nath K.A. A proposal for a serology-based approach to membranous nephropathy J Am Soc Nephrol 28 2017 421 430 27777266 \n13 Ruggenenti P. Chiurchiu C. Abbate M. Rituximab for idiopathic membranous nephropathy: who can benefit? Clin J Am Soc Nephrol 1 2006 738 748 17699281 \n14 Dahan K. Gillion V. Johanet C. The role of PLA2R antibody in treatment of membranous nephropathy Kidney Int Rep 3 2018 498 501 29725656 \n15 Zhou X.J. Zhou F.D. Wang S.X. A case report of remission of refractory membranous nephropathy progressing to stage 4 chronic kidney disease using low-dose rituximab: a long-term follow-up Medicine (Baltimore) 97 2018 e11184 29924035 \n16 Seitz-Polski B. Dahan K. Debiec H. High-dose rituximab and early remission in PLA2R1-related membranous nephropathy Clin J Am Soc Nephrol 14 2019 1173 1182 31340979 \n17 Couser W.G. Primary membranous nephropathy Clin J Am Soc Nephrol 12 2017 983 997 28550082 \n18 Hofstra J.M. Fervenza F.C. Wetzels J.F. 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Membranous Nephropathy Study Group Cytotoxic therapy for membranous nephropathy and renal insufficiency: improved renal survival but high relapse rate Nephrol Dial Transplant 19 2004 1142 1148 14993502 \n25 Cattran D.C. Greenwood C. Ritchie S. et al Canadian Glomerulonephritis Study Group A controlled trial of cyclosporine in patients with progressive membranous nephropathy Kidney Int 47 1995 1130 1135 7783410 \n26 Pallet N. Chauvet S. Chassé J.F. Urinary retinol binding protein is a marker of extent of interstitial kidney fibrosis PLoS One 9 2014 e84708 \n27 van den Brand J. Hofstra J.M. Wetzetls J.F. Low-molecular-weight proteins as prognostic markers in idiopathic membranous nephropathy Clin J Am Soc Nephrol 6 2011 2846 2853 22157712 \n28 van de Logt A.E. Dahan K. Rousseau A. Immunological remission in PLA2R-antibody–associated membranous nephropathy: cyclophosphamide versus rituximab Kidney Int 93 2018 1016 1017 \n29 Dahan K. Johannet C. Esteve E. Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibody Kidney Int 95 2019 233 234 \n30 Van den Brand J. Ruggenenti P. Chianca A. Safety of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy J Am Soc Nephrol 28 2017 2729 2737 28487395\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "5(3)",
"journal": "Kidney international reports",
"keywords": "CKD; ESKD; PLA2R; immunosuppressive treatment; membranous nephropathy; rituximab",
"medline_ta": "Kidney Int Rep",
"mesh_terms": null,
"nlm_unique_id": "101684752",
"other_id": null,
"pages": "331-338",
"pmc": null,
"pmid": "32154454",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": "27777266;7783410;28487395;28550082;29924035;24416268;30665568;26854647;8510707;25804280;29571438;23820815;30606419;25035272;14993502;19571279;24610926;22157712;23813556;17943078;31269364;17699281;17702725;29725656;12354476;31340979;27352623;21474589;22822077",
"title": "Rituximab in Patients With Phospholipase A2 Receptor-Associated Membranous Nephropathy and Severe CKD.",
"title_normalized": "rituximab in patients with phospholipase a2 receptor associated membranous nephropathy and severe ckd"
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"abstract": "Hepatitis C virus (HCV) reactivation in patients receiving cancer treatment has been reported in retrospective studies. We sought to determine prospectively the incidence, predictors, and clinical significance of HCV reactivation during cancer treatment. HCV-infected patients receiving cancer treatment at our institution between November 2012 and July 2016 were studied. Reactivation was defined as an increase in HCV-RNA ≥1 log10 IU/mL over baseline and hepatitis flare as an increase in alanine aminotransferase to ≥3 times the upper limit of normal. One hundred patients were studied, 50 with hematologic malignancies and 50 with solid tumors. Reactivation occurred in 23 (23%) patients, including 18 (36%) patients with hematologic malignancies and 5 (10%) patients with solid tumors. In univariate analysis, patients with reactivation were more likely than those without reactivation to have prolonged lymphopenia (median, 95 versus 22 days; P = 0.01) and to have received rituximab (44% versus 9%; P < 0.0001), bendamustine (22% versus 0%; P < 0.001), high-dose steroids (57% versus 21%; P = 0.001), or purine analogs (22% versus 5%; P = 0.02). Rituximab (odds ratio = 9.52; P = 0.001), and high-dose steroids (odds ratio = 5.05; P = 0.01) retained significance in multivariable analysis. Of the 23 patients with reactivation, 10 (43%) had hepatitis flare. No patient with reactivation experienced liver failure or liver-related death within 36 weeks after initiation of cancer treatment. Fourteen patients with hepatitis flare, six of whom had reactivation, required discontinuation or dose reduction of cancer treatment.\n\n\n\nHCV reactivation occurred in 23% of HCV-infected patients receiving cancer treatment, and most had an unremarkable clinical course. However, reactivation can affect the cancer treatment plan. Our findings suggest that HCV infection should not contraindicate cancer therapy and infected patients should have access to multiple cancer treatments with close monitoring while receiving regimens associated with HCV reactivation. (Hepatology 2018;67:36-47).",
"affiliations": "Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.",
"authors": "Torres|Harrys A|HA|;Hosry|Jeff|J|;Mahale|Parag|P|;Economides|Minas P|MP|;Jiang|Ying|Y|;Lok|Anna S|AS|",
"chemical_list": "D012367:RNA, Viral",
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"doi": "10.1002/hep.29344",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D015897:Comorbidity; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012367:RNA, Viral; D018570:Risk Assessment; D016896:Treatment Outcome; D014775:Virus Activation",
"nlm_unique_id": "8302946",
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"pages": "36-47",
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"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "27730654;22871500;12200395;20350666;7910911;1983820;20823454;26256943;7475549;25765930;26171595;8639788;10408633;8020662;18378948;27181544;23591280;23703931;25527793;14576438;26495859;27443290;27427916;25517948;22586011;28683174;7666104;8538348;24879981;8194562;22271089;16481640;24944464;22138369;21306291;8037177;1653063;17712791;12107020;19725787;10576374;9107080;9740089;21811782;26202751;16107965;15710990",
"title": "Hepatitis C virus reactivation in patients receiving cancer treatment: A prospective observational study.",
"title_normalized": "hepatitis c virus reactivation in patients receiving cancer treatment a prospective observational study"
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"abstract": "BACKGROUND\nIntra-abdominal abscesses associated with Crohn's disease (CD) can rarely occur in the psoas muscle. An intra-psoas abscess is prone to misdiagnosis because its location mimics other diseases, like appendicitis and diverticulitis [1].\n\n\nMETHODS\nWe present the case of a 25-year-old female with an 11-year history of CD, previously well-controlled on Remicade, who presented with right lower quadrant (RLQ) pain and CT findings of a right psoas abscess initially attributed to perforated appendicitis. Two percutaneous drainages pre-ileocecectomy, laparoscopic ileocecectomy, three percutaneous drainages post-ileocolectomy, and evidence of a recurrent abscess prompted diagnostic laparoscopy. The abscess was unroofed and debrided. A flap of omentum was used to fill the abscess cavity. A comprehensive literature search was performed using the terms 'Crohn's abscess', 'intra-psoas abscess', and 'omental patches' in Medline and on PubMed.\n\n\nCONCLUSIONS\nWe attribute the abscess' recurrence to possible epithelialization of the abscess cavity. Intra-psoas abscesses, albeit rare, are a known manifestation of CD. Percutaneous drainage is the initial standard of care, although diagnosis can be difficult given its association with several diseases, which can delay definitive treatment. We summarize a recently proposed and agreed upon treatment scheme for the management of the Crohn's patient with an abdominal abscess. We also propose the novel technique of omental packing in abscess management.\n\n\nCONCLUSIONS\nClinician awareness must be heightened for perforating CD in the setting of abscess refractory to either multiple drainage procedures, although care should be taken to individualize treatment to each CD patient who presents with an abdominal abscess.",
"affiliations": "Department of Surgery, University of Illinois College of Medicine Peoria, 624 NE Glen Oak, Peoria, IL 61603, United States.;Department of Surgery, University of Illinois College of Medicine Peoria, 624 NE Glen Oak, Peoria, IL 61603, United States.;Department of Surgery, University of Illinois College of Medicine Peoria, 624 NE Glen Oak, Peoria, IL 61603, United States.;Department of Surgery, University of Illinois College of Medicine Peoria, 624 NE Glen Oak, Peoria, IL 61603, United States. Electronic address: jonathan.nitz@gmail.com.;Department of Surgery, University of Illinois College of Medicine Peoria, 624 NE Glen Oak, Peoria, IL 61603, United States.",
"authors": "Gao|David|D|;Medina|Melissa G|MG|;Alameer|Ehab|E|;Nitz|Jonathan|J|;Tsoraides|Steven|S|",
"chemical_list": null,
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"doi": "10.1016/j.ijscr.2019.11.021",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(19)30655-810.1016/j.ijscr.2019.11.021ArticleA case report on delayed diagnosis of perforated Crohn’s disease with recurrent intra-psoas abscess requiring omental patch Gao David Medina Melissa G. Alameer Ehab Nitz Jonathan jonathan.nitz@gmail.com⁎Tsoraides Steven Department of Surgery, University of Illinois College of Medicine Peoria, 624 NE Glen Oak, Peoria, IL 61603, United States⁎ Corresponding author. jonathan.nitz@gmail.com19 11 2019 2019 19 11 2019 65 325 328 26 10 2019 7 11 2019 © 2019 The Authors2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Psoas muscle abscess can be misdiagnosed for other etiologies, such as appendicitis.\n\n• The current management of a Crohn’s abscess is debated.\n\n• Treatment is influenced by abscess size, quantity of abscesses, and response to antibiotics and/or percutaneous drainage.\n\n• Our patient, whose abscess was managed with the novel use of omental packing, has not demonstrated abscess recurrence.\n\n\n\nIntroduction\nIntra-abdominal abscesses associated with Crohn’s disease (CD) can rarely occur in the psoas muscle. An intra-psoas abscess is prone to misdiagnosis because its location mimics other diseases, like appendicitis and diverticulitis [1].\n\nPresentation of case\nWe present the case of a 25-year-old female with an 11-year history of CD, previously well-controlled on Remicade, who presented with right lower quadrant (RLQ) pain and CT findings of a right psoas abscess initially attributed to perforated appendicitis. Two percutaneous drainages pre-ileocecectomy, laparoscopic ileocecectomy, three percutaneous drainages post-ileocolectomy, and evidence of a recurrent abscess prompted diagnostic laparoscopy. The abscess was unroofed and debrided. A flap of omentum was used to fill the abscess cavity. A comprehensive literature search was performed using the terms ‘Crohn’s abscess’, ‘intra-psoas abscess’, and ‘omental patches’ in Medline and on PubMed.\n\nDiscussion\nWe attribute the abscess’ recurrence to possible epithelialization of the abscess cavity. Intra-psoas abscesses, albeit rare, are a known manifestation of CD. Percutaneous drainage is the initial standard of care, although diagnosis can be difficult given its association with several diseases, which can delay definitive treatment. We summarize a recently proposed and agreed upon treatment scheme for the management of the Crohn’s patient with an abdominal abscess. We also propose the novel technique of omental packing in abscess management.\n\nConclusion\nClinician awareness must be heightened for perforating CD in the setting of abscess refractory to either multiple drainage procedures, although care should be taken to individualize treatment to each CD patient who presents with an abdominal abscess.\n\nKeywords\nPerforating Crohn’s diseasePsoas abscessOmental packingCase report\n==== Body\n1 Introduction\nIn patients with Crohn’s Disease (CD), two findings include intra-abdominal abscess (affecting 10–30% of patients with CD) and fistulas (affecting 17–50% of patients) [[2], [3], [4]]. A rare location for an abscess is on the psoas muscle, affecting between 0.4–4.3% of patients with CD [5]. Psoas abscesses are both rare and often complicated by misdiagnosis, due to their tendancy to mimic other disease processes [1]. Fistulas associated with CD most commonly present in the perianal region (54%), entero-enteric (24%), and recto-vaginal (9%) regions [3]. Reports of both psoas abscess and psoas-enteric fistula have only surfaced a handful of times [6]. We present a rare case of a 25-year old female with CD, psoas abscess, and psoas-enteric fistula, who was managed in an academic institution. She was initially misdiagnosed with acute appendicitis, thus delaying appropriate treatment. This work has been reported in line with the SCARE criteria [7].\n\n2 Presentation of case\nA 25-year old Caucasian female with a 10-year history of well-controlled CD, on infliximab, presented to a surgical outpatient facility with right lower quadrant (RLQ) abdominal pain. Her history since her diagnosis had been insignificant, and her symptoms prior to the appointment were well-managed with infliximab. She follows a vegan diet.\n\nTwo weeks prior to presentation at our facility, she walked into the emergency room with a two-week history of shortness of breath, fever, chills, abdominal pain, and diarrhea without hematochezia. Her history since her diagnosis had been insignificant. Septic workup included a CT scan which revealed a RLQ psoas abscess posterior to the cecum that had been attributed to perforated appendicitis. She then underwent CT-guided drainage of the abscess by the interventional radiology (IR) department. Cultures were positive for S. intermedius, and she was subsequently treated with amoxicillin-clavulanate.\n\nNine days after her first IR drain, the patient presented for re-evaluation due to persistent symptoms. Given her history of infectious abscess, infectious disease (ID) was consulted, and she was started on piperacillin/tazobactam and vancomycin. Her symptoms did not resolve, and a subsequent CT scan confirmed the abscess had localized to the psoas muscle, prompting another image-guided drainage.\n\nFollowing this second drain, she continued experiencing low-grade fever, pain, and diarrhea now concerning for retrocecal fistula. 14 days post-admission, she underwent a laparoscopic ileocecectomy and drain removal and ileocecectomy with primary anastomosis. We discovered additional areas of perforation and multiple abscesses smaller than 3 cm (cm). Her percutaneous IR drain was removed during the procedure. Afterwards, her signs and symptoms of infection abated almost immediately, and she was discharged on oral metronidazole.\n\nTwo weeks later, the patient presented with a four-day history of RLQ pain and abdominal cramping. A flare-up of her known CD was suspected. The patient was continued on infliximab and monitored; however, three days later (one month after the initial encounter) she was admitted with acute elbow and knee pain. Her antibiotics were switched to daptomycin, ertapenem, and micafungin. Her pain improved, and she was discharged five days after admission. Two weeks after this visit, she continued care at a separate hospital, where they placed her third IR drain.\n\nOne month later (two months after our initial encounter), she presented to the ED with fever, abdominal pain, and non-bloody diarrhea. Due to concern for a recurrent fistula, she underwent a diagnostic laparoscopy. Significant, dense adhesions were encountered in the right abdomen between the distal ileum and lateral abdominal wall (Fig. 1A). The anastomosis from the prior operation was found to be intact, and no obvious cause for the recurrent psoas abscess was seen. To access the abscess, the existing IR drain was used as a guide. The abscess was unroofed and its cavity thoroughly irrigated with sterile water (Fig. 1B–D). To prevent recurrence, a flap of omentum was freed, packed within the abscess to encourage healing, and secured to the cavity’s edges (Fig. 1E). No pus was noted in the abdomen. She recovered well, and four days following the procedure, she was discharged with a course of oral antibiotics. Two months later, her psoas abscess was imaged via ultrasound and confirmed to have healed with no drainable fluid component.Fig. 1 (A) Bowel and omental adhesions to abdominal wall (B) Abscess cavity localized by instilling sterile water in the existing IR-placed drain (C) Tip of IR drain (Pigtail) brought out after unroofing of the chronic abscess cavity (D) Completion of abscess cavity unroofing after IR drain was externally removed (E) Omental flap used to pack the unroofed chronic abscess cavity and secured in place with sutures.\n\nFig. 1\n\n3 Discussion\nOur patient was initially diagnosed with perforated appendicitis causing a psoas muscle abscess. Given the abdominal pain and abscess at initial presentation, as well as pain extending to the back, fever, and increased CRP, appendicitis was not inappropriate to include on the differential. Ruptured appendicitis was questioned, however, when the patient presented with these persistent symptoms. Moreover, whereas a perforated appendicitis might spread its contents throughout the abdominal cavity, our patient’s abscess localized to the psoas muscle.\n\nCurrent management of a Crohn’s abscess is debated. No randomized control trial comparing PD, surgery, and antimicrobials has to date been conducted. A recent meta-analysis comparing PD and surgery found that PD was associated with a significantly higher likelihood of abscess recurrence (OR = 6.544) but found no difference in complication rates (OR = 0.657) or length of stay (difference in means = −1.006) [8]. Some studies have shown that initial PD makes follow-up surgery more successful [9]. Others have shown that initial surgical management to be more effective in reducing post-operative complications [10]. Other studies retrospectively examining an interventional group (drainage or surgery) and medicine-only antimicrobials group have found no significant difference in rates of abscess recurrence or nonresolution [10].\n\nThe lack of an agreed upon treatment course is further complicated by different recommendations. The European Crohn’s and Colitis Organization recommends that all spontaneous abscesses be managed via broad-spectrum antibiotics and imaging-guided PD [11]. Other physician groups recommend treatment be guided by more factors, such as abscess size, presence of a fistula, immunosuppression, and abscess persistence. For complicated CD, defined as the presence of a structure, fistula, post-op abscess, or a spontaneous abscess larger than 3 cm, these groups recommend antibiotics or PD, followed by surgery should the abscess persist [2]. The American College of Radiology recommends a similar approach: treating abscesses smaller than 4 cm with antibiotics and larger abscesses with PD, high-dose steroids, bowel rest, and hyperalimentation [12].\n\nThese conflicting reports found in our comprehensive literature search make a definitive conclusion about treatment difficult. A treatment algorithm recently proposed by Carvalho et al. and that agrees with current American College of Radiology guidelines takes into account patients’ abscesses characteristics, medication history, and disease progression [13]. They recommend initial imaging, best performed via ultrasonography or CT, to determine the size of the abscess [14]. Size is a good predictor for success in medication-only therapy, making imaging an excellent first step in determining a conservative, antibiotics approach versus procedural intervention [12]. Small (<=4 cm) abscesses can be managed by medical treatment using either extended spectrum beta lactamases (ESBL) or ciprofloxacin/metronidazole, both of which have shown being well-tolerated and efficacious [15]. Should complications arise during treatment (persistent abscess, stricture development, or fistula development), surgery is recommended.\n\nFor abscesses greater than 4 cm, PD is initially done to control peritoneal contamination [16]. If initial antibiotics and PD were successful, and an abscess is discovered during planned resection and primary anastomosis (as in our patient), the patient can still proceed with PD [17]. Should complications arise after PD, surgery is recommended [18]. In a patient for whom PD is not possible (with a comorbid interloop, intra-mesenteric, or multiloculated abscess), immediate surgery has demonstrated efficacy [19]. Patients successfully treated should then continue their routine immunomodulator or biological treatment (TNF-alpha inhibitor).\n\nOmental packing is a technique we did not find to be discussed in any guideline for treating abdominal abscess treatment in a CD patient. We utilized the omentum to encourage wound healing following debridement of the abscess capsule. A 2012 study retrospectively examining 45 patients who had undergone abdominoperineal resection for lower rectal adenocarcinoma found that both wound infection in the packed wound group was significantly lower (5% compared to 32%) and duration of stay shorter (17.8 days compared to 21.0 days) [20]. To date, our patient remains symptom-free and continues on her biologic therapy for Crohn’s. Due to its efficacy in our patient, omental packing ought to be further scrutinized in the treatment of a CD patient with abdominal abscess.\n\n4 Conclusion\nManagement of an abscess in CD should be guided by multiple factors that may influence treatment management. One novel technique we propose is the use of omental packing to prevent abscess recurrence. In our opinion, it may be of worth to investigate its use in addition to traditional management of an abdominal abscess.\n\nSources of funding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nThis study is exempt from ethical approval in our institution.\n\nConsent\nThe head of our medical team has taken responsibility that exhaustive attempts have been made to contact the family and that the paper has been sufficiently anonymised not to cause harm to the patient or their family. A signed document to this effect, has been uploaded.\n\nAuthor contribution\nSteven Tsoraides, Corresponding Author, contributed to the paper as follows: conceptualization, investigation, resources, writing – review and editing, visualization, supervision, and project administration.\n\nMelissa Medina contributed to the paper as follows: investigation, resources, writing – original draft, writing – review and editing, visualization, supervision, and project administration.\n\nEhab Alameer contributed to the paper as follows: investigation, resources, writing – review and editing, and visualization.\n\nJonathan Nitz contributed to the paper as follows: investigation, resources, writing – review and editing, and visualization.\n\nDavid Gao contributed to the paper as follows: investigation, writing – original draft, writing – review and editing, visualization, and project administration.\n\nRegistration of research studies\nNot required.\n\nGuarantor\nThe Guarantor is Dr. Steven Tsoraides, MD.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nDeclaration of Competing Interest\nThe authors declare that they have no personal, financial, or professional relationships with other people or organizations that could inappropriately influence or bias our work.\n==== Refs\nReferences\n1 Hresko M.T. Hall J.E. Latent psoas abscess after anterior spinal fusion Spine 17 5 1992 590 593 1621160 \n2 Feagins L.A. Holubar S.D. Kane S.V. Spechler S.J. Current strategies in the management of intra-abdominal abscesses in Crohn’s disease Clin. Gastroenterol. Hepatol. 9 10 2011 842 850 21679776 \n3 Scharl M. Rogler G. Pathophysiology of fistula formation in Crohn’s disease World J. Gastrointest. Pathophysiol. 5 3 2014 205 212 25133023 \n4 Ibanez-Samaniego L. Diaz-Fontenla F. Miranda-Bautista J. Acosta C. Barcelo I. Flores V. Safety and efficacy of anti-TNFalpha treatment in Crohn’s disease patients with abdominal abscesses Hepato-Gastroenterology 62 139 2015 647 652 26897946 \n5 Jung H.S. Shin K.N. Kang M.J. Baik S.J. Ryu K.H. Jung S.A. Yoo K. Min S.K. A case of Crohn’s disease with psoas abscess and enterocutaneous fistula Intest. Res. 5 2 2007 188 191 \n6 Christodolou D. Tzambouras N. Katsanos K. Familias I. Tsamboulas K. Tsianos E. Psoas fistula and abscess in a patient with Crohn's disease presenting as claudication and hip arthritis Ann. Gastroenterol. 14 4 2001 314 318 \n7 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A.J. Orgill D.P. The SCARE 2018 statement: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. (Lond. Engl.) 60 2018 132 136 \n8 Clancy C. Boland T. Deasy J. McNamara D. Burke J.P. A meta-analysis of percutaneous drainage versus surgery as the initial treatment of Crohn’s disease-related intra-abdominal abscess J. Crohns Colitis 10 2 2016 202 208 26512133 \n9 Xie Y. Zhu W. Li N. Li J. The outcome of initial percutaneous drainage versus surgical drainage for intra-abdominal abscesses in Crohn’s disease Int. J. Colorectal Dis. 27 2 2012 199 206 22052039 \n10 Nguyen D.L. Sandborn W.J. Loftus E.V. Jr. Larson D.W. Fletcher J.G. Becker B. Similar outcomes of surgical and medical treatment of intra-abdominal abscesses in patients with Crohn’s disease Clin. Gastroenterol. Hepatol. 10 4 2012 400 404 22155562 \n11 Dignass A. Van Assche G. Lindsay J.O. Lemann M. Soderholm J. Colombel J.F. The second european evidence-based consensus on the diagnosis and management of Crohn’s disease: current management J. Crohns Colitis 4 1 2010 28 62 21122489 \n12 Lorenz J.M. Funaki B.S. Ray C.E. Jr. Brown D.B. Gemery J.M. Greene F.L. ACR appropriateness criteria on percutaneous catheter drainage of infected fluid collections J. Am. Coll. Radiol. 6 12 2009 837 843 19945038 \n13 Carvalho A.T. Esperard B.C. Moreira A. Current management of spontaneous intra-abdominal abscess in Crohn’s disease J. Coloproctology 38 2 2018 158 163 \n14 Sauer C. Gutgesell M. Ballet dancer with hip and groin pain: Crohn disease and psoas abscess Clin. Pediatr. 44 8 2005 731 733 \n15 Greenbloom S.L. Steinhart A.H. Greenberg G.R. Combination ciprofloxacin and metronidazole for active Crohn’s disease Can. J. Gastroenterol. 12 1 1998 53 56 9544412 \n16 Ertugrul I. Tunc B. Yuksel I. Yolcu O.F. Ulker A. PSOAS abscess: an atypical initial presentation of Crohn’s disease Dig. Liver Dis. 38 5 2006 357 358 16574516 \n17 Poritz L.S. Koltun W.A. Percutaneous drainage and ileocolectomy for spontaneous intraabdominal abscess in Crohn’s disease J. Gastrointest. Surg. 11 2 2007 204 208 17390174 \n18 Alkhouri R.H. Bahia G. Smith A.C. Thomas R. Finck C. Sayej W. Outcome of medical management of intraabdominal abscesses in children with Crohn disease J. Pediatr. Surg. 52 9 2017 1433 1437 28427855 \n19 Ayuk P. Williams N. Scott N.A. Nicholson D.A. Irving M.H. Management of intra-abdominal abscesses in Crohn’s disease Ann. R. Coll. Surg. Engl. 78 1 1996 5 10 8659975 \n20 Oida T. Kawasaki A. Mimatsu K. Kano H. Kuboi Y. Fukino N. Omental packing with continuous suction drainage following abdominoperineal resection Hepato-Gastroenterology 59 114 2012 380 383 22353502\n\n",
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"keywords": "Case report; Omental packing; Perforating Crohn’s disease; Psoas abscess",
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"title": "A case report on delayed diagnosis of perforated Crohn's disease with recurrent intra-psoas abscess requiring omental patch.",
"title_normalized": "a case report on delayed diagnosis of perforated crohn s disease with recurrent intra psoas abscess requiring omental patch"
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"abstract": "To report an accelerated course of visual recovery in a case of Leber's hereditary optic neuropathy (LHON) following treatment with idebenone and hormone replacement therapy (HRT). We hereby demonstrate the clinical utility of estrogen's protective role in LHON in vivo.\nWe present a case of LHON in a menopausal woman carrying the 10197 mitochondrial DNA (mtDNA) mutation, who experienced loss of vision shortly after discontinuing her estrogen replacement regimen. Functional visual outcomes are reported following treatment with idebenone and HRT.\nThe patient exhibited an accelerated course of visual recovery, experiencing improvement in vision as early as one month and complete reversal of vision loss by eight months post-therapy.\nIdebenone treatment combined with HRT may have a synergistic effect in enhancing cellular bioenergetics and may explain the patient's accelerated visual improvement.",
"affiliations": "University of Udine, Department of Ophthalmology, Udine, Italy.;Doheny Eye Institute, Los Angeles, CA, USA.;Doheny Eye Institute, Los Angeles, CA, USA.;Doheny Eye Institute, Los Angeles, CA, USA.",
"authors": "Fantini|Michele|M|;Asanad|Samuel|S|;Karanjia|Rustum|R|;Sadun|Alfredo|A|",
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"fulltext": "\n==== Front\nJ Curr OphthalmolJ Curr OphthalmolJournal of Current Ophthalmology2452-2325Elsevier S2452-2325(18)30211-710.1016/j.joco.2018.10.003ArticleHormone replacement therapy in Leber's hereditary optic neuropathy: Accelerated visual recovery in vivo Fantini Michele abAsanad Samuel samuelasanad@gmail.comsasanad@mednet.ucla.edubc∗Karanjia Rustum bcdeSadun Alfredo bca University of Udine, Department of Ophthalmology, Udine, Italyb Doheny Eye Institute, Los Angeles, CA, USAc Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAd Department of Ophthalmology, University of Ottawa, Ottawa, Ontario, Canadae Ottawa Hospital Research Institute, Ottawa, Ontario, Canada∗ Corresponding author. 1355 San Pablo St, Los Angeles, CA, 90033, USA. samuelasanad@gmail.comsasanad@mednet.ucla.edu03 11 2018 3 2019 03 11 2018 31 1 102 105 14 9 2018 2 10 2018 5 10 2018 © 2018 Iranian Society of Ophthalmology. Production and hosting by Elsevier B.V.2018Iranian Society of OphthalmologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report an accelerated course of visual recovery in a case of Leber's hereditary optic neuropathy (LHON) following treatment with idebenone and hormone replacement therapy (HRT). We hereby demonstrate the clinical utility of estrogen's protective role in LHON in vivo.\n\nMethods\nWe present a case of LHON in a menopausal woman carrying the 10197 mitochondrial DNA (mtDNA) mutation, who experienced loss of vision shortly after discontinuing her estrogen replacement regimen. Functional visual outcomes are reported following treatment with idebenone and HRT.\n\nResults\nThe patient exhibited an accelerated course of visual recovery, experiencing improvement in vision as early as one month and complete reversal of vision loss by eight months post-therapy.\n\nConclusion\nIdebenone treatment combined with HRT may have a synergistic effect in enhancing cellular bioenergetics and may explain the patient's accelerated visual improvement.\n\nKeywords\nLeber's hereditary optic neuropathyMitochondrial diseaseHormone replacement therapyAccelerated visual improvement\n==== Body\nIntroduction\nLeber's hereditary optic neuropathy (LHON), a maternally inherited disease characterized by bilateral central vision loss, remains without cure.[1], [2], [3], [4] Recent in vitro studies have highlighted estrogen's role in preserving vision by increasing mitochondrial biogenesis.[5], [6] However, estrogen's protective role in vivo has yet to be reported.\n\nWe report a case of LHON in a menopausal woman, who experienced accelerated visual recovery following treatment with idebenone and hormone replacement therapy (HRT).\n\nCase report\nA 48-year-old woman presented with a four-month history of painless, progressive loss of vision beginning with the left eye followed by subsequent involvement of the right eye two months later. The patient was previously treated with intravenous (IV) corticosteroids for presumed optic neuritis, however, her vision worsened. Best corrected visual acuities (BCVA) were 20/60 OD and 20/200 OS. Intraocular pressures were 13 OU. Color vision on Ishihara plate testing was 1/14 OD and 0/14 OS. Humphrey visual field (HVF) testing showed bilateral cecocentral scotomas (Fig. 1); dilated funduscopy revealed temporal pallor OU. Neurological examination of motor and sensory function, muscle bulk, tone, and gait were intact. Magnetic resonance imaging (MRI) showed a normal optic nerve appearance bilaterally without enhancement or periventricular white matter lesions. Lumbar puncture cerebrospinal fluid analysis, autoimmune panel, immunoglobulins, and complement levels were all negative. The patient's mother had bilateral vision loss at 58 years of age. Of note, the patient consumed more than a half-bottle of wine daily. She was previously on contraceptive hormonal therapy including etonogestrel 0.12 mg and ethinyl estradiol 0.015 mg daily. Her visual symptoms began three months after discontinuing the hormonal regimen. The patient's presentation was concerning for mitochondrial optic neuropathy. She began idebenone 300 mg TID with vitamin C, resumed her original hormonal regimen of etonogestrel 0.12 mg and ethinyl estradiol 0.015 mg daily and minimized alcohol consumption. Genetic testing of the patient and her mother for OPA1 and LHON mitochondrial DNA (mtDNA) mutations (11778G > A, 14484T > C and 3460G > A) was negative. Intriguingly, the patient's vision markedly improved post-therapy, having BCVAs of 20/40 OD and 20/60 OS by one month; 20/25 OU by two months; 20/20 OD and 20/25 OS by eight months. Color vision significantly improved on Ishihara plate testing, scoring 2/14 OD and 1/14 OS by one month; 6/14 OD and 2/14 OS by six months. 30-2 HVF also markedly improved OU by two months (Fig. 2) and continued to eight months (Fig. 3). Comprehensive mitochondrial genome sequencing genetically confirmed LHON, revealing a 10197 mtDNA mutation.Fig. 1 (A, B) Humphrey visual field (HVF) 24-2 maps of the visual field examination on initial presentation, revealing significant cecocentral scotomas in the left and right eye, respectively. (C, D) Depict total deviation of the visual field examination on initial presentation in the left and right eye, respectively. Mean deviation: –15.66 dB OS, –18.25 dB OD.\n\nFig. 2 (A, B) Humphrey visual field (HVF) 30-2 maps of the visual field examination at two months, revealing mild decrease in cecocentral scotomas in the left and right eye, respectively. (C, D) depict total deviation of the visual field examination on initial presentation in the left and right eye, respectively. Mean deviation: −8.11 dB OD, −13.14 dB OS.\n\nFig. 2Fig. 3 (A, B) Humphrey visual field (HVF) 30-2 maps of the visual field examination at eight months, revealing further decrease of the scotomas in the left and right eye, respectively. (C, D) depict less total deviation of the visual field examination on second visit in the left and right eye, respectively. Mean deviation: −4.56 dB OD, −6.61 dB OS.\n\nFig. 3\n\nDiscussion\nWe present a case of LHON in a menopausal woman whose vision loss began shortly after discontinuing estrogen replacement. While causality cannot be definitively proven, the patient's presentation in association with estrogen deficiency and the absence of alternative triggers is highly suggestive of estrogen's protective role in LHON. Also, LHON 10197, characterized by an ND3 subunit defect in mitochondrial complex I, has been solely identified in patients with Leigh syndrome, Leigh-like syndrome, and LHON and dystonia.[7], [8] Our case provides the first reporting of this mutation with isolated LHON, as the patient had no accompanying neurological deficits.\n\nIdebenone can absorb reactive oxygen species and serve as an electron carrier in the mitochondrial respiratory chain. Visual improvement typically does not occur until two or more years post-therapy, and rarely occurs by one year.[9], [10] Our patient's vision improved shortly after one month with complete visual recovery by eight months. Therefore additional mechanisms must be considered. Recent studies have highlighted the important role of estrogen in preserving vision in LHON. This may explain not only the reduced prevalence of disease in women relative to men overall, but also the increased incidence of disease associated with a decline in estrogen as frequently seen in menopausal patients.[5], [6] In vitro studies have elucidated estrogen's mechanism of action. Through activation of the estrogen β receptor, which localizes to the mitochondrial network of retinal ganglion cells, estrogen upregulates antioxidant enzyme production of superoxide dismutase 2, increases mitochondrial biogenesis, and enhances cellular energy competence.[5], [6] Idebenone treatment combined with HRT may have a synergistic effect in enhancing cellular bioenergetics and may explain the patient's accelerated visual improvement. Nevertheless, additional studies are needed to confirm estrogen's protective role in vivo.\n\nConflicts of interest: The authors declare that there is no conflict of interest regarding the publication of this paper.\n\nPeer review under responsibility of the Iranian Society of Ophthalmology.\n==== Refs\nReferences\n1 Riordan-Eva P. Sanders M.D. Govan G.G. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation Brain 118 Pt 2 1995 319 337 7735876 \n2 Carelli V. Ross-Cisneros F. Sadun A.A. Mitochondrial disfunction as cause of optic neuropathies Prog Retin Eye Res 23 1 2004 53 89 14766317 \n3 Sadun A.A. Carelli V. Salomao S.R. A very large Brazilian pedigree with 11778 Leber's hereditary optic neuropathy Trans Am Ophthalmol Soc 100 2002 169 178 Discussion 178–9 12545691 \n4 De Marinis M. Optic neuropathy after treatment with anti-tuberculous drugs in a subject with Leber's hereditary optic neuropathy mutation J Neurol 248 9 2001 818 819 11596792 \n5 Giordano C. Montopoli M. Perli E. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy Brain 134 Pt 1 2011 220 234 20943885 \n6 Pisano A. Preziuso C. Iommarini L. Targeting estrogen receptor β as preventive therapeuthic strategy for Leber's hereditary optic neuropathy Hum Mol Genet 24 24 2015 6921 6931 26410888 \n7 Huang T.L. Wang J.K. Pang C.Y. Tsai R.K. Leber's hereditary optic neuropathy associated with the m.10197G>A mutation J Clin Exp Ophthalmol 8 673 2017 4 8 \n8 Chae J.H. Lee J.S. Kim K.J. A novel ND3 mitochondrial DNA mutation in three Korean children with basal ganglia lesions and complex I deficiency Pediatr Res 61 5 Pt 1 2007 622 624 17413873 \n9 Sadun A.A. La Morgia C. Carelli V. Leber's hereditary optic neuropathy Curr Treat Options Neurol 13 1 2011 109 117 21063922 \n10 Carelli V. La Morgia C. Valentino M.L. Idebenone treatment in Leber's hereditary optic neuropathy Brain 134 Pt 9 2011 e188 21810891\n\n",
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"journal": "Journal of current ophthalmology",
"keywords": "Accelerated visual improvement; Hormone replacement therapy; Leber's hereditary optic neuropathy; Mitochondrial disease",
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"title": "Hormone replacement therapy in Leber's hereditary optic neuropathy: Accelerated visual recovery in vivo.",
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"abstract": "The nosology of bullous lesions or equivalents (vesicles, erosions, and crusts) in patients with lupus erythematosus (LE) is rarely addressed.The primary aim of this study was to draw up a precise phenotypic inventory of such skin lesions; the secondary objective was to assess a potential relationship between the different types of loss of epidermis and extracutaneous lupus manifestations.We conducted a retrospective multicenter study including 22 patients with definite LE and bullous lesions or equivalents. All biopsies were reviewed. Patients were recruited in the dermatology departments of 6 centers. Patients were included if they met the diagnosis of systemic LE according to American College of Rheumatology and/or Systemic Lupus International Collaborating Clinics criteria or diagnosis of cutaneous LE based on classic clinical criteria and/or histological ascertainment of LE. Patients were recruited through clinician's memory and photographic collections.Three clinico-pathological patterns could be individualized. First, toxic epidermal necrolysis (TEN)-like, sheet-like, skin detachment; sun-exposure, mild mucosal involvement, and dermal mucin deposition allow differential diagnosis with classical Lyell syndrome. Second, vesiculo-bullae and/or crusting occurring on typical lesions of subacute cutaneous lupus erythematosus or chronic cutaneous lupus erythematosus. Third, tense vesicles and/or blisters with an underlying neutrophilic dermatosis and a usual response to dapsone.A careful analysis of 22 LE patients with epidermal detachment reveals 2 main pathomechanisms: a classic LE interface dermatitis, which can be hyperacute and lead to TEN-like skin detachment; and a neutrophilic dermatosis, with tense vesicles and/or blisters, including classic bullous LE.",
"affiliations": "From the Faculté de Médecine, Université de Strasbourg; Clinique Dermatologique, Hôpitaux Universitaires de Strasbourg, Strasbourg (CM-D, DL); Faculté de Médecine, Université de Montpellier; Département de Dermatologie, Hôpital Saint Eloi, CHRU Montpellier, Montpellier (DB); Faculté de Médecine, Université Pierre-et-Marie-Curie Paris-VI, Service de Dermatologie Hôpital Tenon, Paris (CF); Faculté de Médecine, Université Claude Bernard Lyon 1, Service de Dermatologie, CHU Lyon Sud, Pierre-Bénite (NP, SD); and Service de Dermatologie-Médecine interne, CHU de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, (NC) France.",
"authors": "Merklen-Djafri|Carine|C|;Bessis|Didier|D|;Frances|Camille|C|;Poulalhon|Nicolas|N|;Debarbieux|Sébastien|S|;Cordel|Nadège|N|;Lipsker|Dan|D|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2657982610.1097/MD.0000000000002102021024000Observational StudyBlisters and Loss of Epidermis in Patients With Lupus Erythematosus A Clinicopathological Study of 22 PatientsMerklen-Djafri Carine MDBessis Didier MDFrances Camille MD, PhDPoulalhon Nicolas MDDebarbieux Sébastien MDCordel Nadège MDLipsker Dan MD, PhDMaatouk. Ismael From the Faculté de Médecine, Université de Strasbourg; Clinique Dermatologique, Hôpitaux Universitaires de Strasbourg, Strasbourg (CM-D, DL); Faculté de Médecine, Université de Montpellier; Département de Dermatologie, Hôpital Saint Eloi, CHRU Montpellier, Montpellier (DB); Faculté de Médecine, Université Pierre-et-Marie-Curie Paris-VI, Service de Dermatologie Hôpital Tenon, Paris (CF); Faculté de Médecine, Université Claude Bernard Lyon 1, Service de Dermatologie, CHU Lyon Sud, Pierre-Bénite (NP, SD); and Service de Dermatologie-Médecine interne, CHU de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, (NC) France.Correspondence: Dan Lipsker, Department of Dermatology, 1 place de l’Hôpital, 67000 Strasbourg, France (e-mail: dan.lipsker@chru-strasbourg.fr).11 2015 20 11 2015 94 46 e210214 9 2015 16 10 2015 28 10 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nThe nosology of bullous lesions or equivalents (vesicles, erosions, and crusts) in patients with lupus erythematosus (LE) is rarely addressed.\n\nThe primary aim of this study was to draw up a precise phenotypic inventory of such skin lesions; the secondary objective was to assess a potential relationship between the different types of loss of epidermis and extracutaneous lupus manifestations.\n\nWe conducted a retrospective multicenter study including 22 patients with definite LE and bullous lesions or equivalents. All biopsies were reviewed. Patients were recruited in the dermatology departments of 6 centers. Patients were included if they met the diagnosis of systemic LE according to American College of Rheumatology and/or Systemic Lupus International Collaborating Clinics criteria or diagnosis of cutaneous LE based on classic clinical criteria and/or histological ascertainment of LE. Patients were recruited through clinician's memory and photographic collections.\n\nThree clinico-pathological patterns could be individualized. First, toxic epidermal necrolysis (TEN)-like, sheet-like, skin detachment; sun-exposure, mild mucosal involvement, and dermal mucin deposition allow differential diagnosis with classical Lyell syndrome. Second, vesiculo-bullae and/or crusting occurring on typical lesions of subacute cutaneous lupus erythematosus or chronic cutaneous lupus erythematosus. Third, tense vesicles and/or blisters with an underlying neutrophilic dermatosis and a usual response to dapsone.\n\nA careful analysis of 22 LE patients with epidermal detachment reveals 2 main pathomechanisms: a classic LE interface dermatitis, which can be hyperacute and lead to TEN-like skin detachment; and a neutrophilic dermatosis, with tense vesicles and/or blisters, including classic bullous LE.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nTo date, the nosology of bullous lesions during lupus erythematosus (LE) remains poorly defined and often confusing.1,2 During the course of LE, bullous cutaneous lesions or equivalents, including vesicles, erosions, and/or crusts, can occur. Different pathogenetic mechanisms underlie the formation of such lesions, which can occur in heterogeneous groups of cutaneous lupus subtypes. However, their exact frequency in patients with LE is unknown, and most series devoted to cutaneous LE do not even mention them.3–8 If bullous systemic LE (SLE) has been the subject of numerous publications,9–15 bullous lesions or equivalents occurring on specific lesions of LE are less studied. Therefore, LE presenting as toxic epidermal necrolysis (TEN) was the subject of some publications, 16–18,23 but it is probably still largely underdiagnosed. A classification of vesiculobullous lesions in LE was published in 2004 by Ting et al.18 He divided the various types of vesicular or bullous lesions that can be encountered in patients with LE into those that have or do not have LE-specific pathology.\n\nThe aim of this study was to clarify clinical, histological, and immunopathological features of bullous skin lesions or any other form of loss of epidermis in a series of 22 patients with LE. Patients with LE and any form of skin detachment—vesicles, bullae, erosions, and crusts—were included in order to make a precise phenotypic inventory and better assess the pathogenesis of such skin lesions. Pragmatically, these lesions will be grouped under the term “loss of epidermis.” Another objective was to identify whether a relationship exists between the different types of loss of epidermis and extracutaneous lupus manifestations.\n\nMETHODS\nWe conducted a descriptive retrospective multicenter study on 22 patients who had developed vesicles, bullae, erosions, or crusts in the course of LE. Under French law, this type of retrospective study does not need approval of an institutional review board. Patients were recruited in the dermatology departments of 2 secondary referral centers (Pointe-à-Pitre and Colmar) and 4 tertiary referral centers (Lyon, Montpellier, Paris, and Strasbourg) in France.\n\nPatients were included if they met the following criteria:Diagnosis of SLE according to American College of Rheumatology (ACR) and/or Systemic Lupus International Collaborating Clinics (SLICC) criteria or diagnosis of cutaneous LE based on classic clinical criteria and/or histological ascertainment of LE.\n\nLoss of epidermis as a direct consequence of LE except for those lesions resulting from a lupus-related thrombotic vasculopathy or the presence of antiphospholipid antibodies or porphyria cutanea tarda.\n\n\n\nPatients’ recruitment was based on clinicians’ memory and/or review of photographic collections (from 1985 to 2012). In all patients, medical records were reviewed and relevant clinical data including age, sex, duration, distribution and morphology of skin lesions, history of LE, serologic data, medications at the time of diagnosis, and response to treatment were recorded. All biopsies were reviewed by 2 of us (CM-D and DL). Mean duration of follow-up time was 5 years (2 months–25 years).\n\nRESULTS\nThe files of 22 patients with loss of epidermis in the course of LE were reviewed. Two of them have been reported previously.19,20\n\nClinical Findings\nThere were 16 women and 6 men. The average age for the onset of bullous or equivalent lesions was 52 years (7–79 years). The average age for the diagnosis of LE was 46 years. Bullous or equivalent lesions were the presenting manifestation LE in 9 of 22 patients. The individual lesions were flaccid blisters or vesicles, sheet-like detachment, erosions, crusts, tense blisters, or vesicles. Lesions were photodistributed in 7 of 22 patients. Mucous membrane involvement was seen in 7 of 22 patients (genital in 2 patients, oral in 6 patients, and conjonctival in 1 patient). Concomitant-specific LE lesions of either acute, subacute, or chronic type were seen in 14 patients. Thirteen of 22 patients had 4 or >4 ACR criteria and 17 had 4 or >4 SLICC criteria.\n\nHistopathological Findings\nThe histopathological findings of these lesions were highly variable. Besides the typical lupus interface dermatitis, some patients had extensive epidermal necrosis, whereas others had a neutrophilic dermatosis. Fourteen of 22 patients had a typical interface dermatitis with varying degrees of vacuolar changes, basal cell necrosis, basement membrane thickening, epidermal atrophy, superficial and deep dermal lymphocytic infiltrate, and mucin deposition. Extensive necrosis of the epidermis was observed in 5 of 22 patients. Eight of 22 patients had a neutrophilic dermal infiltrate, forming papillary microabscesses in some patients, occupying all the upper dermis or even the whole dermis with important interstitial spreading in other patients, sometimes with leucocytoclasia but without vasculitis. Thus, patients could be grouped into 3 profiles shown in Table 1, Table 2, and Table 3.\n\nTABLE 1 Toxic Epidermal Necrolysis-Like Cutaneous Lupus Erythematosus\n\nTABLE 2 Vesiculobullous Annular Subacute Cutaneous Lupus Erythematosus and Vesiculobullous Chronic Cutaneous Lupus Erythematosus\n\nTABLE 3 Bullous Neutrophilic Lupus Erythematosus\n\nGroup 1: TEN-Like LE\nIn the first group composed of 5 patients, the following common clinical features were observed: flaccid blisters (4/5), sheet-like detachments (4/5), erosions (5/5), and tense blisters (1/5). There was mild vulvar mucosal involvement in 1 patient and cheilitis in 2 of 5 patients. Lesions began on sun-exposed skin or were photodistributed in 4 of 5 patients. Only one of them had a history of previous subacute cutaneous lupus erythematosus (SCLE). Three of 5 patients met ACR criteria for SLE, and 4 of them met SLICC criteria. In 2 of 5 patients, no triggering drug was found. In 3 of 5 patients, sheet-like detachments were preceded by drug intake. These drugs were not classically associated with TEN (diacereine, sulbutiamin, docetaxel, cyclophosphamide, and trastuzumab) (Table 1, Figure 1).\n\nFIGURE 1 A case of TEN-like LE—Patient 1: (A) photodistributed erosions and crusts; (b) epidermal atrophy and vacuolization of the basal layer. TEN = toxic epidermal necrolysis.\n\nAt histological examination, there was an extensive epidermal necrosis in 4 of 5 patients. Basal vacuolization and isolated keratinocytes necrosis were seen in all patients and mucin deposition in 3 patients. Direct immunofluorescence revealed a granular fluorescence at dermal–epidermal junction (DEJ) in 2 of 5 patients, with IgG, IgM, and C3. These patients can be classified as having a TEN-like LE.\n\nGroup 2: Classic Cutaneous LE (Interface Dermatitis) With Loss of Epidermis\nIn the second group composed of 9 patients, the following common clinical features were observed: erosions (7/9), crusts (7/9), localized sheet-like detachment (1/9), tense bullae (2/9), and/or vesicles (1/9). These losses of epidermis arose on LE-specific lesions (SCLE in 8/9 and chronic cutaneous lupus erythematosus [CCLE] in 1/9). There was no mucosal involvement in 7 of 9 patients. Two had oral ulcerations. Lesions were photodistributed in 3 of 9 patients. Five of them had a history of cutaneous LE. Three patients of 9 met ACR criteria for SLE, and 5 of 9 met SLICC criteria (Table 2, Figure 2).\n\nFIGURE 2 Cases of classic cutaneous LE with loss of epidermis: (A) patient 11—annular plaques centered by a crust; (B) patient 11—epidermal atrophy and dermo-epidermal blister; cavity filled with lymphocytes; (C) patient 14—erosions and crust on sun exposed skin; depigmented scars and atrophy; (D) patient 14—epidermal atrophy, interface dermatitis with vacuolization, lichenoid lympho-histiocytic infiltrate and mucin deposition.\n\nAt histopathological examination, there was epidermal atrophy (7/9), isolated keratinocyte necrosis (9/9) or extensive epidermal necrosis (2/9), vacuolization of basal keratinocytes (9/9), and dermo-epidermal detachment (1/9). A lymphocytic infiltrate was present. It could be lichenoid and/or distributed around the vessels or appendages. Mucin deposition was seen in 4 of 8 patients. Direct immunofluorescence revealed a granular fluorescence at DEJ in 2 of 8 patients and a dust-like particle pattern in 2 of 8 patients. These patients can be classified as having a vesiculobullous annular SCLE or CCLE.\n\nGroup 3: Neutrophilic Bullous LE\nIn the third group composed of 8 patients, the following common clinical features were observed: tense vesicles and bullae (2/8), tense bullae (5/8), crusts (3/8), and/or erosions (2/8). Three of 8 patients presented mucosal involvement (isolated oral ulcerations in 2 of 8 patients and oral, genital, and conjonctival ulcerations in 1 of 8 patients). Lesions were not photodistributed. They occurred on normal appearing or inflammatory skin. Only 2 patients had concomitant LE-specific lesions (acute cutaneous lupus erythematosus [ACLE] or CCLE). Four of 8 patients had no history of cutaneous LE. Seven of 8 patients met ACR criteria for SLE and all of them had at least 4 SLICC criteria. Among these 8 patients, 3 had concomitant glomerulonephritis (Table 3, Figure 3).\n\nFIGURE 3 A case of neutrophilic bullous LE: patient 16—(A) tense blisters and crusts on inflammatory skin; (B) blisters and neutrophilic papillary microabscesses.\n\nHistological examination showed either dermal–epidermal cleavage (in 7 of 8 patients) or superficial dermal edema (in 1 patient). A neutrophilic infiltrate was constant, with a pattern of papillary microabscesses in 4 of 8 patients, a dense subepidermal infiltrate in 3 of 8 patients or involving the entire dermis in 1 patient. LE-specific lesions, namely interface dermatitis, were absent in all 8 cases. Direct immunofluorescence examination revealed granular or linear immunoglobulin and C3 deposition at the DEJ (7/8) or a dust-like particles pattern (1/8). By immunoblotting, a 290 kD antigen was found in 2 patients and a 200 kD antigen was found in 1 patient. Immunoblotting was negative in 1 patient and was not performed in the remaining 4 of the 8 patients. These patients can be classified as having a bullous neutrophilic LE.\n\nDISCUSSION\nWe report a series of 22 patients with loss of epidermis in the course of LE. The study of these patients led to distinguish 2 different pathological mechanisms that are likely to induce “loss of epidermis.” In the first group, skin surface alterations are related to a lupus-typical interface dermatitis at varying levels of intensity, which, if carried to the extreme, may cause TEN-like lesions. In the second group, the formation of bullae is underlaid by a neutrophilic dermal infiltrate; this group includes patients with classic bullous LE. To the best of our knowledge, no study has so far specifically addressed skin surface alterations in patients with LE. As the entry point of this study was purely morphologic, it is therefore relevant bedside, also in regards to treatment. Indeed, the erosive variants of DLE or SCLE are treated with antimalarials. In case of TEN-like LE, patients are usually hospitalized. As drug induction is not exceptional, a careful history is mandatory and every suspected drug must be interrupted. Photoprotection and appropriate skin care are essential and antimalarials are indicated. Finally, dapsone is the drug of choice for the neutrophilic variant of LE.\n\nPatients’ recruitment mode (clinicians’ memory and/or review of photographic collections) constitutes a limitation in this study. Some data are missing due to the retrospective nature of the study. Thus, though the methodology of this study does not allow to draw any conclusion about the frequency of the different clinicopathological entities that we report, we nevertheless estimate that it is representative of the different types of surface alterations that are encountered in daily practice. First, because only experienced dermatologists participated in this study, and thus skin surface alterations would not go unnoticed; second, because in most participating centers, photos are taken from all patients with LE, and the systematic study of the photos provided a representative spectrum of the different clinical findings.\n\nLE-Specific Vesiculobullous Skin Disease\nWhen the lupus-typical interface dermatitis is particularly intense and acute, it can lead to epidermal necrosis, as in the course of TEN.16,17,23 This variant still is often not recognized as being LE21 and misdiagnosed as TEN. Ting et al18 distinguished 3 forms of TEN-like LE: TEN-like ACLE, in which the sheet-like cleavage of skin changes evolves rapidly from a preexisting photodistributed confluent or patchy erythema reaction that would otherwise be typical of localized or generalized ACLE; TEN-like SCLE, in which the sheet-like cleavage of skin changes evolves from otherwise typical photodistributed nonscarring annular or papulosquamous SCLE, in association with anti-Ro/SS-A or La/SS-B autoantibody production; TEN occurring in SLE patients with no conventional LE-specific skin lesions.\n\nThe diagnosis of TEN-like LE was made in 5 patients. All of them presented with an extensive epidermal necrosis and interface dermatitis. The presence or absence of anti-Ro is an element allowing the classification into one of the categories according to Ting. Four of our 5 patients had anti-Ro antibodies. The small size of these 2 groups does not allow retaining this finding as a determining factor. Drawing a distinction between subgroups of TEN-like LE seems irrelevant because the clinical features are similar in the 3 forms (flaccid bullae, vesicles, and sheet-like detachment and erosions) as well as histological features. It seems more didactic to group these 3 forms of TEN-like LE under the term “TEN-like hyperacute LE.” This diagnosis should be considered in any patient with sheet-like detachment when a photodistribution is noted, when mucous membrane involvement is discrete or absent, when antinuclear antibodies are present, or when mucin deposition is found in the biopsy specimen, particularly in the absence of high-risk drug intake. This entity remains probably underdiagnosed, as real TEN can also occur in SLE patients.22 It is important, however, to consider LE as a potential cause of acute syndrome of pan-epidermolysis, as are drug-induced Lyell syndrome or some fulminant cases of acute graft-versus-host disease (GVHD). Three of the 5 patients reported here with TEN-like LE had 4 ACR criteria (and 4 of them had 4 or more SLICC criteria), but lacked significant manifestations of visceral LE. Intravenous immunoglobulin therapy has been reported to be useful in TEN-like LE as well as in TEN and acute GVHD.4,23 TNF inhibitors have recently been reported to improve outcome in patients with TEN.24–28 These drugs are known to potentially induce LE and it is so far recommended not to administer them to patients with SLE. If their efficacy in patients with TEN should be confirmed, their use in patients with TEN-like LE should be carefully addressed.17\n\nWe also show here that classical LE lesions can evolve into “loss of epidermis,” through the same, but less acute mechanism. Histologically, there is a continuum between these different forms, supporting the notion of dermo-epidermal LE.29 Although oral mucosa ulcerations are a classic manifestation of LE, and a diagnostic criterion in both ACR and SLICC criteria, our knowledge of loss of epidermis in classic LE lesions is poor. The relatively few patients with bullous evolution in classic LE variant as compared to TEN-like LE is probably biased. Physicians more easily remembered the patients with TEN-like LE who were always hospitalized, often for a few weeks, whereas the other patients are mainly seen on an outpatient basis, and attention is not always paid to crusting or peripheral vesiculation. Vesiculobullous annular SCLE and vesiculobullous CCLE were mainly characterized by erosions and crusts, and more rarely by bullae and vesicles. These losses of epidermis occurred at the active advancing edge of LE skin lesions or at the center of plaques.\n\nNeutrophilic Vesiculobullous Skin Disease in Patients With LE\nIn the second group of patients, histopathological evaluation revealed a neutrophilic infiltrate, often mimicking dermatitis herpetiformis (DH). No lupus-characteristic interface dermatitis was present in cutaneous biopsy specimens. These LE-nonspecific vesiculobullous skin diseases do not occur as an extension of the interface dermatitis that is characteristic of LE-specific skin disease. In these cases, all the criteria for a defined autoimmune bullous dermatosis must be searched. When no autoimmune bullous dermatosis, such as DH, can be nosologically characterized, patients can be classified as having a neutrophilic bullous LE. In these cases, antibodies directed against collagen VII are usually detected, similarly to patients with epidermolysis bullosa acquisita (EBA), though the spectrum of autoantibodies found in these patients can probably be expanded.15\n\nAn explanation of the co-occurrence of these diseases could be that the interface dermatitis of classical LE could lead to the exposure of multiple epidermal and dermal antigens and cause a sensitization against these antigens. This sensitization would lead to the production of autoantibodies responsible for the induction of autoimmune bullous dermatoses, either defined (eg, EBA, DH, linear IgA dermatosis, P200 pemphigoid, or bullous pemphigoid), or not defined, when the antigen is not characterized or when the essential criteria for the definition of these dermatoses are not met. According to this hypothesis, bullous neutrophilic LE associated with the presence of antibodies directed against collagen VII, considered as \"EBA-like vesiculobullous LE” in Ting's classification, would be more an EBA secondary to LE than a subtype of neutrophilic LE.\n\nSimilarly, the individualization of “DH-like vesiculobullous LE” can be put into question. According to Ting, it is characterized by papillary microabscesses in combination with dense granular IgA and/or IgG deposits at the DEJ. It is necessary to differentiate the situation in which antitranglutaminase or antiendomysial antibodies are found, leading to the diagnosis of the DH, from the situation in which these antibodies are absent. In the latter case, in a patient with a history of LE (or in which LE is discovered on this occasion), the clinicopathological and immunopathological clinical picture can be considered as a bullous neutrophilic LE.\n\nWe could apply the same reasoning to other autoimmune bullous dermatoses such as linear IgA dermatosis or P200 pemphigoid occurring in patients with LE. But only half of the patients reported herein had previous LE lesions and thus this pathogenic hypothesis of exaggerated antigen exposition related to the interface dermatitis will not apply to them. We think that a subgroup of patients with LE is more prone to neutrophilic dermatoses in general including the different bullous variants.30,31 This is one more phenotypic dermatological presentation where the distinction between classic and neutrophilic LE is crucial.32–34 The correct recognition and diagnosis of the neutrophilic variant is critical, as treatment with dapsone will often allow complete control.\n\nIn patients with LE, we should definitely separate bullous lesions/loss of epidermis occurring in the setting of an interface dermatitis, from those occurring as a consequence of a neutrophilic dermatosis. The latter usually respond to dapsone, and can or cannot be immunopathologically characterized, whereas the former can either be a bullous variant of classic lupus lesions or, rarely, a life-threatening TEN-like acute dermatosis. Classic “bullous LE” is a dapsone-sensitive neutrophilic dermatosis, which probably encompasses different autoimmune bullous diseases. In the series reported here, the patients with neutrophilic bullous LE were those who had most frequently experienced associated significant renal involvement.\n\nAcknowledgments\nThe authors thank the following dermatologists and pathologists for having provided us the slides for the histologic data: Luc Durand, MD (Montpellier, France), Brigitte Balme, MD (Lyon, France), Stéphane Barete, MD (Paris, France), Jean Sarrouy, MD (Point-à-Pitre, France), Marie-Claire Tortel, MD (Colmar, France). All these physicians gave permission to be named.\n\nAbbreviations: ACLE = acute cutaneous lupus erythematosus, ACR = American College of Rheumatology, CCLE = chronic cutaneous lupus erythematosus, DEJ = dermal–epidermal junction, DH = dermatitis herpetiformis, EBA = epidermolysis bullosa acquisita, GVHD = graft versus host disease, LE = lupus erythematosus, SCLE = subacute cutaneous lupus erythematosus, TEN = toxic epidermal necrolysis.\n\nThe Study Group of Systemic Diseases in Dermatology (EMSED: Etude des Maladies Systémiques en Dermatologie): Didier BESSIS, Nadège CORDEL, Camille FRANCES, Dan LIPSKER\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Mebazaa A El Euch D Sellami M \nLupus érythémateux systémique vésiculo-bulleux . Rev Med Interne \n2009 ; 30 :88 –89 .18433941 \n2. Itoi S Tanemura A Tsuji C \nA rare case of male bullous lupus erythematosus complicated with subsequent annular hypopigmentation . Case Rep Dermatol \n2014 ; 6 :91 –97 .24761141 \n3. Biazar C Sigges J Patsinakidis N \nCutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE) . Autoimmun Rev \n2013 ; 12 :444 –454 .23000206 \n4. Vera-Recabarren MA García-Carrasco M Ramos-Casals M \nComparative analysis of subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus: clinical and immunological study of 270 patients . Br J Dermatol \n2010 ; 162 :91 –101 .19785596 \n5. Vera-Recabarren MA García-Carrasco M Ramos-Casals M \nCutaneous lupus erythematosus: clinical and immunological study of 308 patients stratified by gender . Clin Exp Dermatol \n2010 ; 35 :729 –735 .20015282 \n6. Walling HW Sontheimer RD \nCutaneous Lupus Erythematosus . Am J Clin Dermatol \n2009 ; 10 :365 –381 .19824738 \n7. Callen JP \nChronic cutaneous lupus erythematosus. Clinical, laboratory, therapeutic, and prognostic examination of 62 patients . Arch Dermatol \n1982 ; 118 :412 –416 .7092253 \n8. Wallace DJ Pistiner M Nessim S \nCutaneous lupus erythematosus without systemic lupus erythematosus: clinical and laboratory features . Semin Arthritis Rheum \n1992 ; 21 :221 –226 .1570517 \n9. Christodoulou G Powell M Nguyen VH \nAn atypical case of bullous systemic lupus erythematosus in a 16-year-old boy . Pediatr Dermatol \n2014 ; 31 :e164 –e166 .25040539 \n10. Ranario JS Smith JL \nBullous lesions in a patient with systemic lupus erythematosus . J Clin Aesthet Dermatol \n2014 ; 7 :44 –49 .25276277 \n11. Liu KL Shen JL Yang CS \nBullous systemic lupus erythematosus in a child responding to dapsone . Pediatr Dermatol \n2014 ; 31 :e104 –e106 .24846529 \n12. Maley A Parker S \nBullous systemic lupus erythematosus in a patient with human immunodeficiency virus infection: a paradox of autoimmunity and immunodeficiency . Dermatol Online J \n2014 ; 20 : 9 : \n13. Contestable JJ Edhegard KD Meyerle JH \nBullous systemic lupus erythematosus: a review and update to diagnosis and treatment . Am J Clin Dermatol \n2014 ; 15 :517 –524 .25358414 \n14. Lourenço DMR Cunha Gomes R Aikawa NE \nChildhood-onset bullous systemic lupus erythematosus . Lupus \n2014 ; 23 :1422 –1425 .25074872 \n15. Chan LS Lapiere JC Chen M \nBullous systemic lupus erythematosus with autoantibodies recognizing multiple skin basement membrane components, bullous pemphigoid antigen 1, laminin-5, laminin-6, and type VII collagen . Arch Dermatol \n1999 ; 135 :569 –573 .10328198 \n16. Monga B Ghosh S Jain V \nToxic epidermal necrolysis-like rash of lupus: a dermatologist's dilemma . Indian J Dermatol \n2014 ; 59 :401 –402 .25071264 \n17. Napolitano M Giampetruzzi AR Didona D \nToxic epidermal necrolysis-like acute cutaneous lupus erythematosus successfully treated with a single dose of etanercept: report of three cases . J Am Acad Dermatol \n2013 ; 69 :e303 –e305 .24238188 \n18. Ting W Stone MS Racila D \nToxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP): a case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin lesions . Lupus \n2004 ; 13 :941 –950 .15645750 \n19. Boisnic S Frances C Foldes C \nManifestations cutanées rares au cours du lupus systémique: lésions bulleuses . Ann Dermatol Venereol \n1986 ; 113 :930 –933 .\n20. Lipsker D Hauptmann G \nCutaneous manifestations of complement deficiencies . Lupus \n2010 ; 19 :1096 –1106 .20693203 \n21. Mahfouz A Mahmoud AN Ashfaq PA \nA case report of hydralazine-induced skin reaction: probable toxic epidermal necrolysis (TEN) . Am J Case Rep \n2014 ; 15 :135 –138 .24719674 \n22. Ziemer M Kardaun Sh Liss Y \nStevens-Johnson syndrome and toxic epidermal necrolysis in patients with lupus erythematosus: a descriptive study of 17 cases from a national registry and review of the literature . Br J Dermatol \n2012 ; 166 :575 –600 .22014091 \n23. Mandelcorn R Shear NH \nLupus-associated toxic epidermal necrolysis: a novel manifestation of lupus? \nJ Am Acad Dermatol \n2003 ; 48 :525 –529 .12664014 \n24. Gaitanis G Spyridonos P Patmanidis K \nTreatment of toxic epidermal necrolysis with the combination of infliximab and high-dose intravenous immunoglobulin . Dermatology \n2012 ; 224 :134 –139 .22572593 \n25. Zárate-Correa LC Carrillo-Gómez DC Ramírez-Escobar AF \nToxic epidermal necrolysis successfully treated with infliximab . J Investig Allergol Clin Immunol \n2013 ; 23 :61 –63 .\n26. Hunger RE Hunziker T Buettiker U \nRapid resolution of toxic epidermal necrolysis with anti-TNF-alpha treatment . J Allergy Clin Immunol \n2005 ; 116 :923 –924 .16210071 \n27. Paradisi A Abeni D Bergamo F \nEtanercept therapy for toxic epidermal necrolysis . J Am Acad Dermatol \n2014 ; 71 :278 –283 .24928706 \n28. Wojtkiewicz A Wysocki M Fortuna J \nBeneficial and rapid effect of infliximab on the course of toxic epidermal necrolysis . Acta Derm Venereol \n2008 ; 88 :420 –421 .18709327 \n29. Lipsker D \nClassification of specific cutaneous manifestations in patients with lupus erythematosus: a time for change? The concept of dermal lupus erythematosus . Dermatology \n2006 ; 212 :324 –326 .16707881 \n30. Tobón GJ Toro CE Bravo JC \nLinear IgA bullous dermatosis associated with systemic lupus erythematosus: a case report . Clin Rheumatol \n2008 ; 27 :391 –393 .17932615 \n31. Kurano TL Lum CA Izumi AK \nThe association of dermatitis herpetiformis and systemic lupus erythematosus . J Am Acad Dermatol \n2010 ; 63 :892 –895 .20739096 \n32. Lipsker D Saurat JH \nNeutrophilic cutaneous lupus erythematosus. At the edge between innate and acquired immunity? \nDermatology \n2008 ; 216 :283 –286 .18230975 \n33. Kieffer C Cribier B Lipsker D \nNeutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature . Medicine (Baltimore) \n2009 ; 88 :23 –31 .19352297 \n34. Gusdorf L Bessis D Lipsker D \nLupus erythematosus and neutrophilic urticarial dermatosis: a retrospective study of 7 patients . Medicine (Baltimore) \n2014 ; 93 :e351 .25546692\n\n",
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"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D001768:Blister; D002648:Child; D004817:Epidermis; D005260:Female; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous; D008179:Lupus Erythematosus, Discoid; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055815:Young Adult",
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"title": "Blisters and Loss of Epidermis in Patients With Lupus Erythematosus: A Clinicopathological Study of 22 Patients.",
"title_normalized": "blisters and loss of epidermis in patients with lupus erythematosus a clinicopathological study of 22 patients"
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"abstract": "Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1-74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.",
"affiliations": "Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. JacobP_Laubach@DFCI.HARVARD.EDU.;University of North Carolina, Chapel Hill, NC, USA.;Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Dana-Farber Cancer Institute, Department of Data Sciences, Boston, MA, USA.;Secura Bio, Inc, San Diego, CA, USA.;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.",
"authors": "Laubach|Jacob P|JP|0000-0001-7565-2052;Tuchman|Sascha A|SA|0000-0003-2109-1573;Rosenblatt|Jacalyn M|JM|;Mitsiades|Constantine S|CS|;Colson|Kathleen|K|;Masone|Kelly|K|;Warren|Diane|D|;Redd|Robert A|RA|0000-0002-1329-5288;Grayson|Dena|D|0000-0003-2818-8458;Richardson|Paul G|PG|0000-0002-7426-8865",
"chemical_list": "D000069286:Bortezomib; D003907:Dexamethasone; D000077767:Panobinostat; D000077269:Lenalidomide",
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"fulltext": "\n==== Front\nBlood Cancer J\nBlood Cancer J\nBlood Cancer Journal\n2044-5385 Nature Publishing Group UK London \n\n407\n10.1038/s41408-021-00407-5\nArticle\nPhase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma\nhttp://orcid.org/0000-0001-7565-2052Laubach Jacob P. JacobP_Laubach@DFCI.HARVARD.EDU 1 http://orcid.org/0000-0003-2109-1573Tuchman Sascha A. 2 Rosenblatt Jacalyn M. 3 Mitsiades Constantine S. 1 Colson Kathleen 1 Masone Kelly 1 Warren Diane 1 http://orcid.org/0000-0002-1329-5288Redd Robert A. 4 http://orcid.org/0000-0003-2818-8458Grayson Dena 5 http://orcid.org/0000-0002-7426-8865Richardson Paul G. 1 1 grid.38142.3c000000041936754XDana-Farber Cancer Institute, Harvard Medical School, Boston, MA USA \n2 grid.410711.20000 0001 1034 1720University of North Carolina, Chapel Hill, NC USA \n3 grid.38142.3c000000041936754XBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA \n4 grid.65499.370000 0001 2106 9910Dana-Farber Cancer Institute, Department of Data Sciences, Boston, MA USA \n5 Secura Bio, Inc, San Diego, CA USA \n5 2 2021 \n5 2 2021 \n2 2021 \n11 2 2021 7 2020 8 12 2020 23 12 2020 © The Author(s) 2021Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.\n\nSubject terms\nMyelomaCombination drug therapyissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\nTreatment of multiple myeloma (MM), an incurable plasma-cell neoplasm, has changed substantially in recent decades1. Rapidly evolving treatment standards have led to improvements in overall survival (OS), as well as the depth and duration of response (DOR)2–4. Nevertheless, most patients ultimately relapse and require subsequent lines of therapy, with the depth of response and DOR to each successive regimen typically decreasing over time1. However, different emerging classes of agents, which can be combined in triplet or even quadruplet regimens, have provided clinicians with several new therapeutic options for relapsed and refractory MM (RRMM) patients.\n\nHistone deacetylase inhibitors (HDACis), which influence transcriptional activation and other nuclear events by increasing histone acetylation, have been developed in recent years as a treatment for RRMM1,5–7. Histone deacetylases (HDACs) are overexpressed in MM, leading to reduced expression of tumor suppressor genes and, consequently, increased growth and proliferation of tumor cells. Unsurprisingly, overexpression of class I HDACs is associated with a poorer prognosis in MM8.\n\nBroad-spectrum HDACis can enhance the anti-MM activity of proteasome inhibitors through multiple non-mutually exclusive mechanisms, including the transcriptional repression of ubiquitin/proteasome pathway genes and drivers of tumor cell survival and treatment resistance9,10, as well as the inhibition of the aggresome, which is an alternative route for protein degradation11. Panobinostat is among the most potent HDACis in clinical development and the only HDACi approved for the treatment of RRMM, in combination with bortezomib and dexamethasone12,13. In the phase 2 PANORAMA 2 trial, heavily pre-treated, bortezomib-refractory patients with RRMM had an overall response rate (ORR) of 34.5% with panobinostat plus bortezomib and dexamethasone (pano-Vd), highlighting that the addition of panobinostat can overcome resistance to prior therapeutic agents, including bortezomib14. In the randomized phase 3 PANORAMA 1 study, pano-Vd significantly improved median progression-free survival (PFS) by 12.5 vs. 4.7 months (hazard ratio 0.47; 95% confidence interval [CI] 0.31, 0.72) in patients who had received ≥2 prior regimens including bortezomib and an immunomodulatory drug (IMiD), and nearly tripled the rate of complete response/near complete response, compared with placebo-Vd (22% vs. 8% for pano-Vd and placebo-Vd, respectively)5,6,15.\n\nThe optimal dose and schedule of pano-Vd was confirmed in the randomized phase 3 PANORAMA 3 trial as 20 mg thrice weekly; DOR with this regimen was 22.6 months and tolerability was improved with subcutaneous administration of bortezomib with only 11.5% of patients in the 20 mg TIW dosing group reporting grade 3/4 diarrhea compared with intravenous delivery of bortezomib, as was standard practice at the time of previous clinical trials.16\n\nBroad-spectrum HDACis also enhance the anti-MM activity of IMiDs, such as lenalidomide, by suppressing diverse oncogenic transcriptional programs10, including the interferon regulatory factor-4/MYC axis17. In a phase 2 study of patients with RRMM, panobinostat plus lenalidomide and dexamethasone (pano-Rd) demonstrated an encouraging ORR (41%) and median PFS (7.1 months) in patients with high-risk, lenalidomide-refractory (81%), and/or bortezomib-refractory (52%) MM, suggesting that panobinostat is also able to overcome resistance to IMiDs.\n\nThese data provided the rationale for investigating the quadruplet regimen, panobinostat, lenalidomide, bortezomib and dexamethasone (pano-RVd), in heavily pre-treated patients, particularly in those refractory to proteasome inhibitors and/or IMiDs for whom additional therapy options are needed. Here, we report the findings of a phase 1b dose-escalation study of pano-RVd with extended follow-up.\n\nMethods\nStudy design and objectives\nThis study was an open-label, multicenter, phase 1b, study of pano-RVd in RRMM (NCT01965353). Primary objectives were to identify the maximum tolerated dose (MTD) of panobinostat in combination with RVd and to evaluate the safety profile of pano-RVd. Secondary objectives were to evaluate ORR, DOR, time to progression (TTP), PFS and OS. A modified Fibonacci design was used, with 3–6 patients planned at each dose level followed by a dose-expansion phase with an additional ten patients to evaluate the tolerability of the MTD.\n\nThe study was conducted in accordance with the Declaration of Helsinki, US Code of Federal Regulations governing clinical study conduct, state laws and Dana-Farber/Harvard Cancer Center research policies and procedures. The institutional review board for each center approved the protocol and amendments. All patients provided written informed consent before enrollment.\n\nPatient eligibility\nEligible patients were aged ≥18 years with measurable RRMM (2011 International Myeloma Working Group consensus)18, an Eastern Cooperative Oncology Group performance status <2, and had received ≥2 lines of therapy. Patients with primary refractory disease, prior HDACi treatment, creatinine clearance <45 mL/min, platelet count <75,000 cells/mm3, absolute neutrophil count <1500 cells/mm3, or hemoglobin level <8.0 g/dl at screening were excluded. Patients with ≥grade (G) 2 peripheral neuropathy (PN) or hepatic impairment (bilirubin > 1.5 × institutional upper limit of normal, or aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >2 × institutional upper limit of normal) within 21 days of study therapy initiation were also excluded.\n\nTreatments administered\nPatients received oral panobinostat 10 mg or 15 mg plus subcutaneous bortezomib 1 mg/m2, oral lenalidomide 15 mg, and oral dexamethasone 20 mg in 21-day cycles per the schema in Fig. 1. After eight cycles, patients switched to a maintenance schedule, with reduced bortezomib and dexamethasone dosing. Treatment continued until disease progression, unacceptable toxicity, consent was withdrawn, or discontinuation was in the best interest of the patient. Doses could be held for up to 21 days or reduced to manage therapy-related adverse events (TRAEs).Fig. 1 Each cycle consisted of 21 days, patients received eight treatment cycles before switching to maintenance cycles.\nProgression to the next higher dose level occurred, if appropriate, when the safety and tolerability of the prior dose level(s) had been determined at the end of the first cycle.\n\n\n\nNecessary concomitant medications were allowed, except for those which may cause QTcF prolongation or induce torsades de pointes. Leukocyte growth factors were only administered during cycle 1 in the event of a dose-limiting toxicity (DLT) (if appropriate), but could be prescribed for severe neutropenia after cycle 1.\n\nDose escalation, MTD, and DLTs\nA standard 3 + 3 dose-escalation schema was used (Supplementary Fig. S1). If ≥2 of 3 patients within a cohort experienced a DLT during the dose-escalation phase, the dose immediately below the current dose was defined as the MTD. The 3 + 3 schema was chosen, rather than an alternative methodologic phase 1 study design, due to the limited number of patients in the study and the fact that only three dose levels were planned. DLTs were assessed during the first cycle and defined as a QTcF interval >500 ms, or an absolute increase of >60 ms, a ≥ G3 non-hematological AE or a G4 hematological AE (including thrombocytopenia with platelets <25,000/mm3 on >1 occasion, or G4 neutropenia for >5 days and/or resulting in neutropenic fever on two occasions). Lymphopenia, an AE associated with bortezomib use, was not considered a DLT. Inability to take ≥75% of the planned study drug doses, or receive day 1 doses for cycle 2 due to a drug-related AE occurring in cycle 1, were also considered DLTs.\n\nAssessments\nAEs, graded using Cancer Therapy Evaluation Program Version 4 of the National Cancer Institute Common Terminology Criteria for Adverse Events19, were assessed throughout the study and for 30 days after completion of study therapy. Patients who discontinued for any reason other than disease progression were followed every three months until disease progression. Disease response/progression were assessed at the start of each treatment and maintenance cycle, at the end of study, and during the follow-up phase. Disease response was assessed locally using the International Myeloma Working Group Response Criteria18 with M-protein quantification and immunofixation in serum and 24-h urine samples, and serum-free light chain testing. OS was assessed every three months after disease progression.\n\nStatistical analyses\nData cut-off was 24 January 2019. Descriptive statistics are provided for the reported outcomes. All participants who had received ≥1 dose of any study treatment were evaluated for AEs from treatment initiation. All patients who had received study treatment and had ≥1 follow-up assessment were included in the response evaluation. Only patients who responded to treatment (≥minimal response) were included in the DOR analysis. DOR, TTP, PFS, and OS were estimated using Kaplan–Meier methodology. DOR was measured as the time from initiation of first response to time of disease progression, death, or last follow-up (for those patients who had not progressed or died). TTP was defined as time from registration to progression or to last follow-up (for those who had not progressed). PFS was defined as the time from registration to disease progression, death, or last follow-up (for those who had not progressed or died). OS was defined as time from registration to death or last follow-up (for patients who had not died).\n\nResults\nPatient characteristics\nBetween November 2013 and October 2016, 20 patients were enrolled: median age was 63 years (range: 50–77), 70% male (Table 1). Cytogenetic data were available for 17 patients; two had t(4;14), and one had t(14;16). The median number of prior lines of treatment was four (range: 2–14); five patients had received >5 prior lines of treatment. Overall, 95% and 90% had been previously treated with bortezomib and lenalidomide, respectively. Most patients (n = 17, 85%) had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]; dexamethasone [85%]).Table 1 Patient baseline characteristics.\n\n\tTotal population n = 20 (%)\t\nMale\t14 (70)\t\nRace\t\n Black/African American\t4 (20)\t\n White\t15 (75)\t\n Other\t1 (5)\t\nAge, median (range)\t63 (50–77)\t\nAge group\t\n ≤55\t4 (20)\t\n 56–65\t9 (45)\t\n >65\t7 (35)\t\nDisease status\t\n Relapsed\t3 (15)\t\n R/R\t17 (85)\t\nECOG PS\t\n 0\t9 (45)\t\n 1\t11 (55)\t\nISS classification\t\n I\t5 (25)\t\n II\t7 (35)\t\n III\t7 (35)\t\nMissing\t1 (5)\t\nNumber of prior treatments, median (range)\t4 (2–14)\t\nPrior treatment\t\n Bortezomib\t19 (95)\t\n Dexamethasone\t20 (100)\t\n Lenalidomide\t18 (90)\t\n Pomalidomide\t15 (75)\t\n Carfilzomib\t0\t\nRefractory to any prior treatment\t\n Bortezomib\t15 (75)\t\n Dexamethasone\t17 (85)\t\n Lenalidomide\t16 (80)\t\nRefractory most recent prior treatment\t\n Bortezomib\t9 (45)\t\n Dexamethasone\t16 (80)\t\n Lenalidomide\t2 (10)\t\nPrior autologous transplants\t\n 1\t9 (45)\t\nCytogenetics\t\n No FISH failure\t17 (85)\t\n\nt (4;14)a\t2 (10)\t\n\nt (14;16)b\t1 (5)\t\nECOG PS Eastern Cooperative Oncology Group Performance Status, FISH fluorescence in situ hybridization, ISS International Staging System, R/R relapsed/refractory.\n\naMissing: n = 9.\n\nbMissing: n = 10.\n\n\n\nMTD and DLTs\nThree patients were treated with panobinostat 10 mg; one experienced a DLT; per protocol, three additional patients were treated with panobinostat 10 mg. No further DLTs were reported, and the dose was escalated. Three patients were treated with panobinostat 15 mg; two experienced DLTs. One of these DLTs (syncope) was a pre-existing condition and not considered related to study treatment, thus, one additional patient was treated with panobinostat 15 mg; this patient subsequently experienced a DLT (thrombocytopenia). Therefore, 10 mg was defined as the MTD for panobinostat in the pano-RVd combination. In the expansion phase, ten patients were treated with pano-RVd with panobinostat dosed at 10 mg; two experienced a DLT. Overall, four patients experienced one DLT, one patient experienced two DLTs and one patient experienced three DLTs (Table 2).Table 2 Dose limiting toxicities.\n\n\tn (panobinostat dose)\t\nDecreased platelet count\t3 (15 mg, n = 2; 10 mg, n = 1)\t\nDecreased neutrophil count\t2 (15 mg)\t\nFatigue\t1 (15 mg)\t\nHyperglycemia\t1 (10 mg)\t\nHypophosphatemia\t1 (10 mg)\t\nSyncope\t1a (15 mg)\t\naNot related to treatment.\n\n\n\nTreatment summary\nPatients completed a median of six cycles (range: 1–74) (Supplementary Table S1). Three patients completed one cycle before withdrawing due to progressive disease. Eight patients completed all eight treatment cycles and ≥1 cycle of maintenance therapy. At the data cut-off date, one patient remained on treatment (Supplementary Fig. S2).\n\nSafety and tolerability\nAll 20 patients experienced ≥1 TRAE. The distribution of worst overall TRAEs experienced was G1 (n = 1), G2 (n = 3), G3 (n = 11) or G4 (n = 5). The most common TRAEs included diarrhea (60%, all were G1/2), PN (60%), anemia (55%), fatigue (55%), neutropenia (55%), constipation (50%) and hypokalemia (50%) (Table 3). The median (95% CI) duration of neutropenia and thrombocytopenia AEs was 7 (4; 11) days and 8 (4; 11) days, respectively. Overall, 37 G3/4 TRAEs were reported; the most common were decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts; anemia (25%); and hypophosphatemia (25%). The rate of cardiac TRAEs was low (atrial fibrillation, n = 1; atrial flutter, n = 1; sinus bradycardia, n = 1; sinus tachycardia, n = 1; palpitations, n = 1; prolongation of QTcF interval, n = 1; heart racing, n = 1; chronic right bundle branch block, n = 1; ectopy and murmur n = 1), and all events were G1/2. No G3/4 diarrhea TRAEs were observed. The only reported G4 TRAEs were decreased platelet (25%) and white blood cell counts (5%). In total, nine serious AEs were experienced by six patients, including treatment-related hyperglycemia, decreased neutrophil count, fatigue, and decreased platelet count. TRAE rates were generally balanced in patients in patients <65 (n = 11) and ≥65 (n = 9) years old, although G4 thrombocytopenia TRAEs were more common in patients ≥65 years old.Table 3 AEs experienced by ≥20% of patients and all grade 4 AEs.\n\n\tTotal, n (%)\tGrade 1\tGrade 2\tGrade 3\tGrade 4\t\n(n = 20)\tn (%)\tn (%)\tn (%)\tn (%)\t\nBlood and lymphatic system disorders\t\n Anemia\t11 (55)\t2 (10)\t4 (20)\t5 (25)\t–\t\n Neutrophil count decreased\t11 (55)\t1 (5)\t1 (5)\t9 (45)\t–\t\n Platelet count decreased\t9 (45)\t4 (20)\t–\t–\t5 (25)\t\n White blood cell count decreased\t7 (35)\t–\t2 (10)\t4 (20)\t1 (5)\t\n Blood and lymphatic system disorders – other\t4 (20)\t1 (5)\t3 (15)\t–\t–\t\n Bruising\t4 (20)\t4 (20)\t–\t–\t–\t\n Cardiac disorders\t\n Dizziness\t5 (25)\t4 (20)\t1 (5)\t–\t–\t\n Cardiac disorders – other\t4 (20)\t4 (20)\t–\t–\t–\t\nEye disorders\t\n Eye disorders—other\t4 (20)\t2 (10)\t2 (10)\t–\t–\t\nGastrointestinal disorders\t\n Diarrhea\t12 (60)\t7 (35)\t5 (25)\t–\t–\t\n Constipation\t10 (50)\t6 (30)\t4 (20)\t–\t–\t\n Nausea\t7 (35)\t5 (25)\t2 (10)\t–\t–\t\n Gastrointestinal disorders—other\t5 (25)\t3 (15)\t2 (10)\t–\t–\t\n Dysgeusia\t4 (20)\t2 (10)\t2 (10)\t–\t–\t\nGeneral disorders and administration site conditions\t\n Fatigue\t11 (55)\t1 (5)\t9 (45)\t1 (5)\t–\t\n Edema limbs\t7 (35)\t4 (20)\t3 (15)\t–\t–\t\nInfections and infestations\t\n Upper respiratory infection\t8 (40)\t–\t8 (40)\t–\t–\t\n Infections and infestations – other\t6 (30)\t2 (10)\t2 (10)\t2 (10)\t–\t\nInvestigations\t\n Hypokalemia\t10 (50)\t8 (40)\t2 (10)\t–\t–\t\n Hypomagnesemia\t8 (40)\t8 (40)\t–\t–\t–\t\n Hypophosphatemia\t7 (35)\t1 (5)\t1 (5)\t5 (25)\t–\t\n Hypocalcemia\t5 (25)\t4 (20)\t1 (5)\t–\t–\t\n Hyponatremia\t5 (25)\t5 (25)\t–\t–\t–\t\nMetabolism and nutrition disorders\t\n Anorexia\t7 (35)\t5 (25)\t2 (10)\t–\t–\t\n Hyperglycemia\t7 (35)\t4 (20)\t2 (10)\t1 (5)\t–\t\nMusculoskeletal and connective tissue disorders\t\n Musculoskeletal and connective tissue disorder – other\t4 (20)\t2 (10)\t2 (10)\t–\t–\t\nNervous system disorders\t\n Peripheral sensory neuropathy\t12 (60)\t6 (30)\t6 (30)\t–\t–\t\nPsychiatric disorders\t\nInsomnia\t6 (30)\t3 (15)\t3 (15)\t–\t–\t\nRespiratory, thoracic, and mediastinal disorders\t\n Cough\t6 (30)\t1 (5)\t5 (25)\t–\t–\t\n Dyspnea\t6 (30)\t3 (15)\t2 (10)\t1 (5)\t–\t\nAEs that were possibly, probably, or definitely related to any study treatments are reported. Each AE represents the highest grade for that AE per patient, so patients may be included in each row at most once.\n\nAE adverse event.\n\n\n\nThere were no instances of treatment-related death or study discontinuation. Dose levels of lenalidomide, bortezomib, dexamethasone, and panobinostat were reduced in at least one cycle for three, six, six, and three patients, respectively. Dose reductions for panobinostat and lenalidomide only occurred in patients in the panobinostat 15 mg cohort. At least one cycle of the pano-RVd regimen was delayed in 18 patients. The most common reason for dose holds was AEs (73%), of which upper respiratory infection, decreased neutrophil count and peripheral sensory neuropathy were the most common (Supplementary Table S2). Reasons for treatment withdrawal included progressive disease (85%), death (5%) and autologous stem cell transplantation (5%).\n\nResponses and outcomes\nThe median follow-up was ~14 months. Per protocol, two patients were not eligible for response evaluation; one died due to factors unrelated to study treatment 2 weeks after starting study treatment, and one withdrew from the study 3 days after starting treatment, due to rapid disease progression. In response-evaluable patients (n = 18), the rate of very good partial response or better was 17%, the ORR (≥partial response) was 44% (90% CI 24, 66) and the clinical benefit response rate (≥minimal response) was 61% (90% CI 39, 80) (Table 4). In patients refractory to both lenalidomide and bortezomib (n = 10), the ORR was 30% (90% CI 9, 61) and the clinical benefit rate was 50% (90% CI 22, 78). Median time-to-first response was approximately 1 month (range: 0.79–4.6), and the median DOR was 9.2 months (range: 2.1–50.4 months). At data cut-off, four patients had a DOR of at least 10 months, median (95% CI) TTP was 7.8 (7.2, not reached) months, median (95% CI) PFS was 7.4 (4.2, not reached) months (Fig. 2), and median (95% CI) OS had not been reached (13.5, not reached). In patients refractory to both lenalidomide and bortezomib, median (95% CI) DOR was 22.1 (9.2, not reached) months, median (95% CI) TTP and PFS were both 22.9 (0.9, not reached) months (Fig. 2), and median (95% CI) OS was not reached (6.8, not reached).Table 4 Patient responses.\n\nAll patients, N = 18a\tN (%)\t90% CI\t\nStringent complete response\t1 (6)\tNA\t\nComplete response\t0 (0)\tNA\t\nVery good partial response\t2 (11)\tNA\t\nPartial response\t5 (28)\tNA\t\nMinimal response\t3 (17)\tNA\t\nStable disease\t7 (39)\tNA\t\nOverall response rate (partial response or better)\t8 (44)\t24, 66\t\nClinical benefit rate (minimal response or better)\t11 (61)\t39, 80\t\nPatients refractory to both lenalidomide and bortezomib, N = 10\tN (%)\t90% CI\t\nOverall response rate (partial response or better)\t3 (30)\t9, 61\t\nClinical benefit rate (minimal response or better)\t5 (50)\t22, 78\t\nCI confidence interval, NA not applicable. M-spike evaluation.\n\naNon evaluable: n = 2 (10%).\n\nFig. 2 Kaplan–Meier distributions of PFS in all 20 patients receiving pano-RVd and lenalidomide/bortezomib-refractory patients.\nLen/Btz lenalidomide/bortezomib. Pano-RVd panobinostat/lenalidomide/bortezomib/dexamethasone, PFS progression free survival.\n\n\n\nDiscussion\nDespite recent approvals of new therapeutic agents for RRMM, nearly all patients ultimately still experience disease relapse. The pano-RVd regimen investigated in this study provides a potential treatment option that can restore responses in heavily treated patients with refractory disease. The MTD of panobinostat in the pano-RVd regimen was 10 mg, dosed in a 2-weeks-on/1-week-off schedule, in combination with bortezomib 1 mg/m2, lenalidomide 15 mg and dexamethasone 20 mg. Although all patients experienced at least one TRAE, no patients discontinued therapy or were withdrawn from the study due to a TRAE. Importantly, this regimen demonstrated promising activity in RRMM patients, including those who were refractory to bortezomib and/or lenalidomide and had received a median of four prior lines of therapy. Furthermore, DOR, TTP, and PFS efficacy outcomes were favorable, even in patients refractory to both lenalidomide and bortezomib.\n\nMost patients in the study were refractory to bortezomib or lenalidomide (75% and 80%, respectively) and 50% were refractory to both bortezomib and lenalidomide. The overall ORR of 44% and clinical benefit rate of 61% demonstrates that pano-RVd can provide disease control in patients previously treated with and resistant to lenalidomide and/or bortezomib, a finding that is consistent with previous studies involving panobinostat-containing regimens7,14. This observation is likely due to the unique epigenetic mechanism of action of panobinostat, which targets multiple pathways that contribute to high-risk biology in MM and abrogates resistance to more established agents caused by epigenetic changes9,10,20.\n\nAEs commonly associated with regimens incorporating panobinostat, bortezomib, and/or lenalidomide include neutropenia, diarrhea, PN, and thrombocytopenia2,13,21. The most commonly reported TRAEs in this study included diarrhea and PN, which were all G1/2. This finding contrasts with the phase 3 PANORAMA 1 study in which 25% of patients experienced G3/4 diarrhea and 18% experienced G3/4 PN5,6. The toxicity profile differences observed between the present study and PANORAMA 1 may be related to the different method of bortezomib administration (subcutaneous vs. intravenous) and the reduced dose of panobinostat (10–15 mg vs. 20 mg). At the MTD for pano-RVd, G3/4 AEs were experienced by 80% of patients, the majority of which were hematological. This high percentage of G3/4 AEs reflects chemotherapy-related bone marrow suppression in the context of a four-drug treatment regimen administered to patients who had received a median of four prior lines of therapy22. Importantly, no patients were withdrawn because of TRAEs, and 40% of patients were able to receive maintenance therapy as part of the study, including one patient who had received 74 cycles at the time of data cut-off. Collectively, these data demonstrate that a reduced panobinostat dose (10 mg) can be effective and tolerated as part of a quadruplet regimen.\n\nThe reported patient response to pano-RVd is similar to outcomes reported with pano-Rd in the phase 2 study by Chari et al. (ORR 44% vs. 41%)7. However, the inclusion of bortezomib within the pano-RVd regimen resulted, as expected, in a higher rate of AEs, particularly neuropathy and thrombocytopenia. The two study populations were similar in terms of exposure to prior therapies, and percentage of patients refractory to bortezomib and lenalidomide at time of study entry. However, the studies had different approaches to dosing panobinostat7. In the pano-Rd study, panobinostat was dosed every other week, rather than the 2-weeks-on/1-week-off schedule in the current study. This alternative dosing schedule used by Chari et al. may have enabled patients to tolerate higher doses of study treatment.\n\nAnticipation of overlapping toxicities, particularly bone marrow suppression, led to the dosing strategy in this study, in which both lenalidomide and bortezomib were dose reduced relative to standard dosing of these agents. In spite of this strategy, dose reduction of lenalidomide, bortezomib and dexamethasone was required in 15%, 30%, and 30% of patients, respectively, and at least one treatment delay was required in 90% of patients. However, these reductions in dose enabled longer-term administration of all four agents, which presumably contributed to the sustained responses observed in some patients.\n\nThe small sample size is an important limitation of this study and inherent to phase 1 studies in general. While patients had received a substantial number of prior therapies, they were also relatively young, and thus it will be important to ascertain whether this quadruplet regimen could be tolerated in elderly patients23. However, the similar rates of TRAEs observed in patients <65 and ≥65 years old suggest that, indeed, pano-RVd may be tolerated in fit elderly patients.\n\nThis study was not designed or powered to definitively evaluate efficacy. However, the exploratory data reported herein are promising. Of note, in a previous study, pano-RVd was shown to have a favorable safety and efficacy profile in the front-line setting24. Panobinostat has also been shown to be effective and well tolerated when administered 1-week-on/1-week-off in a 28-day cycle in combination with lenalidomide and dexamethasone7 or with carfilzomib25, and once-weekly administration of bortezomib has been shown to improve the safety profile while maintaining efficacy26–28. As such, it would be of interest to evaluate a modified dosing regimen of pano-RVd using a 28-day cycle in which panobinostat is administered 1-week-on/1-week-off, along with weekly bortezomib, as such an approach may reduce the rates of thrombocytopenia and PN, while maintaining efficacy, and so translate efficiently into real-world practice23.\n\nThe relative lack of significant patient exposure to more recently approved agents such as carfilzomib, daratumumab, and elotuzumab is also a potential limitation of the study. Nonetheless, the results highlight the ability of panobinostat to re-sensitize patients to agents which, in most instances, they had previously become refractory to and were resistant. These data underscore the utility of panobinostat as an oral therapy with a unique, multifaceted mechanism of action that can partner with other agents to overcome resistance and enhance treatment response. Given the use of continuous/treat-to-progression therapy as a standard of care in MM, patients are more likely to become refractory to multiple agents after fewer lines of therapy, pointing to the need for additional treatment options for RRMM. As the dose and schedule of panobinostat are optimized, regimens incorporating this agent, such as pano-RVd, may contribute to further improvements in patient outcomes by targeting patterns of resistance to IMiDs and/or PIs, as well as to other novel agents29.\n\nSupplementary information\nSupplementary Figures\n\n Supplementary Table 1\n\n Supplementary Table 2\n\n Reproducibility checklist\n\n This work was presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, June 2016, and the European Hematology Association Virtual Congress, June 2020.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nThe online version contains supplementary material available at 10.1038/s41408-021-00407-5.\n\nAcknowledgements\nThe authors thank all patients involved in the study, as well as investigators and research staff in participating institutions. The authors thank Cara Valvona, PhD, of Watermeadow Medical, part of Ashfield Healthcare, Witney, UK, for providing medical writing support, funded by Secura Bio, Inc. San Diego, US, in accordance with Good Publication Practice guidelines. Funding: Novartis Pharmaceuticals Corporation funded this study. Secura Bio, Inc. funded the publication of this manuscript, including medical writing support.\n\nAuthor contributions\nAll authors were involved in data collection, analysis, and interpretation. All authors critically revised and approved the manuscript.\n\nData sharing statement\nAll data requests should be submitted to the corresponding author for consideration. Access to anonymized data may be granted following review.\n\nConflict of interest\nJ.P.L., J.M.R., K.C., K.M., D.W., and R.A.R. report no conflicts of interest. S.A.T. reports grants and personal fees from Celgene, grants and personal fees from Karyopharm, grants and personal fees from Sanofi, personal fees from Caelum, grants from Amgen, and grants from Janssen, outside the submitted work. C.S.M. discloses employment of a relative with Takeda; consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals; past research funding from Novartis; as well as research funding outside the scope of this submitted work from Janssen/Johnson & Johnson, TEVA, EMD Serono, AbbVie, Karyopharm, Sanofi, and Arch Oncology. D.G. is a consultant to Secura Bio, Inc. P.G.R. reports grants from BMS, grants and honoraria (advisory committee member) from Oncopeptides, Celgene, Takeda, and Karyopharm; and honoraria (advisory committee member) from Janssen, Sanofi, and Secura Bio, Inc. outside the submitted work.\n==== Refs\nReferences\n1. Rajkumar SV Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management Am. J. Hematol. 2018 93 981 1114 10.1002/ajh.25117 30400719 \n2. Durie BGM Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial Lancet 2017 389 519 527 10.1016/S0140-6736(16)31594-X 28017406 \n3. Pineda-Roman M VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma Leukemia 2008 22 1419 1427 10.1038/leu.2008.99 18432260 \n4. Siegel DS Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma J. Clin. Oncol. 2018 36 728 734 10.1200/JCO.2017.76.5032 29341834 \n5. 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Richardson PG Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting Blood Cancer J. 2018 8 109 10.1038/s41408-018-0141-0 30413684 \n24. Manasanch EE Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial Lancet Haematol. 2018 5 e628 e640 10.1016/S2352-3026(18)30174-1 30501870 \n25. Berdeja JG Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma Haematologica 2015 100 670 676 10.3324/haematol.2014.119735 25710456 \n26. Bringhen S Efficacy and safety of once-weekly bortezomib in multiple myeloma patients Blood 2010 116 4745 4753 10.1182/blood-2010-07-294983 20807892 \n27. Reeder CB Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma Blood 2010 115 3416 3417 10.1182/blood-2010-02-271676 20413666 \n28. Yagi H. F. A., et al. Once-weekly bortezomib in combination with reduced-dose dexamethasone and continuous low-dose oral cyclophosphamide for elderly patients with multiple myeloma. J. Hematol. Thrombo. Dis.5, (2017).\n29. Chim CS Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond Leukemia 2018 32 252 262 10.1038/leu.2017.329 29257139\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2044-5385",
"issue": "11(2)",
"journal": "Blood cancer journal",
"keywords": null,
"medline_ta": "Blood Cancer J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D000077767:Panobinostat",
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"pubdate": "2021-02-05",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "12531799;30413684;20807892;16728695;28504846;25482492;20413666;29296798;28017406;30501870;23950178;30400719;18432260;26362997;25710456;33301738;27751707;28203307;29341834;25242045;29257139;14695887;21497966;21292775;29317217",
"title": "Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.",
"title_normalized": "phase 1 open label study of panobinostat lenalidomide bortezomib dexamethasone in relapsed and relapsed refractory multiple myeloma"
} | [
{
"companynumb": "US-TAKEDA-2021TUS010724",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
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{
"abstract": "The effect of a direct-acting oral anticoagulant (DOAC) dose on intracerebral hemorrhage (ICH) severity and outcome remains unclear. The aim of this study is to clarify the frequency of off-label dosing of DOAC treatments in ICH patients and compare clinical characteristics.\n\n\n\nWe studied 43 patients with ICH who were treated with DOAC for nonvalvular atrial fibrillation before the onset of ICH. DOAC treatments were categorized into three groups based on the following doses: optimal dose, under-dose, and overdose.\n\n\n\nOverall, 31 patients were optimally dosed, 10 were under-dosed, and 2 were overdosed. CHADS2 and CHA2DS2-VASc scores were the highest in the overdose group (median, 4, 6, respectively) and the lowest in the optimal dose group (median, 2, 4, respectively) (p = 0.006, p = 0.005, respectively). ICH severity measured using the National Institutes of Health Stroke Scale scores was the highest in the overdose group (median, 26.5) and the lowest in the under-dose group (median, 6.5) (p = 0.244). Larger initial hematoma volume was observed in the overdose group. The ratio of good outcome (modified Rankin Scale score ≤ 2) was higher in the under-dose group (40%) than the other groups, but this difference was not significant.\n\n\n\nOur study shows only a few patients received overdosing of a DOAC before the onset of ICH, and they were associated with poorer functional outcomes. Conversely, under-dosing was associated with better functional outcomes than the other groups.",
"affiliations": "Department of Cerebrovascular Surgery, Saitama Medical University International Medical Center, Japan.;Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Japan. Electronic address: yujik@saitama-med.ac.jp.;Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Japan.;Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Japan.;Department of Cerebrovascular Surgery, Saitama Medical University International Medical Center, Japan.;Department of Cerebrovascular Surgery, Saitama Medical University International Medical Center, Japan.",
"authors": "Suzuki|Kaima|K|;Kato|Yuji|Y|;Hayashi|Takeshi|T|;Maruyama|Hajime|H|;Kikkawa|Yuichiro|Y|;Kurita|Hiroki|H|",
"chemical_list": "D000925:Anticoagulants",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2018.09.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "174()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Hematoma volume; Optimal dose; Outcome; Overdose; Under-dose",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D002543:Cerebral Hemorrhage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "63-67",
"pmc": null,
"pmid": "30216809",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The dose of direct oral anticoagulants and outcomes of intracerebral hemorrhage: Preliminary findings.",
"title_normalized": "the dose of direct oral anticoagulants and outcomes of intracerebral hemorrhage preliminary findings"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-NB-000749",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nHoigne's syndrome is characterized by the development of acute clinical manifestations which are mainly psycho-sensorial. Classically, these features immediately follow the injection of procaine penicillin G.\n\n\nMETHODS\nWe report a 59-year-old man who presented with psycho-organic manifestations that occurred just after the intravenous injection of ceftriaxone; to our knowledge, this is the first case of Hoigne's syndrome reported after an injection of this antibiotic.\n\n\nCONCLUSIONS\nThe pathophysiologic basis of this syndrome is still unknown. It is important to keep in mind its clinical characteristics, which may mimic immuno-allergic symptoms. It should be differentiated from anaphylactic manifestations because Hoigne's syndrome allows the continuation of the treatment.",
"affiliations": "Service de neurologie A, CHU Gui-de-Chauliac, Montpellier, France. Electronic address: landais-anne@voila.fr.;Service de neurologie A, CHU Gui-de-Chauliac, Montpellier, France.;Service de dermatologie, CHU Gui-de-Chauliac, Montpellier, France.;Service de neurologie A, CHU Gui-de-Chauliac, Montpellier, France.;Service de neurologie A, CHU Gui-de-Chauliac, Montpellier, France.",
"authors": "Landais|A|A|;Marty|N|N|;Bessis|D|D|;Pages|M|M|;Blard|J-M|JM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "35(3)",
"journal": "La Revue de medecine interne",
"keywords": "Allergie; Allergy; Ceftriaxone; Hoigne's syndrome; Syndrome de Hoigné",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001922:Brain Abscess; D002443:Ceftriaxone; D004342:Drug Hypersensitivity; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D013577:Syndrome",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "199-201",
"pmc": null,
"pmid": "23541140",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Hoigne syndrome following an intravenous injection of ceftriaxone: a case report.",
"title_normalized": "hoigne syndrome following an intravenous injection of ceftriaxone a case report"
} | [
{
"companynumb": "PHHY2014FR061461",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nRibociclib, one of the cyclin-dependent kinases (CDK) 4 and 6 inhibitors, in combination with endocrine therapies has been approved in the treatment of hormonal receptor positive, HER-2 negative metastatic breast cancer worldwide. Long-term usage of ribociclib with concomitant drugs, potential drug-drug interaction may develop which can limit the therapeutic value of CDK4/6 inhibitor.\n\n\nMETHODS\nA 62-year-old with history of non-insulin dependent diabetic, dyslipidemia, and essential hypertension was diagnosed with HR-positive, HER-2 negative metastatic breast cancer and treated with fulvestrant plus ribociclib. Four weeks after administration, elevated serum creatinine was observed, and then severe lactic acidosis with acute respiratory failure was subsequently reported. Ribociclib and fulvestrant were temporarily discontinued. Three days after renal replacement therapy, her clinical was stabilized. Combination ribociclib with metformin resulted in high plasma metformin levels and dangerous consequences. Hence, special precaution should be considered during concomitant treatment with sensitive transporter substrates.\n\n\nCONCLUSIONS\nMetformin associated lactic acidosis may potentially occur after combination with ribocilib, an uncommon but lethal complication from the interaction of these drugs, especially in patients who had preexisting renal impairment.",
"affiliations": "Division of Medical Oncology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand.;Division of Medical Oncology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand.;Division of Medical Oncology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand.",
"authors": "Lagampan|Chalita|C|;Poovorawan|Nattaya|N|;Parinyanitikul|Napa|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cnr2.1575",
"fulltext": "\n==== Front\nCancer Rep (Hoboken)\nCancer Rep (Hoboken)\n10.1002/(ISSN)2573-8348\nCNR2\nCancer Reports\n2573-8348\nJohn Wiley and Sons Inc. Hoboken\n\n34739192\n10.1002/cnr2.1575\nCNR21575\nCase Report\nCase Reports\nLactic acidosis, a potential toxicity from drug–drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report\nLagampan et al.\nLagampan Chalita 1\nPoovorawan Nattaya 1\nParinyanitikul Napa 1 napaparinyanitikul@gmail.com\nnapa.p@chula.ac.th\n\n1 Division of Medical Oncology, Department of Medicine, Faculty of Medicine King Chulalongkorn Memorial Hospital and Chulalongkorn University Bangkok Thailand\n* Correspondence\nNapa Parinyanitikul, Division of Medical Oncology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand.\nEmail: napaparinyanitikul@gmail.com; napa.p@chula.ac.th\n\n05 11 2021\n8 2022\n5 8 10.1002/cnr2.v5.8 e157526 9 2021\n30 5 2021\n28 9 2021\n© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nRibociclib, one of the cyclin‐dependent kinases (CDK) 4 and 6 inhibitors, in combination with endocrine therapies has been approved in the treatment of hormonal receptor positive, HER‐2 negative metastatic breast cancer worldwide. Long‐term usage of ribociclib with concomitant drugs, potential drug–drug interaction may develop which can limit the therapeutic value of CDK4/6 inhibitor.\n\nCase\n\nA 62‐year‐old with history of non‐insulin dependent diabetic, dyslipidemia, and essential hypertension was diagnosed with HR‐positive, HER‐2 negative metastatic breast cancer and treated with fulvestrant plus ribociclib. Four weeks after administration, elevated serum creatinine was observed, and then severe lactic acidosis with acute respiratory failure was subsequently reported. Ribociclib and fulvestrant were temporarily discontinued. Three days after renal replacement therapy, her clinical was stabilized. Combination ribociclib with metformin resulted in high plasma metformin levels and dangerous consequences. Hence, special precaution should be considered during concomitant treatment with sensitive transporter substrates.\n\nConclusion\n\nMetformin associated lactic acidosis may potentially occur after combination with ribocilib, an uncommon but lethal complication from the interaction of these drugs, especially in patients who had preexisting renal impairment.\n\nconcomitant\ndrug–drug interaction\nlactic acidosis\nrenal insufficiency\nsource-schema-version-number2.0\ncover-dateAugust 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:04.08.2022\nLagampan C , Poovorawan N , Parinyanitikul N . Lactic acidosis, a potential toxicity from drug–drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report. Cancer Reports. 2022;5 (8 ):e1575. doi:10.1002/cnr2.1575\n==== Body\npmc1 INTRODUCTION\n\nCyclin‐dependent kinase 4 and 6 inhibitors (CDK4/6), one of the significant milestone treatments have been broadly approved for the treatment of hormone‐receptor‐positive advanced breast cancer in the first, second, or later‐line settings. Adding palbociclib, ribociclib or abemaciclib with endocrine therapy have consistent significantly improved progression‐free survival and recently overall survival compared to endocrine therapy alone by several months regardless of line of treatment, menopausal status and visceral or bone metastases. All CDK4/6 inhibitors are generally well tolerated; neutropenia but not febrile neutropenia, fatigue, and nausea are the most common adverse events. 1 , 2 , 3 Moreover, patient‐reported outcome (PRO) from MONALEESA‐3 demonstrated that a combination of ribociclib and fulvestrant maintains the quality of life (QoL) compared with fulvestrant plus placebo. Besides, a clinically meaningful improvement from baseline in pain score was observed in the ribociclib group. 4 , 5\n\nNot only long‐term usage of ribociclib but also the problem of polypharmacy in the advanced breast cancer setting, potential drug–drug interactions (DDIs) may occur which can limit the therapeutic value of CDK4/6 inhibitor. Unlike palbociclib, ribociclib with a dose of 600 mg is a strong CYP3A4 inhibitor. Therefore, concomitant drugs either CYP3A4 inhibitors or CYP3A4 inducers that regularly prescribed in daily practice should be cautious. These interactions possibly will affect drug metabolisms which influence the efficacy and adverse toxicities. Additionally, previous in vitro study indicated that ribociclib has the potential to inhibit the activities of several drug transporters such as P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion‐transporting polypeptide (OATP1B1/1B3), organic cationic transporter‐1 and ‐2 (OCT1, OCT2), multidrug and toxin extrusion protein‐1 (MATE1), and bile salt export pump (BSEP). However, only BCRP, OCT2, MATE1 and BSEP were inhibited at clinically relevant concentration. 6 Metformin, one of widely used oral hypoglycemic drugs, is generally excreted unchanged into urine via the renal transporters MATE1, MATE2‐K, and OCT2. Therefore, inhibition of these transporters by ribociclib while metformin administers concomitantly can lead to increased metformin exposure and may deepens the harmful side effect of metformin. 7\n\nHere, we reported clinical information of HR‐positive, HER‐2 negative metastatic breast cancer patient treated with fulvestrant plus ribociclib. Possible adverse events such as elevated serum creatinine and lactic acidosis were observed and discussed with the current knowledge of scientific evidence.\n\n2 CASE REPORT\n\nA 62‐year‐old female with a history of NIDDM, dyslipidemia, and HT, previously was diagnosed with stage IIB left triple‐negative breast cancer in 2008. Left modified radical mastectomy and completed AC (doxorubicin and cyclophosphamide) followed by paclitaxel were given. Postoperative radiotherapy was performed after adjuvant chemotherapy. In December 2014, she developed a new right breast mass. She underwent right nipple‐sparing mastectomy with sentinel lymph node dissection with reconstruction. Rt breast pathology showed invasive ductal carcinoma, second primary breast cancer, pT1cN0M0, stage IA, (ER: 10%, PR: 10%, HER2‐negative, Ki67: 10%). Adjuvant TC (docetaxel and cyclophosphamide) for 4 cycles followed by tamoxifen was administered since July 2015. In February 2018, she developed chronic cough with weight loss for 5 kg. chest computed tomography (CT) scan showed mediastinal, right hilar, right interlobar lymph nodes metastases with multiple discrete lung nodules. The liver and bone were unremarkable. Mediastinal lymph node biopsy at 11R and 4R station was performed and reported invasive ductal carcinoma (ER: 60%, PR: negative, HER‐2 2+, and negative by ISH testing). She was then diagnosed with recurrent HR positive HER2 negative breast cancer. Due to her cough with dyspnea, palliative chemotherapy, docetaxel was given for eight cycles with partial response. Letrozole was then maintained for 9 months from August 2018 to May 2019. Because of disease progression with no visceral crisis and reimbursement policy, a second‐line combination of fulvestrant and palbociclib has been subsequently started since May 2019. Neither neutropenia nor GI toxicity was observed during this treatment. The following chest CT scan for evaluation was performed and showed a partial response as shown in Figure 1. She regularly took metformin 2000 mg/day, glipizide 5 mg/day, losartan 100 mg/day, amlodipine 10 mg/day, and simvastatin 10 mg/day since May 2019. Her serum creatinine was stable approximately 0.9–1.07 mg/dl during palbociclib treatment.\n\nFIGURE 1 Chest computed tomography (CT) scan of target lesion during palbociclib plus fulvestrant. In April 2019, baseline chest CT scan before fulvestrant plus palbociclib was started (A); In September 2019, chest CT scan showed decreasing in size of mediastinal and hilar lymph nodes (chest CT scan before changing palbociclib to ribociclib plus fulvestrant according to Thai OCPA) (B)\n\nIn September 2019, due to the Thai Oncology Prior Authorization (OCPA) program, the patient had been requested to change treatment from palbociclib to ribociclib (600 mg/day) plus fulvestrant. Otherwise, she cannot do reimbursement for palbociclib's cost. During follow up, occasional mild palpitation without QTc prolongation was reported. Neither neutropenia nor GI toxicity was observed during this treatment like previous palbociclib. However, approximately 4 weeks after changing to ribociclib, her serum creatinine gradually increased from 0.94 to 1.31 mg/dl. She currently took antidiabetic, antihypertensive and antidyslipidemic drugs without dose modification. Moreover, no herbal products or oral supplements or NSAIDs were reviewed. Her disease and treatment timeline were shown in Figure 2.\n\nFIGURE 2 Summary disease and treatment timeline\n\nIn November 2019, she was sent to the emergency department with progressive dyspnea for 1 week with intermittent epigastric pain, nausea but no vomiting. On admission, she had blood pressure 124/65 mmHg, pulse 106 beats per minute, respiratory rate 22 times per minute, and core body temperature 36.3°C. Initial investigations showed blood urea nitrogen 56 mg/dl, creatinine 2.8 mg/dl, sodium 133 mEq/L, potassium 5.6 mEq/L, chloride 102 mEq/L, bicarbonate 6 mEq/L, CPK 715 U/L (29–168 U/L), glucose 217 mg/dl and blood lactate 13.7 mmol/L (<2 mmol/L). Arterial blood gas showed severe mix wide anion gap acidosis plus normal gap metabolic acidosis (pH 7.12, pCO2 20.8 mmHg, Po2 66.8 mmHg, anion gap 25). Complete blood count indicated leukocytosis with left shift (WBC 21320/mm3, N 94%, L2.9%). The 12‐leads electrocardiogram (ECG) was performed in the emergency room as shown in Figure 3.\n\nFIGURE 3 Electrocardiograms (ECGs) 12‐lead during treatment with ribociclib. In September 2019 (prior ribociclib initiation), QTcF (Fridericia's correction formula for prolongation of QT interval) was 406 ms (A); In November 2019 at ER, ECG develops new‐onset arrhythmia with 423 ms QTcF (B)\n\nThis patient was diagnosed with severe lactic acidosis, suspected from metformin‐associated with preexisting renal insufficiency with acute respiratory failure. Ribociclib and fulvestrant were temporarily discontinued. Three days after renal replacement therapy, her clinical was stabilized; she was able to extubate and remove double lumen. Her renal function gradually recovered, and serum creatinine was reduced to 2.25 mg/dl. Additionally, her creatinine further decreased to 1.51 mg/dl in 1 month after discharge to the hospital. All changes in serum creatinine were shown in Figure 4. Drug–drug interactions from ribociclib with metformin have been reviewed previously. So, the potential reason for severe lactic acidosis is considered to be from metformin associated lactic acidosis (MALA) predisposing from pre‐renal acute kidney injury with drug–drug interaction from ribociclib with metformin.\n\nFIGURE 4 Changes of serum creatinine between October 2018 and April 2020. GRADE: Grade of serum creatinine increase according to Common Terminology Criteria for Adverse Events version.5.0; IPD, inpatient department; ER, emergency department\n\nOwing to her severe renal impairment persist after discharge, permanent withholding ribociclib was continued but fulvestrant monotherapy was given since December 2020. At that time, her chest CT scan in January 2020 showed progressive disease at lymph nodes, lung, and liver nodules. Fulvestrant was stopped and then capecitabine was given. Currently, she continuously received capecitabine with good performance status and response. No adverse event was observed.\n\n3 DISCUSSION\n\nHere, we demonstrate potential lethal toxicity from co‐administration of ribociclib, metformin, losartan, and amlodipine with simvastatin in advanced breast cancer patients who had preexisting renal impairment. However, no special adverse events have been identified during palbociclib treatment. Renal impairment was detected in 4 weeks after ribociclib initiation. Then, severe metabolic acidosis, lactic acidosis (blood lactate level 13.7 mmol/L) unfortunately occurred after 8 weeks of administration. After renal replacement therapy and drug interruption, she gradually recovered. Her serum creatinine turned to her baseline level previously.\n\nIn drug–drug interactions (DDIs), both palbociclib and ribociclib are substrates of the CYP3A4 enzymatic complex. 6 The co‐administration of palbociclib or ribociclib with strong or moderate CYP3A4 inhibitors or inducers may be either leading a risk of increased toxicity or diminished efficacy. Slightly different in the CYP3A4 enzymatic complex between two drugs, co‐administration with standard dose ribociclib may increase plasma concentrations of CYP3A4 substrates and accounts for more toxicities than palbociclib. Consistent with our report, no adverse event was observed during the administration of palbociclib. In contrast, elevation of serum creatinine and mild GI toxicities were reported a few weeks after the administration of ribociclib. Simvastatin, losartan, and amlodipine are the major CYP3A4 substrates. Taking ribociclib with these drugs affects drug metabolisms which subsequence develops toxicities as gradual renal impairment. Previously, concomitant simvastatin with palbociclib showed statin‐induced rhabdomyolysis in a case study. 11 Changing ribociclib to palbociclib may report similar adverse reactions. According to effect in membrane transporters, both palbociclib and ribociclib can potentially inhibit different membrane transporters and different locations. However, unlike ribociclib, palbociclib has a low potential inhibition of OATP1B1, OATP1B3, BSEP, OAT1, OAT3, and OCT2.\n\nTherefore, combination metformin with ribociclib can lead to the hypothetical inhibition of renal transporters which increase in metformin concentration and harmfulness which is higher frequency than combination with palbociclib.\n\nElevation of serum creatinine has been commonly recognized in many studies of abemaciclib. 2 , 12 Abemaciclib can inhibit renal efflux transporters, including MATE1 and MATE2‐K, thereby preventing the secretion of creatinine into the renal tubule. However, no impaired renal function, glomerular filtration rate, was established. 13 Similarly, ribociclib may inhibit renal transporters for instance OCT2, MATE1, BCRP, and BSEP at clinically relevant concentrations which lead to serum creatinine rising. 14 , 15 Additionally, close monitoring of creatinine levels in patients who have impaired renal function is critical. Unlike MONALEESA‐2 16 and MONALEESA‐7 study, 17 the elevation of serum creatinine was recognized in MONALEESA‐3. 4 , 5 The incidence of all grades and grade 3–5 of renal toxicity in patients who received ribociclib plus fulvestrant was 12.6% and 1.4%, respectively.\n\nLactic acidosis arises from the accumulation of blood lactate and protons in the body fluids and is related to cellular dysfunction and poor clinical outcomes. Disorders associated with tissue hypoxia from sepsis, cardiogenic or hypovolemic shock, and heart failure are the major causes of this problem. Furthermore, cancer itself and several drugs including metformin can trigger lactic acidosis. Metformin, a widely used oral antidiabetic drug in the biguanide class, is excreted unchanged via active tubular secretion by MATE1/2 and OCT2 in urine. 18 Under therapeutic conditions, ribociclib has a potential to inhibit OCT2, MATE1, BCRP, and BSEP. Hence, administration of metformin concomitant with ribociclib results in the increased exposure to metformin and a decrease in metformin renal clearance. 8 Ribociclib acts as inhibitors of various membrane transporters as shown in Figure 5. In our study, even though the plasma concentration of metformin was not evaluated, in the patient who had preexisting renal impairment, high plasma metformin levels well recognized and prompted initiating of MALA.\n\nFIGURE 5 According to an in vitro study, ribociclib acts as inhibitors of various membrane transporters especially BRCP, OCT2, MATE1, and BSEP. Metformin is a drug substrate demonstrated in the gray color transporter. However, only OCT2 and MATE1 play potential role of DDI between ribociclib and metformin demonstrated in green star. As a result, a greater amount of metformin would accumulate in the blood causing the appearance of adverse effects. ABC, ATP‐binding cassette; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; MATE1, multidrug and toxin extrusion protein; OATP, organic anion‐transporting polypeptide; OCT, organic cationic transporter; P‐gp, P‐glycoprotein; Adapted from Ther Adv Med Oncol 2019, Vol. 11: 1–43. 8 , 9 , 10\n\nClinical presentations of MALA are nonspecific and sometimes life threatening. Hypotension, hypothermia, cardiac dysrhythmias, and respiratory failure requiring mechanical ventilation have been reported. After metformin discontinuation, adequate supportive care includes mechanical respiratory support in patients with respiratory distress, assurance of suitable systemic perfusion, correction of fluid deficits and electrolyte abnormalities, treatment of hypothermia and hypoglycemia are suggested. 19 Other identified causes must also be effectively managed. Since metformin has a large distribution volume and slow rate of elimination from the deep compartment, long and multiple sessions of hemodialysis are necessary for preventing the rebound lactic acidosis in severe cases.\n\nIn resuming treatment with ribociclib, no available evidence supports using this drug in severe renal impairment (CrCl <30 ml/min). However, only a small proportion of ribociclib is eliminated by the renal route. 9 , 20 Ongoing study of ribociclib in healthy patients with various degrees of renal impairment is currently recruiting participants and waiting for good outcomes.\n\n4 CONCLUSION\n\nLactic acidosis may occur after the coadministration of ribociclib and metformin in patients with pre‐existing renal impairment. Change in metformin pharmacokinetics from drug–drug interactions with CDK4/6 inhibitors should be monitored cautiously especially in patients with preexisting renal impairment.\n\nHUMAN AND ANIMAL RIGHTS\n\nNo animals were used in this research. All research procedures were in accordance with the Helsinki Declaration of 1975, as revised in 2008.\n\nCONSENT FOR PUBLICATION\n\nThe study has been approved by Institutional Ethical Committee. Informed consent for publication was obtained from the patient.\n\nCONFLICT OF INTEREST\n\nThe authors have stated explicitly that there are no conflicts of interest in connection with this article.\n\nAUTHOR CONTRIBUTIONS\n\nAll authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. CL: Data curation, investigation, methodology, formal analysis, writing‐original draft, C.L.; Data curation, investigation, supervision, validation, N.Po.; Data curation, investigation, project administration, methodology, supervision, validation, N.Pa.\n\nACKNOWLEDGMENTS\n\nWe sincerely thankful to our patient for giving us opportunity to treat her. Special thanks to our general medicine staff who help provided us the database.\n\nDATA AVAILABILITY STATEMENT\n\nThe Authors allow the Journal to share all the published data, although there is not an online repository which they have been collected in.\n==== Refs\nREFERENCES\n\n1 Gao JJ , Cheng J , Bloomquist E , et al. CDK4/6 inhibitor treatment for patients with hormone receptor‐positive, HER2‐negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2020;21 (2 ):250‐260.31859246\n2 Spring LM , Wander SA , Andre F , Moy B , Turner NC , Bardia A . Cyclin‐dependent kinase 4 and 6 inhibitors for hormone receptor‐positive breast cancer: past, present, and future. Lancet. 2020;395 (10226 ):817‐827.32145796\n3 Petrelli F , Ghidini A , Pedersini R , et al. Comparative efficacy of palbociclib, ribociclib and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of randomized controlled trials. Breast Cancer Res Treat. 2019;174 (3 ):597‐604.30659432\n4 Slamon DJ , Neven P , Chia S , et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer: MONALEESA‐3. J Clin Oncol. 2018;36 (24 ):2465‐2472.29860922\n5 Slamon DJ , Neven P , Chia S , et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382 (6 ):514‐524.31826360\n6 Bellet M , Ahmad F , Villanueva R , et al. Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication. Ther Adv Med Oncol. 2019;11 :175883591983386. doi:10.1177/10.1177/1758835919833867\n7 Yu J , Petrie ID , Levy RH , Ragueneau‐Majlessi I . Mechanisms and clinical significance of pharmacokinetic‐based drug‐drug interactions with drugs approved by the U.S. Food and Drug Administration in 2017. Drug Metab Dispos. 2019;47 (2 ):135‐144.30442649\n8 König J , Müller F , Fromm MF . Transporters and drug‐drug interactions: important determinants of drug disposition and effects. Pharmacol Rev. 2013;65 (3 ):944‐966.23686349\n9 Thill M , Schmidt M . Management of adverse events during cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor‐based treatment in breast cancer. Ther Adv Med Oncol. 2018;10 :175883591879332. doi:10.1177/10.1177/1758835918793326\n10 Giacomini KM , Huang SM , Tweedie DJ , et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9 (3 ):215‐236.20190787\n11 Nersesjan V , Hansen K , Krag T , Duno M , Jeppesen TD . Palbociclib in combination with simvastatin induce severe rhabdomyolysis: a case report. BMC Neurol. 2019;19 (1 ):1‐7.30606131\n12 Sledge GW Jr , Toi M , Neven P , et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35 (25 ):2875‐2884.28580882\n13 Chappell JC , Turner PK , Pak YA , et al. Abemaciclib inhibits renal tubular secretion without changing glomerular filtration rate. Clin Pharmacol Ther. 2019;105 (5 ):1187‐1195.30449032\n14 Pabla N , Gibson AA , Buege M , et al. Mitigation of acute kidney injury by cell‐cycle inhibitors that suppress both CDK4/6 and OCT2 functions. Proc Natl Acad Sci USA. 2015;112 (16 ):5231‐5236.25848011\n15 Wilson BE , Mok K , Kiely BE , Nguyen R , Moylan E . Association between ribociclib and changes in creatinine in patients with hormone receptor positive metastatic breast cancer. Intern Med J. 2019;49 (11 ):1438‐1442.31713335\n16 O'Shaughnessy J , Petrakova K , Sonke GS , et al. Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2− advanced breast cancer in the randomized MONALEESA‐2 trial. Breast Cancer Res Treat. 2018;168 (1 ):127‐134.29164421\n17 Tripathy D , Im SA , Colleoni M , et al. Ribociclib plus endocrine therapy for premenopausal women with hormone‐receptor‐positive, advanced breast cancer (MONALEESA‐7): a randomised phase 3 trial. Lancet Oncol. 2018;19 (7 ):904‐915.29804902\n18 Gong L , Goswami S , Giacomini KM , Altman RB , Klein TE . Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22 (11 ):820‐827.22722338\n19 Teale KF , Devine A , Stewart H , Harper NJ . The management of metformin overdose. Anaesthesia. 1998;53 (7 ):698‐701.9771180\n20 Spring LM , Zangardi ML , Moy B , Bardia A . Clinical management of potential toxicities and drug interactions related to cyclin‐dependent kinase 4/6 inhibitors in breast cancer: practical considerations and recommendations. Oncologist. 2017;22 (9 ):1039‐1048.28706010\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2573-8348",
"issue": null,
"journal": "Cancer reports (Hoboken, N.J.)",
"keywords": "concomitant; drug-drug interaction; lactic acidosis; renal insufficiency",
"medline_ta": "Cancer Rep (Hoboken)",
"mesh_terms": null,
"nlm_unique_id": "101747728",
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"pages": "e1575",
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"pmid": "34739192",
"pubdate": "2021-11-05",
"publication_types": "D002363:Case Reports",
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"title": "Lactic acidosis, a potential toxicity from drug-drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report.",
"title_normalized": "lactic acidosis a potential toxicity from drug drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency a case report"
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"abstract": "At a time when the population shows increasing longevity, entities such as cancer and chronic kidney disease (CKD) are more frequently connected. In the United States, approximately 6% of the patients on hemodialysis have cancer. The challenge to manage oncologic patients with CKD in a hemodialytic program represents a great shortage of available information on the choice of the best drug, timing, dosage adjustments, dialysis method, and treatment safety. We present the case of a patient with prostate cancer and terminal CKD in hemodialysis, and the treatment sequence after the development of resistance to hormonal blockade therapy, which included docetaxel, enzalutamide, and radium-223.",
"affiliations": "University of Porto, Centro Hospitalar de São João, Department of Oncology . Porto , Portugal .;University of Porto, Centro Hospitalar de São João, Department of Oncology . Porto , Portugal .;University of Porto, Centro Hospitalar de São João, Department of Oncology . Porto , Portugal .;University of Porto, Centro Hospitalar de São João, Department of Urology . Porto , Portugal .;University of Porto, Centro Hospitalar de São João, Department of Radiation Oncology . Porto , Portugal .",
"authors": "Simões|Joana|J|;Augusto|Isabel|I|;Meireles|Sara|S|;Vendeira|Lurdes|L|;Silva|Carlos|C|",
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"doi": "10.4322/acr.2018.011",
"fulltext": "\n==== Front\nAutops Case RepAutops Case RepAutopsy & Case Reports2236-1960\nSão Paulo, SP: Universidade de São Paulo, Hospital Universitário\n 29780751autopsy-08-02e201801110.4322/acr.2018.011Article / Clinical Case Report\nMetastatic castration-resistant prostate cancer and the challenge of a patient with chronic\nkidney disease in hemodialysis\n \nMetastatic castration-resistant prostate cancer and the challenge of a patient with chronic\nkidney disease in hemodialysis\n\nSimões J, Augusto I, Meireles S, Vendeira L, Silva C\nSimões Joana aAugusto Isabel aMeireles Sara aVendeira Lurdes bSilva Carlos c\na \nUniversity of Porto, Centro Hospitalar de São João,\nDepartment of Oncology\n.\nPorto\n,\nPortugal\n.\n\nb \nUniversity of Porto, Centro Hospitalar de São João,\nDepartment of Urology\n.\nPorto\n,\nPortugal\n.\n\nc \nUniversity of Porto, Centro Hospitalar de São João,\nDepartment of Radiation Oncology\n.\nPorto\n,\nPortugal\n.\n\nAuthor contributions: Simões J drafted the manuscript and approved the final version\nto be published. Augusto I, Meireles S, Vendeira L and Silva C reviewed the manuscript and\napproved the final version to be published.\n\n\nConflict of interest: None\n\n\nCorrespondence\nJoana Simões\nDepartment of Oncology - Centro Hospitalar\nSão João - University of Porto\nAlameda Prof. Hernâni Monteiro\n– Porto – Portugal\nCEP: 4200-319\nPhone: +351 (91) 40 25 29\n7\n\njoana_clsimoes_29@hotmail.com18 4 2018 Apr-Jun 2018 8 2 e201801126 12 2017 09 2 2018 \nAutopsy and Case Reports. ISSN 2236-1960. Copyright © 2018.\n2018Autopsy and Case Reports\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution\nNon-Commercial License, which permits unrestricted non-commercial use, distribution,\nand reproduction in any medium provided the article is properly cited.\n\nAt a time when the population shows increasing longevity, entities such as cancer and chronic\nkidney disease (CKD) are more frequently connected. In the United States, approximately\n6% of the patients on hemodialysis have cancer. The challenge to manage oncologic patients\nwith CKD in a hemodialytic program represents a great shortage of available information on\nthe choice of the best drug, timing, dosage adjustments, dialysis method, and treatment safety.\nWe present the case of a patient with prostate cancer and terminal CKD in hemodialysis, and\nthe treatment sequence after the development of resistance to hormonal blockade therapy,\nwhich included docetaxel, enzalutamide, and radium-223.\n\n\nKeywords\nProstate cancerDialysisDocetaxelEnzalutamideRadium-223\n==== Body\nCASE REPORT\n\nA 57-year-old Caucasian man was referred to the Oncologic Center due to the diagnosis of prostate\ncancer. Besides being a smoker, he denied any other known disease, cardiovascular risk factors,\nuse of any medication, and had no family history of oncologic disorders. Eight years ago, he was\ndiagnosed with obstructive acute renal failure due to an enlarged and heterogeneous prostate\ndetected by ultrasound and the total prostate-specific antigen (tPSA) of 250 ng/mL (reference\nvalue: 4 ng/mL). He was treated with percutaneous nephrostomy and was submitted to a transrectal\ncore prostate biopsy afterward. The anatomic pathologic report showed a prostatic acinar adenocarcinoma\nGleason 8 (4+4). The computed tomography (CT) scan and bone scan showed metastatic lesions (mainly\npelvic and in the dorsal and lumbosacral spine). Therefore, he was submitted to bilateral subalbuginea\norchiectomy, and a month after the surgery his tPSA dropped to 26.34 ng/mL. Over the next 3 months,\nhe presented a marked renal function deterioration and started regular hemodialytic treatment.\nThe case was discussed in a multidisciplinary meeting, and it was decided to keep surveillance\nsince the patient’s neoplasia was steady.\n\n\n\nFive years after the initial symptoms, the castration-resistant status ensued. The disease\npresented clinical progression and the patient complained of severe bone pain, his tPSA rose\nto 768 ng/mL, and a bone scan showed new lesions—parietal bone, right scapula, D4-5,\n6th to 7th left costal ribs and right iliac (\nFigure 1\n).\n\n\nFigure 1 \nBone scans in the last 4 years. Image C corresponds to the bone scan at the time of progression,\nwith new lesions in parietal bone, right scapula, D4-5, 6th to 7th left costal ribs and right\niliac.\n\n\nEastern Cooperative Oncology Group (ECOG) performance status (PS) was 1. In face of the disease\nprogression, antalgic radiotherapy to the dorso-lumbar spine (D3-5 and D11-L4) with total\ndoses of 30 Gy, and chemotherapy with docetaxel 75 mg/m2 intravenously (21-21 days),\nprednisolone 10 mg/day, and bisphosphonate therapy with zoledronic acid 3 mg (with the dose\nadjusted to the renal failure) (21-21 days) were started. The latter was withdrawn after 6 months\nbecause of symptomatic hypocalcemia, and peripheral grade-1 sensory neuropathy was observed\nand considered to be an adverse event of docetaxel. After completing 10 cycles of chemotherapy,\nthe disease seemed steady, and the patient’s tPSA was 231 ng/mL.\n\n\n\nOne year after he started the first chemotherapy, the patient presented a new disease progression,\nwith worsening bone pain; the tPSA persistently increased (318 ng/mL) and the bone scan showed\nnew lesions (8th to 11th costal ribs and right pubis) (\nFigure 2\n).\n\n\nFigure 2 \nBone scan in March 2015. New progression with new lesions at the 8th to 11th costal ribs and\nright pubis.\n\n\nA second-line treatment with enzalutamide 160 mg per day was started. No adverse events were\nobserved during the whole treatment. One year later, the disease was stable with the tPSA 3,9\nng/mL and the bone scan results were unchanged. However, over the following 9 months, the patient\npresented new biochemical (tPSA of 217 ng/mL) and radiologic progression (new bone metastasis:\n3rd, 6th, 7th, and 11th right costal ribs) (\nFigure 3\n).\n\n\nFigure 3 \nBone scan in December 2016. New progression with new lesions in the 3rd, 6th, 7th, and 11th\nright costal ribs.\n\n\nAt the multidisciplinary meeting a third-line treatment with radium-223 (injections from\n4-4 weeks) was indicated. He completed six cycles of radium-223 in the following 8 months. No\nadverse events were reported. In the final evaluation, the patient was without pain and ECOG\nPS was 0. During the treatment, the tPSA determinations remained high, and at the end of the treatment\nit was 2364 ng/mL. However, the alkaline phosphatase (ALP) decreased and normalized at the end\nof the treatment (123 U/L) (\nFigure 4\n).\n\n\nFigure 4 \nBehavior of the total prostate-specific antigen (tPSA [ng/mL]) and alkaline phosphatase\n(ALP [U/L]) determinations during and after the treatment with radium-223.\n\n\nParadoxically, the bone scan showed new lesions in frontal bone, 4th to 5th left costal ribs,\n8th right and left costal ribs, sternum, and the right and left femurs, but less intensity of previous\nparietal, costal ribs and iliac lesions (\nFigure 5\n). The CT scan was unchanged.\n\n\nFigure 5 \nEvolution of bone scans through the years. The image on the right corresponds to the last\nevaluation, in September 2017, after the end of the treatment with radium-223.\n\n\nThe patient is currently undergoing regular follow-up examinations and will repeat the imaging\nrevaluation scan in 3 months.\n\n\nDISCUSSION\n\nDue to the increasing number of patients in hemodialysis requiring oncologic treatment with\nchemotherapy, oncologists are now expected to face serious dilemmas. A multidisciplinary\ndecision involving oncologists, urologists, and nephrologists is crucial to start a chemotherapeutic\nregimen in these types of patients. Experience with these patients is very scarce, as is the available\npublished information. The scarcity of case reports and small case series led us to raise the\nimportance of this theme.\n\n1\n\n,\n\n2\n\nThe drug selection is the first critical step.\n\n\n\nThe several therapeutic interactions and the need for treatment adjustments have to be considered.\nRegarding the docetaxel, although the main metabolic pathway is hepatic, and only a small part\nof the drug is excreted in the urine (less than 5-6%),\n\n3\n\n,\n\n4\n\nsome authors recommend the use of a reduced dose of 65 mg/m2 (level of evidence\nC).\n\n4\n\n,\n\n5\n\nHowever, we decided to use the full dose in our patient, according to the safety indicated by Ito\net al.\n\n6\n\n\n\n\nThe time of the administration of the chemotherapy in the setting of a hemodialytic patient should\nalso be taken into account to avoid drug clearance during the dialysis. In our case, the patient\nunderwent chemotherapy after the dialysis sessions; however, since docetaxel is non-dialyzable,\n\n3\n\nthe treatment may be administered regardless of the dialysis session. These adaptations should\nbe carefully carried out to optimize the efficacy of the selected drug.\n\n\n\nConcerning enzalutamide, although there is scarce information on the dose adjustments in hemodialysis\npatients,\n\n7\n\ncaution is advised in patients with severe renal impairment. The drug is primarily eliminated\nby hepatic metabolism, and the renal excretion is insignificant.\n\n8\n\nOur patient received the full dose of 160 mg per day, without toxicity and with a normal and controlled\ntensional profile.\n\n\n\nRegarding radium-223, it is considered a safe and well-tolerated option for castration-resistant\nprostate cancer (CRPC) patients with symptomatic bone metastases and no known visceral metastases.\nThe drug is rapidly cleared from the blood and is essentially excreted into the intestine, with\napproximately 5% being excreted in the urine.\n\n9\n\nNo dose adjustment is necessary for patients with renal function impairment.\n\n9\n\n\n\n\nThere are still some questions to be answered concerning the patient’s evaluation during\nand after treatment with radium-223. In this setting, the precise value of the tPSA and ALP as\nbiomarkers is still unclear, although there is a suggestion that ALP better represents the therapeutic\nresponse.\n\n10\n\nIn a phase 3 radium-223 trial (ALSYMPCA), 87% of the patients showed a decrease in ALP determination.\n\n10\n\nSimilarly, the imaging evaluation may not accurately document the clinical response. Eventual\nchanges in the bone scan and the CT scan have to be interpreted with caution, due to the flare phenomenon.\nThe right timing for this evaluation is uncertain; however, according to the last Saint Gallen’s\nconsensus, the majority of the panel (41%) considered 3-4 months after the beginning of the treatment,\nalthough 27% favored the imaging study at the end, after completion of radium-223, and every\n3-4 months thereafter.\n\n11\n\n,\n\n12\n\nIn our case, we decided to do it after the end of the treatment. The results we have are certainly\nrelated to a flare situation since the patient had an optimal clinical response.\n\n\nCONCLUSION\n\nThere are many problems that oncologists find in patients with chronic kidney disease, especially\nregarding the safety of treatments in hemodialysis patients. For patients with CRPC, the exact\nchoice of drug, timing, and sequence of various therapies remains an inexact science, essentially\ndepending on the clinical history and performance status of the patient. In patients progressing\nduring or after docetaxel chemotherapy, other safe therapeutic options are available on a hemodialysis\nprogram. Cases like this are a challenge, given the lack of evidence in these types of patients.\nFor these reasons, pharmacokinetic and pharmacodynamic studies in cancer patients undergoing\nrenal replacement therapy, a population that is typically excluded from clinical trials, should\nbe further investigated.\n\n\nDECLARATION \n\nThis manuscript is in accordance with the institutional ethics committee, and the patient signed\nan informed consent.\n\n\n\nHow to cite: Simões J, Augusto I, Meireles S, Vendeira L, Silva C. Metastatic\ncastration-resistant prostate cancer and the challenge of a patient with chronic kidney\ndisease in hemodialysis. Autops Case Rep [Internet]. 2018;8(2):e2018011.\n\nhttp://dx.doi.org/10.4322/acr.2018.011\n\n\n\nFinancial support: None\n==== Refs\nREFERENCES\n1 \nJanus N , Launay-Vacher V , Thyss A , et al \n\nManagement of anticancer treatment in patients under chronic dialysis: results of the\nmulticentric CANDY (CANcer and DialYsis) study .\nAnn Oncol . 2013 ;24 (2 ):501 -7 .\n10.1093/annonc/mds344 .\n23038759 \n2 \nJanus N , Launay-Vacher V , Deray G , Thyss A , Thariat J .\nManagement of chemotherapy in hemodialysis patients .\nBull Cancer . 2012 ;99 (3 ):371 -80 .\n22133734 \n3 \nClarke SJ , Rivory LP \nClinical pharmacokinetics of docetaxel .\nClin Pharmacokinet . 1999 ;36 (2 ):99 -114 .\n10.2165/00003088-199936020-00002 .\n10092957 \n4 \nJanus N , Thariat J , Boulanger H , Deray G , Launay-Vacher V \n\nProposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients .\nAnn Oncol . 2010 ;21 (7 ):1395 -403 .\n10.1093/annonc/mdp598 .\n20118214 \n5 \nHochegger K , Lhotta K , Mayer G , Czejka M , Hilbe W \n\nPharmacokinetic analysis of docetaxel during haemodialysis in a patient with locally\nadvanced non-small cell lung cancer .\nNephrol Dial Transplant . 2007 ;22 (1 ):289 -90 .\n10.1093/ndt/gfl498 .\n16935890 \n6 \nIto H , Inamura S , Taga M , et al \n\nA case on hemodialysis with castration-resistant prostate cancer which responded to combination\nchemotherapy with docetaxel and prednisolone .\nGan To Kagaku Ryoho . 2013 ;40 (9 ):1245 -7 .\n24047790 \n7 \nTsang ES , de Haan M , Eigl BJ \n\nA case report of enzalutamide administration in a dialysis-dependent patient with castration-resistant\nprostate cancer .\nJ Oncol Pharm Pract . 2017 :1 .\n28147927 \n8 \nGibbons JA , Ouatas T , Krauwinkel W , et al \nClinical pharmacokinetic studies of enzalutamide .\nClin Pharmacokinet . 2015 ;54 (10 ):1043 -55 .\n10.1007/s40262-015-0271-5 .\n25917876 \n9 \nNguyen NC , Shah M , Appleman LJ , Parikh R , Mountz JM \n\nRadium-223 therapy for patients with metastatic castrate-resistant prostate cancer:\nan update on literature with case presentation\n .\nInt J Mol Imaging . 2016 ;2016 :1 .\n10.1155/2016/2568031 .\n27774318 \n10 \nSartor O , Coleman RE , Nilsson S , et al \n\nAn exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific\nantigen dynamics in the phase 3 ALSYMPCA trial with radium-223 .\nAnn Oncol . 2017 ;28 (5 ):1090 -7 .\n10.1093/annonc/mdx044 .\n28453701 \n11 \nParker C , Nilsson S , Heinrich D , et al \n\nAlpha emitter radium-223 and survival in metastatic prostate cancer .\nN Engl J Med . 2013 ;369 (3 ):213 -23 .\n10.1056/NEJMoa1213755 .\n23863050 \n12 \nKeizman D , Fosboel MO , Reichegger H , et al \n\nImaging response during therapy with radium-223 for castration-resistant prostate cancer\nwith bone metastases-analysis of an international multi- center database .\nProstate Cancer Prostatic Dis . 2017 ;20 (3 ):289 -93 .\n10.1038/pcan.2017.6 .\n28244493\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2236-1960",
"issue": "8(2)",
"journal": "Autopsy & case reports",
"keywords": "Dialysis; Docetaxel; Enzalutamide; Prostate cancer; Radium-223",
"medline_ta": "Autops Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101640070",
"other_id": null,
"pages": "e2018011",
"pmc": null,
"pmid": "29780751",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "10092957;22133734;23038759;27774318;28453701;16935890;24047790;28147927;25917876;28244493;23863050;20118214",
"title": "Metastatic castration-resistant prostate cancer and the challenge of a patient with chronic kidney disease in hemodialysis.",
"title_normalized": "metastatic castration resistant prostate cancer and the challenge of a patient with chronic kidney disease in hemodialysis"
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"activesubstancename": "PREDNISOLONE"
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"abstract": "BACKGROUND\nMetformin-associated lactic acidosis is a well-known life-threatening complication of metformin. We here report the case of a patient who developed metformin-associated lactic acidosis without organ manifestations, due to the simultaneous ingestion of an overdose of metformin and alcohol, and who recovered with high-flow high-volume intermittent hemodiafiltration.\n\n\nMETHODS\nA 44-year-old Asian woman with type 2 diabetes attempted suicide by ingesting 10 tablets of metformin 500 mg and drinking approximately 600 mL of Japanese sake containing 15% alcohol. She was transferred to our emergency department because of disturbed consciousness. Continuous intravenous administration of noradrenalin (0.13 μg/kg per minute) was given because she was in shock. Laboratory findings included a lactate level of 119 mg/dL (13.2 mmol/L), bicarbonate of 14.5 mmol/L, and serum metformin concentration of 1138 ng/mL. She was diagnosed as having metformin-associated lactic acidosis worsened by alcohol. After 4560 mL of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl- 113 mEq/L, HCO3- 25 mEq/L) was administered, high-flow high-volume intermittent hemodiafiltration. (dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h to treat metabolic acidosis and remove lactic acid and metformin. Consequently, serum metformin concentration decreased to 136 ng/mL and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 12, she was moved to the psychiatry ward.\n\n\nCONCLUSIONS\nHFHV-iHDF may be able to remove metformin and lactic acid efficiently and may improve the condition of hemodynamically unstable patients with metformin-associated lactic acidosis.",
"affiliations": "Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan. hideshi@gifu-u.ac.jp.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Division of Clinical Laboratory, Gifu University Hospital, Gifu, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.;Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.",
"authors": "Suzuki|Kodai|K|;Okada|Hideshi|H|;Yoshida|Shozo|S|;Okamoto|Haruka|H|;Suzuki|Akio|A|;Suzuki|Keiko|K|;Yamada|Yuto|Y|;Hayashi|Hideki|H|;Yasuda|Ryu|R|;Fukuta|Tetsuya|T|;Kitagawa|Yuichiro|Y|;Miyake|Takahito|T|;Kawaguchi|Tomonori|T|;Watanabe|Takatomo|T|;Doi|Tomoaki|T|;Kumada|Keisuke|K|;Ushikoshi|Hiroaki|H|;Sugiyama|Tadashi|T|;Itoh|Yoshinori|Y|;Ogura|Shinji|S|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
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"doi": "10.1186/s13256-018-1809-6",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 180910.1186/s13256-018-1809-6Case ReportEffect of high-flow high-volume-intermittent hemodiafiltration on metformin-associated lactic acidosis with circulatory failure: a case report Suzuki Kodai koudysir@gifu-u.ac.jp 1Okada Hideshi +81-58-230-6448hideshi@gifu-u.ac.jp 1Yoshida Shozo shozo@gifu-u.ac.jp 1Okamoto Haruka palpal_4leaves@yahoo.co.jp 1Suzuki Akio akio@gifu-u.ac.jp 2Suzuki Keiko ksuzuki@gifu-u.ac.jp 2Yamada Yuto yy1108@gifu-u.ac.jp 2Hayashi Hideki hayashih@gifu-pu.ac.jp 34Yasuda Ryu yasuryu1984@gmail.com 1Fukuta Tetsuya tetsuya.fukuta.05.05@gmail.com 1Kitagawa Yuichiro northdog1985@yahoo.co.jp 1Miyake Takahito kyounin_com@hotmail.com 1Kawaguchi Tomonori tomtomdomo@yahoo.co.jp 1Watanabe Takatomo takawata-cardio@gifu-u.ac.jp 5Doi Tomoaki tomo-you-kei@mbr.nifty.com 1Kumada Keisuke kkumada@gifu-u.ac.jp 1Ushikoshi Hiroaki hiroakiu@gifu-u.ac.jp 1Sugiyama Tadashi tsugi@gifu-pu.ac.jp 34Itoh Yoshinori yositou@gifu-u.ac.jp 2Ogura Shinji oguras@gifu-u.ac.jp 11 0000 0004 0370 4927grid.256342.4Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194 Japan 2 grid.411704.7Department of Pharmacy, Gifu University Hospital, Gifu, Japan 3 0000 0000 9242 8418grid.411697.cLaboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan 4 0000 0000 9242 8418grid.411697.cCommunity Healthcare Pharmacy, Gifu Pharmaceutical University, Gifu, Japan 5 grid.411704.7Division of Clinical Laboratory, Gifu University Hospital, Gifu, Japan 29 9 2018 29 9 2018 2018 12 28011 7 2018 20 8 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\nMetformin-associated lactic acidosis is a well-known life-threatening complication of metformin. We here report the case of a patient who developed metformin-associated lactic acidosis without organ manifestations, due to the simultaneous ingestion of an overdose of metformin and alcohol, and who recovered with high-flow high-volume intermittent hemodiafiltration.\n\nCase presentation\nA 44-year-old Asian woman with type 2 diabetes attempted suicide by ingesting 10 tablets of metformin 500 mg and drinking approximately 600 mL of Japanese sake containing 15% alcohol. She was transferred to our emergency department because of disturbed consciousness. Continuous intravenous administration of noradrenalin (0.13 μg/kg per minute) was given because she was in shock. Laboratory findings included a lactate level of 119 mg/dL (13.2 mmol/L), bicarbonate of 14.5 mmol/L, and serum metformin concentration of 1138 ng/mL. She was diagnosed as having metformin-associated lactic acidosis worsened by alcohol. After 4560 mL of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl− 113 mEq/L, HCO3− 25 mEq/L) was administered, high-flow high-volume intermittent hemodiafiltration.\n\n(dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h to treat metabolic acidosis and remove lactic acid and metformin. Consequently, serum metformin concentration decreased to 136 ng/mL and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 12, she was moved to the psychiatry ward.\n\nConclusions\nHFHV-iHDF may be able to remove metformin and lactic acid efficiently and may improve the condition of hemodynamically unstable patients with metformin-associated lactic acidosis.\n\nKeywords\nMetforminMetformin-associated lactic acidosisHemodiafiltrationDiabetesissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCurrently, metformin is the first-line agent for the treatment for type 2 diabetes [1]. Metformin-associated lactic acidosis (MALA) is a well-known, life-threatening, rare complication, with an incidence of less than 10 per 100,000 patients a year [2]. Intensive care management is known to have gradually decreased the MALA-associated mortality rate. However, the mortality rate is still more than 20% [3].\n\nMALA usually occurs in metformin-treated diabetic patients with kidney manifestations due to reduced metformin excretion. Additionally, renal insufficiency decreases hydrogen excretion by the kidneys and leads to the development of acidosis independent of metformin [4]. Even if kidney function is normal, metformin overdose or ingestion of alcohol are risk factors for developing MALA. In kidney or non-kidney comorbidity, treatment for MALA comprises conventional renal replacement therapy (RRT), particularly continuous venovenous hemofiltration (CVVH) or hemodialysis (HD); however, the effort of RRT itself has been still unknown in the treatment for MALA due to both metformin overdose and alcohol ingestion.\n\nWe here report the case of a patient who developed MALA without organ manifestations by ingesting an overdose of metformin and alcohol simultaneously and who recovered with high-flow high-volume intermittent hemodiafiltration (HFHV-iHDF). This case suggests that HFHV-iHDF may become effective therapy for hemodynamically unstable patients with MALA due to simultaneous alcohol ingestion.\n\nCase presentation\nA 44-year-old Asian woman with type 2 diabetes and schizophrenia was being treated at our hospital. For type 2 diabetes, she received 1250 mg of metformin and 50 mg of sitagliptin phosphate hydrate a day and an intermediate-acting insulin 6 unit injection before bedtime. For schizophrenia, she received 8 mg of biperiden hydrochloride, 600 mg of valproic acid, 600 mg of carbamazepine, 15 mg of mirtazapine, 25 mg of clomipramine, 25 mg of chlorpromazine, 12.5 mg of promethazine, and 40 mg of phenobarbital. There was no other medical history. Her father had type 2 diabetes. She smokes two packs of cigarettes per day for 24 years, and drinks socially. After a quarrel with her mother, she attempted suicide by ingesting 10 tablets of 500 mg metformin and drinking about 600 mL of Japanese sake containing 15% alcohol.\n\nShe was transferred to our emergency department because of disturbed consciousness. On physical and neurological examination, her Glasgow Coma Scale was 3 (eye, 1; verbal, 1; motor, 1). Both pupils were 1.5 mm, and light reflexes were rapid. Her respiratory rate was 30 breaths per minute. Her heart rate was 120 beats per minute and blood pressure was 120/60 mmHg. She then received continuous intravenous administration of noradrenalin (0.13 μg/kg per minute) because she was in shock. Her body temperature was 35.5 °C. On auscultation, no crackles and wheezing were detected. There were no murmurs. Aspiration pneumonia was detected in both the lungs by computed tomography. Laboratory findings (normal ranges in parentheses) demonstrated aspartate transaminase level of 16 (7 to 35) IU/L, alanine transaminase level of 15 (7 to 40) IU/L, lactate dehydrogenase level of 273 (125 to 225) IU/L, creatinine level of 0.94 (0.60 to 1.20) mg/dL, and blood urea nitrogen level of 12.7 (8 to 20) mg/dL. Arterial blood gas analysis on 100% oxygen revealed a pH of 7.067, partial pressure of oxygen in arterial blood of 143 mmHg, partial pressure of carbon dioxide in arterial blood of 52.9 mmHg, bicarbonate of 14.5 mmol/L, base excess of − 16 mmol/L, lactate of 119 mg/dL (13.2 mmol/L), and blood glucose of 632 mg/dL. Serum metformin concentration was 1138 ng/mL (Table 1). Serum osmolality and sodium concentration were 309 mOsm/kg and 135 mEq/L, respectively. No ketone bodies were detected in her urine.Table 1 Laboratory findings on admission\n\nBiochemistry\t\n Total protein (g/dL)\t5.7\t\n Albumin (g/dL)\t3.6\t\n Aspartate transaminase (IU/L)\t16\t\n Alanine transaminase (IU/L)\t15\t\n Lactate dehydrogenase (IU/L)\t273\t\n Alkaline phosphatase (IU/L)\t225\t\n γ-glutamyltranspeptidase (IU/L)\t35\t\n Creatinine (mg/dL)\t0.94\t\n Blood urea nitrogen (mg/dL)\t12.7\t\n Sodium (mEq/L)\t135\t\n Potassium (mEq/L)\t3\t\n Chloride (mEq/L)\t96\t\n Total bilirubin (mg/dL)\t0.2\t\n C-reactive protein (mg/dL)\t0.39\t\n Hemoglobin A1c (%)\t9.9\t\n Blood sugar (mg/dL)\t632\t\n Serum osmolality (mOsm/kg)\t135\t\n Metformin concentration (ng/mL)\t1138\t\nComplete blood cell counts\t\n White blood cell (/μL)\t25,320\t\n Red blood cell (× 104/μL)\t459\t\n Hemoglobin (g/dL)\t13.7\t\n Platelet (×104/μL)\t24.9\t\nCoagulation status\t\n Activated partial thromboplastin time (sec)\t30.3\t\n Prothrombin time (%)\t> 120\t\n Prothrombin time-international normalized ratio\t0.86\t\nArterial blood gas\t\n FIO2\t1.0\t\n pH\t7.067\t\n PaCO2 (mmHg)\t52.9\t\n PaO2 (mmHg)\t143\t\n HCO3- (mmol/L)\t14.5\t\n Base excess (mmol/L)\t−16\t\n Lactate (mg/dL)\t119\t\n (mmol/L)\t13.2\t\n\n\nShe was diagnosed as having MALA worsened by alcohol. First, enforced sedation with midazolam was performed because of restlessness, tracheal intubation was carried out, and activated carbon and magnesium citrate were used for decontamination after gastric lavage. After 4560 ml of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl− 113 mEq/L, HCO3− 25 mEq/L) was administered, HFHV-iHDF (dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h using a polysulfone high-performance membrane (APS-15E, Asahi Kasei Medical, Tokyo, Japan) to treat metabolic acidosis and remove lactic acid and metformin. After that, her serum metformin concentration decreased to 136 ng/mL (Fig. 1) and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 2, HFHV-iHDF was carried out again, which improved her consciousness. On hospital day 10, she was extubated after aspiration pneumonia healed. On hospital day 12, she was moved to the psychiatry ward. She left the hospital 1 month after she moved to the psychiatry ward. When she left the hospital, she was discontinued from metformin administration. Although there is no recurrence of lactic acidosis, she was re-hospitalized into the psychiatry ward because she took an overdose of sleeping pills, 2 months after she left the hospital. Since then, she was in the hospital for the control of her schizophrenia and diabetes for more than 2 months.Fig. 1 Plot of bicarbonate (black rectangle), lactate (filled circle), and metformin (rectangle) versus time. HCO3- bicarbonate, HFHV-iHDF high-flow high-volume intermittent hemodiafiltration\n\n\n\nDiscussion and conclusions\nIn the present case, the lactic acidosis was caused by an excessive consumption of alcohol and metformin, in spite of no renal dysfunction. CVVH was generally performed for cases like this [5]. However, HFHV-iHDF was performed under stabilization of hemodynamics in the present case [5], and it was successful for rapidly removing metformin and lactic acid.\n\nMetformin, a first-line drug for type 2 diabetes, has a molecular weight of 165 g/mol, high water solubility, minimal plasma protein binding, and a large volume of distribution [4, 5]. It is excreted predominantly unchanged by the kidneys [4]. RRT is considered adequate for the treatment of MALA because it efficiently removes metformin and lactic acid by diffusion through the dialyzer membrane [6]. Additionally, a bicarbonate-buffered and high-sodium dialysate improves the metabolic acidosis and increases blood volume, thus enhancing the renal blood flow [6].\n\nCVVH and HD are some of the RRT methods that were previously studied. The clearance of a drug by CVVH was less than that with conventional HD. Therefore, CVVH should only be considered in patients who are too hemodynamically unstable to tolerate HD [7]. The reason of selecting HFHV-iHDF therapy for this hemodynamically unstable patient was that this therapy could remove metformin and lactate molecules more efficiently and sooner than CVVH does. A previous study reported that the plasma concentration of metformin after 24 h of CVVH was about one-third of that before CVVH. [5] Our data suggested that the plasma concentration of metformin after 6 h of HFHV-iHDF was about one-seventh as that before HFHV-iHDF. Considering MALA pathogenesis, removing metformin is a fundamental solution for curing MALA. A recent study suggested that metformin and lactate plasma concentration significantly correlated with mortality [8]. In HFHV-iHDF, hemodynamics of patients with critical MALA could worsen because of a large dialysate flow rate and a high filtration flow rate. However, HFHV-iHDF can be conducted for patients with MALA if sufficient transfusion can be maintained and under adequate critical care management.\n\nMALA can occur in patients without organ manifestations due to the simultaneous ingestion of an overdose of metformin and alcohol. Several factors are involved in the development of MALA because metformin has multiple mechanisms of producing lactic acidosis. Simultaneous ingestion of alcohol simultaneously markedly promotes the development of MALA. Metformin decreases blood sugar concentration by reducing gluconeogenesis, increasing the peripheral uptake of glucose, and decreasing fatty acid oxidation [4]. The inhibition of gluconeogenesis by metformin is localized to the primary energy-consuming reactions, and in the negative shift of the NADH/NAD+ redox potential [9]. Alcohol ingestion causes a sharp rise in hepatic NADH/NAD+ ratio, which in turn inhibits gluconeogenesis from lactate [9]. The MALA in our patient was caused by ingestion of an overdose of metformin (5 g); however, this dose was considered too small to cause MALA [10]. A report suggested that increasing the dose was associated with the development of MALA, with a median ingested dose of 15 g causing lactic acidosis compared to 2.8 g without lactic acidosis [10]. In this case, removal of metformin by HFHV-iHDF was useful, because alcohol ingestion influenced metformin metabolism.\n\nThis case demonstrated the effectiveness of HFHV-iHDF for MALA due to simultaneous alcohol ingestion. HFHV-iHDF may improve the conditions of hemodynamically unstable patients with MALA.\n\nAcknowledgements\nWe thank Chihiro Takada of Gifu University.\n\nAvailability of data and materials\nThe datasets obtained and analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nKodaiS, HOkada, SY, HOkamoto, RY, TF, YK.TM, TK, TW, TD, KK, HU, and SO treated the patient. AS, KeikoS, YY, HH, TS, and YI measured serum metformin concentration. KodaiS wrote the manuscript. HO revised and edited the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nIn Japan, a case report does not require ethics approval. The study adhered to the Ethical Guidelines for Medical and Health Research Involving Human Subjects established by the government of Japan.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report as well as any accompanying images. A copy of the written consent is available for review from the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Inzucchi SE Bergenstal RM Buse JB Diamant M Ferrannini E Nauck M Peters AL Tsapas A Wender R Matthews DR Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of diabetes Diabetes Care 2015 38 1 140 149 10.2337/dc14-2441 25538310 \n2. Lalau JD Kajbaf F Protti A Christensen MM De Broe ME Wiernsperger N Metformin-associated lactic acidosis (MALA): moving towards a new paradigm Diabetes Obes Metab 2017 19 1502 1512 10.1111/dom.12974 28417525 \n3. Kajbaf F Lalau JD Mortality rate in so-called “metformin-associated lactic acidosis”: a review of the data since the 1960s Pharmacoepidemiol Drug Saf 2014 23 1123 1127 10.1002/pds.3689 25079826 \n4. Kopec KT Kowalski MJ Metformin-associated lactic acidosis (MALA): case files of the Einstein Medical Center medical toxicology fellowship J Med Toxicol 2013 9 61 66 10.1007/s13181-012-0278-3 23233435 \n5. Guo PY Storsley LJ Finkle SN Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin Semin Dial 2006 19 80 83 10.1111/j.1525-139X.2006.00123.x 16423187 \n6. Seidowsky A Nseir S Houdret N Fourrier F Metformin-associated lactic acidosis: a prognostic and therapeutic study Crit Care Med 2009 37 2191 2196 10.1097/CCM.0b013e3181a02490 19487945 \n7. Nguyen HL Concepcion L Metformin intoxication requiring dialysis Hemodial Int 2011 15 S68 S71 10.1111/j.1542-4758.2011.00605.x 22093605 \n8. Boucaud-Maitre D Ropers J Porokhov B Altman JJ Bouhanick B Doucet J Girardin E Kaloustian E Lassmann Vague V Emmerich J Lactic acidosis: relationship between metformin levels, lactate concentration and mortality Diabet Med 2016 33 1536 1543 10.1111/dme.13098 26882092 \n9. Dubas TC Johnson WJ Metformin-induced lactic acidosis: potentiation by ethanol Res Comm Chem Pathol Pharmacol 1981 33 21 31 \n10. Wills BK Bryant SM Buckley P Seo B Can acute overdose of metformin lead to lactic acidosis? Am J Emerg Med 2010 28 857 861 10.1016/j.ajem.2009.04.012 20887905\n\n",
"fulltext_license": "CC BY",
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"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Diabetes; Hemodiafiltration; Metformin; Metformin-associated lactic acidosis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000140:Acidosis, Lactic; D000328:Adult; D003924:Diabetes Mellitus, Type 2; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "280",
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"pmid": "30266098",
"pubdate": "2018-09-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Effect of high-flow high-volume-intermittent hemodiafiltration on metformin-associated lactic acidosis with circulatory failure: a case report.",
"title_normalized": "effect of high flow high volume intermittent hemodiafiltration on metformin associated lactic acidosis with circulatory failure a case report"
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"companynumb": "JP-BEXIMCO-2018BEX00026",
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"abstract": "Postpartum pain management is critical after vaginal delivery involving a second, third, or fourth degree laceration as patients heal from their repair. Uncontrolled postpartum pain can affect both the physical and mental recovery period, extend hospital stays, and increase the potential for serious adverse reactions with pain medications. In light of the opioid crisis and increase in dependency after utilization, finding alternatives for pain management after procedures is paramount. The need for a safe, effective, long-acting medication to treat postpartum and postoperative pain has reached a critical point in the current healthcare climate.\n\n\n\nTo minimize pain after vaginal delivery, we assessed the effectiveness of liposomal bupivacaine vs plain bupivacaine injected into the perineum after second, third, or fourth degree lacerations. We hypothesized that the liposomal bupivacaine study group would have less vaginal pain, analgesic usage, and improved quality of life compared with the plain bupivacaine control group.\n\n\n\nThis is a single-blinded randomized controlled trial with 120 subjects enrolled at Walter Reed National Military Medical Center, Bethesda, Maryland, from February 2018 to February 2019. After vaginal delivery and repair, study participants were randomized into 20-mL liposomal bupivacaine (study group) or 20-mL 0.25% plain bupivacaine (control group) injected into and around the perineal body bilaterally. On postpartum days 1, 3, and 7, pain scores and analgesics were recorded. Our primary outcome was vaginal pain score at postpartum day 3, analyzed with Wilcoxon rank-sum test. Our secondary outcomes included vaginal pain at postpartum days 1 and 7, pain with bowel movement, sleep disturbance, and pain's impact on activity, stress, and mood. Desired statistical power was achieved with 48 patients per group (total of 96 patients).\n\n\n\nA total of 60 patients were randomized to each group; 108 patients completed the study. Most patients (94%) had regional anesthesia. There was no statistically significant difference in the demographics between these groups. There were 25 obstetric anal sphincter injuries, equally distributed between the 2 groups (P>.99). There was no significant difference between vaginal pain scores at postpartum day 3 (control, 2 [1-3]; study, 2 [0-3]) (P=.63). This was also seen at postpartum day 1 (control, 2 [0-3]; study, 2 [0-3]) (P=.82) and postpartum day 7 (control, 1 [0-3]; study, 1 [0-2]) (P=.47). Cumulative pain scores for postpartum days 1, 3, and 7 failed to reach significance (study, 5 [3-8]; control, 6 [3-8]) (P=.83). Secondary analysis of pain with bowel movement and impact on sleep, activity, stress, and mood found no differences. Given that only 3 patients required outpatient opioids, there were insufficient data to calculate morphine equivalent differences.\n\n\n\nAfter obstetric lacerations, there is no proven benefit to lateral and intraperineal injection of liposomal bupivacaine over plain bupivacaine in postpartum vaginal pain scores, quality of life scores, or pain medication utilized. This may be due to low pain scores and opioid usage, both groups benefiting from the intervention, or ineffective perineal injection location.",
"affiliations": "Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, Maryland. Electronic address: katidengler13@gmail.com.;Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, Maryland.;Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, Maryland; Department of Obstetrics and Gynecology, Naval Medical Center Portsmouth, Portsmouth, Virginia.;Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, Maryland; Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Research Programs, Walter Reed National Military Medical Center, Bethesda, Maryland.;Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, Maryland.",
"authors": "Dengler|Katherine L|KL|;Simpson|Kelsey J|KJ|;Strauchon|Christopher J|CJ|;Shaddeau|Angela K|AK|;Brooks|Daniel I|DI|;Gruber|Daniel D|DD|",
"chemical_list": "D000779:Anesthetics, Local; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajogmf.2020.100115",
"fulltext": null,
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"issn_linking": "2589-9333",
"issue": "2(3)",
"journal": "American journal of obstetrics & gynecology MFM",
"keywords": "OASIS; liposomal bupivacaine; obstetrical laceration; perineal injection; plain bupivacaine; postpartum pain; quality of life scores; vaginal pain",
"medline_ta": "Am J Obstet Gynecol MFM",
"mesh_terms": "D000779:Anesthetics, Local; D002045:Bupivacaine; D005260:Female; D006801:Humans; D022125:Lacerations; D008396:Maryland; D010147:Pain Measurement; D010149:Pain, Postoperative; D011247:Pregnancy; D011788:Quality of Life",
"nlm_unique_id": "101746609",
"other_id": null,
"pages": "100115",
"pmc": null,
"pmid": "33345866",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A randomized controlled trial of liposomal bupivacaine for pain following obstetrical laceration.",
"title_normalized": "a randomized controlled trial of liposomal bupivacaine for pain following obstetrical laceration"
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"abstract": "OBJECTIVE\nBrain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety.\n\n\nMETHODS\nEligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility.\n\n\nRESULTS\nForty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations.\n\n\nCONCLUSIONS\nErlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.",
"affiliations": "Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. jwelsh@mdanderson.org",
"authors": "Welsh|James W|JW|;Komaki|Ritsuko|R|;Amini|Arya|A|;Munsell|Mark F|MF|;Unger|Wyatt|W|;Allen|Pamela K|PK|;Chang|Joe Y|JY|;Wefel|Jeffrey S|JS|;McGovern|Susan L|SL|;Garland|Linda L|LL|;Chen|Su S|SS|;Holt|Jamie|J|;Liao|Zhongxing|Z|;Brown|Paul|P|;Sulman|Erik|E|;Heymach|John V|JV|;Kim|Edward S|ES|;Stea|Baldassarre|B|",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2011.40.1174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "31(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; D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D016371:Cranial Irradiation; D004334:Drug Administration Schedule; D003875:Drug Eruptions; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D011799:Quinazolines; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "895-902",
"pmc": null,
"pmid": "23341526",
"pubdate": "2013-03-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16076699;20479691;14981169;9128946;21558074;20921461;18974934;15118073;17229875;15629610;21847041;1202204;17931798;10204198;10537357;13172684;18006754;20610543;16642476;15833866;21523486;15254054;17846417;21142856;19942357;12829672;18164847",
"title": "Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer.",
"title_normalized": "phase ii trial of erlotinib plus concurrent whole brain radiation therapy for patients with brain metastases from non small cell lung cancer"
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"abstract": "BACKGROUND\nThe perioperative use of epirubicin, cisplatin, and fluorouracil (ECF) significantly improves outcomes in patients with gastric and gastro-oesophageal (GO) cancers but is cumbersome to administer. Given the equivalence of epirubicin, oxaliplatin, and capectabine (EOX) with ECF in advanced setting, we analyzed the compliance, efficacy, and toxicity of perioperative EOX in resectable but locally advanced cancers.\n\n\nMETHODS\nThis is a retrospective analysis of prospectively maintained database of patients treated between January 2012 and September 2013 at Tata Memorial Centre. Patients were planned to receive 3# of neoadjuvant (NA) and 3# of adjuvant EOX (intravenous epirubicin 50 mg/m 2 D1, oxaliplatin 130 mg/m 2 , on D1, capecitabiine 1250 mg/m 2 D1-21) every 21 days. On completion of NA therapy, patients were planned to undergo gastrectomy and D2 lymphadenectomy.\n\n\nRESULTS\nA total of 99 patients (76% males, median age 51 years) were treated with perioperative EOX. Preoperatively, 93% patients completed EOX. Post-NA chemotherapy, 4 patients progressed, 1 patient died and 94 were taken up for surgery. Of these, 9 were inoperable and 85 patients underwent radical surgery. Of these, 71% (60/85) were able to complete three cycles of adjuvant EOX. The compliance to complete all 6 cycles of perioperative chemotherapy was 64%. Grade 3 and 4 toxicities were comparable to the MAGIC dataset apart from higher number of diarrhea in our patients.\n\n\nCONCLUSIONS\nIn patients with resectable GO adenocarcinoma, it is possible to deliver the MAGIC-type perioperative chemotherapy with EOX with better compliance, toxicity, and efficacy rates.",
"affiliations": "Department of Medical Oncology, Tata Memorial Centre, Mumbai, India.",
"authors": "Sirohi|Bhawna|B|;Barreto|Savio George|SG|;Singh|Ashish|A|;Batra|Swati|S|;Mittra|Abhishek|A|;Rastogia|Sameer|S|;Ramadwar|Mukta|M|;Shetty|Nitin|N|;Goel|Mahesh|M|;Shrikhande|Shailesh V|SV|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D015251:Epirubicin; D000069287:Capecitabine; D002945:Cisplatin; D005472:Fluorouracil",
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"issue": "10(4)",
"journal": "Journal of cancer research and therapeutics",
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"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D016208:Databases, Factual; D004334:Drug Administration Schedule; D015251:Epirubicin; D004938:Esophageal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D059035:Perioperative Period; D012189:Retrospective Studies; D013274:Stomach Neoplasms",
"nlm_unique_id": "101249598",
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"publication_types": "D016428:Journal Article",
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"title": "Epirubicin, oxaliplatin, and capectabine is just as \"MAGIC\"al as epirubicin, cisplatin, and fluorouracil perioperative chemotherapy for resectable locally advanced gastro-oesophageal cancer.",
"title_normalized": "epirubicin oxaliplatin and capectabine is just as magic al as epirubicin cisplatin and fluorouracil perioperative chemotherapy for resectable locally advanced gastro oesophageal cancer"
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"abstract": "The cardiovascular system is a major target of thyroid hormone action and the two systems are closely interlinked. It can be greatly impacted even with subtle alterations in thyroid function. Caution is needed when implementing thyroid hormone replacement in patients with severe hypothyroidism, especially in the setting of ischemic coronary artery disease. If not properly treated, myxedema may ensue. Given the high mortality of myxedema coma, supportive care may not always suffice and patients may require more invasive interventions. We present a challenging case of a patient with overt hypothyroidism with concurrent acute coronary syndrome which subsequently lead to myxedema coma and cardiogenic shock. A transcaval approach for the delivery of an Impella 5.0 (Abiomed Inc., Danvers, MA) was utilized in supporting this patient. To our knowledge, this is the first reported case that describes the use of a mechanical circulatory support in treating myxedema-induced cardiovascular collapse.",
"affiliations": "Division of Cardiovascular Medicine, St. John Providence Ascension Health System, Warren, MI, USA.;Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USA.;Division of Cardiovascular Medicine, St. John Providence Ascension Health System, Warren, MI, USA.",
"authors": "Arnautovic|Jelena Z|JZ|0000-0003-1227-8889;Connor-Schuler|Randi|R|;Ip|Randy|R|",
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"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2019/2595736Case ReportMechanical Circulatory Support in Management of Cardiogenic Shock and Myxedema Coma http://orcid.org/0000-0003-1227-8889Arnautovic Jelena Z. jzarnautovic@gmail.com\n1\nConnor-Schuler Randi \n2\nIp Randy \n1\n\n1Division of Cardiovascular Medicine, St. John Providence Ascension Health System, Warren, MI, USA\n2Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USAAcademic Editor: Manabu Shirotani\n\n2019 6 3 2019 2019 25957365 10 2018 21 1 2019 11 2 2019 Copyright © 2019 Jelena Z. Arnautovic et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The cardiovascular system is a major target of thyroid hormone action and the two systems are closely interlinked. It can be greatly impacted even with subtle alterations in thyroid function. Caution is needed when implementing thyroid hormone replacement in patients with severe hypothyroidism, especially in the setting of ischemic coronary artery disease. If not properly treated, myxedema may ensue. Given the high mortality of myxedema coma, supportive care may not always suffice and patients may require more invasive interventions. We present a challenging case of a patient with overt hypothyroidism with concurrent acute coronary syndrome which subsequently lead to myxedema coma and cardiogenic shock. A transcaval approach for the delivery of an Impella 5.0 (Abiomed Inc., Danvers, MA) was utilized in supporting this patient. To our knowledge, this is the first reported case that describes the use of a mechanical circulatory support in treating myxedema-induced cardiovascular collapse.\n==== Body\n1. Introduction\nThyroid function and the cardiovascular (CV) system have an intricate relationship as patients with untreated thyroid dysfunction may develop an accelerated onset of symptomatic CV disease [1]. Modifiable atherosclerotic risk factors, including hypercholesterolemia, diastolic hypertension, increased carotid intimal-media thickness, and reduced endothelial nitric oxide, accompany overt hypothyroidism and could be reversible with proper TH replacement [2]. Although there is a close relationship between thyroid function and cardiovascular health, there have been no interventional studies of TH replacement in patients with acute myocardial infarction that have been published to date, therefore making a causal relationship between thyroid dysfunction and outcomes difficult to ascertain [1].\n\nWe present a challenging case of a patient with overt hypothyroidism complicated by myxedema with concomitant ischemic heart disease. This case is also remarkable for the use of a transcaval access for the delivery of an Impella 5.0 (Abiomed Inc., Danvers, MA) in supporting myxedema-induced cardiovascular collapse, which to our knowledge has not been previously documented.\n\n2. Case Report\nA 41-year-old male, without regular medical care, initially presented in the outpatient setting with progressive fatigue, weight gain, shortness of breath, and lower extremity edema over the past year. At that time, he was diagnosed with hypothyroidism (TSH 136 uIU/mL) and was started on 50 μcg PO levothyroxine daily. Two days later, he presented to the emergency room with chest pain and worsening shortness of breath. The patient was admitted for further evaluation which included an ischemic workup for coronary artery disease.\n\nA diagnostic cardiac catheterization was performed and the patient was noted to have multivessel obstructive coronary disease with a severely reduced ejection fraction. The patient subsequently underwent stenting of the left anterior descending and left circumflex coronary arteries. However, within 24 hours, the patient developed cardiogenic shock and a second percutaneous intervention was emergently done to address the right coronary artery lesion. Due to patient's condition, an intra-aortic balloon pump (IABP) was utilized and he was transferred to another institution for escalation of care.\n\nUpon arrival to the second institution, vital signs demonstrated a blood pressure of 67/31 mmHg, a heart rate of 68 bpm, an oral temperature of 35.7°C, a respiratory rate of 14, and an oxygen saturation of 99% on 4 L nasal cannula. Evaluation of the patient was significant for altered mental status and signs of systemic hypoperfusion with cold extremities in the lower extremities. The physical exam also was positive for bilateral nonpitting edema in all extremities. Further pertinent positives on the physical exam were notable for thinned hair to the lateral eyebrows, macroglossia, a waxy, yellow appearance to his skin, and an absence of hair on the lower extremities.\n\nInitial laboratory findings included hemoglobin of 7.7 g/dL, platelets of 24 K/μL, and a TSH level of 51.09 uIU/mL with free T4 of 0.26 ng/dL and free T3<1.0 pg/mL. Thyroid peroxidase was also noted to be elevated at 209 IU/mL (normal < 9 IU/mL). An electrocardiogram was obtained which showed diffuse Q waves (Figure 1). Cardiac monitoring was reviewed which demonstrated low-voltage complexes with an intermittent junctional bradycardia. Bedside echocardiogram revealed severely reduced systolic ejection fraction of 10% with mild to moderate RV dysfunction.\n\nPatient's clinical presentation was consistent with myxedema coma, and the patient was treated with stress-dose steroids and intravenous levothyroxine. Given the refractory cardiogenic shock, the IABP was upgraded to a transcaval Impella 5.0 upon admission. Patient's clinical condition subsequently improved as his lactate cleared from 5.5 mmol/L to 1.1 mmol/L; vasopressors were discontinued; Impella wean commenced over the course of a few days. Unfortunately, his clinical course was complicated with acute ischemia of his right lower extremity on day 6 leading to acute renal failure and sepsis. Ischemia was likely multifactorial with a large 24F venous sheath from the Impella exerting pressure on the femoral artery also containing 5F arterial line; the patient also developed an aortic thrombus further impairing perfusion. Despite emergent revascularization efforts and Impella removal, the muscles were nonviable. Family was informed of the need for an above the knee amputation; however, the family decision was to proceed with comfort care and the patient died on the 8th day of hospitalization.\n\n3. Discussion\nThyroid function plays a significant role in the health of the cardiovascular system. Thyroid hormone activates cytoprotective mechanisms, stimulates cell growth, and promotes neoangiogenesis and metabolic adaptation. In the acute myocardial infarction setting, optimal thyroid function aids in cardioprotection by reducing myocardial damage and reversing left ventricular (LV) remodeling [3]. A recent meta-analysis showed that patients with subclinical hypothyroidism are at higher risk of developing cardiovascular events, particularly with TSH levels > 10 μU/L, and patients with untreated hypothyroidism are at an increased risk of bradycardia, systolic and diastolic dysfunction, and increased peripheral vasoconstriction [3, 4].\n\nPatients with newly diagnosed severe hypothyroidism and significant cardiovascular risk factors may present a difficult challenge for the clinician. Great caution is needed when implementing TH replacement in this subset of patients, as thyroxine (T4) therapy increases the metabolic demands of the body which can provoke myocardial ischemia. Patients at risk for ischemic heart disease may require risk stratification for coronary disease. If coronary insufficiency is apparent, prompt management should be implemented to improve the oxygen supply to the ischemic myocardium before increasing the myocardial demand with T4 [5].\n\nIt was likely that our patient infarcted prior to initial presentation to the outside facility and had a preexisting cardiomyopathy from long-standing, untreated, hypothyroidism in addition to underlying ischemic disease. Patient's presentation may be explained by cardiogenic shock alone. However, patient's preexisting cardiac insufficiency may have been further exacerbated after the initiation of T4 therapy along with an additional iodine load from the cardiac catheterization. This may have triggered a cascade of events that lead to the development of myxedema coma complicating the treatment plan.\n\nThe incidence of myxedema is roughly 0.22 per million people per year with mortality rates approaching 30-60% with treatment [6]. It can develop idiopathically or after additional stresses to the body such as infection, stroke, iodine contrast, and myocardial infarction in patients with preexisting hypothyroidism, as presented in our study [7, 8]. A common source of excess iodine exposure in many patients results from the use of iodinated contrast media (ICM) for radiological studies and procedures such as coronary angiography, which is well tolerated in most euthyroid individuals but may lead to thyroid dysfunction in susceptible groups [9, 10]. The prevalence of thyroid dysfunction after coronary angiogram contrast exposure is not very well described, and no specific guidelines exist [9]. Several studies have shown a clear and definitive association between ICM exposure and the development of overt hypothyroidism [9, 11, 12]. Case control studies suggest that ICM exposure at least doubles the risk of subsequent overt hyperthyroidism and triples the risk of overt hypothyroidism [9], and Lee et al. noted that 22% of their study population developed an abnormal TSH within one to four weeks of receiving an elective computed tomography scan [13].\n\nThe main mechanism for iodine contrast-induced hypothyroidism is known as a failure to escape the Wolff-Chaikoff effect, first described in 1948 [14]. This effect is usually transitory and does not typically lead to overt hypothyroidism. This escape process is mainly due to the downregulation and reduction in sodium/iodide symporter (NIS) expression resulting in decreased iodine transport into the thyroid and subsequent resumption of thyroid hormone synthesis, typically occurring 24 hours after excess iodine exposure [15–17].\n\nMonitoring of thyroid function should be considered especially in at-risk patients, as there is a potential for serious complications including the development of myxedema, as presented in this case study. Traditional treatment in patients who develop myxedema includes the use of steroids and TH replacement therapy. In patients with significant risk factors for coronary disease, caution should be exercised as giving high-dose TH replacement will exert an increase in metabolic demand in an otherwise ischemic prone heart. The use of invasive therapies, such as the use of mechanical circulatory support (MCS), can be considered especially in patients with concomitant myxedema coma and cardiogenic shock as they can help support myocardial function by unloading the left ventricle and reduce diastolic volume. Multiple trials have demonstrated Impella's hemodynamic superiority when compared to IABP in shock and postarrest patients; its use in patients with concomitant myxedema has not been studied [18, 19].\n\nPatients who develop myxedema coma and subsequent cardiovascular collapse are rarely encountered in clinical practice. Myxedema carries a high mortality alone, and concomitant coronary ischemia increases the complexity of the management for these patients. Timing and magnitude of hemodynamic support are imperative to consider given the high mortality and complex nature of these patients. Our case demonstrates the potential for use of MCS for such patients with carefully designed protocols to preemptively detect and ameliorate serious complications, such as bleeding and limb ischemia.\n\nAbbreviations\nCV:Cardiovascular\n\nCT:Computed tomography\n\nCAD:Coronary artery disease\n\nEKG:Electrocardiogram\n\nIABP:Intra-aortic balloon pump\n\nICM:Iodinated contrast media\n\nLV:Left ventricle\n\nMCS:Mechanical circulatory support\n\nNIS:Sodium/iodide symporter\n\nTH:Thyroid hormone\n\nT4:Thyroxine\n\nTSH:Thyroid-stimulating hormone.\n\nDisclosure\nThe abstract was presented at the Critical Care Congress 2017, Honolulu, HI.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Admission electrocardiogram. Low-voltage junctional bradycardia with anteroseptal and inferior Q waves.\n==== Refs\n1 Razvi S. Jabbar A. Pingitore A. Thyroid hormones and cardiovascular function and diseases Journal of the American College of Cardiology 2018 71 16 1781 1796 10.1016/j.jacc.2018.02.045 29673469 \n2 Cappola A. R. Ladenson P. W. Hypothyroidism and atherosclerosis The Journal of Clinical Endocrinology & Metabolism 2003 88 6 2438 2444 10.1210/jc.2003-030398 2-s2.0-0037631308 12788839 \n3 de Castro A. L. Fernandes R. O. Ortiz V. D. Thyroid hormones improve cardiac function and decrease expression of pro-apoptotic proteins in the heart of rats 14 days after infarction Apoptosis 2016 21 2 184 194 10.1007/s10495-015-1204-3 2-s2.0-84954377463 26659365 \n4 Klein I. Danzi S. Thyroid disease and the heart Circulation 2007 116 15 1725 1735 10.1161/CIRCULATIONAHA.106.678326 2-s2.0-35148895083 17923583 \n5 Grais I. M. Sowers J. R. Thyroid and the heart The American Journal of Medicine 2014 127 8 691 698 10.1016/j.amjmed.2014.03.009 2-s2.0-84905649243 24662620 \n6 Klubo-Gwiezdzinska J. Wartofsky L. Thyroid emergencies Medical Clinics of North America 2012 96 2 385 403 10.1016/j.mcna.2012.01.015 2-s2.0-84858761164 22443982 \n7 Byrum D. Kirkwood P. Pituitary, thyroid, and adrenal disorders Advanced Critical Care Nursing 2009 St Louis, MO, USA Saunders Elsevier Inc 951 957 \n8 Gardner D. Endocrine emergencies Greenspan’s Basic & Clinical Endocrinology 2007 8th New York, NY, USA McGraw-Hill 868 871 \n9 Rhee C. M. Bhan I. Alexander E. K. Brunelli S. M. Association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism Archives of Internal Medicine 2012 172 2 153 159 10.1001/archinternmed.2011.677 2-s2.0-84856190005 22271121 \n10 Lee S. Y. Rhee C. M. Leung A. M. Braverman L. E. Brent G. A. Pearce E. N. A review: radiographic iodinated contrast media-induced thyroid dysfunction The Journal of Clinical Endocrinology & Metabolism 2015 100 2 376 383 10.1210/jc.2014-3292 2-s2.0-84922570751 25375985 \n11 Gartner W. Weissel M. Do iodine-containing contrast media induce clinically relevant changes in thyroid function parameters of euthyroid patients within the first week? Thyroid 2004 14 7 521 524 10.1089/1050725041517075 2-s2.0-3543039413 15307941 \n12 Rhee C. M. Lynch K. E. Zandi-Nejad K. Pearce E. N. Alexander E. K. Brunelli S. M. Iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism in a community-based cohort Endocrinology Studies 2013 3 2, article e8 10.4081/es.2013.e8 \n13 Lee S. Y. Chang D. L. F. He X. Pearce E. N. Braverman L. E. Leung A. M. Urinary iodine excretion and serum thyroid function in adults after iodinated contrast administration Thyroid 2015 25 5 471 477 10.1089/thy.2015.0024 2-s2.0-84928894263 25744578 \n14 Wolff J. Chaikoff I. L. Plasma inorganic iodide as a homeostatic regulator of thyroid function Journal of Biological Chemistry 1948 174 2 555 564 18865621 \n15 Eng P. H. K. Cardona G. R. Fang S. L. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein Endocrinology 1999 140 8 3404 3410 10.1210/endo.140.8.6893 2-s2.0-0033305353 10433193 \n16 Serrano-Nascimento C. da Silva Teixeira S. Nicola J. P. Nachbar R. T. Masini-Repiso A. M. Nunes M. T. The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/Akt signaling pathway Endocrinology 2014 155 3 1145 1156 10.1210/en.2013-1665 2-s2.0-84896878820 24424051 \n17 Pramyothin P. Leung A. M. Pearce E. N. Malabanan A. O. Braverman L. E. A hidden solution New England Journal of Medicine 2011 365 22 2123 2127 10.1056/NEJMcps1008908 2-s2.0-82555168424 22129257 \n18 Seyfarth M. Sibbing D. Bauer I. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction Journal of the American College of Cardiology 2008 52 19 1584 1588 10.1016/j.jacc.2008.05.065 2-s2.0-54349107151 19007597 \n19 Ouweneel D. M. Eriksen E. Sjauw K. D. Percutaneous mechanical circulatory support versus intra-aortic balloon pump in cardiogenic shock after acute myocardial infarction Journal of the American College of Cardiology 2017 69 3 278 287 10.1016/j.jacc.2016.10.022 2-s2.0-85010015292 27810347\n\n",
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"title": "Mechanical Circulatory Support in Management of Cardiogenic Shock and Myxedema Coma.",
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"abstract": "Classical Hodgkin lymphoma (cHL) is a non-AIDS-defining cancer with a good response to chemotherapy in the combined antiretroviral therapy (cART) era. The aim of the present study was to compare the characteristics, the response to treatment and the survival of advanced-stage cHL treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) between cART-treated HIV-positive and HIV-negative patients.\n\n\n\nWe retrospectively analyzed advanced-stage cHL patients from a single institution, uniformly treated with ABVD. All HIV-positive patients received cART concomitantly with ABVD.\n\n\n\nA total of 69 patients were included in the study: 21 were HIV-positive and 48 were HIV-negative. HIV-positive patients had more aggressive features at cHL diagnosis, such as worse performance status, more frequent bone marrow involvement and mixed cellularity histologic subtype. There were no differences in complete response rate (89% in HIV-positive vs. 91% in HIV-negative), P = 1; disease-free survival (DFS) [10-year DFS probability (95% CI) 70% (41-99%) vs. 74% (57-91%)], P = 0.907 and overall survival (OS) [10-year OS probability (95% CI) 73% (52-94%) vs. 68% (51-85%)], P = 0.904. On multivariate analysis, HIV infection did not correlate with worse OS.\n\n\n\nAlthough HIV-positive patients with cHL had more aggressive baseline features in this series, there were no differences in response rate or survival between HIV-positive and HIV-negative patients.",
"affiliations": "aDepartment of Hematology, ICO-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute bDepartment of Pathology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.",
"authors": "Sorigué|Marc|M|;García|Olga|O|;Tapia|Gustavo|G|;Baptista|Maria-Joao|MJ|;Moreno|Miriam|M|;Mate|José-Luis|JL|;Sancho|Juan M|JM|;Feliu|Evarist|E|;Ribera|Josep-Maria|JM|;Navarro|José-Tomás|JT|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D015658:HIV Infections; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "HIV-infection has no prognostic impact on advanced-stage Hodgkin lymphoma.",
"title_normalized": "hiv infection has no prognostic impact on advanced stage hodgkin lymphoma"
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{
"abstract": "This study was undertaken to evaluate safety and pharmacokinetics and to determine treatment doses of vorinostat plus bortezomib in Japanese patients with relapsed or refractory multiple myeloma (MM). Of 9 originally enrolled patients, 2 were refractory to bortezomib, and both experienced dose-limiting toxicity (DLT), prompting a protocol amendment to exclude bortezomib-refractory individuals. Patients not considered bortezomib refractory (N = 7) received 21-day cycles of 1.3 mg/m(2) intravenous bortezomib (Days 1, 4, 8, and 11) and oral vorinostat 400 mg (Days 1 through 14) and were further evaluated. Vorinostat and bortezomib treatment doses were determined by DLT and safety, tolerability, and treatment response were assessed. Of 7 enrolled patients, 6 were evaluated, and one developed DLTs. The most common adverse events were leukopenia, neutropenia, thrombocytopenia, diarrhea, nausea, decreased appetite, and vomiting. Combination of vorinostat plus bortezomib did not increase vorinostat exposure at Day 11 [AUC0-24 h ratio (95% CI) = 1.08 (0.80, 1.45)]; geometric mean AUC0-24 h ratio for bortezomib (90% CI) was 1.96 (1.24-3.12). Objective therapeutic response occurred in 3 patients, including 1 complete response and 2 partial responses. Vorinostat 400 mg plus bortezomib 1.3 mg/m(2) was safe and well-tolerated in Japanese patients with relapsed or refractory MM not considered bortezomib refractory (NCT00858234).",
"affiliations": "Department of Hematology and Oncology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan. yoshioga@is.icc.u-tokai.ac.jp.;Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.;Department of Hematology and Oncology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan.;Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.;Department of Hematology and Oncology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan.;Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Merck and Co., Inc., Kenilworth, NJ, USA.;MSD K.K., Tokyo, Japan.;MSD K.K., Tokyo, Japan.;MSD K.K., Tokyo, Japan.;National Cancer Center, Tokyo, Japan.",
"authors": "Ogawa|Yoshiaki|Y|;Ogura|Michinori|M|;Tobinai|Kensei|K|;Ando|Kiyoshi|K|;Suzuki|Tatsuya|T|;Watanabe|Takashi|T|;Ohmachi|Ken|K|;Uchida|Toshiki|T|;Hanson|Mary E|ME|;Tanaka|Yoshinobu|Y|;Koh|Yasuhiro|Y|;Shimamoto|Takashi|T|;Hotta|Tomomitsu|T|",
"chemical_list": "D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D000069286:Bortezomib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-015-1897-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "103(1)",
"journal": "International journal of hematology",
"keywords": "Bortezomib; HDAC inhibitor; Multiple myeloma; Phase I study; Vorinostat",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D000069286:Bortezomib; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D016896:Treatment Outcome; D000077337:Vorinostat",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "25-33",
"pmc": null,
"pmid": "26619834",
"pubdate": "2016-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "12780789;21501555;21247388;22072815;22726546;24055414;22234637;20306195;11535817;23040438;15461622;21799510;15173093;19575752;12826635;22506596;17970782;21351269;16855634;18297527;19671864;23293914;9753033",
"title": "A phase I study of vorinostat combined with bortezomib in Japanese patients with relapsed or refractory multiple myeloma.",
"title_normalized": "a phase i study of vorinostat combined with bortezomib in japanese patients with relapsed or refractory multiple myeloma"
} | [
{
"companynumb": "JP-TAKEDA-2016MPI001214",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCalcium channel inhibitors are being investigated as potential therapeutic adjuncts to reduce painful ciliary muscle spasm and control intraocular pressure in glaucoma. Relatively little is known about the effect of topical administration of calcium channel blockers in humans.\n\n\nOBJECTIVE\n(1) To describe prolonged fixed pupil dilation resulting from exposure to topical amlodipine (2) to review the evidence that links calcium channel blockers with mydriasis and (3) to discuss the implications for glaucoma pharmacotherapy.\n\n\nMETHODS\nSingle interventional case report, literature review (including human and animal studies) and analysis of reported adverse drug reactions (ADRs) records in the USA and UK.\n\n\nMETHODS\nA 35-year-old female doctor presented to eye casualty with blurred vision and bilateral, fixed, dilated pupils. A history of exposure to liquid amlodipine while preparing a paediatric chemotherapy regimen for a neuroblastoma patient was elicited. The patient was reassured and observed.\n\n\nRESULTS\nPupil function returned to normal within 48 h. A multi-national review of adverse drug reactions reports was conducted, as well as an extensive literature search for case reports and experimental studies. To the authors' knowledge this is the first report of amlodipine causing mydriasis and we discuss the potential molecular mechanism.\n\n\nCONCLUSIONS\nThis case is the first to suggest that calcium channel blockers can cause prolonged mydriasis. These agents have been investigated as potential adjuncts in glaucoma therapy. As accidental topical exposure to amlodipine can cause prolonged pupil dilation, it could precipitate angle closure in predisposed patients.",
"affiliations": "Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust , Cambridge , UK.",
"authors": "Roos|Jonathan C P|JC|;Haridas|Anjana S|AS|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2014.896016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "34(1)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Accidental exposure; amlodipine; antagonist; calcium channel blocker; fixed dilated pupil; glaucoma; preparation; pupil dilatation",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D017311:Amlodipine; D002121:Calcium Channel Blockers; D005260:Female; D005901:Glaucoma; D006801:Humans; D015878:Mydriasis",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "84-7",
"pmc": null,
"pmid": "24754408",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged mydriasis after inadvertent topical administration of the calcium channel antagonist amlodipine: implications for glaucoma drug development.",
"title_normalized": "prolonged mydriasis after inadvertent topical administration of the calcium channel antagonist amlodipine implications for glaucoma drug development"
} | [
{
"companynumb": "PHHY2015GB042908",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDespite the availability of various treatment options, a large proportion of patients with asthma have uncontrolled asthma in the United States. Consequently, the economic burden of suboptimal asthma control is anticipated to substantially grow in the next 20 years, adversely impacting patients' quality of life. Therefore, there is an urgent need for effective treatments to achieve and maintain asthma control. The Global Initiative for Asthma recommends tiotropium as a controller medication for patients with asthma aged ≥6 years, based on evidence from several randomized controlled trials. However, more real-world data on the effectiveness of tiotropium are required to establish a broad picture of its use in everyday clinical practice.\n\n\nMETHODS\nHerein, we present 3 case reports of patients diagnosed with uncontrolled or fixed obstructive asthma not responding to inhaled corticosteroids (ICS) or ICS + long-acting β2-agonists (LABAs) and/or leukotriene receptor antagonists (LTRAs).\n\n\nRESULTS\nAll 3 patients were prescribed tiotropium, irrespective of their age. Tiotropium improved lung function and quality of life, as indicated by the forced expiratory volume in 1 s/forced vital capacity ratio and the Asthma Control Test score. Furthermore, the addition of tiotropium reduced the use of rescue medication.\n\n\nCONCLUSIONS\nHence, the results from these case reports highlight that tiotropium could be an effective and safe add-on treatment option for patients across a range of age groups with uncontrolled or fixed obstructive asthma receiving prior ICS or ICS + LABA and/or LTRA therapy.",
"affiliations": "Division of Pulmonary, Allergy and Critical Care, Department of Medicine, NorthShore University HealthSystem, IL, USA.;Terry Reilly Health Centers, ID, USA.;Piedmont Healthcare Department of Pulmonary, Critical Care and Sleep Medicine, GA, USA.;Allergy Immunology & Asthma Medical Group, Inc, CA, USA.",
"authors": "Mosnaim|Giselle|G|;Bizik|Brian K|BK|;Wilson|Christy|C|;Bensch|Gregory|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/02770903.2021.1914648",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0903",
"issue": null,
"journal": "The Journal of asthma : official journal of the Association for the Care of Asthma",
"keywords": "Case reports; control/management; education; pharmacotherapy; treatment",
"medline_ta": "J Asthma",
"mesh_terms": null,
"nlm_unique_id": "8106454",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "33974467",
"pubdate": "2021-05-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of add-on tiotropium in the management of uncontrolled asthma: a patient case series.",
"title_normalized": "efficacy and safety of add on tiotropium in the management of uncontrolled asthma a patient case series"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-08953",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALBUTEROL SULFATE"
},
"drugadd... |
{
"abstract": "We present a 66 year old gentleman with constrictive pericarditis and persistent atrial flutter. Initial management with oral loop diuretics was successful until he developed persistent atrial flutter. Once in atrial flutter the patient developed progressive signs of right heart failure resistant to high dose intravenous loop diuretics. He was referred to a tertiary electrophysiology service where he underwent successful isthmus catheter ablation and reverted to sinus rhythm. His responsiveness to diuretics improved immediately. His symptoms improved and he was discharged 48 h later on oral diuretics. He remains well one month after discharge. This is the first reported case of symptomatic improvement in a patient with constrictive pericarditis and persistent atrial flutter with targeted treatment of the dysrhythmia. This offers a possible short-term palliation option in a group of patients where definitive surgical management carries too high a risk.",
"affiliations": "Department of Cardiology, Barts Health NHS Trust, United Kingdom.;Department of Cardiology, Barts Health NHS Trust, United Kingdom.;Department of Cardiology, Barts Health NHS Trust, United Kingdom.;Department of Cardiology, Barts Health NHS Trust, United Kingdom. Electronic address: krishnarajrathod@gmail.com.;Department of Cardiology, Barts Health NHS Trust, United Kingdom.",
"authors": "Pittaway|James F|JF|;Presern|Emma|E|;Rathod|Vrijraj S|VS|;Rathod|Krishnaraj S|KS|;Deaner|Andrew|A|",
"chemical_list": "D004232:Diuretics",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-4832",
"issue": "67(4)",
"journal": "Indian heart journal",
"keywords": "Ablation; Atrial flutter; Constrictive pericarditis; Heart failure",
"medline_ta": "Indian Heart J",
"mesh_terms": "D000368:Aged; D001282:Atrial Flutter; D017115:Catheter Ablation; D004232:Diuretics; D004351:Drug Resistance; D004452:Echocardiography; D004562:Electrocardiography; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D010494:Pericarditis, Constrictive; D013902:Radiography, Thoracic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0374675",
"other_id": null,
"pages": "377-80",
"pmc": null,
"pmid": "26304574",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3812191;10426832;22893247",
"title": "Atrial flutter ablation in a case of diuretic resistant constrictive pericarditis.",
"title_normalized": "atrial flutter ablation in a case of diuretic resistant constrictive pericarditis"
} | [
{
"companynumb": "GB-CONCORDIA PHARMACEUTICALS INC.-E2B_00007648",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditio... |
{
"abstract": "A 72-year-old man presented to our ED less than 24 hours following the acute onset of nausea, vomiting, and diarrhea. Within 12 hours of symptom onset, he noted bilateral lower extremity pain and swelling. His pain was associated with a new violaceous irregular rash on the anterior aspect of both feet and legs. There was no history of inciting trauma or recent wounds. In addition, there was no history of consumption of raw or undercooked food (including seafood) or recent change in food source. There was accompanying fever and chills for the same duration and painful swelling of his left thumb. His comorbidities included stage IIIb classical Hodgkin lymphoma diagnosed 4 months prior. His last dose of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy was 4 days before presentation. He had previously failed anti-CD30 monoclonal therapy resulting from attributed pancolitis.",
"affiliations": "Department of Internal Medicine, Yale-New Haven Health/Bridgeport Hospital, New Haven, CT.;Department of Internal Medicine, Yale-New Haven Health/Bridgeport Hospital, New Haven, CT. Electronic address: johnrossclarke@gmail.com.;Department of Rheumatology, Thomas Jefferson University, Philadelphia, PA.;Division of Pulmonary, Critical Care and Sleep Medicine, Yale-New Haven Health/Bridgeport Hospital, New Haven, CT.",
"authors": "Gittens|Ayesha T|AT|;Clarke|John-Ross D|JD|;Abdelbaki|Shady|S|;Kwon|Jeff S|JS|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2019.08.2186",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "157(2)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002481:Cellulitis; D003646:Debridement; D005759:Gastroenteritis; D006689:Hodgkin Disease; D006801:Humans; D016867:Immunocompromised Host; D007868:Leg Dermatoses; D008297:Male; D009220:Myositis; D052097:Quadriceps Muscle; D018805:Sepsis; D018461:Soft Tissue Infections; D014057:Tomography, X-Ray Computed; D014735:Vibrio Infections; D041261:Vibrio vulnificus",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e41-e45",
"pmc": null,
"pmid": "32033660",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A 72-Year-Old Man With a Violaceous Rash and Sepsis.",
"title_normalized": "a 72 year old man with a violaceous rash and sepsis"
} | [
{
"companynumb": "US-BAXTER-2020BAX004161",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nCollagenase Clostridium histolyticum (CCH), also know as Xiaflex, with penile modeling is considered to be the gold standard non-surgical option for management of Peyronie's disease and is known to be safe and efficacious. Corporal rupture is a rare but known adverse event of CCH treatment, however there are limited studies describing corporal herniation without rupture. Here we present a patient who experienced a rare complication following CCH injections for Peyronie's disease: lateral herniation of the tunica albuginea in the setting of a dorsal penile plaque.\n\n\nMETHODS\nA 58-year-old male presented to our clinic seeking treatment for Peyronie's disease. On exam, he was found to have a palpable dorsal plaque and > 30 degrees leftward curvature of the penis. He was deemed an appropriate candidate for and patient decided to proceed with CCH and modeling. He received 2 cycles of CCH injections (4 total CCH injections) with in-office and at-home penile modeling, per manufacturer's protocol. Two weeks following in-office modeling during his second CCH cycle, the patient reported a painless, soft swelling involving the left side of his penile shaft only occurring with erection. Exam and history were suggestive of lateral herniation rather than corporal rupture. CCH was discontinued. Patient declined further evaluation with penile ultrasound.\n\n\nCONCLUSIONS\nThis is the first case report detailing lateral herniation with CCH injections. Symptoms and exam that should raise suspicion of corporal herniation are a soft, painless mass with erection.",
"affiliations": "Department of Urology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. margegannonmd@gmail.com.;Department of Urology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.",
"authors": "Gannon|Margaret K|MK|http://orcid.org/0000-0002-3557-6902;Pearlman|Amy M|AM|",
"chemical_list": "D003012:Microbial Collagenase",
"country": "England",
"delete": false,
"doi": "10.1186/s12894-021-00858-9",
"fulltext": "\n==== Front\nBMC Urol\nBMC Urol\nBMC Urology\n1471-2490\nBioMed Central London\n\n858\n10.1186/s12894-021-00858-9\nCase Report\nLateral herniation during treatment with collagenase Clostridium histolyticum (Xiaflex) for Peyronie’s disease\nhttp://orcid.org/0000-0002-3557-6902\nGannon Margaret K. margegannonmd@gmail.com\n\nPearlman Amy M.\ngrid.214572.7 0000 0004 1936 8294 Department of Urology, Carver College of Medicine, University of Iowa, Iowa City, IA USA\n27 6 2021\n27 6 2021\n2021\n21 9430 11 2020\n4 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nCollagenase Clostridium histolyticum (CCH), also know as Xiaflex, with penile modeling is considered to be the gold standard non-surgical option for management of Peyronie’s disease and is known to be safe and efficacious. Corporal rupture is a rare but known adverse event of CCH treatment, however there are limited studies describing corporal herniation without rupture. Here we present a patient who experienced a rare complication following CCH injections for Peyronie’s disease: lateral herniation of the tunica albuginea in the setting of a dorsal penile plaque.\n\nCase presentation\n\nA 58-year-old male presented to our clinic seeking treatment for Peyronie’s disease. On exam, he was found to have a palpable dorsal plaque and > 30 degrees leftward curvature of the penis. He was deemed an appropriate candidate for and patient decided to proceed with CCH and modeling. He received 2 cycles of CCH injections (4 total CCH injections) with in-office and at-home penile modeling, per manufacturer’s protocol. Two weeks following in-office modeling during his second CCH cycle, the patient reported a painless, soft swelling involving the left side of his penile shaft only occurring with erection. Exam and history were suggestive of lateral herniation rather than corporal rupture. CCH was discontinued. Patient declined further evaluation with penile ultrasound.\n\nConclusions\n\nThis is the first case report detailing lateral herniation with CCH injections. Symptoms and exam that should raise suspicion of corporal herniation are a soft, painless mass with erection.\n\nKeywords\n\nXiaflex\nHerniation\nPeyronie’s disease\nCollagenase\nCollagenase Clostridium histolyticum\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nPeyronie’s disease is a penile condition characterized by pain, curvature, and/or shortening of the penis and is often associated with erectile dysfunction and difficulty engaging in sexual intercourse [1]. Disorganized and excessive deposition of collagen likely results in the formation of a fibrous penile plaque within the tunica albuginea [2], most commonly observed in the dorsal midline [3].\n\nCollagenase Clostridium histolyticum (CCH), also known as Xiaflex, injections with in-office and at-home penile modeling is an effective treatment option for reducing penile curvature for patients with Peyronie’s disease who meet specific inclusion criteria [4]. Common adverse events include penile hematoma formation (50.2%), pain (33.5%), and swelling (28.9%), however, these often resolve without intervention [1]. One of the most serious adverse events is corporal body rupture/penile fracture (0.9%) which may be related to modeling, resumption of sexual intercourse prior to recommended hiatus, or the injection itself [5].\n\nHere, we present a patient who experienced a rarely reported complication following CCH injections for Peyronie’s disease: a lateral herniation following injection of a dorsal penile plaque.\n\nCase presentation\n\nA 58-year-old Caucasian male with history of hyperlipidemia and recurrent nephrolithiasis presented to our clinic with treatment naive Peyroni’s disease. The patient reported a stable, leftward penile curvature that had been present for 3 years. The patient denied pain with erections or erectile dysfunction, however the curvature was affecting his ability to have intercourse. Using a goniometer to measure his curvature in the erect state, he was noted to have 20 and 32 degrees of leftward curvature at proximal one third and distal one third of penile shaft, respectively. A dorsal penile plaque was palpated approximately 2 cm distal to the penopubic junction. After discussing treatment options, the patient decided to proceed with CCH injections and penile modeling.\n\nThe patient received 0.58 mg intralesional CCH injection at the side of maximal curvature (the distal 1/3 of the penile shaft for this patient) on 2 occasions 1 day apart followed by in-office modeling 6 days after the second CCH injection, per protocol. He performed regular at-home penile modeling for 6 weeks. The patient then repeated the above injections, in-office modeling procedure, and daily at-home stretches, per protocol, for 2 total cycles. Other than transient ecchymosis, there were no complications or adverse events following either of the CCH cycles.\n\nThe patient returned to clinic 6 weeks after completion of his second round of CCH injections to receive the first injection of his third cycle, however, he reported painless swelling on the left side of his penile shaft that he noticed 2 weeks after the second CCH injection of his second cycle. He denied engaging in intercourse, experiencing penile trauma or hearing any “popping” associated with the onset of the swelling. On exam, the flaccid penis did not have a palpable corporal defect, tunical thickening, or hematoma, and appeared grossly normal. Exam following a 20 mcg alprostadil injection showed a small amount of swelling was noted on the left side of the penile shaft distal to the base of the penile shaft (Figs. 1, 2). The swelling was soft and nontender without any overlying skin changes. The third cycle of CCH was deferred and the patient was instructed to wrap the penis in Coban and return to clinic in 1 week to reassess the swelling. At time of follow up, the patient reported continued outpouching of his left erectile body with erections. A repeat exam following a 20 mcg alprostdil injection was consistent with his previous exam. The patient declined further investigation of the swelling with Doppler ultrasound.Fig. 1 Lateral penile swelling following second cycle of Xiaflex/penile modeling; superior view\n\nFig. 2 Lateral penile swelling following second cycle of Xiaflex/penile modeling; lateral view\n\nDiscussion and conclusions\n\nThis case illustrates a rarely reported complication of lateral herniation following CCH injections and penile modeling.\n\nCCH with penile modeling is considered to be the gold standard non-surgical option for management of Peyronie’s disease [6]. The safety and efficacy of CCH has been demonstrated in large scale well-designed clinical trials [4, 5] and the adverse events of the treatment are well-known. Most patients (~ 93%) treated with CCH and modeling report at least one treatment associated adverse event, most commonly penile hematoma (≥ 25% of patients) [5]. Although most patients do experience treatment related adverse events, the vast majority are only mild or moderate in severity [5]. The minority of patients (~ 10%) who experience severe treatment related adverse events most commonly experience a severe penile hematoma (3.7%).\n\nCorporal rupture or penile fracture is also a known treatment related serious adverse event of CCH and modeling. Large scale clinical trials have reported rates of less than 1%, although anecdotally there is controversy among experts about the prevalence of corporal rupture with CCH treatments. One study surveying providers reported a rupture rate of 34%, and found that most occurred after the second CCH cycle (28%) and 16% of those ruptures did not occur over the plaque/injection site [7].\n\nThe unique aspect of this case is that our patient’s adverse event described above was not consistent with a corporal rupture but rather lateral herniation, not well characterized in the existing literature. In fact, only one published case report has ever described this phenomenon [8]. Similar to our patient, this case report describes a painless, soft penile mass present only during erections. Doppler penile ultrasound confirmed the mass was vascular and upon surgical exploration, the patient was found to have local tunical attenuation and an aneurysmal dilation of the corpora. Tunica herniation was briefly mentioned in Brant et al. as a complication seen when injecting CCH into lateral penile plaques. In fact, the authors recommend avoiding CCH injections for lateral plaques in order to prevent herniation or microrupture of the tunica based on their anecdotal experience [9]. Although studies citing lateral herniation of the tunica following CCH are limited, it may be that this complication happens more than is currently appreciated in the current literature.\n\nThis case highlights a tunical herniation that did not occur at the site of the plaque or previous CCH injections. We can only speculate about the etiology of this complication. We do know that the lateral tunica thickness is less than that of the dorsal/ventral tunica (0.8 mm vs 2.2 mm), making it more susceptible to injury [10]. At-home modeling protocol involves stretching of the penis in its flaccid state, as well as straightening of the penis when erect, as per recommended protocol. It is possible that the patient may have caused trauma to the tunica during modeling though the patient denied any known occurrence of trauma. It is possible that the Peyronie’s disease complex of disordered collagen deposition and scar tissue formation had weakened the tunica in locations other than where a palpable plaque was formed. Alternatively, a CCH injection into healthy tissue or extravasation of the medication with manipulation of the needle in and out of the plaque could have compromised the surrounding tunica, although injections for our patient were localized to his plaque according to detailed procedure notes.\n\nThis is the first case report detailing lateral herniation following CCH injections and penile modeling for a palpable dorsal plaque. Symptoms of corporal herniation are a soft, painless mass with erection, and diagnosis can be confirmed with imaging or surgical exploration. Although this condition is rare, it is important to characterize such injuries so we can better understand how to prevent and manage them.\n\nAbbreviation\n\nCCH Collagenase Clostridium histolyticum\n\nAcknowledgements\n\nNone.\n\nAuthors' contributions\n\nMG and AP both contributed to the writing and editing of the case report. All authors have read and approved the manuscript for publish.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nThe patient completed written consent for his pictures and clinical course to be published without any patient identifiers.\n\nCompeting interests\n\nAmy Pearlman is a consultant for Endo Pharmaceuticals.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Shin D Shah T Sadeghi-Nejad H Xiaflex for treatment of Peyronie's disease Eur Urol Focus 2018 4 3 302 303 10.1016/j.euf.2018.08.021 30213657\n2. Brock G Hsu GL Nunes L The anatomy of the tunica albuginea in the normal penis and Peyronie’s disease J Urol 1997 157 276 281 10.1016/S0022-5347(01)65359-X 8976279\n3. Mulhall JP, Schiff J, Guhring P. An analysis of the natural history of Peyronie's disease. J Urol 2006;175:2115–8; discussion 8.\n4. Gelbard M Goldstein I Hellstrom WJ Clinical efficacy, safety and tolerability of collagenase Clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies J Urol 2013 190 199 207 10.1016/j.juro.2013.01.087 23376148\n5. Carson CC 3rd Sadeghi-Nejad H Tursi JP Smith TM Kaufman GJ Gilbert K Honig SC Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD) BJU Int 2015 116 5 815 822 10.1111/bju.13120 25818264\n6. Abdel Raheem A Johnson M Ralph D Garaffa G Collagenase clostridium histolyticum: a novel medical treatment for Peyronie's disease Minerva Urol Nefrol 2018 70 4 380 385 10.23736/S0393-2249.18.03118-1 29761688\n7. Yafi FA Anaissie J Zurawin J Sikka SC Hellstrom WJ Results of SMSNA survey regarding complications following intralesional injection therapy with collagenase Clostridium histolyticum for Peyronie's disease J Sex Med 2016 13 4 684 689 10.1016/j.jsxm.2016.02.105 27045265\n8. Watson DL Morgentaler A Spontaneous corporeal herniation of the penis: a new abnormality of the tunica albuginea? J Urol 1995 153 3 Pt 1 737 740 7861525\n9. Brant WO Reed-Maldonado A Lue TF Injection therapy for Peyronie's disease: pearls of wisdom Transl Androl Urol 2015 4 4 474 477 26812930\n10. Hsu GL Brock G Martínez-Piñeiro L von Heyden B Lue TF Tanagho EA Anatomy and strength of the tunica albuginea: its relevance to penile prosthesis extrusion J Urol 1994 151 5 1205 1208 10.1016/S0022-5347(17)35214-X 8158761\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2490",
"issue": "21(1)",
"journal": "BMC urology",
"keywords": "Collagenase; Collagenase Clostridium histolyticum; Herniation; Peyronie’s disease; Xiaflex",
"medline_ta": "BMC Urol",
"mesh_terms": "D006547:Hernia; D006801:Humans; D008297:Male; D003012:Microbial Collagenase; D008875:Middle Aged; D010409:Penile Diseases; D010411:Penile Induration",
"nlm_unique_id": "100968571",
"other_id": null,
"pages": "94",
"pmc": null,
"pmid": "34176473",
"pubdate": "2021-06-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23376148;8158761;25818264;27045265;16697815;29761688;7861525;8976279;26812930;30213657",
"title": "Lateral herniation during treatment with collagenase Clostridium histolyticum (Xiaflex) for Peyronie's disease.",
"title_normalized": "lateral herniation during treatment with collagenase clostridium histolyticum xiaflex for peyronie s disease"
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"companynumb": "US-ENDO PHARMACEUTICALS INC-2021-010158",
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"abstract": "A 72-year old male presented with muscle invasive bladder cancer was counseled on the standard of care neoadjuvant chemotherapy and he started treatment. He then presented with anemia, blood in the stool and gas in the right renal pelvis and was diagnosed with Pyeloduodenal fistula. The fistula was treated with clipping by gastroenterology and the bladder tumor treated with robotic partial cystectomy.",
"affiliations": "Vattikuti Urology Institute, Detroit, MI, USA.",
"authors": "Alanee|Shaheen|S|",
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"doi": "10.1016/j.eucr.2019.100931",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(19)30194-910.1016/j.eucr.2019.100931100931OncologyPyeloduodenal fistula complicating neoadjuvant chemotherapy in a patient diagnosed with muscle invasive bladder cancer Alanee Shaheen salanee1@hfhs.org∗Vattikuti Urology Institute, Detroit, MI, USA∗ Wayne State University and Henry Ford Health System, Detroit, Michigan, USA. salanee1@hfhs.org06 6 2019 9 2019 06 6 2019 26 10093123 5 2019 29 5 2019 © 2019 The Author2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 72-year old male presented with muscle invasive bladder cancer was counseled on the standard of care neoadjuvant chemotherapy and he started treatment. He then presented with anemia, blood in the stool and gas in the right renal pelvis and was diagnosed with Pyeloduodenal fistula. The fistula was treated with clipping by gastroenterology and the bladder tumor treated with robotic partial cystectomy.\n==== Body\nIntroduction\nFistulae between the gastrointestinal tract and the urinary system most commonly occur between the sigmoid colon and the urinary bladder after an episode of diverticulitis, but very few cases of Pyeloduodenal fistula (PDF) are reported in the literature. PDF account are rare and generally associated with chronic kidney disease or trauma.1 The retrograde pyelogram is positive in 60% of the patients and in upper gastrointestinal barium study is less than 20%, which is attributable to unidirectional flow from the kidney supported by lack of amylase in the urine of patients affected by PDF.1 New modalities are available to treated PDF.\n\nCase presentation\nThis is a 72 y.o. male with multiple comorbidities including Atrial fibrillation, chronic kidney disease with an atrophic right kidney due to childhood ureteropelvic junction obstruction, coronary artery disease (stent x 5), diabetes, hypothyroidism, obstructive sleep apnea, morbid obesity, and high grade papillary urothelial carcinoma with muscularis propria invasion and lymphovascular invasion diagnosed in an outside hospital. He was referred to Henry Ford Urology late 2018 and discussion was done with the patient about neoadjuvant chemotherapy with partial cystectomy. He underwent repeat transurethral resection of the bladder which showed high grade urothelial carcinoma with focal micropapillary/plasmacytoid features and muscle invasion. He then received 3 cycles of gemcitabine/cisplatin neoadjuvant chemotherapy, which was then discontinued due to severe fatigue and anemia. Shortly after the family called because he was dizzy and were asked to take him to the nearest hospital. There the patient was found to be severely anemic, having blood in his stool and computerized tomography imaging of the abdomen showed air in the collecting system of the right kidney (Fig. 1). It was suspected that he is suffering from pyelonephritis and sepsis caused by gas forming organisms and empiric antibiotics treatment started. However, repeat imaging during placement of nephrostomy tubes showed flow of contrast from the duodenum to the pelvis of the right kidney (Fig. 2) and a diagnosis of PDF was made. Such flow of contrast from the duodenum to the kidney is not usual with PDF, but the fact that his right kidney was atrophic may have reversed the commonly seen unidirectional from the kidney to the duodenum.Fig. 1 CT showing air in the collecting system of an atrophic right kidney (Arrow) in a patient who developed pyeloduodenal fistula after receiving neoadjuvant chemotherapy for bladder cancer.\n\nFig. 1Fig. 2 Antegrade pyelogram showing contrast leaking from the right kidney into the duodenum (Arrow) in a patient who developed pyeloduodenal fistula after receiving neoadjuvant chemotherapy for bladder cancer.\n\nFig. 2\n\nTo better treat the patients PDF, he was transferred to our main hospital and gastroenterology were consulted. Their team then proceeded with upper gastrointestinal tract endoscopy which showed patchy moderately erythematous gastropathy in the stomach and biopsies were taken with cold forceps for Helicobacter pylori testing. Moving into the duodenum, the team found 2–3 mm fistula in the second portion of in the bed of a crescent-shaped cratered ulcer roughly 15 mm × 6 mm. Contrast fluid (from recent pyelogram) was visualized exiting the opening. To repair the PDF defect, argon plasma at 25 W on 0.8L/min setting was used to coagulate the mucosa in and around the fistula and assist in eventual fistula closure. Attempts at tissue approximation with endoclips failed due to the central fibrosis and the marginal congestion. The tissue edges were therefore clipped circumferentially using 4 Duraclips. An endoloop was then placed around the clips to successfully close the tissue around the fistula using the “Tulip Bundle\" method of closure (Fig. 3). On repeat inspection no further contrast fluid was noted to be exiting the region of the fistula. The patient recovered from the procedure and proceeded to be treated with robotic assisted partial cystectomy for his bladder cancer.Fig. 3 Endoscopic view of the fistula before (figure 3a) and after (figure 3b) clipping (arrow) in a patient who developed pyeloduodenal fistula after receiving neoadjuvant chemotherapy for bladder cancer.\n\nFig. 3\n\nDiscussion\nChemotherapy-induced gastrointestinal side effects include a wide array of discomforting symptoms among 50%–80% of patients with cancer.2 Direct or indirect reactive oxygen species generation is one of the mechanisms of action behind many chemotherapeutic drugs and used in cancer treatment to induce neoplastic cell death. Increased cellular oxidative stress, characterized by a higher concentration of reactive oxygen species, favors the formation of toxic compounds leading to cell necrosis and death in both the tumor and normal health tissue like the lining of the gastrointestinal tract, which in turn cause epithelial ulcers.3 These toxic side effects of cancer treatment are not limited to chemotherapeutic agents, and gastrointestinal side effects are commonly reported with immune check point inhibitors, the leading agents in treating many patients with bladder cancer. In fact, a recent study from a group at MD Anderson cancer center reported that, in patients treated with immune check point inhibitors, histological signs of inflammation of the stomach were evident in 83% of patients, and inflammation of the duodenum in 38%. The authors also reported that the rates of ulceration were similar in the cohorts with and without other risk factors for gastritis.4 Our case report highlights an extreme case of gastrointestinal ulceration due to chemotherapy that, with the presence of atrophic kidney tissue with limited healing capacity and reduced thickness, lead to the development of a PDF. Fortunately, the availability of advanced endoscopic techniques for managing diseases of the gastrointestinal tract has enabled us to treat this patient's PFD in a timely manner to allow him to proceed with the definitive treatment of his bladder cancer.\n==== Refs\nReferences\n1 Morris D.B. Siegelbaum M.H. Pollack H.M. Renoduodenal fistula in a patient with chronic nephrostomy drainage: a case report J Urol 146 1991 835 1875505 \n2 Gibson R.J. Keefe D.M. Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies Support Care Canc 14 2006 890 \n3 Merendino N. Costantini L. Manzi L. Dietary omega -3 polyunsaturated fatty acid DHA: a potential adjuvant in the treatment of cancer BioMed Res Int 310186 2013 2013 \n4 Tang T. Abu-Sbeih H. Luo W. Upper gastrointestinal symptoms and associated endoscopic and histological features in patients receiving immune checkpoint inhibitors Scand J Gastroenterol 1 2019\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "26()",
"journal": "Urology case reports",
"keywords": null,
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "100931",
"pmc": null,
"pmid": "31297326",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "16604351;1875505;23762838;31079556",
"title": "Pyeloduodenal fistula complicating neoadjuvant chemotherapy in a patient diagnosed with muscle invasive bladder cancer.",
"title_normalized": "pyeloduodenal fistula complicating neoadjuvant chemotherapy in a patient diagnosed with muscle invasive bladder cancer"
} | [
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-214383",
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"abstract": "BACKGROUND\nOver recent years, several types of freezing of gait (FOG) have been described, mainly according to their response to levodopa. FOG in Parkinson's disease presents in a variety of ways due to differences within the underlying pathophysiology. In a number of patients, increasing the dopaminergic stimulation may not improve this condition, and may even worsen it.\n\n\nMETHODS\nWe present two patients with Parkinson's disease who were evaluated during off, on and supra-on periods. Motor function was assessed with Unified Parkinson's Disease Rating Scale III, tapping test on lower limbs and quantification of FOG episodes during each of these periods. Both patients presented FOG episodes while in off period, experiencing a significant improvement during on period. However, when increasing the dopaminergic stimulation in order to try to improve their motor response, FOG episodes worsened to the point of impairing gait.\n\n\nCONCLUSIONS\nFOG episodes are not always a consequence of akinesia or rigidity. Regarding the pathophysiology, the lack of an appropriate response to treatment would be explained by the involvement of structures exceeding the substantia nigra and the dopaminergic deficit. FOG worsening during periods of dopaminergic overstimulation could be related to a neurotransmitters disbalance affecting other nuclei involved in postural and gait control.",
"affiliations": "Hospital General de Ciudad Real, Ciudad Real, Espana.;Hospital General de Ciudad Real, Ciudad Real, Espana.;Hospital General de Ciudad Real, Ciudad Real, Espana.;Hospital General de Ciudad Real, Ciudad Real, Espana.;Hospital General de Ciudad Real, Ciudad Real, Espana.",
"authors": "Gallardo-Alcaniz|M José|MJ|;Cabello-De la Rosa|Juan P|JP|;Bravo-Gomez|José J|JJ|;Diaz-Gomez|Samuel|S|;Vaamonde-Gamo|Julia|J|",
"chemical_list": "D000978:Antiparkinson Agents; D007980:Levodopa",
"country": "Spain",
"delete": false,
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"issn_linking": "0210-0010",
"issue": "62(8)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents; D005260:Female; D005684:Gait; D006801:Humans; D007980:Levodopa; D008297:Male; D010300:Parkinson Disease",
"nlm_unique_id": "7706841",
"other_id": null,
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"references": null,
"title": "Supra-on state freezing of gait: two case reports.",
"title_normalized": "supra on state freezing of gait two case reports"
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"activesubstancename": "LEVODOPA"
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"abstract": "Letermovir was approved by the Food and Drug Administration (FDA) in November 2017 for use in adult cytomegalovirus (CMV)-seropositive allogeneic stem cell transplant (SCT) recipients for primary prophylaxis of CMV infection and disease. We report off-label use of letermovir for secondary prophylaxis of genotype-confirmed ganciclovir-resistant cytomegalovirus (CMV) syndrome (UL 97 mutation [C603W]) in a heart transplant recipient initially treated with intravenous cidofovir followed by foscarnet, both discontinued due to unacceptable toxicities.",
"affiliations": "Division of Infectious Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Infectious Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Infectious Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.;Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.",
"authors": "Chong|Pearlie P|PP|http://orcid.org/0000-0003-2475-7932;Teiber|Dagny|D|;Prokesch|Bonnie C|BC|;Arasaratnam|Reuben J|RJ|;Peltz|Matthias|M|;Drazner|Mark H|MH|;Garg|Sonia|S|",
"chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
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"issn_linking": "1398-2273",
"issue": "20(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "UL97 mutation; cytomegalovirus; ganciclovir resistance; heart transplant; letermovir",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000085:Acetates; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D024882:Drug Resistance, Viral; D015774:Ganciclovir; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor); D011799:Quinazolines; D055502:Secondary Prevention; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
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"pmc": null,
"pmid": "29989279",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation).",
"title_normalized": "letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir resistant cytomegalovirus syndrome ul97 mutation"
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"abstract": "Glioblastoma is the most common and aggressive primitive brain tumor in adults. Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ has become the standard treatment. Although TMZ treatment has been considered to have a low toxicity profile, studies have noted the development of a severe myelosuppression, especially during the concomitant treatment; this toxicity may in some cases be prolonged and consequently treatment must be definitively discontinued. We analyzed two cases treated at our oncological center who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy treatment with TMZ. Hypothesizing that radiation therapy and daily TMZ could be the major causes of severe hematological toxicity during the concomitant phase, we decided to treat both patients with maintenance TMZ at the time of recovery of hematological values. Patients showed good tolerability without important myelosuppression. In conclusion, we suggest that glioblastoma patients with severe myelotoxicity during daily TMZ and radiation therapy be treated with maintenance TMZ at the time of blood value recovery.",
"affiliations": "Department of Oncology, Medical Oncology 1.;Department of Oncology, Medical Oncology 1.;Unit of Radiation Therapy, Veneto Institute of Oncology IOV-IRCCS.;Department of Oncology, Medical Oncology 1.;Department of Oncology, Medical Oncology 1.;Unit of Radiation Therapy, Veneto Institute of Oncology IOV-IRCCS.;Department of Medicine, Surgical Pathology and Cytopathology Unit, University Hospital of Padua.;Neurosurgery Unit.;Neurosurgery Unit, University of Padua, Padua, Italy.;Unit of Neuroradiology, Padua Hospital.;Department of Oncology, Medical Oncology 1.",
"authors": "Lombardi|Giuseppe|G|;Caccese|Mario|M|;Bellu|Luisa|L|;Pambuku|Ardi|A|;Bergo|Eleonora|E|;Berti|Franco|F|;Gardiman|Marina P|MP|;Della Puppa|Alessandro|A|;Denaro|Luca|L|;Dal Pos|Sandro|S|;Zagonel|Vittorina|V|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D000077204:Temozolomide",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000678",
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"issn_linking": "0959-4973",
"issue": "29(9)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D001932:Brain Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D005909:Glioblastoma; D006402:Hematologic Diseases; D006801:Humans; D008875:Middle Aged; D000077204:Temozolomide",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "924-928",
"pmc": null,
"pmid": "30080691",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Good tolerability of maintenance temozolomide in glioblastoma patients after severe hematological toxicity during concomitant radiotherapy and temozolomide treatment: report of two cases.",
"title_normalized": "good tolerability of maintenance temozolomide in glioblastoma patients after severe hematological toxicity during concomitant radiotherapy and temozolomide treatment report of two cases"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-190242",
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"activesubstancename": "TEMOZOLOMIDE"
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"abstract": "The novel corona virus (SARS-CoV-2) continuous to spread around the globe causing high mortality, tremendous stress on healthcare systems and an unprecedented disruption of everyday life with unpredictable socioeconomic ramifications. The diseaseis typically affecting the respiratory system and some patients will develop refractory hypoxemic respiratory insufficiency requiring mechanical ventilation. The role of non-invasive ventilation (NIV), high flow nasal cannula (HFNC) or continuous positive airway pressure devices (C-PAP) in the treatment of the 2019 corona virus disease (COVID-19) is not yet clear. We hereby report a case of a 44-year-old COVID-19 positive male patient suffering from hypoxic respiratory failure that was successfully treated with high flow nasal cannula oxygen therapy in a negative pressure intensive care room. Although specific criteria for the use of high flow nasal canula devices COVID-19 are not available at this time, clinicians could use this non-invasive modality as analternative method of respiratory support in selected patients presenting with respiratory failure.",
"affiliations": "Intensive Care Unit, University Hospital of Patras, Rion. vkaramouzos@hotmail.com.;Intensive Care Unit, University Hospital of Patras, Rion. fflig@yahoo.com.;Internal Medicine Department, University Hospital of Patras, Rion. cgogos@upatras.gr.;Internal Medicine Department, University Hospital of Patras, Rion. dvelissaris@upatras.gr.",
"authors": "Karamouzos|Vasileios|V|;Fligou|Fotini|F|;Gogos|Charalambos|C|;Velissaris|Dimitrios|D|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2020.1323",
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"issn_linking": "1122-0643",
"issue": "90(2)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
"keywords": null,
"medline_ta": "Monaldi Arch Chest Dis",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D000072601:Cannula; D018352:Coronavirus Infections; D003422:Critical Care; D006801:Humans; D008297:Male; D063087:Noninvasive Ventilation; D010102:Oxygen Inhalation Therapy; D058873:Pandemics; D011024:Pneumonia, Viral; D012131:Respiratory Insufficiency; D016896:Treatment Outcome",
"nlm_unique_id": "9307314",
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"pmid": "32512988",
"pubdate": "2020-06-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High flow nasal cannula oxygen therapy in adults with COVID-19 respiratory failure. A case report.",
"title_normalized": "high flow nasal cannula oxygen therapy in adults with covid 19 respiratory failure a case report"
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"companynumb": "GR-ABBVIE-20K-066-3563806-00",
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{
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"activesubstance": {
"activesubstancename": "LOPINAVIR\\RITONAVIR"
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"drugadditional":... |
{
"abstract": "It is still unknown whether there is an association between the use of certolizumab pegol (CZP) in rheumatic patients and the onset of cardiac arrhythmias. We describe the cases of two patients with rheumatoid arthritis (RA) treated with CZP as the first-line biological drug and methotrexate (MTX), who developed an arrhythmic event. The first was a 60-year-old, hypertensive male smoker, the second a 66-year-old dyslipidemic female non-smoker. Both were diagnosed as having RA in 2010, and started treatment with MTX plus CZP. The first patient developed undatable atrial fibrillation, which was resistant to pharmacological treatment and electrical cardioversion. The second patient developed an atrial flutter, which was treated with a betablocker. In both cases, we set a cautious interval between two consecutive administrations of CZP and, in the first case, also reduced the dose of MTX without any worsening of RA activity. Although many studies have shown that tumor necrosis factor (TNF)-alpha plays a pathogenetic role in inducing an arrhythmogenic substrate that is apparently rescued by anti-TNF drugs, there is still a lack of conclusive data. We suggest caution in any patient developing a cardiac event (including rhythm disorders) during treatment with a conventional or biological disease-modifying anti-rheumatic drug.",
"affiliations": "Rheumatology Unit, Luigi Sacco University Hospital, Milan. talotta1@virgilio.it.",
"authors": "Talotta|R|R|;Atzeni|F|F|;Batticciotto|A|A|;Ventura|D|D|;Sarzi-Puttini|P|P|",
"chemical_list": "D018501:Antirheumatic Agents; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D011728:Pyridones; D013565:Sympatholytics; C522181:apixaban; D000068582:Certolizumab Pegol; D017298:Bisoprolol",
"country": "Italy",
"delete": false,
"doi": "10.4081/reumatismo.2016.869",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0048-7449",
"issue": "68(2)",
"journal": "Reumatismo",
"keywords": null,
"medline_ta": "Reumatismo",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001145:Arrhythmias, Cardiac; D001172:Arthritis, Rheumatoid; D017298:Bisoprolol; D000068582:Certolizumab Pegol; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D011728:Pyridones; D012307:Risk Factors; D012907:Smoking; D013565:Sympatholytics; D016896:Treatment Outcome",
"nlm_unique_id": "0401302",
"other_id": null,
"pages": "104-8",
"pmc": null,
"pmid": "27608800",
"pubdate": "2016-09-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Possible relationship between certolizumab pegol and arrhythmias: report of two cases.",
"title_normalized": "possible relationship between certolizumab pegol and arrhythmias report of two cases"
} | [
{
"companynumb": "IT-TEVA-755327ACC",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "3",
... |
{
"abstract": "Polyclonal antibodies, used for both induction and rejection therapy in renal transplant recipients, are associated with such side effects as chills and fever. We describe two patients who developed a coagulopathy during antithymocyte globulin (ATGAM) therapy, a previously unknown complication. The laboratory tests revealed prolonged prothrombin and partial thromboplastin times and thrombocytopenia. Discontinuation of ATGAM therapy resulted in correction of these abnormalities.",
"affiliations": "Department of Internal Medicine, University of Missouri, Columbia, USA.",
"authors": "Trivedi|H S|HS|;Lal|S M|SM|;Gupta|N|N|;Ross|G|G|",
"chemical_list": "D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D011516:Prothrombin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-3988",
"issue": "19(8)",
"journal": "The International journal of artificial organs",
"keywords": null,
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D000328:Adult; D000961:Antilymphocyte Serum; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D010314:Partial Thromboplastin Time; D010531:Peritoneal Dialysis, Continuous Ambulatory; D011183:Postoperative Complications; D011516:Prothrombin; D006435:Renal Dialysis; D013921:Thrombocytopenia; D044465:Whites",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "448-50",
"pmc": null,
"pmid": "8841842",
"pubdate": "1996-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "ATGAM associated coagulopathy in renal transplant patients: a report of two unusual cases.",
"title_normalized": "atgam associated coagulopathy in renal transplant patients a report of two unusual cases"
} | [
{
"companynumb": "US-PFIZER INC-0009483702PHAMED",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EQUINE THYMOCYTE IMMUNE GLOBULIN"
},
"dr... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to investigate the pathogenesis, symptoms and individualized surgical management in pediatrics with gastroduodenal perforation (GDP).\n\n\nMETHODS\nPatients diagnosed with GDP from January 2013 to December 2016 in our hospital were collected and divided into gastric perforation (GP) group and duodenal perforation (DP) group. Demographics, clinical events, etiological factors, symptoms, the time from symptom onset to operation, intraoperative findings and surgical procedures were analyzed. Follow-ups including ulcer, perforations occurrence, and digestive symptoms were carried out by out-patient review or telephones.\n\n\nRESULTS\nA total of 20 patients aged from 3 months to 14 years were enrolled in this study. The average age, main clinical presentations, size of perforations and operating time between two groups had no difference. The male to female ratio in DP group was higher than GP (P < 0.05). The high risk factor for DP was the use of dexamethasone, and for GP was HP infection. The most common site of perforation in DP group was duodenal bulb, and in GP group was pylorus area. Simple suture is the main management for both DP and GP, but distal gastrectomy combined with gastrojejunal Roux-en-Y anastomosis may be an alternative procedure for large perforation with diameter > 2 cm. The length of hospital days in GP group is shorter than DP group (P < 0.05). For follow-up, no patients had digestive symptoms.\n\n\nCONCLUSIONS\nThe general condition had no difference between GP and DP patients. But the risk factors and surgical repair differ depending on the patient's fundamental illness and the complexity of the perforation.",
"affiliations": "Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.;The Research Institute at Nationwide Children's Hospital, The Ohio State University School of Medicine, 700 Children's Drive, Columbus, OH, 43205, USA. xuyong.chen@nationwidechildrens.org.",
"authors": "Yan|Xueqiang|X|;Kuang|Houfang|H|;Zhu|Zhenchuang|Z|;Wang|Haibin|H|;Yang|Jun|J|;Duan|Xufei|X|;Bian|Hongqiang|H|;Zheng|Nannan|N|;Chen|Xuyong|X|http://orcid.org/0000-0001-5069-0896",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00383-018-4420-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-0358",
"issue": "35(4)",
"journal": "Pediatric surgery international",
"keywords": "Gastroduodenal perforation; H. pylori; Laparoscopy-assisted simple suture; Peptic ulcer",
"medline_ta": "Pediatr Surg Int",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002681:China; D013505:Digestive System Surgical Procedures; D004381:Duodenal Ulcer; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D010439:Peptic Ulcer Perforation; D012189:Retrospective Studies; D012307:Risk Factors; D013276:Stomach Ulcer",
"nlm_unique_id": "8609169",
"other_id": null,
"pages": "473-477",
"pmc": null,
"pmid": "30448888",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "14509505;15937829;17161209;17295765;17592367;21129741;21567292;22404446;22981476;23587203;23833377;24609709;24948965;26011220;26386878",
"title": "Gastroduodenal perforation in the pediatric population: a retrospective analysis of 20 cases.",
"title_normalized": "gastroduodenal perforation in the pediatric population a retrospective analysis of 20 cases"
} | [
{
"companynumb": "CN-BAUSCH-BL-2018-034212",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Gastric ischemia (GI) results from diffuse or localized vascular insufficiency caused by different aetiologies such as systemic hypotension, vasculitis, disseminated thromboembolism and celiac or mesenteric stenosis. We present a case of gastric ischemia due to critical stenosis of the celiac artery treated using endovascular therapy. The celiac artery is the first major branch of the abdominal aorta and provides some of the blood supply to the stomach through the left gastric artery and other organs like the spleen (splenic artery branch) and the liver. Although the collateral blood supply to the stomach is protective, systemic hypotension or occlusion of the main arteries, as in the case of our patient, may result in gastric ischemia. The stent placement is an alternative to surgery in patients with high comorbidity and with good outcomes. The clinical awareness of this syndrome will allow gastroenterologists and radiologists to appropriately diagnose and manage affected patients.",
"affiliations": "Complejo Hospitalario de Navarra. crisaldu@hotmail.com.",
"authors": "Saldaña Dueñas|C|C|;Elosua González|A|A|;Guerra Lacunza|A|A|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.23938/ASSN.0248",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1137-6627",
"issue": "41(1)",
"journal": "Anales del sistema sanitario de Navarra",
"keywords": null,
"medline_ta": "An Sist Sanit Navar",
"mesh_terms": "D000368:Aged; D001157:Arterial Occlusive Diseases; D002445:Celiac Artery; D003251:Constriction, Pathologic; D005260:Female; D006801:Humans; D007511:Ischemia; D013270:Stomach",
"nlm_unique_id": "9710381",
"other_id": null,
"pages": "123-127",
"pmc": null,
"pmid": "29582857",
"pubdate": "2018-04-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gastric ischemia due to critical stenosis of the celiac trunk.",
"title_normalized": "gastric ischemia due to critical stenosis of the celiac trunk"
} | [
{
"companynumb": "ES-ZYDUS-020260",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report the adverse effects of topical tosufloxacin in two patients with corneal deposits in compromised cornea.\n\n\nMETHODS\nTosufloxacin was administered topically to a 13-month-old girl after penetrating keratoplasty in the left eye. Three days posttransplantation, corneal precipitations appeared and thereafter continuously increased. An 80-year-old woman, who maintained postoperative multiple topical medications including tosufloxacin, presented dense white deposits in the left eye a month postoperation. In both cases, the deposits showed a granular pattern and were limited to areas of large epithelial defects. After discontinuation of tosufloxacin, the deposits slowly decreased and completely disappeared in a few weeks. In the former case, corneal re-epithelialization was significantly disturbed and resulted in anterior stromal opacity, whereas visual acuity and visualization of the retina were severely interfered in the latter case.\n\n\nCONCLUSIONS\nTosufloxacin can precipitate especially on compromised corneal surfaces. Therefore, topical tosufloxacin should be avoided in patients who are at risk of losing corneal surface integrity.",
"affiliations": "*MD †MD, PhD Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea (all authors); Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea (MKK, WRW, and HJC); and Department of Ophthalmology, Seoul National University Hospital, Healthcare System Gangnam Center, Seoul, Republic of Korea (HJC).",
"authors": "Kim|Yong Dae|YD|;Kim|Mee Kum|MK|;Wee|Won Ryang|WR|;Choi|Hyuk Jin|HJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; C055185:tosufloxacin",
"country": "United States",
"delete": false,
"doi": "10.1097/OPX.0000000000000348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-5488",
"issue": "91(9)",
"journal": "Optometry and vision science : official publication of the American Academy of Optometry",
"keywords": null,
"medline_ta": "Optom Vis Sci",
"mesh_terms": "D000287:Administration, Topical; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003316:Corneal Diseases; D005260:Female; D024841:Fluoroquinolones; D015745:Granuloma, Foreign-Body; D006801:Humans; D007223:Infant; D015948:Keratoplasty, Penetrating; D009287:Naphthyridines; D014792:Visual Acuity",
"nlm_unique_id": "8904931",
"other_id": null,
"pages": "e241-4",
"pmc": null,
"pmid": "25036547",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tosufloxacin deposits in compromised corneas.",
"title_normalized": "tosufloxacin deposits in compromised corneas"
} | [
{
"companynumb": "PHHY2015KR011109",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.\n\n\n\nTo evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.\n\n\n\nData were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.\n\n\n\nFinally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.\n\n\n\nSingle-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.",
"affiliations": "Department of Gastroenterology, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM) and Centro de Investigación Biomódica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.;Department of Gastroenterology, Agencia Sanitaria Costa del Sol, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Málaga, Spain.;Department of Gastroenterology, Hospital de Valme, Sevilla, Spain.;Department of Gastroenterology, Molinette Hospital, Turin, Italy.;Department of Gastroenterology, Hospital General Universitario de Valencia, Valencia, Spain.;Department of Gastroenterology, Hospital Universitario Central de Asturias, Oviedo, Spain.;Department of Gastroenterology, Hospital Universitari i Politecnic La Fe, Valencia, Spain.;Department of Gastroenterology, Hospital Quiron Sagrado Corazón, Sevilla, Spain.;Department of Gastroenterology, Centro Hospitalar do Porto, Institute of Biomedical Sciences Abel Salazar, Porto, Portugal.;Department of Gastroenterology, Center for Health Technology and Services Research (CINTESIS), University of Porto, Porto, Portugal.;Department of Gastroenterology, Hospital Quiron, Marbella, Spain.;Department of Gastroenterology, Hospital Universitario Sanitas La Moraleja, Madrid, Spain.;Department of Gastroenterology, Università degli Studi della Campania \"Luigi Vanvitelli\", Napoli, Italy.;Department of Gastroenterology, Università degli Studi della Campania \"Luigi Vanvitelli\", Napoli, Italy.;Department of Gastroenterology, Hospital Mérida, Badajoz, Spain.;Department of Gastroenterology, Clinica San Francisco, Cáceres, Spain.;Department of Gastroenterology, Otto-von-Guericke University Hospital, Magdeburg, Germany.;Department of Gastroenterology, Otto-von-Guericke University Hospital, Magdeburg, Germany.;Department of Gastroenterology, Hospital Clinico Universitario de Valladolid, Valladolid, Spain.;Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy.;Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.;Althaia Xarxa Assistencial Universitària de Manresa and Universitat de Vic-Universitat Central de Catalunya (UVicUCC), Manresa, Spain.;Laboratoire de Bacteriologie, Hôpital Pellegrin, Bordeaux Cedex, France.;Department of Gastroenterology, Faculty of Health Sciences, Trinity College Dublin, Dublin, Ireland.;Department of Gastroenterology, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM) and Centro de Investigación Biomódica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.",
"authors": "Nyssen|Olga P|OP|;Perez-Aisa|Angeles|A|;Castro-Fernandez|Manuel|M|;Pellicano|Rinaldo|R|;Huguet|Jose M|JM|;Rodrigo|Luis|L|0000-0003-1717-9345;Ortuñ|Juan|J|;O|||;Gomez-Rodriguez|Blas J|BJ|;Pinto|Ricardo M|RM|;Areia|Miguel|M|0000-0001-9787-8175;Perona|Monica|M|;Nuñez|Oscar|O|;Romano|Marco|M|;Gravina|Antonietta G|AG|;Pozzati|Liliana|L|;Fernandez-Bermejo|Miguel|M|;Venerito|Marino|M|0000-0001-8581-0974;Malfertheiner|Peter|P|;Fernanadez-Salazar|Luis|L|;Gasbarrini|Antonio|A|;Vaira|Dino|D|;Puig|Ignasi|I|0000-0002-9059-8602;Megraud|Francis|F|;O'Morain|Colm|C|;Gisbert|Javier P|JP|0000-0003-2090-3445;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050640620972615",
"fulltext": "\n==== Front\nUnited European Gastroenterol J\nUnited European Gastroenterol J\n10.1002/(ISSN)2050-6414\nUEG2\nUnited European Gastroenterology Journal\n2050-6406\n2050-6414\nJohn Wiley and Sons Inc. Hoboken\n\n33176617\n10.1177/2050640620972615\nUEG212025\nOriginal Article\nNeurogastroenterology\nEuropean Registry on Helicobacter pylori management: Single‐capsule bismuth quadruple therapy is effective in real‐world clinical practice\nNyssen Olga P. 1\nPerez‐Aisa Angeles 2\nCastro‐Fernandez Manuel 3\nPellicano Rinaldo 4\nHuguet Jose M. 5\nRodrigo Luis https://orcid.org/0000-0003-1717-9345\n6\nOrtuñ Juan\no 7\nGomez‐Rodriguez Blas J. 8\nPinto Ricardo M. 9 10\nAreia Miguel https://orcid.org/0000-0001-9787-8175\n10 11\nPerona Monica 12\nNuñez Oscar 13\nRomano Marco 14\nGravina Antonietta G. 14\nPozzati Liliana 15\nFernandez‐Bermejo Miguel 16\nVenerito Marino https://orcid.org/0000-0001-8581-0974\n17\nMalfertheiner Peter 17\nFernanadez‐Salazar Luis 18\nGasbarrini Antonio 19\nVaira Dino 20\nPuig Ignasi https://orcid.org/0000-0002-9059-8602\n21\nMegraud Francis 22\nO'Morain Colm 23\nGisbert Javier P. https://orcid.org/0000-0003-2090-3445\n1 javier.p.gisbert@gmail.com\n\nThe Hp‐EuReg investigators\n1 Department of Gastroenterology Hospital Universitario de La Princesa Universidad Autónoma de Madrid (UAM) and Centro de Investigación Biomódica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) Madrid Spain\n2 Department of Gastroenterology Agencia Sanitaria Costa del Sol Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC) Málaga Spain\n3 Department of Gastroenterology Hospital de Valme Sevilla Spain\n4 Department of Gastroenterology Molinette Hospital Turin Italy\n5 Department of Gastroenterology Hospital General Universitario de Valencia Valencia Spain\n6 Department of Gastroenterology Hospital Universitario Central de Asturias Oviedo Spain\n7 Department of Gastroenterology Hospital Universitari i Politecnic La Fe Valencia Spain\n8 Department of Gastroenterology Hospital Quiron Sagrado Corazón Sevilla Spain\n9 Department of Gastroenterology Centro Hospitalar do Porto Institute of Biomedical Sciences Abel Salazar Porto Portugal\n10 Department of Gastroenterology Center for Health Technology and Services Research (CINTESIS) University of Porto Porto Portugal\n11 Department of Gastroenterology Portuguese Oncology Institute of Coimbra Coimbra Portugal\n12 Department of Gastroenterology Hospital Quiron Marbella Spain\n13 Department of Gastroenterology Hospital Universitario Sanitas La Moraleja Madrid Spain\n14 Department of Gastroenterology Università degli Studi della Campania “Luigi Vanvitelli” Napoli Italy\n15 Department of Gastroenterology Hospital Mérida Badajoz Spain\n16 Department of Gastroenterology Clinica San Francisco, Cáceres Spain\n17 Department of Gastroenterology Otto‐von‐Guericke University Hospital Magdeburg Germany\n18 Department of Gastroenterology Hospital Clinico Universitario de Valladolid Valladolid Spain\n19 Fondazione Policlinico Universitario Agostino Gemelli Rome Italy\n20 Department of Surgical and Medical Sciences University of Bologna Bologna Italy\n21 Althaia Xarxa Assistencial Universitària de Manresa and Universitat de Vic‐Universitat Central de Catalunya (UVicUCC) Manresa Spain\n22 Laboratoire de Bacteriologie Hôpital Pellegrin Bordeaux Cedex France\n23 Department of Gastroenterology Faculty of Health Sciences Trinity College Dublin Dublin Ireland\n* Correspondence\nJavier P. Gisbert, Gastroenterology Unit, Hospital Universitario de La Princesa, Diego de León 62, 28006 Madrid, Spain.\nEmail: javier.p.gisbert@gmail.com\n\n11 2 2021\n2 2021\n9 1 10.1002/ueg2.v9.1 3846\n27 7 2020\n13 10 2020\n© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nBackground\n\nThere has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three‐in‐one single‐capsule formulation.\n\nObjective\n\nTo evaluate the effectiveness and safety of the single‐capsule bismuth quadruple therapy.\n\nMethods\n\nData were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention‐to‐treat and per‐protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.\n\nResults\n\nFinally, 2100 patients were prescribed single‐capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention‐to‐treat effectiveness of 92% was achieved. Eradication was over 90% in first‐line treatment (95% modified intention‐to‐treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention‐to‐treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention‐to‐treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.\n\nConclusions\n\nSingle‐capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real‐world clinical practice, both as a first‐line and rescue treatment, with good compliance and a favourable safety profile.\n\nKey Summary\n\nThe development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.\n\nIn the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.\n\nCompliance was the factor most closely associated with treatment effectiveness.\n\nSingle‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.\n\nbismuth\neradication\nHelicobacter pylori\nPylera\nquadruple\nEuropean Helicobacter and Microbiota Study GroupSpanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas source-schema-version-number2.0\ncover-dateFebruary 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:06.07.2021\nThe remaining list of authors, their affiliations, contributions and conflict of interests are listed in File S1. Contribution Log, available online.\n==== Body\n1 INTRODUCTION\n\nHelicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary\n\nThe development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.\n\nIn the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.\n\nCompliance was the factor most closely associated with treatment effectiveness.\n\nSingle‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.\n\nAll therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13\n\nBismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16\n\nOther factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.\n\n2 METHODS\n\n2.1 European Registry on H. pylori management (Hp‐EuReg)\n\nThe Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).\n\n2.2 Data analysis\n\nData were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.\n\n2.3 Effectiveness analysis\n\nThe aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.\n\nThe main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.\n\n2.4 Statistical analyses\n\nContinuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).\n\n3 RESULTS\n\n3.1 Overview and baseline characteristics\n\nFrom its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.\n\nThe two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.\n\nTABLE 1 Patients' basal characteristics\n\nCharacteristics at baseline\tN (%)\t\nSingle‐capsule prescriptions (3 capsules q.i.d. for 10 days)\t2100 (6.1) a\t\n\t\nFemale\t1337 (63.8)\t\nAge, mean (SD)\t50.4 (18.0)\t\nAge 18–30 years\t151 (7.3)\t\nAge 31–50 years\t745 (36.1)\t\nAge 51‐highest years\t1167 (56.6)\t\nEthnic background (N, %)\t\t\nCaucasian\t1994 (95.0)\t\nBlack\t13 (0.6)\t\nAsian\t28 (1.3)\t\nOther\t33 (1.6)\t\nConcurrent medication\t944 (45.0)\t\nProton pump inhibitors (daily or on demand)\t675 (71.6)\t\nAcetylsalicylic acid\t138 (14.6)\t\nNSAIDs\t244 (25.9)\t\nStatins\t313 (33.2)\t\nPenicillin allergy\t670 (3.1)\t\nIndication (N, %)\t\t\nDyspepsia\t1367 (65.6)\t\nUlcer disease\t332 (15.8)\t\nNo culture performed\t2052 (97.7)\t\nCulture (with a result of the antibiotic resistance test)\t48 (2.3)\t\nNo resistance\t3 (6.2)\t\nClarithromycin resistance\t33 (68.7)\t\nMetronidazole resistance\t29 (60.4)\t\nDual clarithromycin + metronidazole resistance\t22 (45)\t\nPPI dose\t\t\nLow\t1121 (53.5)\t\nStandard\t445 (21.2)\t\nHigh\t529 (25.3)\t\nCompliance\t\t\nNo (<90% drug intake)\t66 (3.3)\t\nYes (≥90% drug intake)\t1916 (96.7)\t\nCountry\t\t\nSpain\t1677 (79.9)\t\nItaly\t274 (13.0)\t\nPortugal\t88 (4.2)\t\nGermany\t35 (1.7)\t\nSlovenia\t17 (0.8)\t\nRussia\t3 (0.1)\t\nFrance\t2 (0.1)\t\nCzech Republic\t2 (0.1)\t\nGreece\t1 (0.0005)\t\nLithuania\t1 (0.0005)\t\nNote: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).\n\nAbbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.\n\na %, Percentage relative to the total number of patients in the registry (n = 34,460).\n\n3.2 Treatment use\n\nIn the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).\n\n3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy\n\nThe effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).\n\nTABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment\n\n\tITT\tPP\tmITT\t\n\tN (%)\t95% CI\tN (%)\t95% CI\tN (%)\t95% CI\t\nOverall\t1724 (85.2)\t(83.6–86.7)\t1761 (92.8)\t(91.6–94.0)\t1777 (91.9)\t(90.6–93.1)\t\nFirst‐line\t1135 (88.1)\t(86.3–89.9)\t1158 (95.5)\t(94.2–96.6)\t1166 (94.6)\t(93.2–95.8)\t\nSecond‐line\t361 (81.5)\t(77.7–85.2)\t370 (90.2)\t(87.2–93.2)\t375 (89.3)\t(86.2–92.3)\t\nRescue treatment from third‐line to sixth‐line\t228 (85.2)\t(73.2–82.9)\t233 (85.0)\t(80.6–89.4)\t236 (91.9)\t(79.5–88.4)\t\nNote: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).\n\nAbbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.\n\n3.4 Antibiotic resistance\n\nThe influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).\n\nTABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance\n\n\tOverall\tFirst‐line\tSecond‐line\tThird‐line\tFourth‐line\tFifth‐line\t\nClarithromycin resistant\t\t\t\t\t\t\t\nE\t26\t2\t7\t6\t7\t4\t\nN\t30\t2\t7\t9\t7\t5\t\n%E\t86.7\t100\t100\t66.7\t100\t80\t\n95% CI\t(69–96)\t(16–100)\t(59–100)\t(30–92)\t(59–100)\t(28–99)\t\nClarithromycin susceptible\t\t\t\t\t\t\t\nE\t14\t2\t5\t4\t0\t1\t\nN\t17\t2\t5\t4\t2\t1\t\n%E\t82.4\t100\t100\t100\t0\t100\t\n95% CI\t(56–96)\t(16–100)\t(48–100)\t(40–100)\tNA\t(1.2–99)\t\nMetronidazole resistant\t\t\t\t\t\t\t\nE\t21\t2\t4\t8\t4\t3\t\nN\t27\t2\t4\t11\t6\t4\t\n%E\t77.8\t100\t100\t72.7\t66.6\t75\t\n95% CI\t(58–91)\t(16–100)\t(40–100)\t(39–94)\t(22–95)\t(19–99)\t\nMetronidazole susceptible\t\t\t\t\t\t\t\nE\t19\t2\t8\t2\t3\t2\t\nN\t20\t2\t8\t2\t3\t2\t\n%E\t95\t100\t100\t100\t100\t100\t\n95% CI\t(75–99)\t(16–100)\t(63–100)\t(16–100)\t(29–100)\t(16–100)\t\nDual resistant\t\t\t\t\t\t\t\nE\t16\t1\t3\t5\t4\t3\t\nN\t20\t1\t3\t8\t4\t4\t\n%E\t80.0\t100\t100\t62.5\t100\t75\t\n95% CI\t(56–94)\t(1.2–99)\t(29–100)\t(24–91)\t(40–100)\t(19–99)\t\nDual susceptible\t\t\t\t\t\t\t\nE\t24\t3\t9\t5\t3\t2\t\nN\t27\t3\t9\t5\t5\t2\t\n%E\t88.9\t100\t100\t100\t60\t100\t\n95% CI\t(71–97)\t(29–100)\t(66–100)\t(48–100)\t(14–94)\t(16–100)\t\nAbbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.\n\n3.5 Safety\n\nAt least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.\n\nTABLE 4 Frequency, intensity and duration of adverse events\n\n\tFrequency of AEs\tIntensity of AEs\tLength of AEs\t\n\tN\t%\t95% CI\tMild (N)\t%\t95% CI\tModerate (N)\t%\t95% CI\tSevere (N)\t%\t95% CI\tMean days (SD)\t\nNausea\t199\t9.5\t(8.2–10.7)\t116\t58.3\t(51–65)\t75\t38.0\t(31–44)\t8\t4.0\t(1.0–7.0)\t6.6 (3.2)\t\nDiarrhoea\t174\t8.3\t(7.1–9.5)\t81\t46.6\t(39–54)\t89\t51.1\t(43–59)\t4\t2.3\t(0.6‐5.7)\t6.5 (3.9)\t\nFatigue\t136\t6.5\t(5.4–7.5)\t48\t35.3\t(27–44)\t65\t47.8\t(39–56)\t23\t16.9\t(10.2–23.6)\t8.3 (3.2)\t\nMetallic taste\t108\t5.1\t(4.2–6.1)\t62\t57.4\t(48–67)\t45\t41.7\t(32–51)\t1\t0.9\t(0.02–5.0)\t7.7 (3.7)\t\nDyspepsia\t105\t5.0\t(4.0–5.9)\t40\t38.1\t(28–48)\t60\t57.1\t(47–67)\t5\t4.8\t(1.6–10.8)\t7.8 (3.4)\t\nAbdominal pain\t103\t4.9\t(3.9–5.58)\t46\t44.7\t(35–55)\t51\t49.5\t(39–60)\t6\t5.8\t(0.8–10.8)\t7.3 (5.0)\t\nAnorexia\t79\t3.8\t(2.9–4.6)\t13\t16.5\t(7.6–25)\t55\t69.6\t(59–80)\t11\t13.9\t(5.6–22.2)\t8.4 (2.3)\t\nVomiting\t63\t3.0\t(2.2–3.7)\t30\t47.6\t(34–61)\t29\t46.0\t(33–59)\t4\t6.3\t(1.7–15.5)\t4.8 (2.9)\t\nHeartburn\t40\t1.9\t(1.3–2.5)\t8\t20.0\t(6.3–34)\t28\t70.0\t(54–85)\t4\t10.0\t(2.8–23.6)\t6.8 (2.3)\t\nTotal\t570\t28.8 a\t(27–31)\t444\t22.0 a\t(21–24)\t497\t25.0 a\t(23–27)\t66\t3.3 a\t(2.5–4.2)\t7.2 (3.3)\t\nSerious AEs\t5\t0.9\t(0.3–2.0)\t\t\t\t\t\t\t\t\t\t\t\nCompliance\t1916\t96.7\t(96–97)\t\t\t\t\t\t\t\t\t\t\t\nCeased\t36\t1.7\t(1.1–2.4)\t\t\t\t\t\t\t\t\t\t\t\nMedications\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nDue to AEs\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nAbbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.\n\na Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).\n\n3.6 Univariate analysis\n\nAs shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.\n\n3.7 Multivariable analysis\n\nStepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.\n\n4 DISCUSSION\n\nIn this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.\n\nIn terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14\n\nAlthough information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11\n\nIn addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.\n\nIn contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16\n\nFinally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27\n\nThere are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.\n\nIn summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.\n\nCONFLICT OF INTERESTS\n\nJavier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.\n\nAUTHOR CONTRIBUTIONS\n\nOlga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.\n\nETHICS APPROVAL\n\nThe study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.\n\nSupporting information\n\nSupplementary Material 1\n\nClick here for additional data file.\n\nSupplementary Material 2\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nThe author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.\n==== Refs\nREFERENCES\n\n1 Crowe SE . Helicobacter pylori infection. N Engl J Med. 2019;380 :1158–65.30893536\n2 Malfertheiner P , Megraud F , O'Morain CA , et al. Management of Helicobacter pylori infection—the Maastricht V/Florence consensus report. Gut. 2017;66 :6–30.27707777\n3 Hooi JKY , Lai WY , Ng WK , et al. Global prevalence of Helicobacter pylori infection: systematic review and metaanalysis. Gastroenterology. 2017;153 :420–9.28456631\n4 Graham DY , Lu H , Yamaoka Y . A report card to grade Helicobacter pylori therapy. Helicobacter. 2007;12 :275–8.17669098\n5 Graham DY , Lee Y‐C , Wu M‐S . Rational Helicobacter pylori therapy: evidence‐based medicine rather than medicine‐based evidence. Clin Gastroenterol Hepatol. 2014;12 :177–86.e3.23751282\n6 Megraud F , Coenen S , Versporten A , et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut. 2013;62 :34–42.22580412\n7 Savoldi A , Carrara E , Graham DY , et al. Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta‐analysis in World Health Organization regions. Gastroenterology. 2018;155 :1372–82.e17.29990487\n8 Gisbert JP , Calvet X . Review article: the effectiveness of standard triple therapy for Helicobacter pylori has not changed over the last decade, but it is not good enough. Aliment Pharmacol Ther. 2011;34 :1255–68.22017749\n9 Gisbert JP , McNicholl AG . Optimization strategies aimed to increase the efficacy of H. pylori eradication therapies. Helicobacter. 2017;22 .e12392.\n10 Dore MP , Leandro G , Realdi G , et al. Effect of pretreatment antibiotic resistance to metronidazole and clarithromycin on outcome of Helicobacter pylori therapy: a meta‐analytical approach. Dig Dis Sci. 2000;45 :68–76.10695616\n11 Megraud FH . Pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut. 2004;53 :1374–84.15306603\n12 Fischbach L , Evans EL . Meta‐analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first‐line therapies for Helicobacter pylori . Aliment Pharmacol Ther. 2007;26 :343–57.17635369\n13 Megraud F , Coenen S , Versporten A , et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut. 2013;62 :34–42.22580412\n14 Nyssen OP , McNicholl AG , Gisbert JP . Meta‐analysis of three‐in‐one single capsule bismuth‐containing quadruple therapy for the eradication of Helicobacter pylori . Helicobacter. 2019;24 .e12570.30767339\n15 Malfertheiner P , Bazzoli F , Delchier J‐C , et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin‐based triple therapy: a randomised, open‐label, non‐inferiority, phase 3 trial. Lancet. 2011;377 :905–13.21345487\n16 Laine L , Hunt R , El‐Zimaity H , et al. Bismuth‐based quadruple therapy using a single capsule of bismuth biskalcitrate, metronidazole, and tetracycline given with omeprazole versus omeprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: a prospective, randomized, multicenter, North American trial. Am J Gastroenterol. 2003;98 :562–7.12650788\n17 McNicholl AG , O'Morain CA , Megraud F , et al. Protocol of the European registry on the management of Helicobacter pylori infection (Hp‐EuReg). Helicobacter. 2019;24 .e12630.31282060\n18 Harris PA , Taylor R , Thielke R , et al. Research electronic data capture (REDCap) ‐ a metadata‐driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42 :377–81.\n19 Graham DY , Lu H , Dore MP . Relative potency of proton‐pump inhibitors, Helicobacter pylori therapy cure rates, and meaning of double‐dose PPI. Helicobacter. 2019;24 .e12554.30440097\n20 Kirchheiner J , Glatt S , Fuhr U , et al. Relative potency of proton‐pump inhibitors‐comparison of effects on intragastric pH. Eur J Clin Pharmacol. 2009;65 :19–31.18925391\n21 Gómez Rodriguez BJ , Castro Laria L , Arguelles Arias F , et al. A real life study of Helicobacter pylori eradication with bismuth quadruple therapy in naïve and previously treated patients. Rev Esp Enferm Dig. 2017;109 :552–8.28617030\n22 Agudo‐Fernandez S , Gonzalez Blanco A . Retrospective analysis of the use of quadruple therapy with bismuth (Pylera®) in real‐life clinical practice in Spain. Gastroenterol Hepatol. 2018;41 :483–9.30041999\n23 Tursi A , Franceschi M , Allegretta L , et al. Effectiveness and safety of Pylera® in patients infected by Helicobacter pylori: a multicenter, retrospective, real life study. Dig Dis. 2018;36 :264–8.29669354\n24 Póerez‐Arellano E , Rodriguez‐Garcia MI , Galera Rodenas AB , et al. Eradication of Helicobacter pylori infection with a new bismuth‐based quadruple therapy in clinical practice. Gastroenterol Hepatol. 2018;41 :145–52.29054320\n25 Thung I , Aramin H , Vavinskaya V , et al. Review article: the global emergence of Helicobacter pylori antibiotic resistance. Aliment Pharmacol Ther. 2016;43 :514–33.26694080\n26 Graham DY , Lew GM , Malaty HM , et al. Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology. 1992;102 :493–6.1732120\n27 Li B‐Z , Threapleton DE , Wang J‐Y , et al. Comparative effectiveness and tolerance of treatments for Helicobacter pylori: systematic review and network meta‐analysis. BMJ. 2015;351 :h4052.26290044\n\n",
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"keywords": "Helicobacter pylori; Pylera; bismuth; eradication; quadruple",
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"title": "European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.",
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"abstract": "BACKGROUND\nGlatiramer acetate is worldwide used as first line treatment in relapsing remitting multiple sclerosis. Local skin reactions associated with glatiramer acetate are common, however, only isolated cases of severe local injection site reactions known as Nicolau Syndrome have been reported so far.\n\n\nMETHODS\nWe describe the case of a recurrent Nicolau Syndrome occurred during longstanding glatiramer acetate treatment in a woman with multiple sclerosis. The haemorrhagic patch necrotized and was treated locally as a deep second degree burn with excision of dead skin tissue and was healed. Treatment with glatiramer acetate was definitely suspended.\n\n\nCONCLUSIONS\nGA injections can be complicated by isolated or recurrent Nicolau Syndrome, a potentially life-threatening condition of which neurologists should be aware.",
"affiliations": "Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Ospedale Regionale, Lugano, 6903, Switzerland. chiara.zecca@eoc.ch.;Department of Dermatology, Ospedale Regionale Bellinzona e Valli, Bellinzona, 6500, Switzerland. info@carlomainetti.ch.;Department of Dermatology, Inselspital, University Hospital, University of Bern, Bern, 3010, Switzerland. Roland.Blum@insel.ch.;Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Ospedale Regionale, Lugano, 6903, Switzerland. claudio.gobbi@eoc.ch.",
"authors": "Zecca|Chiara|C|;Mainetti|Carlo|C|;Blum|Roland|R|;Gobbi|Claudio|C|",
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"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 50410.1186/s12883-015-0504-0Case ReportRecurrent Nicolau syndrome associated with subcutaneous glatiramer acetate injection—a case report Zecca Chiara chiara.zecca@eoc.ch Mainetti Carlo info@carlomainetti.ch Blum Roland Roland.Blum@insel.ch Gobbi Claudio claudio.gobbi@eoc.ch Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Ospedale Regionale, Lugano, 6903 Switzerland Department of Dermatology, Ospedale Regionale Bellinzona e Valli, Bellinzona, 6500 Switzerland Department of Dermatology, Inselspital, University Hospital, University of Bern, Bern, 3010 Switzerland 2 12 2015 2 12 2015 2015 15 24926 8 2015 21 11 2015 © Zecca et al. 2015\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\nGlatiramer acetate is worldwide used as first line treatment in relapsing remitting multiple sclerosis. Local skin reactions associated with glatiramer acetate are common, however, only isolated cases of severe local injection site reactions known as Nicolau Syndrome have been reported so far.\n\nCase presentation\nWe describe the case of a recurrent Nicolau Syndrome occurred during longstanding glatiramer acetate treatment in a woman with multiple sclerosis. The haemorrhagic patch necrotized and was treated locally as a deep second degree burn with excision of dead skin tissue and was healed. Treatment with glatiramer acetate was definitely suspended.\n\nConclusions\nGA injections can be complicated by isolated or recurrent Nicolau Syndrome, a potentially life-threatening condition of which neurologists should be aware.\n\nKeywords\nGlatiramer acetateMultiple sclerosisNicolau syndromeSkin reactionsissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nGlatiramer acetate (GA) [1] is worldwide one of the most frequently prescribed immune modulatory treatment for multiple sclerosis (MS) and considered both an efficacious and safe compound [2, 3]. GA may cause common albeit generally unserious local skin reactions. These may have potentially negative impact on patient’s health-related quality of life [4] and reduce compliance and adherence, therefore representing a major limitation of GA use [5]. The most common GA related skin reactions include local redness, erythema, swelling, pain, pruritus, bruising, irritation, inflammation, induration of the skin around an injection site, or lipoatrophy, developing in 7–90 % of treated patients [3, 4].\n\nOnly single cases of a severe local injection site reaction known as Nicolau Syndrome (NS) have been reported during GA treatment so far [6–12]. The typical NS presentation is pain around the injection site soon after injection followed by erythema developing within hours with a livid discoloration at the injection site. Irregular lightning-like extensions therefore develop peripherally. The epidermis is intact during the first days and an indurated infiltrate is palpable at the injection site. After several days a central necrosis of the size corresponding to the indurated infiltrate develops. After several weeks, a well-demarcated necrotic area remains.\n\nWe report the case of a recurrent Nicolau Syndrome (NS) occurring during GA treatment.\n\nCase presentation\nThe patient is a 58 year-old female with relapsing remitting MS treated with subcutaneous GA since 2006, and otherwise unremarkable medical history. She presented at our department with a painful livedoid and haemorrhagic skin lesion that developed on her left abdomen approximately 24 h after GA injection. She reported correct injection practice.\n\nShe had no fever. Blood cell count, C-reactive protein, renal function, creatine kinase (CK), IgE, autoimmune screening, lupus anticoagulants and cryoglobulins were unremarkable. Superficial ultrasonography at skin lesion showed diffuse oedema without fluid collections. The patient was dismissed with symptomatic non-steroidal anti-inflammatory treatment and GA was stopped.\n\nAfter 2 days, a livedoid violaceous skin patch with dendritic extensions below the injection site became apparent (Fig. 1a and b). At surgical evaluation at the Emergency Department cellulitis was suspected and a surgical revision proposed to avoid potentially lethal complications (such as sepsis and renal failure following rhabdomyolysis). Considering the negative inflammatory parameters and normal renal and CK values, we referred her before surgery to the Dermatology department for further counselling. Here, a NS was suspected and confirmed by a skin biopsy showing coagulative necrosis of dermal collagen and local adipose tissue, as well as several hyaline thrombi inside small and medium-sized blood vessels (Fig. 2), without skin infection (cellulitis). Bacteriological culture of lesion samples grew only resident flora. The livedoid figures around the central haemorrhagic skin lesions disappeared spontaneously after a week. The haemorrhagic patch of NS necrotized (Fig. 1c). The skin necrosis was limited at the dermis and was removed by a surgical debridement. It was treated with a continuing multifunctional dressing to cleanse, fill, absorb and moisten the wound. A healing by second intention was obtained in 2 months after first evaluation. GA was definitively suspended. At that time, the patient reported that in 2007 a similar lesion had occurred after GA injection in her right abdomen. She experienced immediate and unusual local pain with subsequent appearance of a dark red area around the injection site. A central dark lesion developed within 2 days leading her to the emergency department. The lesion was initially treated conservatively, however, a surgical excision was required after a few days. No histological examination was performed at that time. The lesion evolved into a slightly depressed white scar. A recurrent NS was therefore diagnosed.Fig. 1 \na Nicolau Syndrome (NS) on left abdomen at first dermatological evaluation 2 days after onset. b Magnification of the NS lesion highlighting an erythematous, purpuric and haemorrhagic patch, at the site of the subcutaneous glatiramer acetate (GA) injection. Surrounding livedoid reticular patch as sign of vascular damage. c Three weeks after GA injection the livedoid patch disappeared. A skin necrosis induced by the cutaneous ischemia an atonic superficial wound developed thereafter\n\nFig. 2 Histological picture of the patient’s skin biopsy. a partly necrotic and elevated epidermis (dashed arrows) due to thrombosized small vessels (solid arrows) in the upper dermis with only sparse cellular inflammation. b haematoma in the deeper part of dermis (solid arrow). c cellular inflammation in the deeper dermis (solid arrow) and panniculitis (dashed arrow) with coagulative necrosis of dermal collagen and local adipose tissue. Stain: haematoxylin-eosin, a: x 200, b: x 100, c: x 40. Software: ProgRes CapturePro v2.8.8\n\n\n\nConclusions\nWe describe the case of recurrent NS under GA treatment in a patient with MS.\n\nNS (or Embolia cutis medicamentosa) is a very rare and potentially life threatening complication following injection of several drugs [13]. It consists of a local vasculitis which can evolve in subcutaneous, fat or muscle tissue necrosis. NS is mostly described as a complication of a variety of intra-muscular drug preparations, however it has also been reported to occur with sc. injections, particularly GA and interferons [14]. Typically, NS onset is represented by pain around the injection site, which is followed by erythema progressively evolving in a livedoid and then haemorrhagic patch. Finally, aseptic necrosis of skin, subcutaneous fat, and muscle tissue can occur [13].\n\nThe cause of NS seems to be related to the injection itself rather than to the injected compound or even the administration route (i.e. intramuscular or subcutaneous). Its pathogenesis is not fully understood, and only hypothesis have been proposed so far. An unintended intra-periarterial or perinervous injection might induce severe pain and consequently sympathetic nerve mediated vasospasm. This, in turn, may lead to local necrosis. Injection itself might also cause embolic occlusion of small skin arteries, as well as marked arterial wall inflammation ultimately causing tissue necrosis.\n\nNS is per se rare and only few cases have been previously reported after GA injection so far [7–12]. Notably, only one of these was recurrent [9]. Predominantly females were involved as in our case probably reflecting MS epidemiology. Lesion site was heterogeneous among cases (abdomen, tight, arm, buttock), and NS occurred generally years after GA treatment initiation. No specific trigger factors were identified, and the injection technique was mostly correct with the exception of a single patient referring difficulties with the injection preceding NS onset [8]. In two cases no specific treatment was performed, one resolved completely [10] and the second one evolved in a slightly depressed scar [11]. The remaining patients where treated with surgical excision of the necrotic area, vasodilatative drugs, heparine, fusidic acid and steroids [7, 8, 11, 12] with variable results ranging from no sequelae [8] to muscle involvement [6].\n\nVarious treatments have been used for NS, however, none of them has become standard of care. In the majority of cases treatment of NS remains conservative, with analgesics, antibiotics, and dressing. If tissue necrosis is present, surgical removal is performed first, and advanced dressings according to the extent, depth and severity of the wound is therefore used. In wide lesions skin grafts or flaps may be required [15].\n\nIt has been suggested that the occurrence of a NS does not contraindicate continuation of GA treatment, as NS is believed to be mainly a consequence of the injection technique rather than of the drug itself [9]. We were not able, however, to identify incorrect injection practice in our patient who nevertheless experienced a recurrence of NS, possibly suggesting individual predisposition and/or a role of the specific compound.\n\nNeurologists should be aware of NS as possible consequence of GA injection, as its course might include lethal complications such as sepsis and renal failure following rhabdomyolysis.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nAbbreviations\nCKCreatine kinase\n\nGAGlatiramer acetate\n\nIgEImmunoglobulin E\n\nMSMultiple sclerosis\n\nNSNicolau Syndrome\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nCZ participated in the clinical diagnosis and drafted the manuscript. CM was involved in the dermatological diagnosis. RB carried out the histological analysis and provided the microphotographs. CG participated in the clinical diagnosis and coordinated and helped drafting the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Liliane Petrini for language editing and manuscript submission.\n==== Refs\nReferences\n1. Copaxone Prescribing informations. https://www.copaxone.com, accessed on Jan 2015.\n2. Caporro M Disanto G Gobbi C Zecca C Two decades with glatiramer acetate subcutaneous injection - the current role of standard and new high dose – low frequency glatiramer acetate in relapsing remitting multiple sclerosis treatment Pat Pref Adher. 2014 8 1123 1134 \n3. Johnson KP Brooks BR Cohen JA Ford CC Goldstein J Lisak RP Copolymer I reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III, multicentre, double-blind, placebo-controlled trial. The Copolymer I Multiple Sclerosis Study Group Neurol 1995 45 1268 76 10.1212/WNL.45.7.1268 \n4. Balak DMW Hengstman GJD Çakmak A Thio HB Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review Mult Scler 2012 18 12 1705 17 10.1177/1352458512438239 22371220 \n5. Fernández-Fournier M Tallón-Barranco A Chamorro B Martínez-Sánchez P Puertas I Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon BMC Neurol. 2015 15 141 10.1186/s12883-015-0399-9 26286576 \n6. Feldmann R Schierl M Rauschka H Sator PG Breier F Steiner A Necrotizing skin lesions with involvement of muscle tissue after subcutaneous injection of glatiramer acetate Eur J Dermatol. 2009 19 385 19451051 \n7. Harde V Schwarz T Embolia cutis medicamentosa following subcutaneous injection of glatiramer acetate J Dtsch Dermatol Ges. 2007 5 1122 3 10.1111/j.1610-0387.2007.06391.x 18042092 \n8. Gaudez C Regnier S Aractingi S Heinzlef O [Livedo-like dermatitis (Nicolau’s syndrome) after injection of Copolymer-1 (Glatiramer acetate)] Dermite livedoide de Nicolau après injection de Copolymere-1 (acetate de Glatiramer) Rev Neurol (Paris) 2003 159 571 3 12773903 \n9. Martínez-Morán C Espinosa-Lara P Nájera L Romero-Maté A Córdoba S Hernández-Núñez A Embolia cutis medicamentosa (síndrome de Nicolau) tras inyección de acetado de glatirámero Actas Dermosifiliogr. 2011 102 742 4 10.1016/j.ad.2010.12.018 21741603 \n10. Koller S, Kränke B. Nicolau syndrome following subcutaneous glatiramer-acetate injection. J Am Ac Dermat. 2011:e16-7. doi: 10.1016/j.jaad.2010.09.003.\n11. Pérez AP Blanco VP Fernández RS Síndrome de Nicolau tras la administración de acetato de glatirámero Neurología 2013 28 448 9 10.1016/j.nrl.2012.04.010 22698594 \n12. Lobato-Berezo A, Martínez-Pérez M, Imbernón-Moya A, Gallego-Valdés MÁ. Nicolau syndrome after glatiramer acetate injection. Med Clin (Barc). 2015.\n13. Köhler LD Schwedler S Worret WI Embolia cutis medicamentosa Int J Dermatol. 1997 36 197 10.1046/j.1365-4362.1997.00233.x 9159001 \n14. Sonntag M Hodzic-Avdagic N Bruch-Gerharz D Neumann NJ Embolia cutis medicamentosa after subcutaneous injection of pegylated interferon-alpha Hautarzt 2005 56 10 968 9 16142495 \n15. Corazza M Capozzi O Virgilit A Five cases of livedo-like dermatitis (Nicolau’s syndrome) due to bismuth salts and various other non-steroidal anti-inflammatory drugs J Eur Acad Dermatol Venereol 2001 15 585 8 10.1046/j.1468-3083.2001.00320.x 11843224\n\n",
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"mesh_terms": "D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents; D007279:Injections, Subcutaneous; D008875:Middle Aged; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D065148:Nicolau Syndrome; D012008:Recurrence",
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"title": "Recurrent Nicolau syndrome associated with subcutaneous glatiramer acetate injection--a case report.",
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"drugadditional": null,
... |
{
"abstract": "We report a case of a 79-year-old man who developed severe therapy-related pancytopenia from tegafur uracil(UFT)and Leucovorin(LV)as adjuvant chemotherapy for ascending colon cancer. Laparoscopic right hemicolectomy resection was performed for the ascending colon cancer. Pathohistological analysis revealed that the ascending colon tumor was moderately differentiated tubular adenocarcinoma(T3, N1, M0, and Stage III a). Postoperative adjuvant chemotherapy with UFT and LV was administered. After 2 courses of chemotherapies, severe thrombocytopenia(Grade 4)and neutropenia(Grade 4)were noted. Platelet and granulocyte-colony stimulating factor(G-CSF)were transfused. Furthermore, red blood cell transfusions were given for anemia(Grade 3). Dihydropyrimidine dehydrogenase(DPD)deficiency was suspected as the cause of the pancytopenia, and the ratio of dihydrouracil(DHU)and uracil(URA)was measured. However, the result was negative for DPD deficiency. Bone marrowaspiration revealed that therapy-related leukemia(TRL)and therapy-related myelodysplastic syndrome(T-MDS)were not the causes of the pancytopenia either. A total of 230 units of platelet transfusions and 20 units of red blood cell transfusions have been given for 32 weeks, and the patient currently requires routine blood transfusions. Fortunately, infection and bleeding never occurred. Subsequently, the patient should be monitored carefully.",
"affiliations": "Dept. of Surgery, Chiba Rosai Hospital.",
"authors": "Akiyama|Takahiro|T|;Yasutomi|Jun|J|;Kusashio|Kimihiko|K|;Matsumoto|Masanari|M|;Suzuki|Takeshi|T|;Iida|Ayako|A|;Imamura|Namiko|N|;Yoshizumi|Arihito|A|;Harano|Rina|R|;Udagawa|Ikuo|I|;Ohtsuka|Masayuki|M|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D005641:Tegafur; D002955:Leucovorin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D044682:Colon, Ascending; D003110:Colonic Neoplasms; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D002955:Leucovorin; D008297:Male; D010198:Pancytopenia; D017713:Platelet Transfusion; D005641:Tegafur",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1399-1401",
"pmc": null,
"pmid": "29394647",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Therapy-Related Pancytopenia Caused by UFT and LV in a Patient with Ascending Colon Cancer.",
"title_normalized": "severe therapy related pancytopenia caused by uft and lv in a patient with ascending colon cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2017354714",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEGAFUR\\URACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Gastroparesis is defined by the presence of delayed gastric emptying without mechanical obstruction. Patients may present with severe discomfort that can mimic an acute abdomen including abdominal pain, vomiting, nausea, bloating, fullness and early satiety. The prevalence of gastroparesis is estimated at 24 per 100 000 and women are more commonly affected than men. It is associated with a number of conditions including diabetes, Parkinson's disease, multiple sclerosis, previous abdominal surgeries and connective tissue disorders, including scleroderma and Ehlers-Danlos syndrome. Drugs known to prolong gastric transit time, such as opiates, have been shown to exacerbate symptoms. We report a case of a 20-year-old woman with Ehlers-Danlos syndrome who developed respiratory depression after being administered a therapeutic dose of morphine. This occurred due to opiate toxicity confounded by gastroparesis. The patient required further support from intensive care until she recovered, and eventually underwent a gastric pacing procedure for symptomatic relief.",
"affiliations": "Department of Accident & Emergency, Broomfield Hospital, Chelmsford, UK.;Broomfield Hospital, Chelmsford, UK.;Department of Accident & Emergency, Broomfield Hospital, Chelmsford, UK.",
"authors": "Craven|Henry|H|;Iftikhar|Hina|H|;Bhatnagar|Pallav|P|",
"chemical_list": "D009020:Morphine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D019468:Disease Management; D004535:Ehlers-Danlos Syndrome; D005260:Female; D018589:Gastroparesis; D006801:Humans; D009020:Morphine; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27147632",
"pubdate": "2016-05-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15521026;23414452;26343221;9824125",
"title": "Profound opiate toxicity in gastroparesis following therapeutic dose.",
"title_normalized": "profound opiate toxicity in gastroparesis following therapeutic dose"
} | [
{
"companynumb": "US-ACTAVIS-2016-12293",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "An 86-year- old woman with a history of recurrent bronchitis and giant cell arteritis presented for new onset, cyclic and migratory erythematous nodules associated with fatigue and weight loss. Although a systemic vasculitis was initially suspected, elevated inflammatory markers and symptoms persisted despite aggressive corticosteroid therapy. Excisional biopsy of one nodule showed dense suppurative and granulomatous inflammation that was rife with acid-fast bacilli. The patient was urgently admitted for empiric treatment of disseminated mycobacterial infection. Although T-SPOT Tuberculosis testing and direct mycobacterial PCR were negative, mass spectrometry demonstrated Mycobacterium chelonae. The patient was treated with a macrolide and quinolone combination regimen and then discharged to a rehabilitation facility.",
"affiliations": "Harvard Medical School, Boston, Massachusetts. soraya_azzawi@hms.harvard.edu.",
"authors": "Azzawi|Soraya|S|;Hoang|Mai P|MP|;Smith|Gideon P|GP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "24(8)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D004890:Erythema; D005221:Fatigue; D005260:Female; D006801:Humans; D000069349:Linezolid; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D014382:Tuberculosis, Cutaneous; D015431:Weight Loss",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30677847",
"pubdate": "2018-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New onset erythematous nodules in an elderly woman.",
"title_normalized": "new onset erythematous nodules in an elderly woman"
} | [
{
"companynumb": "US-MYLANLABS-2018M1087922",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Whether the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) would influence the risk of new-onset diabetes remains uncertain. Therefore, we performed a systematic review and meta-analysis to evaluate the association between the use of bDMARDs and the incidence of diabetes in patients with systemic inflammatory conditions. Pubmed, Medline, Embase and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2000 to March 2020. Studies conducted in systemic inflammatory conditions with reports of the incidence of diabetes in subjects treated with bDMARDs were included. With 22 randomized controlled trials and 3 cohort studies included, the overall result indicated that compared with non-bDMARD treatment, the use of bDMARDs was significantly associated with decreased incidence of diabetes in patients with systemic inflammatory conditions (RR = 0.56, 95 % CI, 0.43 to 0.74, P < 0.001, I2 = 69 %), especially in patients with in rheumatoid arthritis (RR = 0.54, 95 % CI, 0.38 to 0.76, P = 0.0005, I2 = 26). Reduced risk of new-onset diabetes was observed in studies with follow-up more than 1 year (RR = 0.73, 95 % CI, 0.54 to 0.99, P = 0.04, I2 = 88). New-onset diabetes was less frequent in patients with TNF-α inhibitor treatment (RR = 0.54, 95 % CI, 0.48 to 0.60, P < 0.001, I2 = 42 %) and abatacept treatment (RR = 0.44, 95 % CI, 0.34 to 0.58, P < 0.001, I2 = 3 %), which might be associated with the inhibition of TNF-α mediated inflammatory responses and dysregulated T cell activation and immune responses respectively. Further investigations are required to validate the glucose metabolism protective effect of bDMARDs and clarify the underlying mechanisms of the crosstalk between bDMARDs and diabetes.",
"affiliations": "Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China. Electronic address: chulin@bjmu.edu.cn.;Department of Endocrinology and Metabolism, Zhengzhou Hospital of Chinese Traditional Medicine, Henan, China. Electronic address: honghu739@126.com.;Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China. Electronic address: dr_junel@sina.com.;Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China. Electronic address: ywjsunshine@126.com.;Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China. Electronic address: lvfang1a@163.com.;Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China. Electronic address: jiln@bjmu.edu.cn.",
"authors": "Lin|Chu|C|;Ji|Hongyu|H|;Cai|Xiaoling|X|;Yang|Wenjia|W|;Lv|Fang|F|;Ji|Linong|L|",
"chemical_list": "D001688:Biological Products; D018836:Inflammation Mediators; C439524:TNF protein, human; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.phrs.2020.105216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-6618",
"issue": "161()",
"journal": "Pharmacological research",
"keywords": "Abatacept; IL inhibitor; New-onset diabetes; Rituximab; TNF-α inhibitor; bDMARD",
"medline_ta": "Pharmacol Res",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D003920:Diabetes Mellitus; D005260:Female; D006801:Humans; D015994:Incidence; D018836:Inflammation Mediators; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D012307:Risk Factors; D013601:T-Lymphocytes; D013997:Time Factors; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8907422",
"other_id": null,
"pages": "105216",
"pmc": null,
"pmid": "33007415",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review",
"references": null,
"title": "The association between the biological disease-modifying anti-rheumatic drugs and the incidence of diabetes: A systematic review and meta-analysis.",
"title_normalized": "the association between the biological disease modifying anti rheumatic drugs and the incidence of diabetes a systematic review and meta analysis"
} | [
{
"companynumb": "CN-UCBSA-2020054737",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB PEGOL"
},
"drugadditional": "3",
... |
{
"abstract": "Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary.",
"affiliations": "Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatric Pneumonology and Allergy, Medical University of Warsaw, Warsaw, Poland.;Department of Pediatric Pneumonology and Allergy, Medical University of Warsaw, Warsaw, Poland.;Department of Radiology, Jan Polikarp Brudziński Pediatric Hospital, Warsaw, Poland.;Department of Pathology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland.;Department of Pediatrics, Hematology and Oncology, Collegium Medicum Bydgoszcz, UMK Toruń, Bydgoszcz, Poland.;Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.;Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.;The Pulmonology Outpatient's Clinic, Children's Memorial Health Institute, Warsaw, Poland.;University Children Hospital in Cracow, Medical College, Jagiellonian University, Cracow, Poland.;Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, Bialystok, Poland.;Histocompatibility Laboratory, Children's Memorial Health Institute (IPCZD), Warsaw, Poland.;Histocompatibility Laboratory, Children's Memorial Health Institute (IPCZD), Warsaw, Poland.;Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pneumonology, Pediatric Allergology and Clinical Immunology, Poznań University of Medical Sciences, Poznań, Poland.;Department of Pediatric Pneumonology and Allergy, Medical University of Warsaw, Warsaw, Poland.",
"authors": "Pac|Małgorzata|M|;Bielecka|Teresa|T|;Grzela|Katarzyna|K|;Komarnicka|Justyna|J|;Langfort|Renata|R|;Koltan|Sylwia|S|;Dabrowska-Leonik|Nel|N|;Bernat-Sitarz|Katarzyna|K|;Pronicki|Maciej|M|;Dmenska|Hanna|H|;Pituch-Noworolska|Anna|A|;Mikoluc|Bozena|B|;Piatosa|Barbara|B|;Tkaczyk|Katarzyna|K|;Bernatowska|Ewa|E|;Wojsyk-Banaszak|Irena|I|;Krenke|Katarzyna|K|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.01950",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.01950\nImmunology\nOriginal Research\nInterstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders—A Multicenter Observational Study\nPac Małgorzata 1† Bielecka Teresa 2† Grzela Katarzyna 2* Komarnicka Justyna 34 Langfort Renata 5 Koltan Sylwia 6 Dabrowska-Leonik Nel 1 Bernat-Sitarz Katarzyna 1 Pronicki Maciej 7 Dmenska Hanna 8 Pituch-Noworolska Anna 9 Mikoluc Bozena 10 Piatosa Barbara 11 Tkaczyk Katarzyna 11 Bernatowska Ewa 1 Wojsyk-Banaszak Irena 12 Krenke Katarzyna 2 1Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland\n2Department of Pediatric Pneumonology and Allergy, Medical University of Warsaw, Warsaw, Poland\n3Department of Radiology, Jan Polikarp Brudziński Pediatric Hospital, Warsaw, Poland\n4Department of Radiology, Children's Memorial Health Institute, Warsaw, Poland\n5Department of Pathology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland\n6Department of Pediatrics, Hematology and Oncology, Collegium Medicum Bydgoszcz, UMK Toruń, Bydgoszcz, Poland\n7Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland\n8The Pulmonology Outpatient's Clinic, Children's Memorial Health Institute, Warsaw, Poland\n9University Children Hospital in Cracow, Medical College, Jagiellonian University, Cracow, Poland\n10Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, Bialystok, Poland\n11Histocompatibility Laboratory, Children's Memorial Health Institute (IPCZD), Warsaw, Poland\n12Department of Pneumonology, Pediatric Allergology and Clinical Immunology, Poznań University of Medical Sciences, Poznań, Poland\nEdited by: Andrew R. Gennery, Newcastle University, United Kingdom\n\nReviewed by: Matthew S. Buckland, Great Ormond Street Hospital for Children NHS Foundation Trust, United Kingdom; Saul Oswaldo Lugo Reyes, National Institute of Pediatrics, Mexico\n\n*Correspondence: Katarzyna Grzela katarzyna.grzela@gmail.comThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n†These authors have contributed equally to this work\n\n\n27 8 2020 \n2020 \n11 195030 4 2020 20 7 2020 Copyright © 2020 Pac, Bielecka, Grzela, Komarnicka, Langfort, Koltan, Dabrowska-Leonik, Bernat-Sitarz, Pronicki, Dmenska, Pituch-Noworolska, Mikoluc, Piatosa, Tkaczyk, Bernatowska, Wojsyk-Banaszak and Krenke.2020Pac, Bielecka, Grzela, Komarnicka, Langfort, Koltan, Dabrowska-Leonik, Bernat-Sitarz, Pronicki, Dmenska, Pituch-Noworolska, Mikoluc, Piatosa, Tkaczyk, Bernatowska, Wojsyk-Banaszak and KrenkeThis 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.Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary.\n\ncomputed tomographychildrenCVIDinterstitial lung diseaseprimary immunodeficiencyGLILD\n==== Body\nIntroduction\nPrimary immunodeficiencies (PIDs) are inherited disorders of the immune system encompassing inborn errors of immunity. The clinical spectrum of PIDs is broad, ranging from relatively mild disorders selectively affecting immune defense mechanisms to serious, life-threatening diseases characterized by profound lack of immune functions. According to a report by the International Union of Immunological Societies (IUIS), over 400 distinct disorders are recognized (1). Estimates by Bousfiha et al. suggest that ~6 million people may be affected worldwide, though only ~60,000 cases of PIDs are currently definitively diagnosed (2). Ten phenotypic categories of PIDs are recognized according to the underlying immune defects (3). Primary antibody deficiencies (PADs) are the largest group of PIDs, accounting for ~55% of PIDs in Europe (www.esid.com) and up to 78% in the USA (4). PADs predominantly result from a primary defect in B cells, but can also be caused by defects in T cells or other immune cell populations that contribute to B-cell or plasma cell development and function. Antibody deficiencies are characterized by a malfunctioning antibody response, which is reflected in low or undetectable levels of immunoglobulin(s).\n\nCommon variable immunodeficiency (CVID), with an incidence of 1:25,000–1:50,000, is one of the most prevalent symptomatic PADs (5–7). Some well-defined disorders (e.g., combined immunodeficiencies—CID) accompanied by antibody deficiency can mimic CVID, and only new diagnostic tools, including next-generation sequencing (NGS), enable the verification of the final diagnosis (8, 9).\n\nPatients with antibody deficiency present with a broad spectrum of manifestations. In addition to recurrent infections, non-infectious complications such as interstitial lung disease (ILD), gastrointestinal inflammatory disease, hematologic or organ-specific autoimmunity, lymphoproliferation, and lymphoma may occur (5–8). Respiratory diseases are a cause of morbidity and mortality among PID patients, and in some cases lung disease may play an important role in diagnosis as the first manifestation of PID (10–14). Lung involvement in patients with PID can be infection-related, immune-mediated, or associated with the occurrence of neoplastic diseases. In cases of infection-related lung disease, effective protection can be provided by immunoglobulin replacement therapy (IgRT); however, it does not prevent non-infectious pulmonary involvement (6, 12). ILDs represent one of the most significant immune-mediated complications of PID (14). The most common form of PID-related ILD is granulomatous-lymphocytic ILD (GLILD), an umbrella term that encompasses a spectrum of lung pathologies: various forms of pulmonary lymphoid hyperplasia [lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis (FB), nodular lymphoid hyperplasia, and granulomatous disease], as well as organizing pneumonia (10, 14, 15). The risk of death in CVID patients with non-infectious complications like ILD has been shown to be several times higher than in patients with infectious complications only (16). CVID-related GLILD significantly shortens life expectancy (17).\n\nPrevious reports concerning PID-related ILD are mainly limited to adults; data regarding disease specificity and exceptionality of pediatric patients available in the literature are insufficient. Herein we present a retrospective analysis of the clinical, radiological, and histological characteristics, as well as treatment strategies and outcomes, in a unique group of children with PID-related ILD, predominantly CVID patients.\n\nMaterials and Methods\nRetrospective analysis of clinical data from children with PID-related ILD consulted or treated consecutively in the Department of Immunology at the Children's Memorial Health Institute (CMHI) of Warsaw and the Department of Pediatric Pneumonology and Allergy at the Medical University of Warsaw between 2012 and 2019 is presented.\n\nThe major inclusion criterion was the diagnosis of PID, mostly CVID. Diagnosis of CVID was established according to ESID diagnostic criteria (18). Since CVID encompasses a group of heterogenous antibody deficiencies with many monogenic forms, detailed immunophenotyping and genetic studies using next-generation sequencing (NGS), Sanger sequencing, or fluorescence in situ hybridization (FISH) were performed in six individuals to better characterize the study group. In five patients genetic tests were not performed because of: technical problems with genetic testing and consent not given by parents. Following laboratory and/or molecular studies, combined immunodeficiency (CID) was diagnosed in three individuals: one with Nijmegen breakage syndrome (NBS), one with DiGeorge Syndrome (DGS), and one with LRBA.\n\nDiagnosis of PID-related ILD was based on (1) clinical signs and symptoms [tachypnea [defined as respiratory rate >90th percentile (19)], retractions, crackles]; (2) typical computed tomography (CT) findings [multiple nodules of different densities with perilymphatic or interlobular distribution predominantly in the middle and lower zones of the lungs and hilar or mediastinal lymphadenopathy (transverse dimension of the lymph nodes >1 cm)]; and (3) histopathology of lung biopsy with findings consistent with GLILD, cryptogenic organizing pneumonia (COP), LIP, FB, or lymphoid hyperplasia.\n\nExclusion criteria were other ILDs, coexistence of other chronic lung diseases (e.g., cystic fibrosis), and acute or chronic respiratory infections.\n\nData Collection\nPrespecified data on all children with PID and related ILD were collected. These included (1) demographic data; (2) clinical signs and symptoms such as dyspnea, tachypnea, cough, cyanosis, crackles, wheezing, respiratory failure, finger clubbing, splenomegaly, hepatomegaly, lymphadenopathy, hemolytic anemia, thrombocytopenia, and history of chronic lung diseases; (3) the results of the following laboratory tests: total blood count, detailed immunological screening (including immunoglobulin level and immunophenotyping of lymphocytes, with B- and T-cell functional tests and genetic testing in some cases); (4) the results of pulmonary function tests, including spirometry, body plethysmography, and diffusing capacity for carbon monoxide (DLCO); (5) the results of lung high-resolution computed tomography (HRCT) and chest magnetic resonance imaging (MRI); (6) histopathology of lung biopsy; and (7) treatment regimens [corticosteroids, other immunosuppressive drugs (e.g., azathioprine, mycophenolate mofetil, rapamycin, cyclosporin), IgRT, and hematopoietic stem cell transplantation (HSCT)], duration, and outcomes.\n\nThe immune status of patients was assessed based on serum immunoglobulin concentration, antibody response to vaccines and/or isohemagglutinins titer, immunophenotyping of lymphocytes with switch memory B cells numbers, and lymphoproliferation tests as described previously [(20–22); data not shown]. The sources of data were an electronic database of patients with PID and medical records of patients with PID-related ILD.\n\nImaging Studies\nIn eight children, volumetric CT examinations were performed with either a 320-row multidetector computed tomography scanner (Aquilion ONE, Toshiba, Japan; three children) or a 128-row multidetector computed tomography scanner (SOMATOM Definition AS, Siemens, Germany; five children) and images were reconstructed using a high-resolution reconstruction algorithm. In the remaining two patients, CT scans performed in local hospitals were used for analysis. Contrast medium was administered in eight patients. Pulmonary involvement in the child with NBS with a known radiosensitivity was monitored with chest MRI.\n\nPulmonary Function Tests\nSpirometry tests were obtained in nine cooperating individuals and included forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). All pulmonary function tests were performed in the sitting position using a spirometer (Lungtest 1000 MES, Poland, or JAEGER MasterScreen, Germany) according to the ERS (European Respiratory Society) guidelines for lung function testing (23). All spirometric results were presented as percentiles (pc). FVC, FEV1, and FEV1/FVC ≥5th pc were considered normal. Obstruction was diagnosed if the FEV1/FVC ratio was below the 5th pc. DLCO was measured using the single-breath method using a Vmax22 spirometer (SensorMedics, USA), or MasterScreen (CareFusion, USA) and results between the 5th and 95th pc were considered to be within the normal range. The whole-body plethysmography was performed using a Lungtest 1000 (MES, Poland), or MasterScreen (CareFusion, USA). Total lung capacity (TLC) and residual volume (RV) were calculated for each patient. TLC lower than the 5th pc was considered to indicate restriction. Air trapping was defined as a RV/TLC ratio above the 95th pc.\n\nHistological Assessment\nLung biopsies were performed in eight of the 11 patients. The obtained material was then fixed in 10% buffered formalin solution and paraffin embedded (FFPE). Microscopic slides with 4-μm FFPE sections were stained with hematoxylin and eosin (H + E) and in some cases immunohistochemical markers were used (CD3, CD20, CD5, CKAE1/AE3, and Ki-67; Ventana Roche, USA). Immunohistochemical tests were performed using an automated Ventana Benchmark GX Slide Staining System according to the manufacturer's protocol. In two cases, mediastinal lymph nodes biopsies were analyzed.\n\nStatistical Analysis\nThe results of the study were summarized using standard descriptive statistics. Data are presented as median and range.\n\nThe studies involving human participants were reviewed and approved by The Bioethics Committee of the Children's Memorial Health Institute in Warsaw (approval no.9/KBE/2020). All parents or legal guardians, as well as patients older than 16 years of age, gave their written consent to participate in the study.\n\nResults\nDemographic and Clinical Data\nEleven children with interstitial lung disease were selected from the database of 796 children with PID followed-up between 2012 and 2019. Detailed immunological and genetic diagnostics enabled the diagnosis of CVID in nine patients however, in one of these patients, finally an NGS panel revealed an LRBA mutation. The other two patients with a provisional diagnosis of PAD were eventually diagnosed with CID with associated features (NBS in the patient with hydrocephaly and DGS in the patient without an expressive dysmorphia). In three patients with CVID no mutations were confirmed.\n\nAll of the children diagnosed with PID-related ILD were boys.\n\nThe median age at the diagnosis of antibody deficiency was 9.5 years (range 4–17 years). Six patients had never developed respiratory symptoms (except respiratory tract infections). Chest imaging studies were performed for other reasons (e.g., generalized lymphadenopathy) and revealed pulmonary involvement. Five patients were symptomatic in terms of respiratory involvement. In two children, the symptoms of ILD preceded the recognition of immunodeficiency, so the median age at the onset of ILD symptoms was 6.5 years (range 2–16). The severity of ILD symptoms was diverse, with one child presenting with a mild cough (patient No. 4; Table 1) and three others with life-threatening respiratory failure (patients No. 3, 7, and 8).\n\nTable 1 Baseline clinical characteristics at diagnosis.\n\nPatient\t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t\nAge, sex\t13, M\t19, M\t13, M\t19, M\t5, M\t16, M\t10, M\t12, M\t11, M\t18, M\t17, M\t\nAge at symptom onset\t4 yr\t11 yr\t11 yr\t3 yr\t3 yr\t16 yr\t2 yr\t8 yr\t5 yr\t10 yr\t9 yr\t\nPresenting symptoms\tSplenomegaly, thrombocyte-penia,\tPain in the lower limbs, lymphadenopathy, splenomegaly, anemia, leucopenia\tDyspnea, crackles, acute respiratory failure\tGeneralized lymphadenopathy\tSkin nodules, generalized lymphadenopathy, hepatospleno-megaly, pancytopenia\tHepatospleno-megaly, anemia, lymphadenopathy\tDyspnea, crackles, acute respiratory failure\tSevere viral enterocolitis, parakeratosis, facial dysmorphia, hydrocephalus, strabismus, hypospadias, cryptorchidism\tHepatospleno-megaly, pancytopenia\tLymphadeno-pathy, hepatospleno-megaly\tRecurrent pneumonia, lymphadeno-pathy\t\nRecurrent respiratory infections\t+\t–\t–\t–\t–\t–\t–\t–\t+\t+\t+\t\nAge at ILD diagnosis\t8 yr\t17 yr\t11 yr\t13 yr\t4 yr\t16 yr\t2.5 yr\t10 yr\t9 yr\t10 yr\t14 yr\t\nAge at PID diagnosis\t5 yr\t17 yr\t12 yr\t12 yr\t4 yr\t16 yr\t7 yr\t4 yr\t5 yr\t15 yr\t14 yr\t\nImmunodeficiency\tCVID\tCVID\tCVID\tCVID\tLRBA\tCVID\tCVID\tNBS\tCVID\tDGS\tCVID\t\nGenetic testing\t–\t–\t–\t+ \n No changes\t+ \n LRBA\t–\t+ \n No changes\t+ \n NBS\t+ \n No changes\t+ \n DGS\t–\t\nILD manifestation:\t\nChronic cough\t+\t–\t–\t+\t–\t–\t–\t+\t–\t–\t–\t\nDyspnea\t–\t–\t+\t–\t–\t–\t+\t+\t–\t–\t–\t\nCrackles\t+\t–\t+\t+\t–\t–\t+\t+\t–\t–\t–\t\nClubbed fingers\t–\t–\t–\t–\t–\t–\t+\t–\t–\t–\t–\t\nAcute respiratory insufficiency\t–\t–\t+\t–\t–\t–\t+\t+\t–\t–\t–\t\nExtra-pulmonary manifestation:\t\nHepatomegaly\t+\t+\t+\t–\t+\t+\t+\t–\t+\t+\t–\t\nSplenomegaly\t–\t+\t+\t–\t+\t+\t+\t–\t+\t+\t_\t\nLymphadenopathy\t+\t+\t–\t+\t+\t+\t–\t–\t+\t+\t+\t\nCytopenia:\t\nAnemia\t–\t+\t–\t–\t+\t+\t+\t–\t–\t–\t–\t\nLeukopenia\t–\t+\t–\t–\t+\t+\t–\t–\t+\t–\t–\t\nThrombocytopenia\t+\t–\t–\t–\t+\t+\t+\t–\t+\t–\t–\t\nLung HRCT findings*:\t\nNodules\t+\t+\t+\t+\t+\t+\t+\t+\t+\t+\t+\t\nPerilymphatic distribution\t+\t+\t+\t+\t+\t+\t–\t–\t–\t+\t+\t\nMiddle and lower zone predominance\t+\t+\t+\t+\t–\t+\t–\t+\t–\t+\t–\t\nIntrathoracic lymhadenopathy\t+\t–\t–\t+\t+\t–\t+\t+\t–\t+\t+\t\nGround-glass opacities\t–\t–\t+\t+\t–\t+\t+\t–\t–\t–\t–\t\nLung consolidations\t+\t–\t+\t+\t+\t–\t+\t–\t–\t–\t+\t\nLungbiopsyresult\tGLILD/LIP\tGLILD/LIP\tGLILD\tGLILD/LIP\tGLILD/LIP\tGLILD\tGLILD/LIP\tGranulomas\t–\t–\t–\t\nLymph node biopsy result\t\t\t\t\t\tGranulomas\t\t\t\tGranulomas\t\t\n* Patient 8 had only chest X-ray and chest MRI done. Due to increased risk of cancer after radiation exposure, he was disqualified from chest CT.\n\nPID, primary immunodeficiency; CVID, common variable immunodeficiency; LRBA, mutation in the lipopolysaccharide-responsive and beige-like anchor protein (LRBA) gene; NBS, Nijmegen breakage syndrome; ILD, interstitial lung disease; HRCT, high resolution chest tomography; GLILD, granulomatous-lymphocytic interstitial lung disease; FB, follicular bronchiolitis; LIP, lymphocytic interstitial pneumonia; COP, cryptogenic organizing pneumonia.\n\nDetailed demographic data and clinical symptoms are presented in Table 1.\n\nComputed Tomography\nLung CT was performed in 10 patients. One child with NBS had been diagnosed and followed with chest MRI to avoid radiation exposure.\n\nMultiple, mostly poorly defined pulmonary nodules were revealed in all children assessed. The diameter of the nodules ranged from 2 to 30 mm and their density varied from solid to part-solid to ground glass opacity (Figures 1A, 2, 3). Solid nodules were surrounded by a ground-glass halo in four patients. In most of the children, nodules had a perilymphatic distribution with a predilection for the middle and lower lung zones. The lesions formed rosettes and a “tree-in-bud” pattern in one patient (Figure 2). Interlobular septal thickenings or irregular linear opacities were found in one case each. The changes described above were accompanied by hilar and/or mediastinal lymphadenopathy in seven patients (Figure 4).\n\nFigure 1 (A) Lung high-resolution computed tomography (HRCT): multiple, poorly defined nodules merging in larger areas of ground-glass opacities and consolidations. (B) Lung HRCT: complete regression of pulmonary changes; residual irregular linear opacities are visible. (C) Chest X-ray: diffuse poorly defined nodules creating larger areas of lung consolidations with adjacent areas of ground-glass opacities. Middle and lower zone predominance is clearly marked. (D) Chest X-ray: complete resolution of pulmonary opacities with residual irregular linear thickenings.\n\nFigure 2 Lung high-resolution computed tomography: multiple ground-glass and solid nodules scattered across the lungs, with perylimphatic distribution. Larger clusters of nodules and tree-in-bud pattern are visible peripherally.\n\nFigure 3 Lung high-resolution computed tomography: multiple small pulmonary nodules with perilymphatic distribution (clearly seen along pleural fissures).\n\nFigure 4 Contrast-enhanced lung computed tomography (soft tissue window): marked enlargement of mediastinal and hilar lymph nodes with areas of subpleural lung consolidations.\n\nDuring the exacerbations of ILD, progression of lung involvement in imaging studies was observed, with an increase in the number, size, and density of lung nodules as well as extensive areas of ground-glass opacities and parenchymal lung consolidations (Figures 1A,C).\n\nPulmonary Function Tests\nPulmonary function tests (PFTs) were performed in nine children. Two children were unable to perform PFT, one due to the young age and the other due to intellectual disability. All of the PFTs were performed in the stable phase of the ILD. The results of PFT are shown in Table 2. We found one patient (No. 3) with a restrictive ventilatory pattern and five with air trapping (No. 2, 4, 9, 10, and 11). DLCO was abnormal in two patients. A mild reduction of DLCO was found in patient No. 2 (74% of predicted value) and a moderate reduction was observed in patient No. 3 (50% of predicted value).\n\nTable 2 Results of pulmonary function tests.\n\nPulmonary function tests\tPatient\t1\t2\t3\t4*\t5\t6\t7*\t8\t9\t10\t11\t\nSpirometry\tFEV1, percentile\t94\t15.64\t0.03\t11.39\tND\t75\t22\tND\t29.96\t25.43\t97.03\t\n\tFVC; percentile\t10\t18.50\t0.02\t7.08\tND\t50\t13\tND\t48.97\t13.91\t80.49\t\n\tFEV1/FVC; percentile\t38\t36.29\t84.84\t46.88\tND\t70\t80\tND\t20.11\t60.37\t94.58\t\nPlethysmography\tRV; percentile\tND\t100\t0.07\t99.98\tND\t97\tND\tND\t100\t100\t100\t\n\tTLC; percentile\tND\t99.96\t0.0\t90.35\tND\t>99\tND\tND\t99.82\t98.94\t99.97\t\n\tRV/TLC; percentile\tND\t99.91\t0.78\t99.62\tND\t73\tND\tND\t99.94\t99.82\t99.17\t\nDiffusing capacity for carbon monoxide\tDLCO; percentile\tND\t0\t0\t55.08\tND\t41\tND\tND\t97.39\t90.13\tND\t\n* Lung function tests were performed in a stable phase of the disease, during treatment.\n\nND, No data.\n\nDLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.\n\nThe results of the PFTs are presented in Table 2.\n\nLung Biopsy Results\nThe most common histopathological diagnosis was GLILD (seven cases), with a predominance of the LIP pattern (five cases; Figure 5). Microscopic features of LIP were dominated by abundant diffuse interstitial infiltrates of lymphoid cells composed of CD3+ and CD20+ lymphocytes. In some patients, the inflammatory infiltration formed clusters with single, small lymph nodules. In addition to the intensive interstitial infiltration, a marked peribronchial and perivascular chronic inflammation was present (Figure 6).\n\nFigure 5 Lung parenchyma with diffuse interstitial and peribronchiolar lymphocytic infiltration. Microphotograph: hematoxylin and eosin stain.\n\nFigure 6 Diffuse intensive lymphocytic infiltration, both interstitial and around blood vessels. Alveolar spaces are filled with numerous macrophages. Microphotograph: hematoxylin and eosin stain.\n\nFoci of COP and FB were found in addition to LIP features in one of the patients (Figure 7).\n\nFigure 7 Diffuse interstitial inflammation with small focus of organizing pneumonia (black arrow). The surrounding alveoli are filled with numerous macrophages. Microphotograph: hematoxylin and eosin stain.\n\nInterstitial lymphocytic infiltrates were accompanied by the presence of multiple non-necrotizing granulomas in two children.\n\nIn the child diagnosed with NBS, the only histopathological abnormality in the lung biopsy was non-necrotizing granulomas.\n\nIn two patients (No. 6 and 10), a mediastinal lymph node biopsy was performed and revealed non-caseating granulomas.\n\nTreatment Strategies\nIn eight children with PID-related ILD, the immunosuppressive treatment was introduced (No. 1–8). In three patients (No. 3, 7, and 8) severe pulmonary symptoms were the only reason for initiating the treatment. Patients 1, 4, 5, and 6 (one symptomatic, three asymptomatic) were treated due to autoimmune cytopenia and/or lymphoproliferation with coexisting extensive lung involvement. Patient No. 2, who didn't present with respiratory symptoms, was qualified for treatment because of decreased DLCO results, progression of lung infiltrates in chest HRCT and features of fibrosis in the lung biopsy.\n\nThree patients, due to a lack of clinical symptoms and stable, low-intensity changes in the lung HRCT, did not qualify for any immunosuppressive therapy (No. 9, 10, and 11).\n\nSystemic glucocorticoids (GCs) were introduced in all eight children at the onset of treatment. Two children were initially treated with corticosteroid pulses. GCs were the only drugs used in four patients (No. 2, 4, 6, and 7). In one of the patients (No. 4), initially a recurrence of symptoms was observed during GC dose reduction. It is worth noting that despite the treatment discontinuation after the patient's decision at the age of 18, he remains clinically and radiologically stable. In patient No. 7, a recurrence of ILD occurred after an asymptomatic period of several months. Patient No. 6 (clinically asymptomatic) started treatment with GCs due to autoimmune hemolytic anemia. Hematological improvement after 3 months of GC therapy was achieved, without resolution of radiological findings.\n\nGC treatment resulted in rapid improvement of general condition and resolution of respiratory failure in patient No. 3. However, exercise intolerance, significant radiological abnormalities, and abnormal PFT results persisted despite the therapy.\n\nTwo boys were additionally treated with azathioprine (No. 1 and 3), achieving a meaningful clinical improvement, but due to serious side effects of the therapy (Table 3), the treatment was discontinued. In patient No. 1, mycophenolate mofetil was introduced, but the treatment was ineffective (thrombocytopenia did not resolve) so the boy was eventually qualified for HSCT. The post-transplant period was complicated by infections caused by HHV-6, Pneumocystis jiroveci and Streptococcus viridans shortly after transplantation. After HSCT a resolution of respiratory symptoms and regression of pulmonary abnormalities in imaging studies were achieved. Some months after the transplantation, due to the refractory thrombocytopenia, splenectomy was performed with a satisfactory effect. Despite the discontinuation of azathioprine, patient No. 3 maintained the significant clinical and radiological improvement obtained on the therapy (Figures 1B,D). In patient No. 8, the resolution of ILD symptoms was achieved after adding cyclosporin to GCs.\n\nTable 3 Treatment strategies.\n\nPatient (lung biopsy)\tTreatment line\tTreatment effect\tTreatment complications\tComments\t\n1(GLILD/LIP)\tFirst Line: DEX 1.0 mg/kg 10 days, PRED, initial dose: 1.0 mg/kg, maintenance dose: 0.2 mg/kg\tClinical and radiological improvement, but persistence of residual lesions in lung HRCT\tCushing syndrome\tIntroduction of second-line treatment\t\n\tSecond Line (1): AZA 2mg/kg\tClinical stabilization\tPancreatitis\tDue to pancreatitis, AZA was changed to MMF\t\n\tSecond Line (2): MMF 500 mg/day\tClinical and radiological progression\tProgression of lung infiltrates, persistent lymphadenopathy, splenomegaly, leukopenia, and hypogammaglobulinemia on a low dose of steroids and MMF\tPatient qualified for HSCT, infectious complications after HSCT (HHV-6, Pneumocystis jiroveci, Str. viridans), splenectomy due to refractory thrombocytopenia and finally clinical and radiological improvement\t\n2 (GLILD/LIP)\tPRED initial dose: 0.75 mg/kg, maintenance dose: 0.33 mg/kg for 6 months\tRadiological improvement\t–\tPatient had no clinical respiratory symptoms\t\n3 (GLILD)\tFirst Line: MPRED i.v. pulses 3 days (30 mg/kg), PRED initial dose: 2.0 mg/kg, maintenance dose: 0.4 mg/kg\tResolution of respiratory failure, incomplete clinical (exercise intolerance) and radiological (partial resolution of nodular lesions) improvement\tCushing syndrome, osteoporosis with multiple compression fractures of lumbar vertebrae\tClinical and radiological deterioration observed while reducing the steroid dose; therefore, AZA was introduced\t\n\tSecond Line: AZA 2.0–3.5 mg/kg\tSignificant clinical and radiological improvement\tHepatitis with liver injury and cholestasis\tAZA dose was modified depending on the 6-thioguanine levels; due to adverse effects, treatment was discontinued\t\n4 (GLILD/LIP)\tPRED initial dose: 2.0 mg/kg, maintenance dose: 0.6 mg/kg\tResolution of clinical symptoms, partial radiological improvement\tCushing syndrome\tRecurrence of radiological changes while trying to discontinue the drug\t\n5 (GLILD/LIP)\tFirst Line: PRED initial dose: 2.0 mg/kg, maintenance treatment: MPRED 0.1 mg/kg in tapered doses\tAlmost total resolution of radiological changes\tSevere steroid-dependent thrombocytopenia\t\t\n\tSecond Line (1): MMF 400 mg/day\tAlmost total resolution of radiological changes\t\tMMF was introduced almost simultaneously with PRED\t\n\tSecond Line (2): RAP 1.6–1.4 mg/kg\t\tTransient leucopenia, hypertransaminasemia\tDue to thrombocytopenia, MMF was replaced with RAP\t\n6 (GLILD)\tPRED initial dose: 0.7 mg/kg, maintenance dose: 0.5 mg/kg\tWithout radiological improvement\tCushing syndrome, depression\tThe patient reports periodically a subjective feeling of dyspnea\t\n7 (GLILD/LIP)\tPRED initial dose: 2.0 mg/kg, maintenance dose 0.2 mg/kg\tSignificant clinical and radiological improvement\tCushing syndrome\t\t\n8 (G)\tFirst Line: PRED Initial dose: 1.0 mg/kg, maintenance dose: 0.2 mg/kg\tClinical and radiological improvement\tCushing syndrome\t\t\n\tSecond Line: CsA 2.5–3.0 mg/kg\tClinical stabilization\t\t\t\nAZA, azathioprine; CsA, cyclosporine A; DEX, dexamethasone; G, granulomas; GLILD, granulomatous-lymphocytic interstitial lung disease; HSCT, hematopoietic stem cell transplantation; HRCT, high-resolution chest tomography; LIP, lymphocytic interstitial pneumonia; MMF, mycophenolate mofetil; MPRED, Methylprednisolone; PRED, prednisone; RAP, rapamycin.\n\nAll of the patients remain alive. A clinical and radiological improvement or stability of the lung disease is observed in all the patients.\n\nSignificant side effects were observed during the immunosuppressive treatment. Six children treated with GCs presented with symptoms of Cushing syndrome. In patient No. 3, compression fractures of the lumbar vertebrae occurred due to post-steroid osteoporosis.\n\nThe azathioprine treatment was complicated by pancreatitis in patient No. 1 and by liver damage with cholestasis in patient No. 3. In both patients, signs of drug-induced organ damage resolved after discontinuation of the treatment. Transient cytopenia and elevated transaminase levels were observed during the treatment with rapamycin (second-line therapy, patient No. 5). In this case, almost total resolution of radiological changes was observed.\n\nAll of the children were receiving IgRT during the study.\n\nThe treatment strategies are presented in Table 3.\n\nDiscussion\nClinical presentations of PIDs are diverse, and PIDs are often a diagnostic challenge. This is due in part to pulmonary changes in patients with PIDs, as these changes may have different etiologies and varied clinical as well as radiological presentations, including ILD. Although our study showed a low prevalence of PID-related ILD in children, it highlights various clinical courses of ILDs, including life-threatening complications. Importantly, the study demonstrated that ILD may precede PID diagnosis and that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and a second-line treatment may be necessary in some patients. It should be highlighted that in 3 patients, the initial symptoms suggested CVID. However, further observation and the occurrence of other symptoms, including those suggestive of ILD, led to an in-depth diagnostics and the final diagnoses were established based on genetic testing. The achieved diagnoses resulted in changing both, the diagnostic (e.g., NBS) and therapeutic (e.g., DGS and LRBA) management. We would like to emphasize that this is the largest case series on PID-related ILDs ever reported in a pediatric population. Thus, we believe our findings may add to the existing literature on the topic.\n\nGLILD was originally described in patients with CVID (17). Currently, there is a growing number of studies reporting this disease in other PIDs, including DGS and LRBA deficiency (24–26). Moreover, interstitial lymphocytic lung disease was recognized in 4 NBS patients (11%) described by Deripapa et al. (27). However, in the largest group of NBS patients, published by Wolska-Kuśnierz et al., infections clearly dominated among pulmonary complications (28).\n\nThe clinical picture of PID-related ILD in our study was very diverse. It should be stressed that in two of the 11 children (No. 3 and 7), ILD was the first presentation, documented even before PID diagnosis. Similar sequences of symptoms and diagnosis were recently reported in adults (29). Importantly, in both children, the presenting symptoms were severe and progressed to respiratory failure. The first child had four episodes of ILD exacerbations with respiratory failure and biopsy-proven LIP diagnosis 3 years before CVID diagnosis. In the second child, pulmonary signs and symptoms, which were initially interpreted as pneumonia, deteriorated rapidly to respiratory failure (Figures 1A,C). The clinical picture, imaging studies, and lung biopsy were consistent with GLILD, but the definitive diagnosis of CVID was established only 7 months later. Respiratory failure also occurred in the other child, but in contrast to the patients mentioned above, ILD symptoms appeared 3 years after the diagnosis of NBS.\n\nIn contrast to the three patients with severe lung disease, the majority of children with PID-related ILD were asymptomatic or presented mild respiratory symptoms, but had extensive pulmonary involvement in imaging studies. Thus, we strongly agree with the British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus (BLF/UKPINC) that patients with CVID should be screened for pulmonary complications despite the absence of symptoms. HRCT, lung function tests, and other diagnostic procedures are recommended as a part of the diagnostic workup (30). Regular clinical monitoring for lung involvement should also apply to patients with other PIDs (31).\n\nIn addition to respiratory symptoms, patients with PIDs present with a wide spectrum of symptoms involving other organs. In a significant number of patients, autoimmune cytopenias, especially autoimmune thrombocytopenia, are observed as the first manifestation of the disease (32). This was the case of two our patients with autoimmune cytopenia, in whom autoimmune cytopenia was the first presenting symptom. Quinti et al. described autoimmune cytopenia as the only complication in 2.3% of CVID patients and autoimmune phenomena as the most common complication [17%; (33)]. Lymphadenopathy, hepatomegaly, and splenomegaly were the most common presentations in our study group. The other non-infectious manifestations included chronic diarrhea, allergic diseases, lymphoid hyperplasia, and failure to thrive.\n\nGLILD can be also found as a serious complication of PIDs in adults. As in children, the clinical course of PID-related ILD in adults can be asymptomatic. Symptomatic patients usually present with dyspnea, tachypnea, cough, exercise intolerance of various severity, and crepitations. Similar to children, hypoxemic respiratory failure may occur in the most severe cases (17, 29, 34).\n\nAccording to the BLF/UKPINC, the most typical radiologic findings in GLILD are solid or semisolid nodules, ground-glass opacities, and enlarged thoracic lymph nodes (30). These data are consistent with our observations. Nodules of different sizes and densities were found in all children, with perilymphatic distribution (along pleura, fissures, interlobular septa, and bronchovascular bundles) predominating in eight out of 11 patients. A similar distribution of nodules was previously observed in patients with CVID-related ILD (35–38). However, other radiographic patterns were also reported, including random distribution (35–37, 39, 40) and mixed distribution with randomly scattered small nodules (<5 mm) and peribronchial localization of larger nodules (39).\n\nGround-glass opacities were identified in four patients with PID-related ILD. In GLILD, patchy areas of ground-glass opacities are usually located peripherally and in peribronchial and subpleural regions. These changes may reflect organizing pneumonia areas (10, 35, 39, 41, 42). “Halo sign” was found in two patients in our study group. Bouvry et al. reported that this sign was a common feature of GLILD and was associated with the presence of granulomas, which may be surrounded by foci of organizing pneumonia (37).\n\nIn two of the children in this study, CT revealed a tree-in-bud pattern. This pattern may reflect a spectrum of endo- and peribronchiolar disorders, including mucoid impaction. Tree-in-bud sign was reported by Bang et al. in CVID patients with pulmonary infections (43). This sign may also reflect non-infectious peribronchial or bronchiolar inflammation and was found in patients with follicular bronchiolitis (44) or, less commonly, in organizing pneumonia (44, 45).\n\nIn our patients, lung HRCT did not reveal reticular abnormalities, which appear to be common features of GLILD in adults (17, 39–41, 46). As reticular opacities seem to be features of more advanced stages of ILD (47), we propose that the presence of a reticular pattern in adults is associated with more prolonged lung involvement resulting in irreversible fibrotic changes in the lung architecture.\n\nThe data on pulmonary function in patients with PID-related ILDs mainly come from adult studies. Restrictive or mixed obstructive and restrictive patterns, as well as decreased DLCO, were the most frequently observed abnormalities. However, it must be underlined that the results of PFT can be completely normal in the majority of patients (14, 35, 43). Similar observations were made in the very few studies on children. A restrictive pattern was reported by Tillman et al. in a 13-year-old girl with GLILD and by van de Ven et al. in eight children with CVID and CVID-like disease (48, 49). In our study, restrictive pulmonary dysfunction was demonstrated in one child (patient No. 3). Interestingly, an increased RV/TLC ratio indicating air trapping in the absence of FEV1/FVC reduction was the most common finding in our study. According to some authors, an increased RV/TLC ratio may be a more sensitive indicator of airflow obstruction than the FEV1/FVC ratio (50, 51). This parameter is thought to reflect distal airway narrowing or closure resulting from inflammation (50, 51). As nodular peribronchiolar lymphocytic inflammation is common in CVID patients with GLILD (52), we can hypothesize that our findings reflect small airway obstruction caused by an increased number of lymphocytes in this region. Decreased DLCO, which is an early indicator of ILD (35, 36), was noted in two of our patients (No. 2 and 3).\n\nIn the light of data demonstrating that GLILD is associated with significantly increased mortality in patients with CVID, identifying an effective treatment is a critical issue (16). Although no standard treatment has been established, the consensus statement of the BLF/UKPINC (30) recommends optimizing IgRT as an initial step in the treatment of CVID. However, despite adequate IgRT, complications like CVID-related ILD may occur in some patients, making additional therapy necessary.\n\nAccording to the aforementioned consensus statement, systemic corticosteroids should be applied as the first-line therapy in symptomatic patients. In our group, GCs were administered to all eight patients who required an intervention in addition to IgRT. In four patients decision about treatment was made due to the coexistence of autoimmune cytopenia or lymphoproliferation and extensive lung involvement in imaging studies. In patient No. 2 the treatment with GCs was started owing to significant progression in imaging studies, decreasing DLCO, as well histopathological features of irreversible lung scarring. The use of GCs as monotherapy led to rapid improvement in almost all the treated individuals. Their effectiveness was particularly evident in patients with the most severe cases of ILD (No. 3, 7, and 8), whose respiratory failure resolved in response to the treatment. However, in the four patients who did not fully respond to the first-line therapy, developed significant side effects, or presented with disease exacerbation during steroid tapering, second-line treatment was applied. The second-line treatment drugs that were effective in our group were mycophenolate mofetil, azathioprine, cyclosporin A and rapamycin. These agents improved the clinical course of GLILD in three of our patients. However, it should be stressed that immunosuppressive treatment was associated with several significant side effects. Among the most relevant were: leucopenia after MMF treatment; pancreatitis, liver injury with hypertransaminasemia and cholestasis after azathioprine therapy; leucopenia and hypertransaminasemia after rapamycin treatment and advanced osteoporosis with compression fractures of lumbar vertebrae after GCs therapy (Table 3). In our study, we used either GCs alone (four patients) or a combination of immune-modulating agents (four patients). Since the second-line drugs rapamycin and azathioprine are directed toward T cells, they are effective in GLILD patients, whose lung biopsies are known to contain infiltrates with T cells. We found that this type of therapy brought about subjective and objective resolution of ILD in PAD patients. As reported by other authors, similar effects may be obtained with the CTLA-4 fusion protein abatacept. The effectiveness of this treatment has been documented, particularly in patients with LRBA deficiency (53–55). Our patient with LRBA deficiency was treated with GCs as a first-line therapy, and mycophenolate mofetil and rapamycin as a second-line therapy, but did not receive abatacept treatment.\n\nAs lung infiltrates also consist of CD20+ B cells, clinical improvement in GLILD may also be achieved after administration of the anti-CD20 antibody rituximab as monotherapy (56) or in combination with azathioprine, as reported by some groups (48, 57).\n\nHSCT is not considered to be a standard therapeutic option in patients with GLILD (5). However, HSCT was reported to be applied to some patients with malignancies, refractory autoimmune cytopenias, ILD/GLILD, and/or autoimmune enteropathy, among others in patients with LRBA deficiency (58). As reported by Tesch et al., HSCT in these patients was associated with an increased risk of death in the course of early post-transplant complications, but HSCT survivors achieved remission of disease symptoms (including ILD), in contrast to patients who had not undergone transplantation (55). The overall survival rate of patients undergoing HSCT was 70.8%, and the vast majority (70.6%) didn't require further immunosuppressive treatment (55).\n\nSince only one of our patients was treated with HSCT due to refractory autoimmune cytopenia, we did not feel entitled to enclosing a more extensive discussion or drawing any binding conclusions.\n\nStrength and Limitations of the Study\nTo our knowledge, this is the largest study on children with PID-related ILD (mostly CVID patients) published so far, presenting detailed description of clinical, radiological, and histological signs of ILD/GLILD. Additionally, the analysis of the first- and second-line treatments is presented.\n\nHowever, this study also has some limitations. First of all, it is a retrospective analysis. As a consequence of the study design, there are further drawbacks, including genetic diagnosis in only a few patients and non-uniform assessment and treatment.\n\nIt is important to point out that two of the three children with the most advanced lung disease were not able to perform PFT due to young age or intellectual disability. Finally, the type of ILD was not confirmed by surgical lung biopsy in three of the children.\n\nWe believe that our study clearly points out the need for developing a uniform and commonly accepted diagnostic and therapeutic algorithm for patients with PID and coexisting ILD. Special attention should be paid to early radiological detection of lung involvement with the use of HRCT. This is supported by our finding that some asymptomatic patients with PID-related ILD may present with advanced structural lung alterations. It also seems necessary to propose a more uniform therapeutic approach and to gather more long-term observations on the relationship between treatment regimen and disease outcomes.\n\nConclusions\nOur analysis showed that the clinical presentation of PID-related ILD can be diverse, ranging from asymptomatic presentation to life-threatening disease. It should be emphasized that ILD symptoms may precede the diagnosis of PID and that aggressive treatment, especially in patients with a rapid clinical course, provides fast but sometimes incomplete improvement. Although corticosteroids seem to be effective in the treatment of PID-related ILD, even in severe cases, the optimal treatment of PID-related ILD patients is hindered by the lack of clinically proven treatment regimens for these diseases. Hence, there is a need for a well-designed, multicenter study that includes an adequate number of patients, including pediatric population, to determine the most effective treatment strategies and the optimal duration of the therapy.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by The Bioethics Committee of the Children's Memorial Health Institute in Warsaw. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written, informed consent was obtained from all individuals AND/OR their parents for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nMPa: conceived the idea for the study. MPa, TB, KG, and KK: study design, coordination and supervision of data collection, data analysis, and manuscript preparation. RL: preparation and assessment of histopathological preparations and manuscript edition. JK: radiological assessment and manuscript preparation. MPr: preparation and assessment histopathological preparations and critical review. BP and KT: contributed to immunologic data collection and critical review. SK, ND-L, KB-S, HD, AP-N, BM, EB, and IW-B: contributed to clinical data collection and critical review. All authors: contributed to the article and approved the submitted version and agree to be accountable for all aspects of the work.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors sincerely thank all our patients and their families who made this study possible, Employees of the Department of Immunology, CMHI/Jeffrey Modell Foundation, Diagnostic Center for Primary Immunodeficiency for their support.\n==== Refs\nReferences\n1. Tangye SG Al-Herz W Bousfiha A Chatila T Cunningham-Rundles C Etzioni A \nHuman inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee\n. J Clin Immunol. (2020 ) 40 :66 –81\n. 10.1007/s10875-019-00737-x 32048120 \n2. Bousfiha AA Jeddane L Ailal F Benhsaien I Mahlaoui N Casanova JL . 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"fulltext_license": "CC BY",
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"issue": "11()",
"journal": "Frontiers in immunology",
"keywords": "CVID; GLILD; children; computed tomography; interstitial lung disease; primary immunodeficiency",
"medline_ta": "Front Immunol",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D008297:Male; D011044:Poland; D000081207:Primary Immunodeficiency Diseases; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101560960",
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"pages": "1950",
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"pmid": "32973798",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
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"title": "Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study.",
"title_normalized": "interstitial lung disease in children with selected primary immunodeficiency disorders a multicenter observational study"
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"abstract": "OBJECTIVE\nThe purpose of this study was to identify the medications that are consumed by a rural obstetric population during pregnancy.\n\n\nMETHODS\nOver a period of 26 months, pregnant women were interviewed about medication use. Interviews on subsequent visits provided a longitudinal study of medication usage and discontinuation. Trend differences were analyzed according to the number of medications, the trimester of use, and insurance status.\n\n\nRESULTS\nFive hundred seventy-eight participants had 2086 interviews. The compilation of the interviews showed that 95.8% of the participants took prescription medications, 92.6% of the participants self-medicated with over-the-counter medications, and 45.2% of the participants used herbal medications. Over time, consumption of over-the-counter medications exceeded prescription medication use. Fifteen percent of the pregnant women took ibuprofen at some point during the pregnancy (5.7% in the third trimester). Eight percent of the women were noncompliant and 20% incompletely compliant with prenatal vitamin and mineral formulations.\n\n\nCONCLUSIONS\nMedication use was substantial in this population. Medications (eg, ibuprofen) that are contraindicated in pregnancy were used at unexpectedly high rates. Of the three medication classes, over-the-counter medications were used most frequently.",
"affiliations": "Department of Obstetrics and Gynecology, School of Medicine, School of Pharmacy, West Virginia University, Morgantown 26506, USA.",
"authors": "Glover|Douglas D|DD|;Amonkar|Mayur|M|;Rybeck|Blanche F|BF|;Tracy|Timothy S|TS|",
"chemical_list": "D008903:Minerals; D004366:Nonprescription Drugs; D014815:Vitamins; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1067/mob.2003.223",
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"issue": "188(4)",
"journal": "American journal of obstetrics and gynecology",
"keywords": null,
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D011307:Drug Prescriptions; D005260:Female; D029001:Herbal Medicine; D006801:Humans; D007052:Ibuprofen; D008903:Minerals; D004366:Nonprescription Drugs; D010349:Patient Compliance; D011247:Pregnancy; D011295:Prenatal Care; D012424:Rural Population; D012651:Self Medication; D014815:Vitamins",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "1039-45",
"pmc": null,
"pmid": "12712107",
"pubdate": "2003-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prescription, over-the-counter, and herbal medicine use in a rural, obstetric population.",
"title_normalized": "prescription over the counter and herbal medicine use in a rural obstetric population"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP017323",
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"abstract": "BACKGROUND\nNebivolol, a beta blocker with 3-10 times more beta1 cardioselectivity than metoprolol, has caused hypotension and bradycardia in overdose. We report a nebivolol-induced cardiac arrest in the setting of a polydrug ingestion, successfully resuscitated with intravenous fat emulsion (IFE) and high-dose insulin (HDI).\n\n\nMETHODS\nA 48-year-old man was brought to the emergency department after ingesting nebivolol and ethanol, along with possibly diazepam and cocaine. He had a heart rate of 71/min and a blood pressure of 98/61 mmHg. The initial ECG showed sinus rhythm with a QTc of 483 ms and a QRS of 112 ms. Over the subsequent 4 h, he became bradycardic and hypotensive and developed bradyasystolic cardiac arrest. Standard resuscitation including epinephrine had no effect. Spontaneous circulation returned 30 s after a 100 mL bolus of 20% IFE, and the patient then became briefly hypertensive and tachycardic with heart rate and blood pressure measured as high as 123/min and 251/162 mmHg, respectively. His care included IFE infusion along with HDI bolus and infusion with doses as high as 21.8 units/kg/h. With subsequent hypotension, vasopressors were withheld in favor of HDI and supportive care. He was discharged with baseline neurologic function.\n\n\nCONCLUSIONS\nWe hypothesize that after the administration of IFE the epinephrine was able to exert its effect on receptors previously occupied with the nebivolol. This would be congruent with the lipid sink theory of IFE mechanism.\n\n\nCONCLUSIONS\nWe report an overdose involving nebivolol in a polydrug ingestion resulting in cardiac arrest, successfully treated with IFE and a very HDI infusion.",
"affiliations": "Regions Hospital Clinical Toxicology Service and Department of Emergency Medicine, St. Paul, MN 55101, USA. samuel.j.stellpflug@healthparnters.com",
"authors": "Stellpflug|Samuel J|SJ|;Harris|Carson R|CR|;Engebretsen|Kristin M|KM|;Cole|Jon B|JB|;Holger|Joel S|JS|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D005217:Fat Emulsions, Intravenous; D007004:Hypoglycemic Agents; D007328:Insulin; D000068577:Nebivolol; D000431:Ethanol",
"country": "England",
"delete": false,
"doi": "10.3109/15563650903555294",
"fulltext": null,
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"issn_linking": "1556-3650",
"issue": "48(3)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004305:Dose-Response Relationship, Drug; D000431:Ethanol; D004983:Ethanolamines; D005217:Fat Emulsions, Intravenous; D006323:Heart Arrest; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008297:Male; D008875:Middle Aged; D000068577:Nebivolol; D013406:Suicide, Attempted",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "227-9",
"pmc": null,
"pmid": "20141425",
"pubdate": "2010-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin.",
"title_normalized": "intentional overdose with cardiac arrest treated with intravenous fat emulsion and high dose insulin"
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"companynumb": "US-MYLANLABS-2018M1085186",
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"abstract": "Methotrexate, a folic acid analogue with anti-proliferative and anti-inflammatory effects, is commonly used to treat patients with severe destructive psoriatic arthritis and has considerable efficacy. Combined anti-tumor necrosis factor and MTX therapy result in less treatment discontinuation due to adverse events. Despite its efficacy, MTX may result in adverse effects including hepatic, pulmonary, and renal toxicity as well as lymphoproliferative disorders and predisposition to infection. We herein report rare adverse effects of MTX treatment, specifically asymptomatic pulmonary tuberculosis, renal cell carcinoma, and lateral uveitis, in three psoriatic arthritis patients treated with MTX. MTX is an important drug for the treatment for psoriatic arthritis patient, but an awareness of the possible adverse effects is needed.",
"affiliations": "Department of Dermatology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0374, Japan, hm4765@yahoo.co.jp.",
"authors": "Maejima|Hideki|H|;Watarai|Akira|A|;Nakano|Toshiaki|T|;Katayama|Chieko|C|;Nishiyama|Hiromi|H|;Katsuoka|Kensei|K|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-012-2649-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "34(4)",
"journal": "Rheumatology international",
"keywords": null,
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D015535:Arthritis, Psoriatic; D058070:Asymptomatic Diseases; D001706:Biopsy; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009392:Nephrectomy; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary; D014605:Uveitis",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "571-4",
"pmc": null,
"pmid": "23274445",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20520552;21918442;15787807;8073808;18173926;11285384;17644547;19806150;15146406;18688259;9361153;18203324;17141365;19884622;11914915;17938029;11791648",
"title": "Adverse effects of methotrexate in three psoriatic arthritis patients.",
"title_normalized": "adverse effects of methotrexate in three psoriatic arthritis patients"
} | [
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"companynumb": "JP-ROXANE LABORATORIES, INC.-2014-RO-01816RO",
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"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"abstract": "OBJECTIVE\nThe purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker.\n\n\nMETHODS\nTwenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg × 3 days followed by 40 mg × 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at -2, -1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7.\n\n\nRESULTS\nThe geometric mean ratio and 90% confidence interval of Cmax and AUC of acetaminophen were within 80-125% suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food.\n\n\nCONCLUSIONS\nIn the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by ∼1.25 h without affecting Cmax or AUC.",
"affiliations": "Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.",
"authors": "Ayalasomayajula|Surya|S|;Meyers|Dan|D|;Koo|Phillip|P|;Salunke|Atish|A|;Majumdar|Tapan|T|;Rebello|Sam|S|;Sunkara|Gangadhar|G|;Chen|Jin|J|",
"chemical_list": "D000085:Acetates; D000631:Aminopyridines; C000594809:pradigastat; D000082:Acetaminophen; D051048:Diacylglycerol O-Acyltransferase",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-015-1822-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "71(4)",
"journal": "European journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D000085:Acetates; D000328:Adult; D000631:Aminopyridines; D019540:Area Under Curve; D018592:Cross-Over Studies; D051048:Diacylglycerol O-Acyltransferase; D004347:Drug Interactions; D005260:Female; D005746:Gastric Emptying; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "425-32",
"pmc": null,
"pmid": "25724644",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "10233184;24619917;15831781;10893655;18757836;7161411;4722050;17463219;22911105",
"title": "Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects.",
"title_normalized": "assessment of pharmacokinetic drug drug interaction between pradigastat and acetaminophen in healthy subjects"
} | [
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"companynumb": "US-JNJFOC-20150317636",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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"drugadditional": null,
... |
{
"abstract": "Women with Eisenmenger syndrome are usually advised to avoid pregnancy because of the high maternal mortality rate of 30-50% which increases up to 65% in the case of a cesarean section. Successful management of Eisenmenger syndrome in pregnancy is tricky and has a narrow margin of safety; however, carefully coordinated multidisciplinary care can profoundly optimize the chances of survival for both mother and baby.\nA 28-year-old, 24-week-pregnant patient with a non-corrective ventricular septal defect (VSD) was diagnosed with Eisenmenger syndrome but elected to continue her pregnancy despite the high risks on her and her fetus. Therefore, a multidisciplinary team was assembled to fully monitor the patient and ensure that she reaches 32 weeks before delivery.\nMultiple scenarios for timing and mode of delivery were discussed. Following the recommendation of the 2018 European Society of Cardiology guidelines and because of the fetus' transverse position, a cesarean section was performed at week 32 and both the patient and her child were saved.\nTermination of pregnancy is the safer option only if it were done early on in the pregnancy. Thus, when the pregnancy is continued, an expert multidisciplinary team is put together to support the patient.",
"affiliations": "Department of Pathology, Cancer Research Center at Tishreen University Hospital, Latakia, Syria.;Department of Cardiology at Al-Bassel Hospital, Tartus, Syria.;Department of Pathology, Cancer Research Center at Tishreen University Hospital, Latakia, Syria.",
"authors": "Slaibi|Anas|A|;Ibraheem|Bassel|B|;Mohanna|Farah|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.amsu.2021.102721",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00671-3\n10.1016/j.amsu.2021.102721\n102721\nCase Report\nChallenging management of a pregnancy complicated by Eisenmenger syndrome; A case report\nSlaibi Anas anas.slaibi@gmail.com\na\nIbraheem Bassel basselib170@gmail.com\nb\nMohanna Farah F.h.mohanna@gmail.com\na∗\na Department of Pathology, Cancer Research Center at Tishreen University Hospital, Latakia, Syria\nb Department of Cardiology at Al-Bassel Hospital, Tartus, Syria\n∗ Corresponding author. F.h.mohanna@gmail.com\n16 8 2021\n9 2021\n16 8 2021\n69 1027213 6 2021\n10 8 2021\n13 8 2021\n© 2021 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nIntroduction and importance\n\nWomen with Eisenmenger syndrome are usually advised to avoid pregnancy because of the high maternal mortality rate of 30–50% which increases up to 65% in the case of a cesarean section. Successful management of Eisenmenger syndrome in pregnancy is tricky and has a narrow margin of safety; however, carefully coordinated multidisciplinary care can profoundly optimize the chances of survival for both mother and baby.\n\nCase presentation\n\nA 28-year-old, 24-week-pregnant patient with a non-corrective ventricular septal defect (VSD) was diagnosed with Eisenmenger syndrome but elected to continue her pregnancy despite the high risks on her and her fetus. Therefore, a multidisciplinary team was assembled to fully monitor the patient and ensure that she reaches 32 weeks before delivery.\n\nClinical discussion\n\nMultiple scenarios for timing and mode of delivery were discussed. Following the recommendation of the 2018 European Society of Cardiology guidelines and because of the fetus’ transverse position, a cesarean section was performed at week 32 and both the patient and her child were saved.\n\nConclusion\n\nTermination of pregnancy is the safer option only if it were done early on in the pregnancy. Thus, when the pregnancy is continued, an expert multidisciplinary team is put together to support the patient.\n\nHighlights\n\n• Women with Eisenmenger syndrome are usually advised to avoid pregnancy.\n\n• The ideal timing and mode of delivery in ES patients with PAH is controversial.\n\n• Older studies suggested that C-section results in higher maternal morbidity and mortality.\n\n• According to recent guidelines, Cesareansections are advised in severe forms of pulmonary hypertension.\n\n• Intensive postoperative monitoring for two weeks is highly recommended.\n\nKeywords\n\nCase report\nCesarean section\nEisenmenger syndrome\nPostpartum management\nPregnancy\n==== Body\n1 Introduction\n\nEisenmenger's syndrome (ES) was first described in 1897 and was later identified as a congenital heart defect characterized by right to left or bidirectional shunting with severe pulmonary hypertension [1]. ES is uncommon, and it usually occurs in patients over 30 years old [2]. Pregnancy-related physiological changes in Eisenmenger syndrome are poorly tolerated, and they lead to high risk of rapidly progressive cardiopulmonary decompensation, thrombotic complications, and sudden death [3], which is why it is recommended for women with Eisenmenger syndrome to avoid pregnancy or to undergo an early pregnancy interruption within the 10th gestational week [4]. This case report has been reported in line with the SCARE Criteria [7].\n\n1.1 Case presentation\n\nA 28-year-old, 24-week-pregnant woman, gravida 1 was referred to the emergency department complaining of a slowly progressive dyspnea over the last month. She had had an uncorrected ventricular septal defect (VSD) at the age of ten, and later, at the age of fifteen, her condition progressed to Eisenmenger syndrome (ES) and was treated with a daily dose (100mg) of Sildenafil. Upon physical examination, she had dyspnea on exertion along with central and peripheral cyanosis. Her oxygen saturation (SpO2) was 60% and blood pressure (BP) 120/70. A transabdominal ultrasound was performed, and the findings were normal (amniotic fluid 700 mL, biparietal diameter (BPD) 59 mm and femur length (FL) 43.5 mm). For further evaluation and monitoring, she was referred to the cardiology department and was placed on continuous oxygen therapy that elevated her SpO2 to 90%, and completely new physical, cardiovascular, and obstetric examinations were performed. Physical examination revealed an SpO2 of 60% at room air BP of 120/70, peripheral and central cyanosis, digital clubbing and no peripheral edema. Auscultation of the chest was clear, and cardiovascular examination showed loud P2 with no murmur and Respiratory rate (RR) of 18 on rest. Echocardiography showed ejection fraction (EF) of 60%, pulmonary artery systolic pressure (PSAP) of 130 mm, a large muscular ventricular septal defect (12mm in diameter) with right-to-left shunting, and dilated right ventricle. The patient elected to continue the pregnancy despite the high risk on her and her fetus. Therefore, a multidisciplinary team consisting of an obstetrician, midwife, cardiologist, anesthetist, intensive care physician and neonatologist was assigned to fully monitor the patient. Our team's original goal was to reach 32 weeks of pregnancy, but because of the patient's low financial status, we decided to admit her at the Cardio department with the following medical plan: bedrest, oxygen administered by mask at 5 L/min, Sildenafil 50mg 1 × 2, Lovenox 40mg 1 × 1, Dopegyt 250mg 1 × 3, and Lasix 40mg 1/2 × 1. Later, we noticed that the patient tolerated her pregnancy well following this regimen; furthermore, her SpO2 levels, EF and PSAP improved grandly which led to a reduction of the dyspnea and cyanosis. At week 28, we started a betamethasone course for fetal lung maturation. At week 30, the patient developed arterial hypertension of 170/90. Preeclampsia and HELLP syndrome were among the major concerns; however, lab tests showed the diagnosis of isolated, pregnancy related hypertension. Thus, Hydralazine was administrated, and the patient was admitted to the cardiac ICU for strict monitoring. When the patient became stable, multiple scenarios for timing and mode of delivery were discussed based on the mother's condition and the fetal position. Risks of vaginal delivery were known to be more endurable than those with cesarean section, but the 2018 European Society of Cardiology guidelines recommend proceeding with a cesarean section in such a case; moreover, the fetus' transverse position rendered vaginal delivery extremely difficult, so we went with a cesarean section. Taking into consideration the state of our patient, we went with epidural anesthesia which was given in the beginning of the surgery with fractionated doses of bupivacaine (65 mg), lidocaine (280 mg), and fentanyl (100 mg) achieving a T-5 anesthesia level after 35 minutes. During the surgery, the patient was asymptomatic. The surgical procedure was uneventful and a female infant of 1,850 g, Apgar score of 9 was delivered. The patient's condition remained stable after delivery, and she was restarted on 7,500 U of subcutaneous heparin which was switched to 40 U of enoxaparin daily on postoperative day 2. She was hospitalized for 1 week and was discharged postoperative day 7 on oral sildenafil 100 mg. Given the risk of further decompensation, she was advised to resume regular close follow-ups after hospital discharge and to implement safe contraception methods.\n\n2 Discussion\n\nEisenmenger's Syndrome is a rare complication of congenital heart disease during pregnancy with a high maternal mortality of 30–50% and even up to 65% in those with Cesarean section [4,5]. Within the first few days postpartum, there is a high risk of sudden death whose major causes could be hypovolemia, thromboembolism and preeclampsia [3,4]. The overall neonatal mortality is 13% and is caused mainly by prematurity. Spontaneous abortion and preterm labor are frequent neonatal morbidity causes whereas intrauterine growth restriction presents only in 30% of pregnancies [6].The presence of Eisenmenger syndrome along with the various hemodynamic changes of pregnancy challenges the brittle cardiopulmonary balance and is regarded as the main cause of cardiopulmonary decompensation [4]. Pregnant women with ES may present with low oxygen saturation, dyspnea, fatigue, dizziness and even right heart failure. Physical examination findings vary from cyanosis, clubbing, and jugular venous distention to mild lower extremity edema. Auscultation may reveal an inspiratory crepitation, loud P2 and a systolic murmur at the pulmonary area [4](1).Restricted antepartum management is necessary when the patient refuses to discuss terminating the pregnancy, or if she presents late in pregnancy. This management includes early hospitalization at 20 weeks of gestation, supplemental oxygen, diuretics, vasodilators and possibly empiric anticoagulation [3]. Maternal arterial oxygen tension should be kept at ≥70 mmHg as it decreases the blood flow across the right-to-left shunt and thereby improves oxygen saturation in patients with ES [4]. Moreover, in the third trimester, oxygen is provided by mask at 5 L/min to improve the patient's hypoxic condition and reduce pulmonary artery pressure [1]. When congestive symptoms are present, loop diuretics may be added with caution because maintaining effective cardiac output needs a critical cardiac preload [3](1), and they may lead to hypovolemia and resulting hypotension, which may worsen right ventricular function. Early initiation or continuation of PDE-5 inhibitors such as sildenafil in pregnancy is recommended [3]. On the other hand, for patients at risk of preterm labor, dexamethasone is prescribed to decrease the risk of respiratory distress syndrome and mortality as premature infants born at <32 weeks' gestation are at significant risk of surfactant deficiency. In normal pregnancies, the physiological decrease of protein S along with the increase in fibrinogen and other prothrombotic factors predispose patients to thrombosis. Additionally, ES may enhance this prothrombotic state of pregnancy and lead to micro-embolisms with severe consequences. Nonetheless, the evidence supporting anticoagulant therapy in patients with ES was insufficient, and it has been suggested that anticoagulants would increase risk of hemoptysis [1](3). Consequently, on a case-by-case basis, weight-adjusted prophylactic dosing of low-molecular-weight heparin (LMWH) or unfractionated heparin (UH) can be considered. LMWH is often preferred over UH as it is easier to administrate and has a lower risk of heparin-induced thrombocytopenia (HIT) [3].\n\nThe ideal timing and mode of delivery in ES patients with PAH is controversial. Older studies suggested that elective cesarean section carries no maternal benefit and results in earlier delivery while vaginal delivery is associated with less blood loss and lower risk of infection [4,5]. Additionally, cesarean section results in higher maternal morbidity and mortality (75%) than vaginal delivery (34%) [3](1). However, according to the 2018 European Society of Cardiology guidelines for the management of cardiovascular diseases during pregnancy, C-sections are advised in severe forms of pulmonary hypertension (including ES). Advantages of cesarean delivery are that the time and opportunity of delivery can be controllable, and the presence of senior staff can usually be ensured. Because our patient had ES with high PAH, and her fetus was in a transverse position, a C-section was inevitable. A carefully executed anesthetic plan can decrease some of the potential side effects of labor and surgical delivery. There are multiple anesthetic techniques; however, taking into consideration the conditions of our case, epidural anesthesia was chosen as it alleviates perioperative pain and reduces the pulmonary and systemic vascular resistances thus causing less tachycardia, less myocardial oxygen consumption and reduction of the right-to-left shunting [4].Nowadays more pregnant women with ES survive because medicine and neonatal care are developing. The first postpartum week is considered a period of maximum mortality; thus, intensive postoperative monitoring is necessary as most hemodynamic changes of pregnancy resolve by two weeks postpartum [5,6]. Fetal outcome is closely related to the hematocrit level. For a successful pregnancy the hematocrit should be lower than 65% and the arterial oxygen tension higher than 70 mmHg. When arterial oxygen saturation is maintained higher than 90% in pregnancies with ES, 92% of the fetuses survive, but when oxygen saturation fell below 85%, survival falls to 12% [1].\n\n3 Conclusion\n\nTermination of pregnancy is the safer option only if it were done early on in the pregnancy. Thus, when the pregnancy is continued, an expert multidisciplinary team is put together to support the patient. Proactive serial clinical assessment, intensive daily monitoring and a closely followed, well-planned medical regiment are the keys to achieve a successful delivery. The mode and time of delivery need to be personalized; caesarean section is indicated for patients with severe forms of pulmonary hypertension according to the 2018 European Society of Cardiology guidelines.\n\nGuarantor\n\nFarah Mohanna, MD.\n\nPatient perspective\n\nThe patient participated in the treatment decision and he was satisfied with the results of the treatment after identifying the final diagnosis.\n\nPatient consent form\n\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nSources of funding\n\nThere are no sources of funding.\n\nEthics approval\n\nNo ethical approval necessary.\n\nRegistration of research studies\n\nNot applicable. Our manuscript is a case report.\n\nAuthor contributions\n\nAnas Slaibi conceived the study, analyzed and interpreted the patient data and drafted the final manuscript. Bassel Ibrahim contributed in the treatment and follow up of the pagathering patient information and drafting the manuscript.\n\nFarah Mohanna supervised the whole project, reviewed the final manuscript and was a major contributor in writing the manuscript.\n\nResearch registration\n\nN/A.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nDeclaration of competing interest\n\nWe have no conflict of interest.\n\nEthical approval\n\nNo ethical approval necessary.\n\nPlease state any sources of funding for your research\n\nNo funding needed.\n\nAuthor contribution\n\nAnas Slaibi conceived the study, analyzed and interpreted the patient data and drafted the final manuscript. Bassel Ibrahim contributed in the treatment and follow up of the pagathering patient information and drafting the manuscript. Farah Mohanna supervised the whole project, reviewed the final manuscript and was a major contributor in writing the manuscript.\n\nPlease state any conflicts of interest\n\nNo conflict of interest.\n\nRegistration of research studies\n\nNot applicable. Our manuscript is a case report.\n\nGuarantor\n\nFarah Mohanna, MD.\n\nAnnals of medicine and surgery\n\nThe following information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAppendix A Supplementary data\n\nThe following are the Supplementary data to this article:Multimedia component 1\n\nMultimedia component 1\n\nMultimedia component 2\n\nMultimedia component 2\n\nAcknowledgements\n\nAll thanks go to Zeinab Mohanna, an English Literature student in Tishreen University, for her linguistic revision and editing of our case.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.102721.\n==== Refs\nReferences\n\n1 Wang H. Zhang W. Liu T. Experience of managing pregnant women with Eisenmenger ’ s syndrome : maternal and fetal outcome in 13 cases 37 1 2011 64 70\n2 Lacassie J. Germain A.M. Valde G. Allamand F. Management of Eisenmenger syndrome in pregnancy with sildena fi l and L -arginine 103 5 2004 1118 1120\n3 Lopez B.M. Malham I. Davies L.K. Velez J.M.G. Marelli A. Eisenmenger Syndrome in Pregnancy : A Management Conundrum 2020 000\n4 Yuan S. Eisenmenger Syndrome in Pregnancy 31 4 2016 325 329\n5 Gour S.D. Emergency Caesarean Section of a Patient with Eisenmenger ’ S Syndrome : A Tight - Rope Walk 2020 95 7\n6 Siu S.C. Colman J.M. Street E. Heart disease and pregnancy 710 2001 710 715\n7 Agha R.A. Franchi T. Sohrabi C. Mathew G. for the SCARE Group The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n\n",
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"issn_linking": "2049-0801",
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"journal": "Annals of medicine and surgery (2012)",
"keywords": "Case report; Cesarean section; Eisenmenger syndrome; Postpartum management; Pregnancy",
"medline_ta": "Ann Med Surg (Lond)",
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"nlm_unique_id": "101616869",
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"pages": "102721",
"pmc": null,
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"publication_types": "D002363:Case Reports",
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"title": "Challenging management of a pregnancy complicated by Eisenmenger syndrome; A case report.",
"title_normalized": "challenging management of a pregnancy complicated by eisenmenger syndrome a case report"
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"abstract": "BACKGROUND\nAspirin overdose, though now infrequently encountered, nevertheless continues to contribute to significant morbidity and mortality. The patient described in this case report intentionally ingested overdoses of aspirin on repeated occasions. The case provided an unusual and possibly one-of-a-kind opportunity to focus on the variability in the time course of plasma salicylate concentrations with current treatment modalities of aspirin overdose in an individual patient.\n\n\nMETHODS\nA 75-year-old Caucasian man who weighed 45 kg and had an extensive history of various drug overdoses and stage 3 chronic kidney disease presented to a tertiary university hospital on three occasions within 2 months after successive overdoses of aspirin. During his third admission, he overdosed with aspirin, while on the ward recovering from the previous aspirin overdose. The overdoses were categorized as \"potentially lethal\" on two occasions and as \"serious\" in the other two, based on the alleged dose of aspirin ingested (over 500 mg/kg in the first two overdoses, and 320 mg/kg and 498 mg/kg in the other two, respectively). However, as assessed by the observed salicylate concentrations, the ingestions would more appropriately have been categorized as being of \"moderate\" severity for the first and second overdose and \"mild\" severity for each of the others. This categorization was more consistent with the clinical severity of his admissions. A single dose of activated charcoal was administered only after the second overdose. On each occasion, he was given intravenous fluid with the aim of achieving euvolemia. Urinary alkalization was not attempted during the first admission, which was associated with the longest apparent elimination half-life of salicylate (30 hours). A plasma potassium concentration of approximately 4 mmol/L appeared to be needed for adequate urinary alkalization.\n\n\nCONCLUSIONS\nIn a patient with impaired renal function, intravenous fluid and urinary alkalization are the mainstays of treatment of aspirin overdose. Correction of hypokalemia is recommended. Repeated doses of charcoal may be a worthwhile intervention when there is no risk of aspiration. Our experience in this case also revealed considerable unexplained variation in management despite the availability of guidelines. It is, therefore, important to monitor the implementation of available guidelines.",
"affiliations": "Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. r.day@unsw.edu.au.",
"authors": "Ghosh|Debasish|D|;Williams|Kenneth M|KM|;Graham|Garry G|GG|;Nair|Priya|P|;Buscher|Hergen|H|;Day|Richard O|RO|",
"chemical_list": "D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-374",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-3742540638510.1186/1752-1947-8-374Case ReportMultiple episodes of aspirin overdose in an individual patient: a case report Ghosh Debasish 12dbasis78@gmail.comWilliams Kenneth M 13ken.williams@unsw.edu.auGraham Garry G 13g.graham@unsw.edu.auNair Priya 23Priya.Nair@svha.org.auBuscher Hergen 23Hergen.Buscher@svha.org.auDay Richard O 13r.day@unsw.edu.au1 Department of Clinical Pharmacology and Toxicology, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia2 Intensive Care Unit, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia3 St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia2014 19 11 2014 8 374 374 23 7 2014 28 8 2014 Copyright © 2014 Ghosh et al.; licensee BioMed Central Ltd.2014Ghosh et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nAspirin overdose, though now infrequently encountered, nevertheless continues to contribute to significant morbidity and mortality. The patient described in this case report intentionally ingested overdoses of aspirin on repeated occasions. The case provided an unusual and possibly one-of-a-kind opportunity to focus on the variability in the time course of plasma salicylate concentrations with current treatment modalities of aspirin overdose in an individual patient.\n\nCase presentation\nA 75-year-old Caucasian man who weighed 45kg and had an extensive history of various drug overdoses and stage 3 chronic kidney disease presented to a tertiary university hospital on three occasions within 2 months after successive overdoses of aspirin. During his third admission, he overdosed with aspirin, while on the ward recovering from the previous aspirin overdose. The overdoses were categorized as “potentially lethal” on two occasions and as “serious” in the other two, based on the alleged dose of aspirin ingested (over 500mg/kg in the first two overdoses, and 320mg/kg and 498mg/kg in the other two, respectively). However, as assessed by the observed salicylate concentrations, the ingestions would more appropriately have been categorized as being of “moderate” severity for the first and second overdose and “mild” severity for each of the others. This categorization was more consistent with the clinical severity of his admissions. A single dose of activated charcoal was administered only after the second overdose. On each occasion, he was given intravenous fluid with the aim of achieving euvolemia. Urinary alkalization was not attempted during the first admission, which was associated with the longest apparent elimination half-life of salicylate (30 hours). A plasma potassium concentration of approximately 4mmol/L appeared to be needed for adequate urinary alkalization.\n\nConclusion\nIn a patient with impaired renal function, intravenous fluid and urinary alkalization are the mainstays of treatment of aspirin overdose. Correction of hypokalemia is recommended. Repeated doses of charcoal may be a worthwhile intervention when there is no risk of aspiration. Our experience in this case also revealed considerable unexplained variation in management despite the availability of guidelines. It is, therefore, important to monitor the implementation of available guidelines.\n\nAspirinEuvolemiaOverdosePotassiumSalicylateToxicityUrinary alkalization\n==== Body\nIntroduction\nAspirin is readily available as an over-the-counter (OTC) medication. Use of this drug has decreased because of the availability of newer anti-inflammatory drugs that are better tolerated for the treatment of musculoskeletal pain and inflammation. Evidence of an association between aspirin and Reye’s syndrome has also contributed significantly to decreasing aspirin use in children. Strategies such as child-resistant packaging and reducing the amount of medication in each package of OTC analgesics have also contributed to a decrease in the incidence of aspirin poisoning [1]. Despite its decreasing incidence, aspirin poisoning remains an important clinical problem involving accidental ingestion in children and intentional overdose in adults [2]. Salicylate, a metabolite of aspirin, seems to be responsible for the toxic effects of the drug [3].\n\nWe present the case of a patient who presented with aspirin overdoses on four occasions over the course of two months at a tertiary university hospital. Our aim in this report was to use the unusual and possibly one-of-a-kind opportunity to describe repeated overdose in the same individual with a focus on (1) the present treatment modalities for aspirin overdose and (2) the variability in the time course of plasma salicylate concentrations between episodes and the potential influences of therapeutic interventions.\n\nCase presentation\nOver the course of two months, a 75-year-old Caucasian man weighing 45kg who had a history of multiple previous drug overdoses, depression, bulimia and stage 3 chronic kidney disease [4] (creatinine between 160μmol/L and 140μmol/L, that is, estimated glomerular filtration rate, 39ml/min/1.73m2 to 46ml/min/1.73m2) presented on three occasions to St Vincent’s Hospital following aspirin overdoses. During his third admission, he overdosed with aspirin while on the ward recovering from the previous aspirin overdose. His alleged ingested dosages Table 1 were classed as “potentially lethal” in two episodes (>500mg/kg in both) and “serious” in the other two (300mg/kg to 500mg/kg) [2]. However, the peak plasma concentrations (Table 1) indicated a “moderate” severity of poisoning after the first and second overdose and “mild” severity after the other two [5]. The patient was dehydrated upon each admission with mild hyperventilation (respiratory rate around 30 breaths/min), nausea and tinnitus. He had no other neurological symptoms or signs. He was normothermic upon all admissions. In the second and third overdoses, the patient presented with respiratory alkalosis (Table 1, Figures 1A and 1B). Raised anion gap levels (that is, anion gap >18mmol/L) were observed upon the first admission (anion gap, 21mmol/L) and the second admission (anion gap, 22mmol/L) and resolved within 24 hours of treatment both times.In each of the four episodes, the patient received intravenous fluids (0.9% saline and/or 4% dextrose diluted 1:5 in saline) with the aim of achieving clinical euvolemia. Potassium supplementation was needed in the first, second and third overdoses. Additionally, sodium bicarbonate was administered after the second, third and fourth overdoses. The bicarbonate therapy led to an increase in urinary pH to between 7.5 and 8 (Figures 1A and 1B) (measured using Siemens Multistix 10 SG (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) (referred to as dipstick below)). Single-dose charcoal was given after the second overdose only. None of the admissions warranted airway support, and there was no incidence of bleeding.\n\nTable 1 Features of four overdoses of aspirin in an individual patient\n\nOverdose\tAspirin allegedly ingested, g (mg/kg)\tPeak salicylate concentration (mg/L)\tAdmission plasma creatinine (μmol/L)\tCreatinine 24 hours post admission (μmol/L)\tAdmission plasma potassium (mmol/L)\tAdmission blood pH\tPotassium replaced (KCl each 24 hours) (mmol)\tInput/output (each 24 hours) (L)\tBicarbonate (mmol/h)\t\n1\t27 (600)\t624\t175\t165\t3.1\t7.41\t60\t4.5/1.3\tNo\t\n40\t3/2.7\t\n2.5/2.8\t\n2\t27 (600)\t548\t180\t133\t3.1\t7.58\t80\t9.02/3.2\t25 for 4h then 40 for 5h\t\n1.9/2.3\t\n3\t22.4 (498)\t441\t141\t159\t4\t7.49\t20\t3.38/2.97\t30 for 10h\t\n2.5/1.1\t\n1.12/no data\t\n4\t14.4 (320)\t432\t142\t142\t4.9\t \t–\t5.3/1.1 + missing data\t60 bolus then 25 for 3h\t\nFigure 1 Time courses of salicylate, pH (blood and urine) and plasma potassium following overdoses. Graphed data for first and second overdoses (OD1 and OD2) (A) and third and fourth overdoses (OD3 and OD4) (B), respectively. t1/2, Half-life. Areas between the dotted lines describe blood pH 7.35 to 7.45 and plasma potassium 3.5 to 4.5; Urinary pH dotted line represents 7.5.\n\nThis patient had short high-dependency unit admissions (<48 hours) after the first, second and third overdoses. His fourth overdose was treated in a general ward. Refractory hypokalemia was encountered after the first and second overdoses, taking more than 20 hours to achieve normokalemia (Figure 1A and Table 1). Urinary pH between 7.5 and 8 was observed only when plasma potassium concentration was ≥3.7mmol/L (Figures 1A and 1B). Subsequently, using urine samples from one healthy volunteer (author DG) across a manipulated pH range of 5.0 to 8.5, dipstick readings were compared to those determined using a pH meter (Mettler Toledo, Columbus, OH, USA). The dipstick readings were consistently lower, by 0.36±0.2 units (based on six readings), than the “gold standard” pH meter readings.\n\nThe longest apparent half-life (t1/2) of elimination of salicylate (t1/2 = 30 hours) was seen after the first overdose, when urinary alkalization was not attempted (Figures 1A and 1B). The most rapid elimination was observed during the second admission (t1/2 = 9.7 hours). On that occasion, compared to the other overdoses, a much greater volume of intravenous fluid was administered, along with bicarbonate therapy and a single dose of charcoal (Table 1, Figures 1A and 1B).\n\nThe patient’s lengths of stay were 21 days (first overdose), 8 days (second overdose) and 6 days (third and fourth overdoses), respectively.\n\nDiscussion\nThere is no antidote for aspirin overdose. The goals of therapy are to limit absorption of aspirin, to enhance elimination of salicylate and to provide supportive care [6]. Guidelines direct that emergency intervention may be required to achieve the following aims:\n\n1. Stabilize the airway and breathing: Mechanical ventilation, if required, should be adjusted to maintain blood alkalosis (for example, hyperventilation to decrease partial pressure of carbon dioxide) [7].\n\n2. Treat dehydration, acid–base disturbance, hypokalemia, pulmonary edema, neuroglycopenia or seizure.\n\nFeatures of the toxicity of salicylate and the management of our patient were generally in accord with findings and recommendations for the management of aspirin overdose. However, variations in the time course of plasma salicylate concentrations may be related to the variable approaches used to treat individual episodes, as outlined below.\n\n• The stated dose of aspirin often does not indicate the potential level of toxicity[1]. Our present case illustrates that the clinical features of severity correlated better with the plasma concentration of salicylate than the reported dosage of aspirin ingested.\n\n• Measurement of plasma concentrations of salicylate should be repeated over several hours because of the slow and erratic absorption of aspirin[1]. Following all four of our patient’s overdoses, his plasma salicylate concentration was measured within one-half hour of admission and repeated at intervals during the management period. On the third occasion, a small, isolated rise in plasma concentration of salicylate was noted (299mg/L to 342mg/L) at 19 hours after ingestion of aspirin, with subsequent concentrations continuing to decline (Figure 1B).\n\n• Gastrointestinal decontamination with activated charcoal is recommended[7]when given early (after ingestion) and when the risk of aspiration is very low. A single dose of charcoal was administered only after the second overdose, although the risk of aspiration was low on all occasions. Charcoal may have been useful in reducing the plasma concentrations of salicylate more rapidly in the other three episodes [8].\n\n• Hypovolemia should be corrected because intravascular volume depletion decreases salicylate excretion[7]. The patient received intravenous fluids for each episode. He presented with the poorest renal function following the second overdose and was treated then with the largest amount of intravenous fluid. This was associated with the greatest fall in plasma creatinine within the first 24 hours of any of the four episodes (Table 1). Some of this decrease was most likely dilutional. Fluid balance is more critical in patients with baseline chronic kidney disease dictating the need for close hemodynamic monitoring.\n\n• Alkalization of urine by administering sodium bicarbonate is advised in order to increase the rate of excretion of salicylate[9]. Titration of urinary pH to between 7.5 and 8 is commonly used to indicate successful alkalization. As mentioned above, urinary dipstick estimation of pH may underestimate the degree of alkalization. Bicarbonate administration in our patient was associated with a shorter half-life of salicylate in the second, third and fourth overdoses compared to the first overdose, when bicarbonate was not administered (Table 1, Figures 1A and 1B).\n\nThe half-life of salicylate at common analgesic doses of aspirin (300mg to 600mg every four to six hours) is two to four hours, but may increase to as much as 20 hours following overdose [7]. The half-lives of salicylate in our patient were therefore within the expected range for the second, third and fourth overdoses (t1/2=10 to 21 hours), but not in the first overdose (t1/2=30 hours), perhaps because bicarbonate was not used (Figures 1A and 1B).\n\n• Hypokalemia should be corrected to achieve effective urinary alkalization with bicarbonate[7]. The importance of this point is illustrated in the second admission, when hypokalemia, despite potassium administration, was associated with failure to alkalinize urine for more than 20 hours (Figure 1A and Table 1).\n\n• Toxicity of salicylate may be greater in the elderly and infants than in young to middle-aged adults[10]. Our patient was 75 years old, and thus an increased sensitivity to aspirin may have been expected.\n\n• Dialysis is indicated if metabolic acidosis is profound and is resistant to therapy and/or central nervous system toxicity is evident. None of the overdoses in our patient appeared to be life-threatening on the basis of the clinical and laboratory features observed. The patient’s fluid balance (Table 1) indicated that there was no progression to oliguria or anuria.\n\nThere was heterogeneity in the approaches used to manage each episode of overdose in this patient. The patient had significant baseline renal impairment, which might have affected his responses to treatment. Urinary pH measured by using a dipstick can be misleading.\n\nConclusion\nIntravenous fluid hydration with the aim of achieving euvolemia was the intervention common to all four aspirin overdose episodes in our patient. Activated charcoal might have helped to decrease absorption [9]. Although urinary alkalization appeared to have increased the clearance of salicylate, it was the combination of treatments, best demonstrated in the management of the second overdose, which, we believe, optimized detoxification. These measures— oral charcoal, intravenous hydration, potassium replacement and urinary alkalization—were most effective in our patient, who had stage 3 chronic kidney disease.\n\nOur experience with treating these four overdoses also reveals the importance of monitoring the implementation of management guidelines, as considerable unexplained variation in management was observed.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. Also, approval to write up this case was obtained from the St Vincent’s Hospital Research and Ethics Committee. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nDG, KW, GG, PN, HB and RD devised the study. DG performed the literature review, data collection and interpretation, review of the patient’s clinical course, manuscript drafting and project coordination. KW, GG, PN, HB and RD were involved in supervision and critical revision of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgments\nWe thank Shaun Kumar, (BMedSc (Hon 1), PhD student), who provided help with statistical analysis conducted using GraphPad Prism software version 6.0. (GraphPad Software, La Jolla, CA, USA). Contribution of ROD was supported by the National Health and Medical Research Council (program grant 1054146).\n==== Refs\nO’Malley GF Emergency department management of the salicylate poisoned patient Emerg Med Clin North Am 2007 25 333 346 10.1016/j.emc.2007.02.012 17482023 \nTemple AR Acute and chronic effects of aspirin toxicity and their treatment Arch Intern Med 1981 141 364 369 10.1001/archinte.1981.00340030096017 7469627 \nLevy G Clinical pharmacokinetics of salicylates: a re-assessment Br J Clin Pharmacol 1980 10 Suppl 2 285S 290S 7437270 \nLevey AS Eckardt KU Tsukamoto Y Levin A Coresh J Rossert J De Zeeuw D Hostetter TH Lameire N Eknoyan G Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO) Kidney Int 2005 67 2089 2100 10.1111/j.1523-1755.2005.00365.x 15882252 \nDargan PI Wallace CI Jones AL An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose Emerg Med J 2002 19 206 209 10.1136/emj.19.3.206 11971828 \nProudfoot AT Toxicity of salicylates Am J Med 1983 75 99 103 10.1016/0002-9343(83)90239-5 6650533 \nPearlman BL Gambhir R Salicylate intoxication: a clinical review Postgrad Med 2009 121 162 168 10.3810/pgm.2009.07.2041 19641282 \nBarone JA Raia JJ Huang YC Evaluation of the effects of multiple dose activated charcoal on the absorption of orally administered salicylate in a simulated toxic ingestion model Ann Emerg Med 1988 17 34 37 3337412 \nProudfoot AT Krenzelok EP Vale JA Position paper on urine alkalinisation J Toxicol Clin Toxicol 2004 42 1 26 10.1081/CLT-120028740 15083932 \nWaseem M Aslam M Gernsheimer JR Corden TE Harchelroad F Kreplick LW Mullins ME Slabinski MS Tarabar A Tucker JR Van De Voort JT Windle ML Salicylate toxicity [http://emedicine.medscape.com/article/1009987-overview#showall] (accessed 7 September 2014)\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000368:Aged; D001241:Aspirin; D062787:Drug Overdose; D006801:Humans; D007008:Hypokalemia; D008297:Male",
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"pages": "374",
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"pubdate": "2014-11-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Multiple episodes of aspirin overdose in an individual patient: a case report.",
"title_normalized": "multiple episodes of aspirin overdose in an individual patient a case report"
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"abstract": "Intraoral localized methotrexate-associated lymphoproliferative disorders can cause antiresorptive agent-related osteonecrosis of the jaw associated with infection due to its immunological abnormalities and ulcer formation.",
"affiliations": "Department of Oral Medicine, Oral and Maxillofacial Surgery Tokyo Dental College Ichikawa Japan.;Department of Oral Medicine, Oral and Maxillofacial Surgery Tokyo Dental College Ichikawa Japan.;Department of Oral Medicine, Oral and Maxillofacial Surgery Tokyo Dental College Ichikawa Japan.;Department of Pathology and Laboratory Medicine Tokyo Dental College Ichikawa General Hospital Ichikawa Japan.;Department of Oral Medicine, Oral and Maxillofacial Surgery Tokyo Dental College Ichikawa Japan.",
"authors": "Minabe|Masaki|M|https://orcid.org/0000-0002-1558-0832;Suzuki|Taiki|T|;Komatsu|Masumi|M|;Hashimoto|Kazuhiko|K|;Nomura|Takeshi|T|",
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"doi": "10.1002/ccr3.3192",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3192\nCCR33192\nCase Report\nCase Reports\nIntraoral localized methotrexate‐associated lymphoproliferative disorders concurrent with antiresorptive agent‐related osteonecrosis of the jaw: A case report and literature review\nMINABE et al.Minabe Masaki https://orcid.org/0000-0002-1558-0832\n1\nminabemasaki@tdc.ac.jp Suzuki Taiki \n1\n\n2\n Komatsu Masumi \n1\n Hashimoto Kazuhiko \n3\n Nomura Takeshi \n1\n \n1 \nDepartment of Oral Medicine, Oral and Maxillofacial Surgery\nTokyo Dental College\nIchikawa\nJapan\n\n\n2 \nDivision of Oral and Maxillofacial Surgery\nSUBARU Health Insurance Society Ota Memorial Hospital\nOta\nJapan\n\n\n3 \nDepartment of Pathology and Laboratory Medicine\nTokyo Dental College\nIchikawa General Hospital\nIchikawa\nJapan\n\n* Correspondence\n\nMasaki Minabe, Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College, 5‐11‐13, Sugano, Ichikawa, Chiba 272‐8513, Japan.\n\nEmail: minabemasaki@tdc.ac.jp\n\n13 9 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.122926 2935\n19 2 2020 18 6 2020 05 7 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nIntraoral localized methotrexate‐associated lymphoproliferative disorders can cause antiresorptive agent‐related osteonecrosis of the jaw associated with infection due to its immunological abnormalities and ulcer formation.\n\nIntraoral localized methotrexate‐associated lymphoproliferative disorders can cause antiresorptive agent‐related osteonecrosis of the jaw associated with infection due to its immunological abnormalities and ulcer formation.\n\n\n\nantiresorptive agent‐related osteonecrosis of the jawdenosumabmethotrexate‐associated lymphoproliferative disordersrheumatismrheumatoid arthritis source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nMinabe \nM \n, \nSuzuki \nT \n, \nKomatsu \nM \n, \nHashimoto \nK \n, \nNomura \nT \n. Intraoral localized methotrexate‐associated lymphoproliferative disorders concurrent with antiresorptive agent‐related osteonecrosis of the jaw: A case report and literature review\n. Clin Case Rep . 2020 ;8 :2926 –2935\n. 10.1002/ccr3.3192\n==== Body\n1 INTRODUCTION\nIntraoral localized methotrexate‐associated lymphoproliferative disorders (MTX‐LPD) may be associated with antiresorptive agent‐related osteonecrosis of the jaw (ARONJ), especially with purulent discharge. In patients who are on oral MTX and have oral ulcers, it is important to perform biopsy, even if they meet the diagnostic criteria for ARONJ.\n\nMethotrexate (MTX) is the first‐line treatment for rheumatoid arthritis (RA), as it has superior bone destruction suppressant effect.\n1\n However, there are many reports on the adverse effects of MTX therapy. Several recent case studies reported that long‐term MTX therapy resulted in MTX‐related lymphoproliferative disorder (MTX‐LPD) in RA patients.\n2\n, \n3\n\n\n\nThe World Health Organization categorizes MTX‐LPD as an “other iatrogenic immunodeficiency‐associated LPD” in the classification of Tumors of Hematopoietic and Lymphoid Tissues.\n4\n Immunosuppression by MTX is thought to reduce the host immunosurveillance of the Epstein‐Barr virus (EBV)‐infected B cells, as approximately 50% of MTX‐LPD patients were EBV positive,\n5\n, \n6\n and lead to MTX‐LPD.\n\nAntiresorptive agents, such as bisphosphonates (BPs) and denosumab, are the primary treatment agents for osteoporosis, bone metastasis, and hypercalcemia. Antiresorptive agents have many benefits for patients with skeletal complications. The use of corticosteroid and MTX is important for immunosuppression in RA treatment, and antiresorptive agents are important to prevent steroidal osteoporosis. In proportion to their use, cases of antiresorptive agent‐related osteonecrosis of the jaw (ARONJ) have been increasing.\n7\n The major clinical symptoms of ARONJ are progressive destruction of the jaw, prolonged pain, bone exposure, soft tissue swelling, fistula, and infections. Most of those symptoms are intractable, and many severe cases have been reported.\n8\n, \n9\n, \n10\n Therefore, the diagnosis and treatment of ARONJ should be made early.\n\nHere, we report a case of MTX‐LPD in an elderly woman who had concurrent exposure of the maxilla, mucosal necrosis, and persistent pain from ARONJ caused by long‐term denosumab to treat steroidal osteoporosis of RA. In addition, we performed a literature review to identify all cases of intraoral localized MTX‐LPD with bone exposure and to investigate the characteristics and prognoses of these cases.\n\n2 CASE REPORT\nPatient: A 75‐year‐old woman.\n\nChief complaint: Persistent pain in the right maxillary mucosa and bone exposure.\n\nMedical history: The patient had RA, osteoporosis, renal cancer, and schizophrenia. She had been taking 8 mg of MTX per week since 1998. Further, she was given denosumab for osteoporosis from 2013 to January 2018 (60 mg subcutaneously once every 6 months; the total dose administered was 600 mg). She underwent left nephrectomy for renal cancer in June 2017. She was undergoing medical therapy for schizophrenia.\n\nFamily history: No relevant family history.\n\nClinical procedures and outcomes: At her first visit to a dentist with pain in the right maxillary mucosa in early February 2018, the dentist suspected ARONJ because of maxillary posterior bone exposure, infection, and pain. She visited our department for further examination and treatment of the right maxillary lesion that was causing her pain in mid‐February 2018. Her dental treatment and tooth extraction history were unknown.\n\n2.1 Presenting symptoms\nGeneral condition: The physical constitution was slightly obese. Oral intake of food was impaired because of severe intraoral pain.\n\nFacial condition: The countenance was symmetric. The cervical lymph nodes were not swollen.\n\nOral condition: There were jaw bone exposure, mucosal necrosis, and infection from the right maxillary incisors to the molars. The lesion gave her severe pain (Figure 1A). The right maxillary canine and lateral incisor were loose, suggesting moderate to severe periodontitis.\n\nFIGURE 1 Oral cavity at the initial examination. A, Large ulceration with no peripheral induration, infection with purulent discharge, and exposed bone in the ulcer were noted on the right maxillary gingiva. B and C, Computed tomography and magnetic resonance imaging showed osteosclerosis in the right maxillary jaw bone, and the upper right maxillary sinus mucosa was hypertrophic\n\nImage findings: Computed tomography (CT) and magnetic resonance imaging (MRI) revealed osteosclerosis in the right maxillary jaw bone, and the upper right maxillary sinus mucosa was hypertrophic, suggesting acute osteomyelitis (Figure 1B and C).\n\nBlood test findings: White blood cell count, 5100/μL; C‐reactive protein, 1.35 mg/dL; creatinine, 1.04 mg/dL; estimated glomerular filtration rate, 20%. It suggested slight inflammation and renal function impairment.\n\nWe performed cytodiagnosis and biopsy at the right maxillary mucosa on the first medical examination day. She was diagnosed negative for intraepithelial lesion and malignancy on cytodiagnosis with granulation tissue on histopathology.\n\nClinical diagnosis: ARONJ.\n\nWe initiated treatment for ARONJ, based on the treatment strategies in previous papers,\n11\n with oral amoxicillin (750 mg/d), oral clarithromycin (400 mg/d), and the use of gargle for infection control.\n\nOn hospital day 18, the inflammatory findings had undergone remission (Figure 2A). However, on hospital day 65, the maxillary jaw bone exposure and mucosal necrosis were found to have spread (Figure 2B). Therefore, we suspected MTX‐LPD because of the long‐term administration history and rise in blood concentration of MTX because of renal function impairment after nephrectomy. Therefore, we performed re‐biopsy at the right maxillary mucosa. On hospital day 72, we diagnosed MTX‐LPD using several immune‐histological examinations. Histopathological examination with hematoxylin and eosin staining revealed severe inflammatory cell infiltration in the submucosal area. Granulation tissue in the deep subepithelial region showed Reed‐Sternberg‐like cells and Hodgkin cell‐like cells. Immunohistochemical staining revealed several large CD20‐ and CD30‐positive cells, which were positive for EBER‐ISH (Figure 3).\n\nFIGURE 2 Oral findings after the initial treatment. A, Inflammatory findings had undergone remission on hospital day 18 after antimicrobial administration. B, The maxillary jaw bone exposure and mucosal necrosis had re‐spread on hospital day 65\n\nFIGURE 3 Histopathological and immunohistochemical findings. A, Histopathological staining with hematoxylin and eosin (×400) revealed severe inflammatory cell infiltration in the submucosal area. Granulation tissue in the deep subepithelial region, Reed‐Sternberg‐like cells (Red arrow), and Hodgkin cell‐like cells (Black arrow) were found in the granulation tissue. B‐D, Immune‐histological findings revealed many large CD20 (×400) (B) and CD30 (×400) (C)‐positive cells, which were positive for EBER‐ISH (×400) (D)\n\nWe consulted the Department of Hematology and Rheumatology in our hospital to look for more lesions and also to replace MTX with other agents for RA. The malignant lymphoma tumor marker test showed that lactate dehydrogenase (277 IU/L) and soluble interleukin‐2 receptor (862 U/mL) were slightly elevated, but there were no findings of lymphoid nodal lesions on contrast‐enhanced CT. Finally, she was diagnosed with intraoral localized MTX‐LPD with ARONJ.\n\nFinal diagnosis: MTX‐LPD (intraoral localized type) with ARONJ stage 2, which is characterized by exposure/necrosis associated with pain, infection, and fistula, in which bone is palpable with a probe.\n\nOn hospital day 72, in consultation with the Department of Hematology and Rheumatology, MTX was switched to salazosulfapyridine.\n\nOn hospital day 85, she was hospitalized because of poor pain control and difficulty in oral intake of food. We started 9 g/d of sulbactam/ampicillin (SBT/ABPC) with topical antibacterial drug (bacitracin, fradiomycin sulfate) delivery using a splint (Figure 4A) and professional oral management and gargling for acute infection from ARONJ. On hospital day 90, the acute symptoms had resolved. We extracted the mobile right canine and performed saucerization with exposure of the maxillary bone. The exposed bone had undergone epithelization and protraction, and pain was under remission. On hospital day 111, she was discharged (Figure 4B).\n\nFIGURE 4 Treatment course after hospitalization. A, In addition to antimicrobial drip infusion, topical antibacterial drug (bacitracin, fradiomycin sulfate) delivery using a splint was started on hospital day 85. B, Exposed bone had undergone epithelization and protraction, and pain was under remission on hospital day 90. C, The right maxillary lesion with infection at the time of re‐hospitalization on day 115. D, Extraction of the mobile right lateral incisor and re‐saucerization with sharp‐edged maxillary bone were performed, and the open wound was covered with dermis defect grafting (Terudermis®) after acute symptomatic relief. E, The exposed bone underwent complete epithelization on hospital day 148. F, A denture combined with a protection plate was fabricated for oral intake of food\n\nHowever, on day 115, she was re‐hospitalized because of fever, fatigue, infection of the right maxillary lesion, and difficulty in oral intake of food (Figure 4C). Her schizophrenia caused poor compliance to instructions, and therefore, she had not taken some prescribed drugs. We started her on SBT/ABPC again. However, the result of re‐culture of the lesion was persistent, so we switched to SBT/ABPC to 1.2 g/d of clindamycin phosphate. After acute symptoms were relieved, we extracted the mobile right lateral incisor and performed re‐saucerization with a sharp‐edged maxillary bone, and the open wound was covered with a dermis defect graft (Terudermis®) (Figure 4D). The exposure bone underwent complete epithelization on hospital day 148, and we prescribed a dosage of antibiotics (Figure 4E).\n\nWe fabricated the denture combined with a protection plate, which was good for oral intake of food (Figure 4F). On hospital day 160, she was discharged. There was no recurrence of MTX‐LPD or ARONJ, and RA remained well‐controlled. She undergoes regular follow‐ups every 3‐6 months.\n\n3 DISCUSSION\nClinically, MTX‐LPD is similar to lymphoma in patients without immunodeficiency. However, both the immunological abnormalities of RA and the immunosuppressive effects of MTX are considered to be involved in the pathogenesis of MTX‐LPD. In RA, specific clonal autoreactive T cells are seen, and in their presence, B cells that produce autoantibodies such as rheumatoid factor are activated. Furthermore, it has been suggested that the immunosuppressive effects of MTX may cause viral infections or reactivation of latent viral infections and also induce abnormal cell proliferation.\n7\n, \n12\n Among viral infections, EBV is considered to be more common and is thought to cause lymphoma by direct viral activity that spreads and propagates the virus from latently infected cells.\n13\n, \n14\n\n\n\nDiffuse large B‐cell lymphoma (DLBCL) accounts for approximately half of all MTX‐LPD histological types, followed by Hodgkin lymphoma (HL) at 10%‐20%.\n15\n Other studies have also mentioned follicular lymphoma and T‐cell lymphoma.\n16\n Since these are not monoclonal lesions, it is necessary to make a comprehensive diagnosis by combining immunohistochemical staining and clinical features.\n\nIn this case as well, HE staining revealed Reed‐Sternberg‐like cells and Hodgkin cell‐like cells in the granulation tissue. Immunohistological staining revealed numerous CD20/30‐positive atypical large cells, which were EBER‐ISH positive. Since MTX was administered for a long duration of 20 years and the total dose was approximately 7680 mg, it was considered that immunosuppression and the proliferation of EBV‐infected cells occurred.\n\nMTX‐LPD may resolve in several weeks after withdrawal of the MTX therapy.\n17\n However, additional treatments, such as chemotherapy and radiotherapy, should be considered for patients with persistent LPD after MTX withdrawal.\n18\n Therefore, definitive diagnostic criteria are lacking, and a definitive diagnosis of MTX‐LPD remains challenging. As in this case, if there are no lymph node lesions, and the diagnostic criteria for ONJ are met, there is a possibility of the misdiagnosis of ARONJ. Therefore, in cases of oral MTX administration, oral surgeons should bear in mind that incisional biopsy and immune‐histological examination are required for the final diagnosis.\n\nRegarding the administration of antiresorptives to patients under ARONJ treatment, it is reported that their discontinuation may be recommended until ARONJ treatments are completed for patients with osteoporosis, excluding those with high fracture risk.\n11\n Since this case was considered to be an advanced complication of MTX‐LPD and ARONJ, we consulted with the department of internal medicine and determined that the risk of fractures was not high. Therefore, we decided to withhold the antiresorptives after ARONJ treatment. In order to balance the risk of ARONJ and fractures, it was considered necessary to determine the discontinuation of antiresorptives after consultation with the medical department.\n\nA review of the literature revealed 22 cases of intraoral localized MTX‐LPD with bone exposure, including our case (Table 1).\n2\n, \n3\n, \n19\n, \n20\n, \n21\n, \n22\n, \n23\n, \n24\n, \n25\n, \n26\n, \n27\n, \n28\n, \n29\n, \n30\n, \n31\n, \n32\n, \n33\n, \n34\n, \n35\n The mean age of the patients was 73 years (range, 44‐92 years), and the male to female ratio was 2:1. The mean duration of MTX treatment was 8.6 years (range, 0.6‐20 years). The frequency of DLBCL was 84% (16/19 cases); the frequency of EBV infection was 95% (19/20 cases); MTX‐LPD resolved in 89% (16/18 cases) of patients after discontinuation of MTX. Data on the mean age, sex ratio, duration of MTX treatment, and frequency of EBV infection were similar to those of previous reports on intraoral localized MTX‐LPD.\n35\n In contrast, the frequency of DLBCL was higher in comparison with previous reports on intraoral localized MTX‐LPD. Intraoral localized MTX‐LPD was considered to show good prognosis after drug withdrawal, with or without bone exposure. In three cases of no remission after withdrawal of MTX, chemotherapy was performed.\n2\n, \n23\n, \n30\n Two of the three cases showed systemic symptoms,\n2\n, \n23\n and in one case, a fistula was detected in the palatal opening in the naso‐genian region.\n30\n It was considered that the presence of extraoral symptoms had an influence on the prognosis of intraoral localized MTX‐LPD.\n\nTable 1 Clinicopathological findings of 22 cases with intraoral localized methotrexate‐related lymphoproliferative disorders (MTX‐LPD) with bone exposure\n\n\tCase\tAge, Sex\tSite\tLocal findings\tSystemic occurrence\tPathological diagnosis\tEBV\tAntiresorptive agent intake (y)\tMTX intake (y)\tPurulent discharge\tAntibiotic therapy\tMTX withdrawl\tChemo therapy\tRecurrence\t\n1\tKalantzis et al\n12\n\n\t72, F\tU. gingiva\t\nUlceration\n\n\nBone exposure\n\n\n\tUK\tPolyclonal B‐cell lesion\t+\t−\tUK\t−\t−\t+\t−\t−\t\n2\tAcero et al\n2\n\n\t79, F\tU. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t−\t15 y\t+\t−\t+\t+\t−\t\n3\tTanaka et al\n3\n\n,\n\na\n\n\t44, M\tU. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\nUnhealed tooth socket\n\n\n\t−\tDLBCL\t+\t−\tUK\t−\t−\t+\t−\t−\t\n4\tHatanaka et al\n13\n\n,\n\na\n\n\t66, F\tU. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t−\t12 y\t+\t+\t+\t−\t−\t\n5\tYamashita et al\n14\n\n,\n\na\n\n\t66, F\tU. gingiva\t\nPain\n\n\nBone exposure\n\n\nUnhealed tooth socket\n\n\n\t−\tDLBCL\t+\t4 y\t12 y\t−\t+\t+\t−\t−\t\n6\tSano et al\n15\n\n,\n\na\n\n\t70, M\tU and L. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t−\t0.4 y\t−\t+\t+\t−\t−\t\n7\tMinami et al\n16\n\n,\n\na\n\n\t60, F\tL. gingiva\t\nPain\n\n\nSwelling\n\n\nBone exposure\n\n\n\t−\tUK\t+\t3 y\t2 y\t−\t+\t+\t+\t+\t\n8\tKimoto et al\n17\n\n,\n\na\n\n\t64, F\tU and L. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t2 y\t3 y\t−\t+\t+\t−\t−\t\n9\tAiko and Michiwaki 2013\n18\n\n,\n\na\n\n\t84, F\tL. gingiva\t\nPain\n\n\nSwelling\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t−\t1.6 y\t−\t+\t+\t−\t−\t\n10\tGoto et al\n19\n\n,\n\na\n\n\t74, F\tU. gingiva\t\nUlceration\n\n\nBone exposure\n\n\nUnhealed tooth socket\n\n\n\tLung Pharyngeal Tonsil\tPolymorphic LPD\t+\t−\t10 y\t−\t−\t+\t−\t−\t\n11\tHorie et al\n20\n\n,\n\na\n\n\t60, M\tU. gingiva\t\nUlceration\n\n\nBone exposure\n\n\nUnhealed tooth socket\n\n\n\t−\tDLBCL\t+\t−\t12 y\t−\t+\t+\t−\t−\t\n12\tYagihara et al\n21\n\n,\n\na\n\n\t87, M\tU. gingiva\t\nUlceration\n\n\nBone exposure\n\n\n\t−\tT‐cell dominant polymorphic LPD\t−\t5 y\t12 y\t−\t+\t+\t−\t−\t\n13\tObata et al\n22\n\n,\n\na\n\n\t80, M\tU. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t−\t6.3 y\t−\t−\t+\t−\t−\t\n14\tSaito et al\n23\n\n,\n\na\n\n\t76, F\tU. gingiva\t\nBleeding\n\n\nUlceration\n\n\nBone exposure\n\n\n\tLung Stomach\tDLBCL\t+\t−\t10 y\t−\t−\t+\t+\t+\t\n15\tMese et al\n24\n\n,\n\na\n\n\t70, F\tU. gingiva\t\nPain\n\n\nSwelling\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t−\t15 y\t−\t+\t+\t−\t−\t\n16\tMiyamoto et al\n25\n\n,\n\na\n\n\t72, F\tU. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t0.5 y\t8 y\t−\t+\t+\t−\t−\t\n17\tKomatani et al\n26\n\n,\n\na\n\n\t88, M\tU. gingiva\t\nBone exposure\n\n\nUnhealed tooth socket\n\n\n\t−\tUK\tUK\t−\t0.6 y\t+\t+\t−\t−\tNo remission\t\n18\tKomatani et al\n26\n\n,\n\na\n\n\t73, M\tL. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tUK\tUK\t−\t2 y\t−\t+\t+\t−\tNot available\t\n19\tHatakeyama et al\n27\n\n,\n\na\n\n\t92, F\tL. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\t−\tDLBCL\t+\t−\t13 y\t−\t−\t+\t−\tNot available\t\n20\tHatakeyama et al\n27\n\n,\n\na\n\n\t80, F\tU. gingiva\t\nPain\n\n\nUlceration\n\n\nBone exposure\n\n\n\tLung Pharyngeal\tDLBCL\t+\t−\t13 y\t−\t−\t+\t−\tNot available\t\n21\tFurukawa et al\n28\n\n,\n\na\n\n\t81, F\tU. gingiva\t\nPain\n\n\nBleeding\n\n\nUlceration Bone exposure\n\n\n\t−\tDLBCL\t+\tUK\t4 y\t−\t−\t+\t−\t−\t\n22\tOur case\t75, F\tU.gigiva\t\nPain\n\n\nBleeding\n\n\nUlceration Bone exposure\n\n\n\t−\tDLBCL\t+\t5 y\t20 y\t+\t+\t+\t−\t−\t\nAbbreviations: C, chemotherapy; DLBCL, diffuse large B‐cell lymphoma; EBV, Epstein‐Barr virus; L, lower jaw; LPD, lymphoproliferative disorder; U, upper jaw; UK, unknown; W, withdrawal of MTX; y, yrars.\n\na Japanese patient.\n\nJohn Wiley & Sons, LtdMost intraoral localized MTX‐LPD patients (20/22) were Japanese.\n3\n, \n20\n, \n21\n, \n22\n, \n23\n, \n24\n, \n25\n, \n26\n, \n27\n, \n28\n, \n29\n, \n30\n, \n33\n, \n35\n However, the reason is unclear. Therefore, a study has been initiated jointly by three academic societies (Japan College of Rheumatology, The Japanese Society of Hematology, The Japanese Society of Pathology) in Japan.\n\nIn this case, it was necessary to administer antimicrobials during hospitalization because of evacuation in the exposed bone, fever, fatigue, elevation of the inflammatory markers, and an eating disorder caused by pain. Although symptom relief was observed after MTX withdrawal, bone exposure was continued, and reinfection of the bone exposed area was observed because of interruption of the antibiotic. Therefore, taking into consideration the combination of ARONJ, orthopedic treatment with dermis defect grafting and topical antibacterial drug delivery using a splint were actively performed in addition to antibiotic instillation, and the bone exposure improved, and the lesion healed.\n\nTwenty‐two cases of intraoral localized MTX‐LPD with bone exposure have been reported, but only four cases had infection with purulent discharge.\n2\n, \n33\n, \n34\n As bone exposure because of LPD is caused by gingival necrosis due to lymphocyte infiltration, and infection is considered to be another pathology, there might be only four cases of true ARONJ complication where infection could not be controlled unless antibacterial drugs were used. Our case had severe infections repeatedly in a short time period; therefore, it was considered that LPD was complicated by ARONJ.\n\n4 CONCLUSION\nIn cases with a history of oral MTX and presence of oral ulcers, it is important to perform biopsy and immunostaining for LPD‐related markers, even if they meet the diagnostic criteria for ARONJ. In addition, when bone exposure involves bacterial infection, aggressive antibiotic administration and surgical treatment are considered important to promote epithelialization of the wound.\n\nCONFLICT OF INTEREST\nThe authors have no conflicts of interest to disclose.\n\nAUTHOR CONTRIBUTIONS\nMM, TS, and KM: managed the patient. KH: made the pathological diagnosis. MM, TS, and TN: wrote the manuscript. All authors: reviewed and approved the final version of the manuscript.\n\nETHICAL APPROVAL\nEthical Approval was not necessary for this case report. Patient's data and photographs are de‐identified.\n\nACKNOWLEDGMENTS\nWe would like to thank Editage (www.editage.com) for English language editing.\n==== Refs\nREFERENCES\n1 \n\nColmegna \nI \n, \nOhata \nBR \n, \nMenard \nHA \n. Current understanding of rheumatoid arthritis therapy\n. Clin Pharmacol Ther . 2012 ;91 :607 ‐620\n.22357455 \n2 \n\nAcero \nJ \n, \nNavarro‐Cuellar \nC \n, \nMenarguez \nJ \n, \nHerencia \nH \n, \nNavarro‐Vila \nC \n. Naso‐maxillary non‐Hodgkin lymphoma associated with methotrexate treatment in a patient with rheumatoid arthritis\n. J Oral Maxillofac Surg . 2006 ;64 :708 ‐711\n.16546655 \n3 \n\nTanaka \nA \n, \nShigematsu \nH \n, \nKojima \nM \n, \nSakashita \nH \n, \nKusama \nK \n. Methotrexate‐associated lymphoproliferative disorder arising in a patient with adult Still's disease\n. J Oral Maxillofac Surg . 2008 ;66 :1492 ‐1495\n.18571037 \n4 \n\nHarris \nNL \n, \nSwerdlow \nSH \n. 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Am J Hematol . 2007 ;82 :1106 ‐1109\n.17654684 \n18 \n\nSoubrier \nM \n, \nArrestier \nS \n, \nBouloudian \nS \n, \nDubost \nJJ \n, \nRistori \nJM \n. Epstein‐Barr virus infection associated hepatic lymphoma in a patient treated with methotrexate for rheumatoid arthritis\n. Joint Bone Spine . 2006 ;73 :218 ‐219\n.16495108 \n19 \n\nKalantzis \nA \n, \nMarshman \nZ \n, \nFalconer \nDT \n, \nMorgan \nPR \n, \nOdell \nEW \n. Oral effects of low‐dose methotrexate treatment\n. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2005 ;100 :52 ‐62\n.15953917 \n20 \n\nHatanaka \nT \n, \nSawaki \nY \n, \nYamada \nJ \n, \nFurue \nH \n, \nFu \nS \n, \nUeda \nM \n. A case of methotrexate‐associated lymphproliferative disorder\n. Jpn J Oral Maxillofac Surg . 2011 ;57 :104 ‐108\n.\n21 \n\nYamashita \nY \n, \nIwai \nT \n, \nMiyazaki \nC \n, \nOmura \nS \n, \nAoki \nN \n, \nTohnai \nI \n. A suspected case of both bisphosphonate‐related osteonecrosis of the maxilla and methotrexate‐associated lymphoproliferative disorder\n. Jpn J Oral Maxillofac Surg . 2012 ;58 :371 ‐375\n.\n22 \n\nSano \nD \n, \nIshibashi \nK \n, \nHikita \nM \n, \nHinoshita \nM \n. A case of methotrexate‐associated lymphoproliferative disorder with jaw necrosis\n. Jpn J Oral Maxillofac Surg . 2012 ;58 :655 ‐659\n.\n23 \n\nMinami \nY \n, \nOhbayashi \nY \n, \nSawai \nF \n, \nWada \nK \n, \nMiyake \nM \n, \nMatsui \nY \n. A case of rheumatoid arthritis associated with bisphosphonate‐related osteonecrosis of the jaw and methotrexate‐associaated lymmphoproliferative disorder\n. Jpn J Oral Maxillofac Surg . 2012 ;58 :484 ‐488\n.\n24 \n\nKimoto \nA \n, \nSuzuki \nH \n, \nFurudoi \nS \n, \nTakeuchi \nJ \n, \nAsai \nT \n, \nKomori \nT \n. A case of methotrexate‐associated lymphoproliferative disorded arising in the gingiva if the maxilla and mndible\n. Jpn J Oral Maxillofac Surg . 2013 ;59 :197 ‐201\n.\n25 \n\nAiko \nK \n, \nMichiwaki \nH \n. A case of methotrexate‐associated lymphoproliferativedisorder in the lower gingiva of the patient with rheumatoid arthritis that completely resolver after drug withdrawal\n. Jpn J Oral Maxillofac Surg . 2013 ;59 :341 ‐345\n.\n26 \n\nGoto \nI \n, \nFurudoi \nS \n, \nTakeuchi \nJ \n, \nIshida \nM \n, \nShibuya \nY \n, \nKomori \nT \n. A case of methotrexate‐associated lymphoproliferative disorder with osteonecrosis of the jaw\n. Jpn J Oral Maxillofac Surg . 2014 ;60 :229 ‐233\n.\n27 \n\nHorie \nN \n, \nKawano \nR \n, \nKaneko \nT \n, \nShimoyama \nT \n. Methotrexate‐related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis\n. Aust Dent J . 2015 ;60 :408 ‐411\n.25302816 \n28 \n\nYagihara \nK \n, \nIshii \nJ \n, \nKatsurano \nM \n, \nIshikawa \nA \n, \nKimishima \nY \n, \nIzumo \nT \n. A case of T‐cell dominant polymorphic methotrexate‐associated lymphoproliferativedisordersin the maxillary gingive\n. Jpn J Oral Maxillofac Surg . 2015 ;61 :13 ‐19\n.\n29 \n\nObata \nK \n, \nKishimoto \nK \n, \nNIshiyama \nA \n, \nYoshida \nS \n, \nNojima \nT \n, \nSasaki \nA \n. A case of methotrexate‐associated lymphoproliferative disorders araising in the maxillary gingiva: areview of the literature of case arising in the oral region in Japan\n. Jpn J Oral Maxillofac Surg . 2015 ;61 :20 ‐24\n.\n30 \n\nSaito \nS \n, \nMurakami \nT \n, \nKoshinuma \nS \n, \nHigo \nT \n, \nTsutsumi \nY \n, \nYamamoto \nG \n. A case of methotrexate‐associated lymphoproliferative disorder accompanied by osteonecrosis of the maxilla\n. J Oral Maxillofac Surg Med Pathol . 2015 ;27 :834 ‐838\n.\n31 \n\nMese \nH \n, \nYamamoto \nD \n, \nHasegawa \nK \n, \nShimo \nT \n, \nSasaki \nA \n. Methotrexate (MTX) –associated lymphoproliferative disorder with a wide range of osteonecrosis of jaw bone: report of a case\n. J Jpn Soc Oral Med . 2017 ;23 :9 ‐16\n.\n32 \n\nMiyamoto \nS \n, \nMiyazaki \nA \n, \nOnishi \nM \n, \nSasaki \nT \n, \nShimanishi \nM \n, \nHaratsuka \nH \n. A case of methotrexate‐associated lymphoproliferative disorders simultaneously arising in the maxilla and the nasal mucosa of a patient receiving bisphosphonate\n. Jpn J Oral Maxillofac Surg . 2017 ;63 :210 ‐215\n.\n33 \n\nKomatani \nT \n, \nSonobe \nJ \n, \nTakahashi \nK \n, \nBessho \nK \n. Methotrexate‐related osteonecrosis of the jaw: report of two cases\n. J Oral Maxillofac Surg Med Pathol . 2017 ;29 :546 ‐549\n.\n34 \n\nHatakeyama \nD \n, \nInoue \nK \n, \nYoshida \nH \n, \nMakita \nH \n, \nShibata \nT \n. Two cases of methotrexate‐associated lymphoproliferative disorders in the gingiva\n. Jpn J Oral Diag/Oral Med . 2017 ;30 :216 ‐222\n.\n35 \n\nFurukawa \nS \n, \nOobu \nK \n, \nMoriyama \nM \n et al Oral methotrexate‐related lymphoproliferative disease presenting with severe osteonecrosis of the jaw: a case report and literature review\n. Intern Med . 2018 ;57 :575 ‐581\n.29225245\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(12)",
"journal": "Clinical case reports",
"keywords": "antiresorptive agent‐related osteonecrosis of the jaw; denosumab; methotrexate‐associated lymphoproliferative disorders; rheumatism; rheumatoid arthritis",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2926-2935",
"pmc": null,
"pmid": "33363853",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "29233703;22357455;17654684;28035494;17117491;16859835;25319961;18571037;29563359;15953917;16546655;17200802;29225245;16495108;20210795;25302816;8656264",
"title": "Intraoral localized methotrexate-associated lymphoproliferative disorders concurrent with antiresorptive agent-related osteonecrosis of the jaw: A case report and literature review.",
"title_normalized": "intraoral localized methotrexate associated lymphoproliferative disorders concurrent with antiresorptive agent related osteonecrosis of the jaw a case report and literature review"
} | [
{
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"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3",
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"abstract": "In recent years, there has been a growing interest in using baclofen for the management of alcohol use disorder. This off-label indication usually involves high doses of the medication. We report a case of severe baclofen overdose in a 66-year-old man. The patient was found severely agitated, and he presented with delirium and auditory hallucinations. At hospital admission, his daily dose was 180 mg baclofen. He was admitted to the intensive care unit for sedation and supportive care. When sedation was withdrawn, the patient presented with a normal neurological status. In this clinical context, baclofen intoxication was suspected. This was confirmed by measuring blood baclofen levels. This intoxication was probably mediated by a combination of risk factors including a high daily dose of baclofen and acute renal failure, conducive to drug accumulation.",
"affiliations": "Department of Internal Medicine, Riviera-Chablais Hospital, Vevey, Switzerland.;Clinical Pharmacy, Pharmacie des Hôpitaux de l'Est Lémanique, Vevey, Switzerland.;Department of Internal Medicine, Riviera-Chablais Hospital, Vevey, Switzerland.",
"authors": "Reichmuth|Philipp|P|;Blanc|Anne-Laure|AL|;Tagan|Damien|D|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D019973:Alcohol-Related Disorders; D001418:Baclofen; D003693:Delirium; D019468:Disease Management; D062787:Drug Overdose; D006212:Hallucinations; D006801:Humans; D008297:Male; D009125:Muscle Relaxants, Central; D056687:Off-Label Use",
"nlm_unique_id": "101526291",
"other_id": null,
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"pmc": null,
"pmid": "26396128",
"pubdate": "2015-09-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15615812;1576599;16113202;16454779;17053268;22292975;22989277;24226812;24887094;9391686",
"title": "Unintentional baclofen intoxication in the management of alcohol use disorder.",
"title_normalized": "unintentional baclofen intoxication in the management of alcohol use disorder"
} | [
{
"companynumb": "CH-WATSON-2016-15621",
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"activesubstancename": "CARVEDILOL"
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"abstract": "Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid neoplasm. However, it is one of the most aggressive forms of malignancy accounting for approximately 50% of mortality associated with all thyroid cancers. Here we report two cases of ATC treated with immune checkpoint inhibitors. Next generation sequencing identified BRAFV600E mutation in one of the patients who also derived benefit from BRAF targeted therapy. We here discuss these cases highlighting the importance of expert pathological review, utilizing molecular testing to identify the underlying genetic targets for personalized therapy, and the potential role of PD-1 inhibitors for the treatment of ATC.",
"affiliations": "Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA. Electronic address: sukaria@karmanos.org.;Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Medical Group, Detroit, MI, USA.;Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA; Division of Neurology, Department of Internal Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan.;Wayne State University School of Medicine, Detroit, MI, USA.;Department of Otolaryngology Head and Neck Surgery, Wayne State University, Detroit, MI, USA.;Department of Otolaryngology Head and Neck Surgery, Wayne State University, Detroit, MI, USA.;Department of Otolaryngology Head and Neck Surgery, Wayne State University, Detroit, MI, USA.;Division of Radiation Oncology, Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA.",
"authors": "Sukari|Ammar|A|;Kukreja|Geetika|G|;Nagasaka|Misako|M|;Shukairy|Mohammad K|MK|;Yoo|George|G|;Lin|Ho-Sheng|HS|;Hotaling|Jeffrey|J|;Kim|Harold|H|",
"chemical_list": "D014408:Biomarkers, Tumor; D000082082:Immune Checkpoint Inhibitors; D000082102:Immune Checkpoint Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor",
"country": "England",
"delete": false,
"doi": "10.1016/j.oraloncology.2020.104744",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1368-8375",
"issue": "109()",
"journal": "Oral oncology",
"keywords": "Anaplastic thyroid carcinoma; BRAF; Chemo-immunotherapy; Molecular testing; PD1 inhibitors",
"medline_ta": "Oral Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D019468:Disease Management; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D000082102:Immune Checkpoint Proteins; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D000072078:Positron Emission Tomography Computed Tomography; D061026:Programmed Cell Death 1 Receptor; D065646:Thyroid Carcinoma, Anaplastic; D016896:Treatment Outcome",
"nlm_unique_id": "9709118",
"other_id": null,
"pages": "104744",
"pmc": null,
"pmid": "32402656",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "The role of immune checkpoint inhibitors in anaplastic thyroid cancer (Case Series).",
"title_normalized": "the role of immune checkpoint inhibitors in anaplastic thyroid cancer case series"
} | [
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"companynumb": "US-009507513-2009USA010063",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
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... |
{
"abstract": "Differences in the incidence, etiology, type, and outcome of infections occurring during the first 6 months after transplantation were evaluated in two consecutive cohorts of kidney recipients who received immunosuppressive regimens based on either azathioprine (plus antilymphocyte globulin, cyclosporine A, and prednisone) (ATG-AZA cohort) or mycophenolate-mofetil (plus cyclosporine A and prednisone) (MMF cohort). The overall incidence of infections in the two cohorts was similar (0.99+/-1.06 infections/patient in the MMF cohort and 1.04+/-0.99 in the ATG-AZA cohort, P=0.3), as was the incidence of bacterial and fungal infections. In patients who received mycophenolate, cytomegalovirus disease occurred at a higher incidence (0.3+/-0.54 vs. 0.1+/-0.34 episodes/patient, P=0.005) and affected the upper gastrointestinal tract more frequently (0.21+/-0.48 vs. 0.025+/-0.16 episodes of cytomegalovirus ulcerative esophagitis, gastritis, or duodenitis per patient; P=0.001). A nonsignificant trend toward a higher recipient survival for patients receiving mycophenolate was noted (100% vs. 95%, P=0.07). In multivariate analysis, the following factors were independently associated with a higher risk of cytomegalovirus disease: the serostatus R-/D+ (seronegative recipients who received a kidney from a seropositive donor) (RR=35.7 [95%CI, 7.4-166.7]), treatment with mycophenolate (RR=10.4 [95%CI, 2.7-38.4]), and the development of any episodes of acute rejection (RR=10.1 [95%CI, 2.5-41.6]). These data show that kidney recipients receiving mycophenolate have a higher incidence of cytomegalovirus disease, mainly affecting the upper gastrointestinal tract, compared to those receiving azathioprine-based immunosuppression.",
"affiliations": "Service of Infectious Diseases, Virgen del Rocío University Hospital, Avenida Manuel Siurot s/n, 41013 Seville, Spain. wittel@cica.es",
"authors": "Bernabeu-Wittel|M|M|;Naranjo|M|M|;Cisneros|J M|JM|;Cañas|E|E|;Gentil|M A|MA|;Algarra|G|G|;Pereira|P|P|;González-Roncero|F J|FJ|;de Alarcón|A|A|;Pachón|J|J|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-001-0684-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "21(3)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": null,
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D001424:Bacterial Infections; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D009181:Mycoses; D009894:Opportunistic Infections; D011446:Prospective Studies; D016896:Treatment Outcome; D014777:Virus Diseases",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "173-80",
"pmc": null,
"pmid": "11957018",
"pubdate": "2002-03",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Infections in renal transplant recipients receiving mycophenolate versus azathioprine-based immunosuppression.",
"title_normalized": "infections in renal transplant recipients receiving mycophenolate versus azathioprine based immunosuppression"
} | [
{
"companynumb": "ES-ROCHE-1945419",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "Cognitive decline and dementia are a growing problem as the population ages. Effective therapies to prevent and treat these problems are limited. Neuro-inflammation has been suggested as a cause of dementia [1]. Montelukast is a leukotriene receptor antagonist used to treat seasonal allergies and asthma. It acts as a cysteinyl leukotriene (CysLT1) receptor antagonist blocking the action of leukotrienes and decreasing inflammation [2]. Animal studies have shown that administering Montelukast improves memory function [3]. This case series of patients in a private Internal Medicine practice between 2013-2014 used Montelukast in patients with various levels of memory impairment and dementia. Patients were given Montelukast 80 mg daily in 4 divided doses every 2-3 hours. Memory impaired patients had subjective improvement in the memory and recall. Patients with dementia were noted by family members to be less agitated, but had no memory improvement at the doses used. Montelukast may be useful to treat memory impairment and dementia. Long term use might act as a prophylactic to prevent dementia.",
"affiliations": "Rozin Internal Medicine - United States.",
"authors": "Rozin|Spencer I|SI|",
"chemical_list": null,
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1874205X01711010007",
"fulltext": "\n==== Front\nOpen Neurol JOpen Neurol JTONEUJThe Open Neurology Journal1874-205XBentham Open. TONEUJ-11-710.2174/1874205X01711010007ArticleCase Series Using Montelukast in Patients with Memory Loss and Dementia Rozin Spencer I. *Rozin Internal Medicine — United States* Address correspondence to this author at the Rozin Internal Medicine, 721 Wellness Way, suite 220 Lawrenceville, GA, 30046 United States; Tel: 770-709-0900; Fax: 770-709-7444; E-mail: askdrrozin@drrozin.com31 1 2017 2017 11 7 10 21 7 2016 27 12 2016 29 12 2016 © Spencer I. Rozin; Licensee Bentham Open2017Bentham Open.This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. Cognitive decline and dementia are a growing problem as the population ages. Effective therapies to prevent and treat these problems are limited. Neuro-inflammation has been suggested as a cause of dementia [1]. Montelukast is a leukotriene receptor antagonist used to treat seasonal allergies and asthma. It acts as a cysteinyl leukotriene (CysLT1) receptor antagonist blocking the action of leukotrienes and decreasing inflammation [2]. Animal studies have shown that administering Montelukast improves memory function [3]. This case series of patients in a private Internal Medicine practice between 2013-2014 used Montelukast in patients with various levels of memory impairment and dementia. Patients were given Montelukast 80 mg daily in 4 divided doses every 2-3 hours. Memory impaired patients had subjective improvement in the memory and recall. Patients with dementia were noted by family members to be less agitated, but had no memory improvement at the doses used. Montelukast may be useful to treat memory impairment and dementia. Long term use might act as a prophylactic to prevent dementia.\n\nKeywords\nAlzheimer’sCognitive impairmentDementiaMemory lossMontelukast\n==== Body\nINTRODUCTION\nCognitive impairment and Alzheimer’s dementia are expected to significantly increase as the population ages. Current therapies have limited utility in preventing and treating these diseases. Alzheimer’s disease is thought to currently affect 5.1 million Americans of age 65 or older, with a 2:1 ratio of women to men being affected. The affected population may increase almost 3 fold by 2050. Out of the top 10 causes of death, Alzheimer’s ranks the 6th and is the only one that is not preventable. The cost to provide care for patients with Alzheimer’s by the year 2050 is expected to be close to $1.1 Trillion [4]. Having a safe, effective drug to reverse the cognitive impairments of dementia would have a dramatic effect on the lives of millions of patients. If the drug also prevented the neurological changes that cause dementia, this could benefit tens of millions more people.\n\nMETHODOLOGY\nAll patients or medical agents gave oral consent to participate in this case series. Patients were treated with Montelukast 20 mg orally upon arising and then 20 mg every 2-3 hours for a total of 4 doses daily following protocol outlined in the USPTO Patent Number: US8575194 filed by Jack William Schultz [5].\n\nAll patients had either a Mini Mental Status Exam (MMSE) [6] or Montreal Cognitive Assessment (MOCA) [7] prior to the treatment. Results were obtained by subjective response of patients or medical agents.\n\nRESULTS\nPatients Treated Without Knowledge of Medication Identity:\nPatients had memory problems, forgetfulness, and issues with word recall, problems with focus or concentration or feeling like being in a fog. All patients had MMSE scores 27-30/30.\n\nPatient #1 was a 69 year old (y/o) White male (WM)\n\nPatient #2 was a 65 y/o WM\n\nPatient #3 was a 69 y/o White female (WF)\n\nPatient #4 was a 52 y/o WF\n\nPatient #5 was a 56 y/o WF\n\nPatient #6 was a 69 y/o WM\n\nAll patients had significant subjective improvement in the symptoms within 24 hours of starting the medication and recurrence of symptoms 24-48 hours after discontinuation. One patient developed insomnia which resolved with dose reduction. No other side effects were reported.\n\nPATIENTS TREATED WITH KNOWLEDGE OF THE MEDICATION NAME AND NORMAL USE\nPatients with Suspected Memory Impairment by Report and Testing\nAll had memory problems, word recall issues, and problems in staying focused. Family also reported declines in the memory. Patients had MMSE exam scores 29-30/30.\n\nPatient #7 was a 70 y/o WM\n\nPatient #8 was a 54 y/o, Black male\n\nPatient #9 was a 75 y/o WM improved with 20 mg dose in AM, but forgot to take other doses during the daytime. Improvement wore off after 2-3 hours.\n\nThese patients had significant improvement in the symptoms. The symptoms recurred in 24-36 hours of discontinuation of the medication. No side effects were reported in any patient.\n\nPatients with Dementia Who Had Agitation and Anxiety Symptoms\nAll patients had MMSE scores 20-26/30.\n\nPatient #10 was an 85 y/o WF who was already on Namenda and PRN Xanax\n\nPatient #11 was an 86 y/o WM who was already on Namenda and Prozac\n\nBoth patients had very dramatic response with the resolution of anxiety, agitation and their families noted that the patients were more interactive. Patients had no significant memory improvement. No side effects were reported.\n\nPatient #12 was an 86 y/o WF who showed no improvement. She was previously intolerant to Aricept, Exelon and Rivastigmine.\n\nPatients with Dementia, Anxiety and Agitation Along with Other CNS Issues\nAll patients had MMSE scores 23-25/30.\n\nPatient #13 was a 77 y/o WM with co-existent mild traumatic brain injury already on Namenda and Aricept\n\nPatient #14 was a 79 y/o WM with severe long lasting post-operative dementia already on Aricept and Ativan\n\nPatient #13 improved significantly and Patient #14 showed mild improvement. No side effects were reported.\n\nPatient #15 Was an 85 y/o WF with MMSE 26/30. She declined Namenda and Aricept. Memory improved within 1 week of starting medication per patient and husband. No side effects were reported. MMSE follow up was 28/30 on medication.\n\nPatient #16 was an 84 y/o WM with a MOCA score of 18/30 on Razadyne 4 mg BID with worsening memory per patient and wife. He declined Namenda or higher dose Razadyne. The family noted improvement in patient’s memory and he was less agitated on Montelukast, but due to frequent dosing schedule, he discontinued the medication after 2 weeks.\n\nPatient #17 was a 78 y/o WF with a MOCA score of 13/30 on Namenda10 mg BID and Aricept 10 mg daily with worsening memory per patient and family. The patient’s agitation and anxiousness improved per family report.\n\nDISCUSSION\nThis case series suggests that Montelukast may have significant potential to improve cognitive impairment and dementia. Montelukast is known to block the activation of the CysLT1 receptor [2]. Activation of CysLT receptors induces neuroinflammation. It has been shown to increase astrocyte proliferation and glial fibrillary acidic protein [8], response to acute neuronal injury after focal cerebral ischemia [9], and the activation of human traumatic brain injury and brain tumors [10] and induce astrocyte proliferation and death after oxygen-glucose deprivation [11]. Prior animal studies have suggested that use of Montelukast may decrease the central nervous system inflammation [12], and attenuate chronic brain injury after induced focal cerebral ischemia [13] and protects against quinolinic acid/malonic acid induced neurotoxicity [14].\n\nIn the rat studies [3, 15] the use of Montelukast was associated with improved neurocognitive function with the proposed mechanism showing improvement in neuroinflammation. These studies have used Montelukast doses up to 10 mg/kg body weight. The use of higher doses than that used in this case series may show memory improvement in patients with dementia. Further studies with Montelukast in patients with cognitive impairment and dementia as well as in a trial of prophylactic use to prevent these illnesses should be done. The reuse of an older medication might speed the development of an effective medication for these devastating diseases and result in a new product that would be affordable to a huge population of patients.\n\nCONCLUSION\nThe use of Montelukast in patients with cognitive impairment improved memory. Its use in patients with dementia led to lessened agitation, but the effect on memory improvement may be limited by the dose selection lower than that used in the animal studies.\n\nACKNOWLEDGEMENTS\nDeclared none.\n\nCONFLICT OF INTEREST\nThe author confirms that this article content has no conflict of interest.\n==== Refs\nREFERENCES\n1 Daniela L. Krause and Norbert Muller Neuroinflammation, Microglia and Implications for Anti-Inflammatory Treatment in Alzheimer’s disease Int. J. Alzheimer’s Dis. 2010 Article ID 732806 9 pages. \n2 FDA, Montelukast. (Singulair, application number 20-830) Pharmacology Review. Available at: http://www.accessdata.fda.gov/drugsatfda_ docs/nda/98/20830_Singulair_pharmr.pdf \n3 Marschallinger J. Schäffner I. Klein B. Gelfert R. Rivera F.J. Illes S. Grassner L. Janssen M. Rotheneichner P. Schmuckermair C. Coras R. Boccazzi M. Chishty M. Lagler F.B. Renic M. Bauer H.C. Singewald N. Blümcke I. Bogdahn U. Couillard-Despres S. Lie D.C. Abbracchio M.P. Aigner L. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat. Commun. 2015 6 8466 10.1038/ncomms9466 26506265 \n4 Alzheimer’s Association Alzheimer’s Association, Available at: http://www.alz.org/facts/ \n5 Treatment methods of cognitive, emotional and mental ailments and disorders. US Patents US 8575194 B1 2013 Publication date 11/15/2013 \n6 Folstein M.F. Folstein S.E. McHugh P.R. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 1975 12 3 189 198 10.1016/0022-3956(75)90026-6 1202204 \n7 Nasreddine Z.S. Phillips N.A. Bédirian V. Charbonneau S. Whitehead V. Collin I. Cummings J.L. Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J. Am. Geriatr. Soc. 2005 53 4 695 699 10.1111/j.1532-5415.2005.53221.x 15817019 \n8 Ciccarelli R. DAlimonte I. Santavenere C. DAuro M. Ballerini P. Nargi E. Buccella S. Nicosia S. Folco G. Caciagli F. Di Iorio P. Cysteinyl-leukotrienes are released from astrocytes and increase astrocyte proliferation and glial fibrillary acidic protein via cys-LT1 receptors and mitogen-activated protein kinase pathway. Eur. J. Neurosci. 2004 20 6 1514 1524 10.1111/j.1460-9568.2004.03613.x 15355318 \n9 Zhang Y.J. Zhang L. Ye Y.L. Fang S.H. Zhou Y. Zhang W.P. Lu Y.B. Wei E.Q. Cysteinyl leukotriene receptors CysLT1 and CysLT2 are upregulated in acute neuronal injury after focal cerebral ischemia in mice. Acta Pharmacol. Sin. 2006 27 12 1553 1560 10.1111/j.1745-7254.2006.00458.x 17112408 \n10 Wei-Ping Z. Ou-Yang M. Steven A. Generation and growth mechanism of metal (Fe, Co, Ni) nanotube arrays. Neurosci. Lett. 2004 363 247 251 15182953 \n11 Huang X.J. Zhang W.P. Li C.T. Shi W.Z. Fang S.H. Lu Y.B. Chen Z. Wei E.Q. Activation of CysLT receptors induces astrocyte proliferation and death after oxygen-glucose deprivation. Glia 2008 56 1 27 37 10.1002/glia.20588 17910051 \n12 Wang L. Du C. Lv J. Wei W. Cui Y. Xie X. Antiasthmatic drugs targeting the cysteinyl leukotriene receptor 1 alleviate central nervous system inflammatory cell infiltration and pathogenesis of experimental autoimmune encephalomyelitis. J. Immunol. 2011 187 5 2336 2345 10.4049/jimmunol.1100333 21804021 \n13 Zhao R. Shi W-Z. Zhang Y-M. Montelukast: much more than an antiasthma drug. J. Pharm. Pharmacol. 2011 63 550 557 10.1111/j.2042-7158.2010.01238.x 21401607 \n14 Kalonia H. Kumar P. Kumar A. Nehru B. Protective effect of montelukast against quinolinic acid/malonic acid induced neurotoxicity: possible behavioral, biochemical, mitochondrial and tumor necrosis factor-α level alterations in rats. Neuroscience 2010 171 1 284 299 10.1016/j.neuroscience.2010.08.039 20813166 \n15 Lai J Hua M Wang H Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates Aβ1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice Neuropharmacol 2014 79 1 707 14\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1874-205X",
"issue": "11()",
"journal": "The open neurology journal",
"keywords": "Alzheimer’s; Cognitive impairment; Dementia; Memory loss; Montelukast",
"medline_ta": "Open Neurol J",
"mesh_terms": null,
"nlm_unique_id": "101480493",
"other_id": null,
"pages": "7-10",
"pmc": null,
"pmid": "28567133",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "21401607;26506265;17910051;15817019;17112408;20813166;1202204;20798769;21804021;15355318;24456746",
"title": "Case Series Using Montelukast in Patients with Memory Loss and Dementia.",
"title_normalized": "case series using montelukast in patients with memory loss and dementia"
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"companynumb": "US-APOTEX-2017AP012777",
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"abstract": "We herein report a case of atypical drug-induced hypersensitivity syndrome (DIHS) involving serological reactivation of cytomegalovirus induced by carbamazepine with pulmonary and skin manifestations. These lesions were not present on admission, but developed on virus reactivation as indicated by the presence of inclusion bodies and multinucleated giant cells in alveolar cells with CD8(+) T lymphocyte infiltration on a transbronchial lung biopsy. Although the precise mechanism of DIHS remains unknown, this case suggests the crucial role of viral reactivation in pulmonary lesions in DIHS.",
"affiliations": "Department of Respiratory Disease, Southern Tohoku General Hospital, Japan.",
"authors": "Hase|Isano|I|;Arakawa|Hiroaki|H|;Sakuma|Hideo|H|;Kaneko|Fumio|F|;Watanabe|Yuzuru|Y|;Fujiu|Koichi|K|;Miyamoto|Hideaki|H|;Ishii|Yoshiki|Y|",
"chemical_list": "D002220:Carbamazepine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6347",
"fulltext": null,
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"issn_linking": "0918-2918",
"issue": "55(18)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D002220:Carbamazepine; D003587:Cytomegalovirus; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D014775:Virus Activation",
"nlm_unique_id": "9204241",
"other_id": null,
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"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bronchoscopic Investigation of Atypical Drug-induced Hypersensitivity Syndrome Showing Viral Lung Involvement.",
"title_normalized": "bronchoscopic investigation of atypical drug induced hypersensitivity syndrome showing viral lung involvement"
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"abstract": "Biopsy-proven acute interstitial nephritis (AIN) secondary to sodium-glucose co-transporter 2 (SGLT2) inhibitors has not been described previously. Here, we report on the management of a patient with severe acute kidney injury that developed 6 weeks after starting empagliflozin. The cause was confirmed as AIN on renal biopsy. Our patient recovered, without the need for dialysis, with discontinuation of empagliflozin and corticosteroid treatment. This novel clinical observation is likely to occur more frequently as these drugs are increasingly being prescribed, given that recent randomized controlled trials including EMPA-REG (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) showed SGLT2 inhibitors can decrease cardiovascular mortality, among other benefits, in high-risk diabetic populations.",
"affiliations": "Nephrology Department, James Cook University Hospital, Middlesbrough, UK.;Nephrology Department, James Cook University Hospital, Middlesbrough, UK.;Nephrology Department, James Cook University Hospital, Middlesbrough, UK.;Histopathology Department, James Cook University Hospital, Middlesbrough, UK.;Histopathology Department, James Cook University Hospital, Middlesbrough, UK.;Nephrology Department, James Cook University Hospital, Middlesbrough, UK.",
"authors": "Ryan|Rebecca|R|0000-0003-1974-2429;Choo|Stephanie|S|;Willows|Jamie|J|;Walker|Julie|J|;Prasad|Kolanu|K|;Tez|Didem|D|",
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"doi": "10.1093/ckj/sfaa033",
"fulltext": "\n==== Front\nClin Kidney J\nClin Kidney J\nckj\nClinical Kidney Journal\n2048-8505\n2048-8513\nOxford University Press\n\n10.1093/ckj/sfaa033\nsfaa033\nExceptional Cases\nAcademicSubjects/MED00340\nAcute interstitial nephritis due to sodium-glucose co-transporter 2 inhibitor empagliflozin\nhttp://orcid.org/0000-0003-1974-2429\nRyan Rebecca 1\nChoo Stephanie 1\nWillows Jamie 1\nWalker Julie 2\nPrasad Kolanu 2\nTez Didem 1\n1 Nephrology Department, James Cook University Hospital, Middlesbrough, UK\n2 Histopathology Department, James Cook University Hospital, Middlesbrough, UK\nCorrespondence to: Rebecca Ryan; E-mail: rebecca.ryan2@nhs.net\n3 2021\n24 3 2020\n24 3 2020\n14 3 10201022\n23 12 2019\n17 2 2020\n© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.\n2020\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBiopsy-proven acute interstitial nephritis (AIN) secondary to sodium-glucose co-transporter 2 (SGLT2) inhibitors has not been described previously. Here, we report on the management of a patient with severe acute kidney injury that developed 6 weeks after starting empagliflozin. The cause was confirmed as AIN on renal biopsy. Our patient recovered, without the need for dialysis, with discontinuation of empagliflozin and corticosteroid treatment. This novel clinical observation is likely to occur more frequently as these drugs are increasingly being prescribed, given that recent randomized controlled trials including EMPA-REG (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) showed SGLT2 inhibitors can decrease cardiovascular mortality, among other benefits, in high-risk diabetic populations.\n\nacute interstitial nephritis\nacute kidney injury\nempagliflozin\nSGLT2 inhibitor\n==== Body\nBACKGROUND\n\nSodium-glucose co-transporter 2 (SGLT2) inhibitors will likely become more widely used following the results of recent large randomized controlled trials that demonstrated improved cardiovascular outcomes and slower progression of chronic kidney disease (CKD). There is an acknowledged initial drop in glomerular filtration rate (GFR) when starting SGLT2 inhibitor therapy, hypothesized to be due to reduced trans-glomerular pressure, which then should stabilize.\n\nWe report a patient who presented with acute kidney injury (AKI) due to biopsy-proven acute interstitial nephritis (AIN), with a convincing timeline to pinpoint empagliflozin as the causative agent. To the authors’ knowledge, this is the first published case of AIN due to an SGLT2 inhibitor.\n\nCASE REPORT\n\nA 63-year-old woman presented with a 5-week history of gradually increasing lethargy, malaise and poor appetite. She was found to have Stage 3 AKI by Acute Kidney Injury Network criteria, with a serum creatinine of 381 µmol/L (normal range 50–120 µmol/L), having been 60 µmol/L 3 months prior. She denied any other symptoms, including rash and fever, on systems enquiry. Her background included well-controlled hypertension and Type 2 non-insulin-dependent diabetes for 10 years. Empagliflozin had been commenced 6 weeks before her presentation. Additional medications—atorvastatin, calcichew D3 forte, diltiazem, enalapril and metformin—were all longstanding (>2 years). She took no over-the-counter medications, supplements or illicit drugs.\n\nOn examination, the patient appeared euvolaemic. Blood pressure was 183/86 mmHg. Serum eosinophils, ANCA, anti-glomerular basement membrane, complement, anti-nuclear antibodies, anti-double stranded DNA, rheumatoid factor, anti-Ro, anti-La, immunoglobulins, electrophoresis, free light chains, hepatitis B, C and HIV testing were all either negative or normal. Urinalysis showed erythrocytes + and glucose ++++, in keeping with SGLT2 inhibitor use. Protein-to-creatinine ratio (taken while serum creatinine was stable) was 168 mg/mmol. Albumin creatinine ratio 3 months previously was 3.9 g/mol. Chest radiograph was normal. Ultrasound and computed tomography urogram revealed a normal left kidney and an enlarged right kidney at 157 mm, without calculi or hydronephrosis.\n\nThe patient was initially managed with intravenous fluid therapy and suspension of enalapril, empagliflozin and metformin. Despite supportive measures, her creatinine remained static. On Day 7, she underwent a renal biopsy, which confirmed the diagnosis of AIN (see Figure 1). While awaiting the results of the biopsy, her creatinine peaked on Day 10 at 466 µmol/L and she was started on intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 60 mg daily. Given the time course, a diagnosis of AKI due to empagliflozin-induced AIN was made, and the drug was permanently discontinued. Her renal function started to improve within 3 days of steroid therapy, but she developed significant glucocorticoid-associated hyperglycaemia that required insulin commencement. Prednisolone was decreased to 35 mg daily after 2 weeks, then gradually tapered down to zero over the next 6 weeks. After 8 weeks of treatment, her creatinine improved to 123 µmol/L.\n\nFIGURE 1 Renal histology following native renal biopsy, showing marked acute tubulointerstitial nephritis with lymphocytic infiltrates and eosinophils in the interstitium and focal tubulitis. No granulomas are present and no significant fibrosis is seen. Background changes are suggestive of early diabetic nephropathy.\n\nDISCUSSION\n\nSGLT2 inhibitors block proximal renal tubule transport proteins to cause glycosuria and natriuresis [1]. By reducing trans-glomerular pressure, they can cause an initial drop in GFR, which then should stabilize, similar to angiotensin-converting enzyme inhibitor initiation. The EMPA-REG (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial [2] compared empagliflozin to placebo in 7020 patients with Type 2 diabetes at high risk of cardiovascular events. At 3.1-year follow-up, it found a 38% relative risk reduction in death from cardiovascular causes in the empagliflozin arm and slower progression of CKD. Weight loss, blood pressure lowering and a modest reduction of HbA1c are other hypothesized health benefits.\n\nAny drug has the potential to cause drug-induced AIN (DI-AIN); therefore, it is vital to remain vigilant when initiating any medication. Our patient presented in an oligosymptomatic fashion without the classic findings of fever, rash or eosinophilia. This non-specific presentation is common in DI-AIN [3] but can make diagnosis challenging. Renal biopsy therefore remains the gold standard for diagnosis [4].\n\nThe strong temporal relationship in our case argues convincingly that empagliflozin was the causative agent of the biopsy-substantiated AIN, given that the patient's symptoms began 1 week after drug commencement. We treated with 8 weeks of corticosteroids, in keeping with evidence that longer durations do not achieve greater renal recovery [3]. Our patient suffered the impact of hospital admission, the risks of renal biopsy and required insulin for glucocorticoid-induced hyperglycaemia.\n\nThe potential benefits of SGLT2 inhibitors greatly outweigh the risks of side effects; a small initial drop in GFR due to haemodynamic effects should be expected and tolerated if not progressive. However, this case should prompt clinicians to obtain baseline renal function when starting empagliflozin and contemplate the diagnosis of DI-AIN if new non-specific symptoms develop or a progressive AKI occurs after SGLT2 inhibitor initiation.\n\nPATIENT CONSENT\n\nWe are grateful to the patient for the informed consent to publish this case report.\n\nAUTHORS’ CONTRIBUTIONS\n\nEach named author contributed to the design, drafting, revision and approval of the report.\n\nCONFLICT OF INTEREST STATEMENT\n\nNone declared. The results presented in this article have not been published previously in whole or part. The subject of the case report has given their informed consent for publication.\n==== Refs\nREFERENCES\n\n1 Fioretto P , ZambonA, RossatoM et al . SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016; 39 : S165–S171 27440829\n2 Zinman B , WannerC, LachinJM et al . Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes. N Engl J Med 2015; 373 : 2117–2128 26378978\n3 Fernandez-Juarez G , PerezJV, Coravaca-FontanF et al .; on behalf of the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Duration of treatment with corticosteroids and recovery of kidney function in acute interstitial nephritis. Clin J Am Soc Nephrol 2018; 13 : 1851–1858 30397027\n4 Nussbaum EZ , PerazellaMA. Diagnosing acute interstitial nephritis: considerations for clinicians. Clin Kidney J 2019; 12: 1–6\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "14(3)",
"journal": "Clinical kidney journal",
"keywords": "SGLT2 inhibitor; acute interstitial nephritis; acute kidney injury; empagliflozin",
"medline_ta": "Clin Kidney J",
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"nlm_unique_id": "101579321",
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"pages": "1020-1022",
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"pmid": "33777384",
"pubdate": "2021-03",
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"title": "Acute interstitial nephritis due to sodium-glucose co-transporter 2 inhibitor empagliflozin.",
"title_normalized": "acute interstitial nephritis due to sodium glucose co transporter 2 inhibitor empagliflozin"
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"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2021-23112",
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"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "The aim of this study was to evaluate the clinical course of COVID-19 in patients who had recently undergone a cardiac procedure and were inpatients in a cardiac rehabilitation department.\n\n\n\nAll patients hospitalized from 1 February to 15 March 2020 were included in the study (n = 35; 16 men; mean age 78 years). The overall population was divided into two groups: group 1 included 10 patients who presented with a clinical picture of COVID-19 infection and were isolated, and group 2 included 25 patients who were COVID-19-negative. In group 1, nine patients were on chronic oral anticoagulant therapy and one patient was on acetylsalicylic acid (ASA) and clopidogrel. A chest computed tomography scan revealed interstitial pneumonia in all 10 patients.\n\n\n\nDuring hospitalization, COVID-19 patients received azithromycin and hydroxychloroquine in addition to their ongoing therapy. Only the patient on ASA with clopidogrel therapy was transferred to the ICU for mechanical ventilation because of worsening respiratory failure, and subsequently died from cardiorespiratory arrest. All other patients on chronic anticoagulant therapy recovered and were discharged.\n\n\n\nOur study suggests that COVID-19 patients on chronic anticoagulant therapy may have a more favorable and less complicated clinical course. Further prospective studies are warranted to confirm this preliminary observation.",
"affiliations": "Division of Cardiology and Cardiac Rehabilitation, Istituto Figlie di San Camillo, Cremona.;Division of Cardiology and Cardiac Rehabilitation, Istituto Figlie di San Camillo, Cremona.;Division of Cardiology and Cardiac Rehabilitation, Istituto Figlie di San Camillo, Cremona.;Division of Cardiology and Cardiac Rehabilitation, Istituto Figlie di San Camillo, Cremona.;Division of Cardiology, ASST del Garda, Ospedale di Manerbio.;Division of Internal Medicine and Respiratory Rehabilitation, Istituto Figlie di San Camillo, Cremona, Italy.;Division of Internal Medicine and Respiratory Rehabilitation, Istituto Figlie di San Camillo, Cremona, Italy.;Division of Internal Medicine and Respiratory Rehabilitation, Istituto Figlie di San Camillo, Cremona, Italy.;Division of Internal Medicine and Respiratory Rehabilitation, Istituto Figlie di San Camillo, Cremona, Italy.",
"authors": "Inama|Giuseppe|G|;Dodi|Claudio|C|;Provini|Martino|M|;Bossoni|Enzo|E|;Inama|Lorenza|L|;Balzarini|Laura|L|;Mancini|Chiara|C|;Ramponi|Sara|S|;Marvisi|Maurizio|M|",
"chemical_list": "D000890:Anti-Infective Agents; D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "United States",
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"issue": "21(10)",
"journal": "Journal of cardiovascular medicine (Hagerstown, Md.)",
"keywords": null,
"medline_ta": "J Cardiovasc Med (Hagerstown)",
"mesh_terms": "D000368:Aged; D000890:Anti-Infective Agents; D000925:Anticoagulants; D017963:Azithromycin; D000086382:COVID-19; D006348:Cardiac Surgical Procedures; D003131:Combined Modality Therapy; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D010043:Outcome and Process Assessment, Health Care; D058873:Pandemics; D010975:Platelet Aggregation Inhibitors; D011024:Pneumonia, Viral; D011183:Postoperative Complications; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101259752",
"other_id": null,
"pages": "765-771",
"pmc": null,
"pmid": "32890069",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Coronavirus disease 2019 infection in patients with recent cardiac surgery: does chronic anticoagulant therapy have a protective effect?",
"title_normalized": "coronavirus disease 2019 infection in patients with recent cardiac surgery does chronic anticoagulant therapy have a protective effect"
} | [
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"actiondrug": "6",
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"activesubstancename": "ASPIRIN"
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{
"abstract": "OBJECTIVE\nTo evaluate the efficiency and safety of clopidogrel treatment in children with heart disease.\n\n\nMETHODS\nWe conducted single center retrospective chart review of children with heart disease at the University Hospital, Leuven, Belgium, in whom clopidogrel was used. The indication, dosage, duration of therapy, and adverse events were examined. Clinical efficacy was defined by an absence of thrombotic events.\n\n\nRESULTS\n46 children were identified. The mean age of first clopidogrel dose was 4.9 +/- 4.1 years. The study dosage ranged from 0.1 to 0.7 mg/kg/day clopidogrel. Almost all patients received concomitant aspirin therapy. No thrombotic events developed. Skin bruising developed in almost every patient, suggesting that clopidogrel has an anti-platelet effect. 2 patients who were treated with concomitant warfarin had bleeding complications (severe epistaxis and gastrointestinal bleeding). Hematological abnormalities were documented in 1 patient who received clopidogrel for 1 year; they reversed with medication cessation.\n\n\nCONCLUSIONS\nClopidogrel therapy in a pediatric population appears to be relatively safe and effective; however, randomized, controlled prospective studies are needed to determine the true efficacy and safety of clopidogrel in children.",
"affiliations": "Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium. luc.mertens@uzleuven.be",
"authors": "Mertens|Luc|L|;Eyskens|Bénédicte|B|;Boshoff|Derize|D|;Gewillig|Marc|M|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin",
"country": "United States",
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"issn_linking": "0022-3476",
"issue": "153(1)",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
"mesh_terms": "D000293:Adolescent; D001241:Aspirin; D002648:Child; D002675:Child, Preschool; D000077144:Clopidogrel; D005260:Female; D006331:Heart Diseases; D006470:Hemorrhage; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D013988:Ticlopidine; D014859:Warfarin",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "61-4",
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"pubdate": "2008-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and efficacy of clopidogrel in children with heart disease.",
"title_normalized": "safety and efficacy of clopidogrel in children with heart disease"
} | [
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"companynumb": "BE-SA-2014SA120431",
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"activesubstancename": "CLOPIDOGREL BISULFATE"
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{
"abstract": "Biliary tract cancers (BTC) are rare and often diagnosed in late stages with advanced, nonresectable disease. The targeted agents panitumumab and bevacizumab have shown promising outcomes in combination with chemotherapy in other gastrointestinal (GI) cancers. We wanted to investigate if panitumumab or bevacizumab was the most promising drug to add to chemotherapy. Eighty-eight patients were randomized to combination chemotherapy supplemented by either panitumumab 6 mg/kg or bevacizumab 10 mg/kg on Day 1 in Arm A and Arm B, respectively. All patients received gemcitabine 1000 mg/m2 on Day 1, oxaliplatin 60 mg/m2 on Day 1 and capecitabine 1000 mg/m2 twice daily from Days 1 to 7. Treatment was repeated every 2 weeks until progression or for a maximum of 6 months. At progression, crossover was made to the other treatment arm. The primary endpoint was progression-free survival (PFS) at 6 months. With 19 of 45 in Arm A and 23 of 43 in Arm B PFS at 6 months, the primary endpoint was not met. The overall response rate (ORR) was 45% vs 20% (P = .03), median PFS was 6.1 months vs 8.2 months (P = .13) and median overall survival (OS) was 9.5 months vs 12.3 months (P = .47) in Arm A and Arm B, respectively. Our study showed no consistent differences between adding panitumumab or bevacizumab to chemotherapy in nonresectable BTC and none of the two regimens qualify for testing in Phase III. However, we found a higher response rate in the panitumumab arm with potential implication for future trials in the neoadjuvant setting.",
"affiliations": "Department of Oncology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark.;Department of Oncology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark.;Department of Oncology, Växjö Hospital, Växjö, Sweden.;Department of Oncology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark.;Department of Clinical Sciences, Division of Oncology, Lund University, Lund, Sweden.;Department of Oncology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark.;Department of Oncology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark.",
"authors": "Amin|Nadia Emad Lotfi|NEL|0000-0002-3506-5176;Hansen|Torben Frøstrup|TF|0000-0001-7476-671X;Fernebro|Eva|E|;Ploen|John|J|;Eberhard|Jakob|J|;Lindebjerg|Jan|J|;Jensen|Lars Henrik|LH|0000-0002-0020-1537",
"chemical_list": "C117307:KRAS protein, human; D000068258:Bevacizumab; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.33509",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "149(1)",
"journal": "International journal of cancer",
"keywords": "KRAS; bevacizumab; biliary tract cancer; biological agents; chemotherapy; cholangiocarcinoma; panitumumab; targeted therapy",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001661:Biliary Tract Neoplasms; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077544:Panitumumab; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "119-126",
"pmc": null,
"pmid": "33561312",
"pubdate": "2021-07-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized Phase II trial of combination chemotherapy with panitumumab or bevacizumab for patients with inoperable biliary tract cancer without KRAS exon 2 mutations.",
"title_normalized": "randomized phase ii trial of combination chemotherapy with panitumumab or bevacizumab for patients with inoperable biliary tract cancer without kras exon 2 mutations"
} | [
{
"companynumb": "DK-ROCHE-2773411",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Chemotherapy regimens, including doxorubicin used in primitive neuroectodermal tumor's (PNET) treatment can cause life-threatening disorders in cardiac functions. Follow-up of cardiac functions in the clinical course is very important during treatment with ejection fraction (EF) and shortening fraction (SF). However, sometimes the detection of cardiac failure with EF and SF cannot be possible. In this condition, we may need new evaluation test. Herein, we wanted to present a child with PNET of the chest wall suffered from antracycline toxicity and indicate that close monitoring of cardiac function could be important.",
"affiliations": "Department of Pediatric Oncology, Gülhane Military Medical Academy, Ankara, Turkey.",
"authors": "Atas|Erman|E|;Kesik|Vural|V|",
"chemical_list": "D018943:Anthracyclines",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.144644",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "11(3)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D018943:Anthracyclines; D001932:Brain Neoplasms; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D018242:Neuroectodermal Tumors, Primitive; D011859:Radiography; D013899:Thoracic Neoplasms; D035441:Thoracic Wall",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "668",
"pmc": null,
"pmid": "26458714",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Antracyclin toxicity in a child with primitive neuroectodermal tumor of the chest wall with and brain metastasis.",
"title_normalized": "antracyclin toxicity in a child with primitive neuroectodermal tumor of the chest wall with and brain metastasis"
} | [
{
"companynumb": "TR-JNJFOC-20190601835",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 61-year-old man with high myopia who had received a systemic α1A-adrenoceptor antagonist had phacoemulsification and in-the-bag intraocular lens implantation in the right eye. One day postoperatively, marked pigment dispersion in the anterior chamber, posterior bowing of the iris, and iridodonesis were noted associated with a subsequent elevation in intraocular pressure (IOP). Pharmacological pupil dilation was effective in reducing pigment dispersion and IOP, and laser peripheral iridotomy was performed to alleviate posterior bowing of the iris. We hypothesize that dynamic changes in the aqueous humor flow by cataract surgery and latent flaccidity of the iris due to the systemic α1A-adrenoceptor antagonist caused reverse pupillary block. High myopia may be another risk factor for this complication.",
"affiliations": "From the Department of Ophthalmology (Itagaki, Kunikata, Hiratsuka, Saito), Hitachi General Hospital, Hitachi, and the Department of Ophthalmology (Oshika), Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: hideo.itagaki.bz@hitachi.com.",
"authors": "Itagaki|Hideo|H|;Kunikata|Toshio|T|;Hiratsuka|Kentaro|K|;Saito|Junichiro|J|;Oshika|Tetsuro|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-3350",
"issue": "39(12)",
"journal": "Journal of cataract and refractive surgery",
"keywords": null,
"medline_ta": "J Cataract Refract Surg",
"mesh_terms": "D001082:Aqueous Humor; D005902:Glaucoma, Open-Angle; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure; D032801:Iridectomy; D019654:Lens Implantation, Intraocular; D008297:Male; D008875:Middle Aged; D047728:Myopia, Degenerative; D018918:Phacoemulsification; D011681:Pupil Disorders",
"nlm_unique_id": "8604171",
"other_id": null,
"pages": "1925-8",
"pmc": null,
"pmid": "24140374",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reverse pupillary block associated with pigment dispersion syndrome after in-the-bag intraocular lens implantation.",
"title_normalized": "reverse pupillary block associated with pigment dispersion syndrome after in the bag intraocular lens implantation"
} | [
{
"companynumb": "JP-TEVA-595353ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TAMSULOSIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nAcute thrombosis has not been reported in the literature so far in lung cancer patients as an immune-related adverse event (irAE) associated with PD-1 pathway inhibitors.\nHere, we for the first time present two NSCLC (non-small cell lung cancer) patients suffering from acute thrombosis as a pembrolizumab-induced irAE. Immediate treatment with continuous heparin infusion improved their symptoms and enabled them to continue pembrolizumab administration.\n\n\nMETHODS\nEthical approval was given by the ethics committee of Osaka International Cancer Institute and the informed consents were given by the patients.\n\n\nMETHODS\nSerum D-dimer level testing, venous ultrasonography, enhanced computed tomography (CT).\n\n\nMETHODS\nContinuous heparin infusion, direct oral anticoagulants (DOAC).\n\n\nRESULTS\nImmediate continuous heparin infusion improved their symptoms and continuing pembrolizumab with direct oral anticoagulant successfully induced tumor shrinkage.\n\n\nCONCLUSIONS\nReinvigoration of exhausted T cells by pembrolizumab induced systemic inflammation possibly resulting in development of thrombosis. Although acute thrombosis is a rare irAE, it may lead to cessation of treatment and can be lethal.",
"affiliations": "Department of Thoracic Oncology, Osaka International Cancer Institute, Otemae Chuoku, Osaka City, Japan.",
"authors": "Kunimasa|Kei|K|;Nishino|Kazumi|K|;Kimura|Madoka|M|;Inoue|Takako|T|;Tamiya|Motohiro|M|;Kumagai|Toru|T|;Imamura|Fumio|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D000074322:Antineoplastic Agents, Immunological; D061026:Programmed Cell Death 1 Receptor; D006493:Heparin; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000010772",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29768369MD-D-18-0033610.1097/MD.0000000000010772107725700Research ArticleClinical Case ReportPembrolizumab-induced acute thrombosis A case reportKunimasa Kei MD, PhD∗Nishino Kazumi MD, PhDKimura Madoka MDInoue Takako MDTamiya Motohiro MDKumagai Toru MD, PhDImamura Fumio MD, PhDNA. Department of Thoracic Oncology, Osaka International Cancer Institute, Otemae Chuoku, Osaka City, Japan.∗ Correspondence: Kei Kunimasa, Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuoku, Osaka City, Osaka, 541-8567, Japan (e-mail: kunimasa-ke@mc.pref.osaka.jp).5 2018 18 5 2018 97 20 e1077215 1 2018 23 4 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:\nAcute thrombosis has not been reported in the literature so far in lung cancer patients as an immune-related adverse event (irAE) associated with PD-1 pathway inhibitors.\n\nPatients concerns:\nHere, we for the first time present two NSCLC (non-small cell lung cancer) patients suffering from acute thrombosis as a pembrolizumab-induced irAE. Immediate treatment with continuous heparin infusion improved their symptoms and enabled them to continue pembrolizumab administration.\n\nMethods:\nEthical approval was given by the ethics committee of Osaka International Cancer Institute and the informed consents were given by the patients.\n\nDiagnosis:\nSerum D-dimer level testing, venous ultrasonography, enhanced computed tomography (CT).\n\nInterventions:\nContinuous heparin infusion, direct oral anticoagulants (DOAC).\n\nOutcomes:\nImmediate continuous heparin infusion improved their symptoms and continuing pembrolizumab with direct oral anticoagulant successfully induced tumor shrinkage.\n\nLessons:\nReinvigoration of exhausted T cells by pembrolizumab induced systemic inflammation possibly resulting in development of thrombosis. Although acute thrombosis is a rare irAE, it may lead to cessation of treatment and can be lethal.\n\nKeywords\nacute thrombosispembrolizumabpulmonary artery thromboembolismOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPembrolizumab is a humanized monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1). It showed a significantly longer progression-free and overall survival than conventional platinum doublets in advanced NSCLC (non-small cell lung cancer) with high PD-L1 protein expression in the first-line setting.[1] Although overall safety profile of pembrolizumab appeared to be better, infrequent but severe immune-mediated adverse events (irAEs) occurred in pembrolizumab group.\n\nSo far, thrombosis have not been reported as an side effect of pembrolizumab in lung cancer.[2] Here, we report a case of acute thrombosis associated with pembrolizumab in non-small cell lung cancer (NSCLC) patient. Pulmonary embolism resulted from deep vein thrombosis (DVT) is often life-threatening,[3] and therefore we should pay attention to thrombotic adverse events of immune check point inhibitors.\n\n2 Methods\nEthical approval was given by the ethics committee of Osaka International Cancer Institute and the informed consents were given by the patient.\n\n3 Results\n3.1 Case presentation\nA 48-year-old, never-smoking woman presented to our hospital complaining of left cervical lymphadenopathy and left shoulder pain. She had been healthy and had no known allergic history and family history. A computed tomography (CT) scan revealed a lung mass invading to the aorta and multiple mediastinal lymph node swelling. Surgical biopsy of a left cervical lymph node revealed adenocarcinoma. After a staging workup with enhanced brain MRI and PET-CT, she was diagnosed as lung cancer of clinical stage IV (cT3N3M1c) with multiple brain metastases. EGFR mutation, ALK and ROS1 fusion genes were not detected. PD-L1 immunohistochemistry using PD-L1 22C3 pharmDx revealed the tumor PD-L1 proportion score (TPS) ≥ 90%. Coagulation tests are within normal limit including complete blood count, Factor V assay, fibrinogen level and prothrombin time. As the first-line chemotherapy, pembrolizumab was administered at a dose of 200 mg every 3 weeks. On day 7 of the first course, she felt pain and numbness in her left lower leg and visited our hospital urgently. Venous ultrasonography of her lower limbs demonstrated deep vein thrombosis, which had not been detected before pembrolizumab administration. Furthermore, enhanced chest CT revealed a thrombus in pulmonary artery, leading to the diagnosis of acute thromboembolism (Fig. 1). Serum D-dimer level increased from 6.9 to 33.5 μg/mL. Continuous infusion of heparin was initiated for resulting in improvement of her symptoms in 7 days. Heparin infusion therapy was changed to apixaban; one of direct oral anticoagulants (DOACs). Pembrolizumab, which had been temporarily stopped, was re-started with apixaban. Continuing pembrolizumab with apixaban showed a favorable clinical effect (Fig. 2) and no recurrence of thrombosis was observed.\n\nFigure 1 Chest-enhanced CT images; (A) Before pembrolizumab administration (B) On day 7 after administration. Yellow arrow indicates enhancement defect suggesting thrombus formation in the left pulmonary artery. CT = computed tomography.\n\nFigure 2 Chest-enhanced CT images; (A) Before pembrolizumab administration (B) After 3 courses of administration. CT = computed tomography.\n\n4 Discussion\nThe antitumor effect of PD-1 pathway inhibitors is mainly due to reinvigoration of exhausted PD-1(+) T cells,[4] which also induces irAEs in more than 20% of the patients treated with them. These irAEs are usually mild and easily manageable in most cases.[5] In this report, we presented a NSCLC patient suffered from acute thrombosis induced by pembrolizumab. Although acute thrombosis is rare and unreported in association with pembrolizumab, it may lead to cessation of treatment and can be lethal.\n\nA combination of blood stasis, plasma hypercoagulability, and endothelial dysfunction is thought to trigger thrombosis.[3] There has been a growing understanding of the central role of inflammation on the local fibrinolytic-thrombotic balance in the initiation of local vascular thrombosis.[6,7] PD-1 pathway inhibitors unleash exhausted T cells in tumors and the reinvigorated T cells evoke inflammation. Reinvigorated PD-1(+) T-cell response to anti-PD-1 therapy in peripheral blood peaks at 3rd week after the initiation of treatment.[4] Thrombosis as an irAE can be associated with the surge of reinvigorated T cells soon after pembrolizumab administration. The present case developed acute thrombosis in the relatively early phase, on day 7 of the first course. This could reflect early phase inflammation induced by pembrolizumab.\n\nCoagulation disorders including thrombosis are common in cancer patients as represented by Trousseau’ syndrome.[8] Although the primary approach to treating hypercoagulopathy associated with cancer is eliminating the causative tumor, heparin is a preferred alternative, which has multiple moderating actions in the coagulation cascade.[8] Specific blocking of factor Xa or thrombin has little data on the efficacy and safety for the treatment of cancer-associated coagulopathy, but appears to be insufficient in the previous reports.[3,8] The present patient started her treatment with continuous heparin infusion followed by DOACs because she declined continuous heparin therapy in the outpatient setting. Pembrolizumab supported by anti-coagulation therapy was efficacious with no recurrence of thrombosis.\n\nThis is the first report of acute thrombosis as an irAE associated PD-1 pathway inhibitors including pembrolizumab in lung cancer. Inflammation from reinvigoration of T cells by pembrolizumab could bring on thrombosis. For mitigating severity of acute thrombosis, its early detection and treatment is critical.\n\nAuthor contributions\nConceptualization: Kei Kunimasa.\n\nData curation: Kei Kunimasa, Kazumi Nishino, Madoka Kimura, Takako Inoue, Motohiro Tamiya.\n\nFormal analysis: Kazumi Nishino.\n\nSupervision: Toru Kumagai, Fumio Imamura.\n\nWriting – original draft: Kei Kunimasa, Fumio Imamura.\n\nWriting – review & editing: Fumio Imamura.\n\nAbbreviations: DOAC = direct oral anticoagulant, irAE = immune-related adverse event, NSCLC = non-small cell lung cancer.\n\nConflicts of Interest and Source of Funding: Dr Imamura reports personal fees from Ono pharmaceutical co., Ltd, personal fees from MSD, personal fees from Bristol-Myers Squibb, outside the submitted work. Other authors have no COI.\n==== Refs\nReferences\n[1] Reck M Rodríguez-Abreu D Robinson AG \nPembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer . N Engl J Med \n2016 ;375 :1823 –33 .27718847 \n[2] Wang M Ma X Guo L \nSafety and efficacy profile of pembrolizumab in solid cancer: pooled reanalysis based on randomized controlled trials . Drug Des Devel Ther \n2017 ;11 :2851 –60 .\n[3] Di Nisio M van Es N Büller HR \nDeep vein thrombosis and pulmonary embolism . Lancet \n2016 ;388 :3060 –73 .27375038 \n[4] Huang AC Postow MA Orlowski RJ \nT-cell invigoration to tumour burden ratio associated with anti-PD-1 response . Nature \n2017 ;545 :60 –5 .28397821 \n[5] Villadolid J Amin A \nImmune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities . Transl Lung Cancer Res \n2015 ;4 :560 –75 .26629425 \n[6] Iba T Levy JH \nInflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis . J Thromb Haemost \n2017 ;16 :231 –41 .29193703 \n[7] Luther N Shahneh F Brähler M \nInnate effector-memory T-cell activation regulates post-thrombotic vein wall inflammation and thrombus resolution . Circ Res \n2016 ;119 :1286 –95 .27707800 \n[8] Varki A \nTrousseau's syndrome: multiple definitions and multiple mechanisms . Blood \n2007 ;110 :1723 –9 .17496204\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "97(20)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006493:Heparin; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D020246:Venous Thrombosis",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e10772",
"pmc": null,
"pmid": "29768369",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27375038;17496204;27718847;29193703;29033546;28397821;27707800;26629425",
"title": "Pembrolizumab-induced acute thrombosis: A case report.",
"title_normalized": "pembrolizumab induced acute thrombosis a case report"
} | [
{
"companynumb": "JP-009507513-1805JPN014372",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "To report a case of fungal keratitis after corneal collagen crosslinking (CXL) surgery.\nWe report a case of fungal keratitis after CXL for post-refractive surgery ectasia. The patient presented 12 days after surgery with a corneal ulcer that was culture positive for Alternaria species of fungus. She subsequently developed a bacterial superinfection. The keratitis resolved with medical therapy, although the patient required a penetrating keratoplasty (PKP) due to central corneal scarring.\nTo our knowledge, this is the first case of fungal keratitis as a complication after CXL in the United States and the first case of Alternaria infection after CXL using the Dresden protocol. Infectious keratitis is a rare but serious complication of CXL, and we suggest continued innovation of operative techniques that may reduce the risk of infectious keratitis.",
"affiliations": "Department of Ophthalmology, Truhlsen Eye Institute at the University of Nebraska Medical Center, 3902 Leavenworth St, Omaha, NE, 68105, USA.;Department of Ophthalmology, Truhlsen Eye Institute at the University of Nebraska Medical Center, 3902 Leavenworth St, Omaha, NE, 68105, USA.;Department of Ophthalmology, Truhlsen Eye Institute at the University of Nebraska Medical Center, 3902 Leavenworth St, Omaha, NE, 68105, USA.",
"authors": "McGirr|Samantha|S|;Andersen|Dallin|D|;Halgren|John|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100616",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(20)30014-110.1016/j.ajoc.2020.100616100616Case ReportAlternaria keratitis after corneal crosslinking McGirr Samantha samantha.mcgirr@unmc.eduAndersen Dallin MDdallin.andersen@unmc.eduHalgren John MDJohnhalgren@omahaeye.com∗Department of Ophthalmology, Truhlsen Eye Institute at the University of Nebraska Medical Center, 3902 Leavenworth St, Omaha, NE, 68105, USA∗ Corresponding author. Johnhalgren@omahaeye.com31 1 2020 3 2020 31 1 2020 17 10061629 1 2020 29 1 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/).Purpose\nTo report a case of fungal keratitis after corneal collagen crosslinking (CXL) surgery.\n\nObservations\nWe report a case of fungal keratitis after CXL for post-refractive surgery ectasia. The patient presented 12 days after surgery with a corneal ulcer that was culture positive for Alternaria species of fungus. She subsequently developed a bacterial superinfection. The keratitis resolved with medical therapy, although the patient required a penetrating keratoplasty (PKP) due to central corneal scarring.\n\nConclusions and Importance\nTo our knowledge, this is the first case of fungal keratitis as a complication after CXL in the United States and the first case of Alternaria infection after CXL using the Dresden protocol. Infectious keratitis is a rare but serious complication of CXL, and we suggest continued innovation of operative techniques that may reduce the risk of infectious keratitis.\n\nKeywords\nInfectious keratitisFungal keratitisCollagen crosslinking\n==== Body\n1 Introduction\nCorneal ectasia, or thinning with anterior bulging of the cornea, is a rare but well known complication of laser in situ keratomileusis (LASIK) resulting in progressive irregular astigmatism and decrease in visual acuity. Post-LASIK ectasia is linked to reduced biomechanical stability of the cornea.1 Corneal CXL is a procedure to delay progression of ectasia by increasing corneal rigidity. Introduced by Wollensak et al., in 2003, CXL uses riboflavin and ultraviolet-A (UV-A) to induce covalent bond formation between collagen fibrils in the cornea.2 It has since been used worldwide to treat keratoconus and related disorders like pellucid marginal degeneration, as well as ectasia arising post-refractive surgery. There are also reports of CXL demonstrating benefit in treatment of cases of microbial keratitis.3 CXL was approved by the Food and Drug Administration in April 2016 and is gaining widespread use in the U.S.\n\n2 Case report\nAn otherwise heathy 57-year-old woman was referred to the Truhlsen Eye Institute (TEI) at the University of Nebraska Medical Center for persistent corneal ulcer and anterior chamber hypopyon due to post-CXL fungal keratitis not resolving with topical antifungal therapy. The patient underwent CXL of the right eye (OD) using the Dresden protocol3 by the referring provider 48 days prior to treat post-refractive ectasia. A bandage contact lens (BCL) was placed postoperatively and routine postoperative topical drops were initiated including prednisolone acetate 1%, gatifloxacin 0.5% and bromfenac 0.07%. Her preoperative best corrected visual acuity (BCVA) using rigid contact lenses was 20/30–2 OD using a Snellen eye chart. The patient presented back to the provider on postoperative day (POD) 1 with a central epithelial defect and her BCL still in place. The BCL was removed without complication on POD 5. On POD 12, the patient complained of blurry vision, photophobia, redness and soreness in the treated eye. A corneal infiltrate was noted (Fig. 1), and topical cefazolin 50 mg/mL and tobramycin 10 mg/mL were started. Cultures were obtained POD 13. On POD 20, due to increasing central infiltrate density, she was started empirically on natamycin 5% and voriconazole eye drops for possible fungal keratitis. Culture results with sensitivities were finalized POD 32 and demonstrated Alternaria species of fungus. Natamycin and voriconazole were stopped, and itraconazole and amphotericin B eye drops were started based on antifungal susceptibility testing. Her fungal infiltrate showed significant improvement by POD 46. However, increasing corneal opacification and persistence of her hypopyon led to referral to TEI.Fig. 1 Corneal infiltrate on POD 12. The photo shows infiltrate in the inferotemporal quadrant of the right eye.\n\nFig. 1\n\nUpon referral on POD 48, best uncorrected visual acuity (UCVA) in the right eye was counting fingers at one inch. Examination of the right eye revealed a 5.0 mm × 4.0 mm corneal ulcer with infiltrate, feathery edges and filamentary extension superiorly into mid-deep stroma. The eye also had 2+ injection of the conjunctiva and a 10% hypopyon in the anterior chamber. The patient was instructed to continue the itraconazole and amphotericin B. She was also started on 200 mg oral voriconazole twice daily, as well as moxifloxacin eye drops every 2 h for possible bacterial superinfection. Subsequent corneal culture was positive for pan-sensitive Staphylococcus haemolyticus.\n\nThe hypopyon resolved with medical treatment POD 62, and the patient had a BCL inserted on POD 67 due to persistent epithelial defect. Due to central corneal scarring and persistent poor vision otherwise without hope of recovery, PKP was performed 92 days post-CXL. Corneal button pathology was negative for fungal or bacterial elements. At one-month postoperative follow-up, the epithelial defect was closed, and the patient had an UCVA of 20/400 in the right eye. At 11 months post-PKP and 14 months post-CXL, her BCVA was 20/25 with a scleral contact lens OD.\n\n3 Discussion\nInfectious keratitis is a rare complication of corneal CXL, with previously reported rates as low as 0.0017%,4 and post-CXL fungal keratitis is especially rare. Previously reported infections after CXL using the Dresden protocol include the bacteria Staphylococcus epidermis,5\nS. aureus,6\nEscherichia coli7 and Pseudomonas aeruginosa,8 the herpes virus,9\nAcanthamoeba10 and the fungi Fusarium11 and Microsporidia.12 The Fusarium and Microsporidia cases occurred in Spain and India, respectively. To our knowledge, this is the first case of fungal keratitis as a complication after CXL in the United States and the first case of Alternaria infection after CXL using the Dresden protocol. Maharana et al.13 recently reported three cases of fungal keratitis at a tertiary center in India following accelerated CXL, a protocol that delivers higher power UV-A radiation over a shorter duration than the Dresden protocol. These cases included one case of Alternaria keratitis, one case of coagulase-negative Staphylococcus and Aspergillus fumigatus co-infection and one case of S. aureus and Mucor co-infection. Notably, the patient with Alternaria keratitis presented three days after aCXL with an ulcer that progressed to corneal perforation despite medical therapy and required PKP. All three cases were pediatric patients, and the study authors hypothesized that young age could be a risk factor for post-CXL infection in developing countries due to poor compliance and postoperative care.\n\n4 Conclusions\nIn a systematic review, Hsiao et al. identified preexisting corneal disease or previous ocular surgery to be a risk factor for Alternaria keratitis.14 The factors that place our patient at higher risk for this infection include prior refractive surgery, corneal ectasia, a postoperative epithelial defect that is routine in the Dresden protocol, and standard use of postoperative topical steroid. Of note, our patient was compliant with her post-operative drop regimen and was noted to have good ocular hygiene. Fungal keratitis should be on the differential for an otherwise healthy patient who presents with a corneal infiltrate after CXL. Infectious keratitis is a rare but serious complication of CXL, and we suggest continued innovation of operative techniques that may reduce the risk of infectious keratitis.\n\nPatient consent\nThe patient consented to publication of the case orally. This report does not contain any personal information that could lead to the identification of the patient.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for authorship.\n\nFunding\nNo funding or grant support.\n\nDeclaration of competing interest\nNone of the authors have any financial disclosures related to this submission.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Bohac M. Koncarevic M. Pasalic A. Incidence and clinical characteristics of post LASIK ectasia: a review of over 30,000 LASIK cases Semin Ophthalmol 33 2018 869 877 30359155 \n2 Wollensak G. Spoerl E. Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus Am J Ophthalmol 135 2003 620 627 12719068 \n3 Papaioannou L. Miligkos M. Papathanassiou M. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis Cornea 35 2016 62 71 26509768 \n4 Shetty R. Kaweri L. Nuijts R.M. Nagaraja H. Arora V. Kumar R. Profile of microbial keratitis after corneal collagen cross-linking BioMed Res Int 2014 2014 340509 \n5 Pérez-Santonja J.J. Artola A. Javaloy J. Alio ´ J.L. Microbial keratitis after corneal collagen crosslinking J Cataract Refract Surg 35 2009 1138–1114 \n6 Rana M. Lau A. Aralikatti A. Shah S. Severe microbial keratitis and associated perforation after corneal crosslinking for keratoconus Contact Lens Anterior Eye 38 2015 134 137 25435381 \n7 Pollhammer M. Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A J Cataract Refract Surg 35 2009 588 589 19251154 \n8 Sharma N. Maharana P. Singh G. Titiyal J.S. Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature J Cataract Refract Surg 36 2010 517 520 20202556 \n9 Kymionis G.D. Portaliou D.M. Bouzoukis D.I. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus J Cataract Refract Surg 33 2007 1982 1984 17964410 \n10 Rama P. Di Matteo F. Matuska S. Paganoni G. Spinelli A. Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use J Cataract Refract Surg 35 2009 788 791 19304108 \n11 Garcia-Delpech S. Díaz-Llopis M. Udaondo P. Salom D. Fusarium keratitis 3 weeks after healed corneal cross- linking J Refract Surg 26 2010 994 995 20795586 \n12 Gautam V.J. Jhanji V. Satpathy G. Khokhar S. Agarwal T. Microsporidial keratitis after collagen cross-linking Ocul Immunol Inflamm 21 2013 495 497 23978264 \n13 Maharana P.K. Sahay P. Sujeeth M. Microbial keratitis after accelerated corneal cross-linking in keratoconus Cornea 37 2018 162 167 29111996 \n14 Hsiao C.H. Yeh L.K. Chen H.C. Clinical characteristics of Alternaria keratitis J Ophthalmol 2014 2014 536985\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "17()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Collagen crosslinking; Fungal keratitis; Infectious keratitis",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100616",
"pmc": null,
"pmid": "32083224",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "12719068;19465303;20795586;25302296;24778867;23978264;19304108;25435381;30359155;17964410;29111996;26509768;20202556;19251154",
"title": "Alternaria keratitis after corneal crosslinking.",
"title_normalized": "alternaria keratitis after corneal crosslinking"
} | [
{
"companynumb": "US-AVEDRO-AVE-2020-0106-AE",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GATIFLOXACIN"
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{
"abstract": "BACKGROUND\nMelioidosis, caused by Burkholderia pseudomallei, is endemic in Singapore and can present as localized or disseminated disease.\n\n\nMETHODS\nDemographic data, clinical features, investigation results, treatments, and outcomes in patients aged <16 years diagnosed with melioidosis at KK Women's and Children's Hospital between January 2002 and January 2014 were retrospectively reviewed. Data for patients with primary skin disease and those with other organ involvement were compared.\n\n\nRESULTS\nSeventeen children were diagnosed with melioidosis. Their median age was 12.5 years (range: 2-15 years). Nine (53%) patients presented with localized cutaneous melioidosis and five (29%) with localized lymphadenitis, pneumonia, or septic arthritis. The remaining three (18%) patients had melioidosis sepsis; two of these patients died from septic shock. Treatment included an initial 1-2 weeks of IV antibiotics followed by 3-6 months of oral combination antibiotics. All cases of localized cutaneous disease resolved completely with no recurrences. Three (60%) of the five patients with localized involvement of other organ systems achieved complete resolution of disease, and the remaining two were lost from follow-up.\n\n\nCONCLUSIONS\nAlthough uncommon, melioidosis can occur in children living in endemic regions. Patients with localized skin disease have good outcomes with no recurrences. Systemic disease can be fatal, especially in the presence of underlying immunodeficiency. Diagnosis requires a high index of suspicion, and treatment requires prolonged combination antibiotic therapy.",
"affiliations": "Dermatology Service, KK Women's and Children's Hospital, Singapore.;Infectious Disease Service, Department of Pediatrics, KK Women's and Children's Hospital, Singapore.;Infectious Disease Service, Department of Pediatrics, KK Women's and Children's Hospital, Singapore.;Infectious Disease Service, Department of Pediatrics, KK Women's and Children's Hospital, Singapore.;Duke-NUS Graduate Medical School , Singapore.;Dermatology Service, KK Women's and Children's Hospital, Singapore.",
"authors": "Foong|Yee-Wah|YW|;Tan|Natalie Woon-Hui|NW|;Chong|Chia-Yin|CY|;Thoon|Koh-Cheng|KC|;Tee|Nancy Wen-Sim|NW|;Koh|Mark Jean-Aan|MJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1111/ijd.12837",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "54(8)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008199:Lymphadenitis; D008297:Male; D008554:Melioidosis; D018410:Pneumonia, Bacterial; D012189:Retrospective Studies; D018805:Sepsis; D012846:Singapore; D016896:Treatment Outcome",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "929-38",
"pmc": null,
"pmid": "25771733",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Melioidosis in children: a retrospective study.",
"title_normalized": "melioidosis in children a retrospective study"
} | [
{
"companynumb": "SG-MYLANLABS-2015M1027014",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugadditio... |
{
"abstract": "Development of cardiac manifestations in patients diagnosed with inflammatory bowel disease undergoing treatment with mesalamine is a rare. When this occurs, it can be difficult to tease out the primary etiology, as both IBD and mesalamine can cause cardiac manifestations independently of each other. The exact mechanism of mesalamine-induced cardiotoxicity is yet to be determined although several mechanisms have been described. We present the case of a gentleman with nonexertional chest pain in the setting of ulcerative colitis exacerbation believed to have occurred secondary to mesalamine.",
"affiliations": "Department of Internal Medicine, Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA, USA.;Department of Internal Medicine, Section of Cardiology, Virginia Tech Carilion School of Medicine and Research Institute, Raonoke, VA, USA.;Department of Internal Medicine, Section of Rheumatology, Virginia Tech Carilion School of Medicine and Research Institute, Raonoke, VA, USA.",
"authors": "Okoro|Kelechukwu U|KU|0000-0001-9751-3926;Roby|Matthew D|MD|;Bankole|Adegbenga A|AA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/9813893",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/9813893Case ReportMyocarditis Secondary to Mesalamine-Induced Cardiotoxicity in a Patient with Ulcerative Colitis http://orcid.org/0000-0001-9751-3926Okoro Kelechukwu U. kele.okoro@gmail.com\n1\nRoby Matthew D. \n2\nBankole Adegbenga A. \n3\n\n1Department of Internal Medicine, Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA, USA\n2Department of Internal Medicine, Section of Cardiology, Virginia Tech Carilion School of Medicine and Research Institute, Raonoke, VA, USA\n3Department of Internal Medicine, Section of Rheumatology, Virginia Tech Carilion School of Medicine and Research Institute, Raonoke, VA, USAAcademic Editor: Masahiro Kohzuki\n\n2018 15 3 2018 2018 981389328 11 2017 22 2 2018 Copyright © 2018 Kelechukwu U. Okoro et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Development of cardiac manifestations in patients diagnosed with inflammatory bowel disease undergoing treatment with mesalamine is a rare. When this occurs, it can be difficult to tease out the primary etiology, as both IBD and mesalamine can cause cardiac manifestations independently of each other. The exact mechanism of mesalamine-induced cardiotoxicity is yet to be determined although several mechanisms have been described. We present the case of a gentleman with nonexertional chest pain in the setting of ulcerative colitis exacerbation believed to have occurred secondary to mesalamine.\n==== Body\n1. Introduction\nUlcerative colitis (UC) is one of the two subtypes of inflammatory bowel disease (IBD). It is a chronic inflammatory disease of the colon whose etiology is unknown but it is thought to occur via an autoimmune mechanism. It usually presents with abdominal discomfort, hematochezia, and diarrhea. UC is also known to cause extraintestinal manifestations such as uveitis and erythema nodosum. At times, UC may affect the heart causing pericarditis or myocarditis. Patients with UC are usually prescribed mesalamine which can also cause cardiac complications. Cardiotoxicity secondary to mesalamine usually improves with withdrawal of the medication while UC cardiotoxicity improves with adequate disease control. When these two entities occur together, it is challenging to tease out the primary etiology.\n\n2. Case Presentation\nA 23-year-old Caucasian gentleman whose past medical history was significant for ulcerative colitis (UC), migraine without aura, allergic rhinitis, grade 3 obesity, obstructive sleep apnea, hypothyroidism, prediabetes, seizure disorder, and gastroesophageal reflux disease presented to the emergency department complaining of symptoms of UC flare including nausea, vomiting, abdominal pain, bright red blood per rectum, and about ten bowel movements a day for approximately seven days. Review of systems was notable for dizziness, palpitations, and chest pain which had been ongoing for some time. The patient reported that he experiences intermittent, substernal, 8 out of 10, crushing left-sided chest pain radiating to his left mandible and left upper extremity. The patient stated that the pain was not exacerbated by activity but noted that whenever he started a steroid taper for his UC, the chest pain resolved only to recur when the taper was stopped. Current medications at time of visit to the ED included mesalamine and Levothyroxine.\n\nPhysical examination was normal except for tachycardia and abdominal pain to palpation without rebound, guarding, or rigidity. Labs were grossly normal except hemoglobin 12.3 g/dl, hematocrit 37.7, sedimentation rate 96 mm/hr, C-reactive protein 20.16 mg/dl, and troponin 14.55 ng/dl. EKG revealed sinus tachycardia without ischemic changes. CT angiogram of the chest was unrevealing. Transthoracic echocardiography (TTE) demonstrated an akinetic apex, but overall preserved ejection fraction. A cardiac magnetic resonance imaging (cMRI) was ordered due to the patient's atypical presentation, young age, and lack of traditional risk factors for coronary artery disease. MRI revealed linear delayed hyper-enhancement involving the midmyocardium of the distal septum suspicious for myocarditis (Figures 1 and 2). The patient's mesalamine was discontinued, and he was started on Methylprednisolone. His condition improved, and he was discharged from the hospital with Adalimumab as his primary UC therapy.\n\n3. Discussion\nInflammatory bowel disease (IBD) as the name implies is an inflammatory condition that affects the gastrointestinal tract. It is mainly divided into two subtypes, ulcerative colitis and Crohn's disease. IBD may also affect a variety of extraintestinal organs such as integumentary, musculoskeletal, and pulmonary organs. Extraintestinal manifestations are common and occur in approximately 25–30% of patients although cardiac involvement is rare [1–3]. Manifestations of cardiac involvement include pericarditis, myocarditis, and myopericarditis.\n\nMesalamine is an aminosalicylate anti-inflammatory drug commonly prescribed in patients with IBD. The exact mechanism of the drug is unknown but it is thought to inhibit prostaglandin formation by inhibition of cyclooxygenase (COX) enzyme thereby decreasing signaling via PPAR-γ pathway leading to decreased activity of nuclear factor ĸB. Inhibiting this cascade leads to decreased colonic inflammation [1]. Common adverse effects of mesalamine include nausea, abdominal discomfort, headache, and fatigue. An additional side effect of mesalamine that has not been extensively described in literature is cardiotoxicity. The drug can cause pericarditis, myocarditis, and coronary vasculitis [3]. The specific mechanism of mesalamine-induced cardiotoxicity is yet to be described, but several hypotheses have been proposed. The first is accelerated metabolism of arachidonic acid to lipoxygenases secondary to inhibition of COX enzyme. This leads to the overproduction of eosinophil-stimulating cytokines thereby initiating a hypersensitivity reaction [4]. Another proposed mechanism involves humoral-mediated hypersensitivity, in which antibodies formed against mesalamine cross react with cardiac tissues causing inflammation [1, 3]. Other hypothesized mechanisms include a direct toxic effect of mesalamine on the myopericardium, a cell-mediated hypersensitive reaction, and an allergic reaction mediated by immunoglobulin E [4, 5]. Irrespective of the mechanism, it is very important to be aware of its cardiotoxic effects as symptomatology may range from benign chest discomfort to florid heart failure and cardiogenic shock. Symptoms usually begin within 2–4 weeks after initiation of the drug although presentation may be delayed due to concomitant use of steroids [3].\n\nThere are no physical findings, symptoms, or laboratory tests that are pathognomonic for mesalamine-induced cardiotoxicity [3]. The diagnosis is supported by relatively early onset of symptoms once the drug is begun, resolution of symptoms within one week after withdrawal, and by worsening of symptomatology once the drug is reintroduced in the acute phase [3]. This is in contrast to IBD cardiotoxicity which usually occurs years after initial diagnosis although it may occur on initial presentation [5, 6]. UC cardiotoxicity is usually a diagnosis of exclusion after connective tissue disorders, malignancy, infection, and metabolic causes have been ruled out [1]. Our patient presented with cardiac symptoms 6 months after initial diagnosis of UC. At time of initial diagnosis, he had no cardiac complaints. He was started on Mesalamine 800 mg PO TID along with 60 mg of prednisone which was to be tapered by 5 mg each week for 12 weeks. His 5 mg taper was decreased to a 10 mg taper, and he completed the regimen. His mesalamine formulation was switched to 2.4 mg daily of a long-acting preparation for easier dosing. 4 months later, he developed acute exacerbation of UC, requiring him to restart steroids and prompting his mesalamine dose to be increased to 4.8 mg daily. This was not sufficient with the patient having to report to the ED the following day.\n\nThe patient could not remember the exact onset of his chest pain but he did note that the pain improved with initiation of steroids and worsened or became more apparent whenever he tried to taper the steroids. We suspect the delayed presentation of myocarditis to be secondary to the coadministration of mesalamine and steroids. Mesalamine was discontinued, and the patient was started on methylprednisolone with eventual resolution of both chest discomfort and UC symptoms. He was started on adalimumab after discharge and has had no further cardiac complaints. He has continued to experience UC flares with associated spondyloarthropathy.\n\n4. Conclusion\nIt is imperative to consider myopericarditis in patients with IBD being treated with mesalamine as both may cause severe cardiotoxicity with development of heart failure symptoms. In the case of mesalamine-induced cardiotoxicity, no specific therapy is needed as prompt withdrawal of the drug leads to rapid amelioration of symptoms although administration of steroids is not a frowned upon alternative. Steroid administration is the first choice of management in patients with IBD cardiotoxicity.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Magnitude reconstructed inversion recovery image of MRI T1-weighted imaging depicting linear delayed hyper-enhancement involving the midmyocardium of the distal septum. This translates to gadolinium lighting up in the midmyocardium due to loss of cellular integrity.\n\nFigure 2 Phase sensitive inversion recovery image depicting delayed hyper-enhancement involving the midmyocardium with endocardial sparing.\n==== Refs\n1 Perez-Colon E. Dadlani G. H. Wilmot I. Miller M. Mesalamine-induced myocarditis and coronary vasculitis in a pediatric ulcerative colitis patient: a case report Case Reports in Pediatrics 2011 2011 5 524364 10.1155/2011/524364 \n2 Belin R. J. Ghasemiesfe A. Carr J. Miller F. H. Parada C. Akhter N. Crohn’s colitis-induced myocarditis Journal of Cardiology Cases 2016 14 1 4 7 10.1016/j.jccase.2016.03.007 2-s2.0-84962729118 \n3 Braga C. G. Martins J. Arantes C. Mesalamine-induced myocarditis following diagnosis of Crohn’s disease: a case report Revista Portuguesa de Cardiologia 2013 32 9 717 720 10.1016/j.repc.2012.12.018 2-s2.0-84888354096 23993290 \n4 Merceron O. Bailly C. Khalil A. Mesalamine-induced myocarditis Cardiology Research and Practice 2010 2010 3 930190 10.4061/2010/930190 2-s2.0-79959457498 \n5 Brown G. 5-aminosalicylic acid-associated myocarditis and pericarditis: a narrative review Canadian Journal of Hospital Pharmacy 2016 69 6 466 472 10.4212/cjhp.v69i6.1610 28123193 \n6 Liu Y. Zhu J. Chen W. Sun Y. Myocarditis due to Mesalamine treatment in a patient with Crohn’s disease in China Turkish Journal of Gastroenterology 2012 23 3 304 306 10.4318/tjg.2012.0357 2-s2.0-84866479653 22798127\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2018()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "9813893",
"pmc": null,
"pmid": "29736172",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "20871830;22611512;23993290;22798127;28123193",
"title": "Myocarditis Secondary to Mesalamine-Induced Cardiotoxicity in a Patient with Ulcerative Colitis.",
"title_normalized": "myocarditis secondary to mesalamine induced cardiotoxicity in a patient with ulcerative colitis"
} | [
{
"companynumb": "US-BAUSCH-BL-2018-012363",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAcute laryngeal dystonia is one of the most life-threatening medication side effects in psychiatry. It is rare and predominately caused by the use of antipsychotics in at-risk individuals. Within days of a patient's initial presentation, several antipsychotics can be administered for the purposes of acute sedation and ongoing pharmacotherapy. In this case report, we describe a 27-year-old at-risk male, who developed acute laryngeal dystonia in the context of antipsychotic polypharmacy.\n\n\nCONCLUSIONS\nClinicians should take into account recent sedation and ongoing antipsychotic use in patients at risk of developing acute laryngeal dystonia. Awareness of this condition and prompt treatment with parenteral anticholinergic medication can be lifesaving.",
"affiliations": "Psychiatry Registrar, Shellharbour Hospital, Mount Warrigal, NSW, Australia.;Senior Staff Specialist, Shellharbour Hospital, Mount Warrigal, NSW, Australia Ali.Altaie@sesiahs.health.nsw.gov.au.;Staff Specialist, Shellharbour Hospital, Mount Warrigal, NSW, Australia.",
"authors": "May|Robert|R|;Al-Taie|Ali|A|;Garg|Vikas|V|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1177/1039856216646231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1039-8562",
"issue": "24(5)",
"journal": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
"keywords": "acute laryngeal dystonia; antipsychotic; polypharmacy",
"medline_ta": "Australas Psychiatry",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D014150:Antipsychotic Agents; D004421:Dystonia; D006801:Humans; D007821:Laryngeal Muscles; D008297:Male; D019338:Polypharmacy; D011618:Psychotic Disorders",
"nlm_unique_id": "9613603",
"other_id": null,
"pages": "497-8",
"pmc": null,
"pmid": "27145799",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute laryngeal dystonia: a persisting psychiatric emergency.",
"title_normalized": "acute laryngeal dystonia a persisting psychiatric emergency"
} | [
{
"companynumb": "AU-DRREDDYS-USA/AUS/16/0085695",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nNonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.\n\n\nMETHODS\nWe analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health-AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.\n\n\nRESULTS\nAspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.\n\n\nCONCLUSIONS\nAspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.",
"affiliations": "Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd, EPS 5032, Rockville, MD 20852, USA. vikrant.sahasrabuddhe@nih.gov",
"authors": "Sahasrabuddhe|Vikrant V|VV|;Gunja|Munira Z|MZ|;Graubard|Barry I|BI|;Trabert|Britton|B|;Schwartz|Lauren M|LM|;Park|Yikyung|Y|;Hollenbeck|Albert R|AR|;Freedman|Neal D|ND|;McGlynn|Katherine A|KA|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1093/jnci/djs452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0027-8874",
"issue": "104(23)",
"journal": "Journal of the National Cancer Institute",
"keywords": null,
"medline_ta": "J Natl Cancer Inst",
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"pubdate": "2012-12-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
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"title": "Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma.",
"title_normalized": "nonsteroidal anti inflammatory drug use chronic liver disease and hepatocellular carcinoma"
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"abstract": "BACKGROUND\nRecent studies have produced treatment algorithms for hand dermatitis, but there are limited current indications of systemic treatments for chronic hand dermatitis.\n\n\nOBJECTIVE\nTo compare the efficacy and safety of methotrexate and acitretin in the treatment of chronic hand dermatitis.\n\n\nMETHODS\nA chart-retrospective review of all patients with hand dermatitis seen by the primary author at the University of North Carolina Dermatology and Skin Cancer Center from September 2007 to April 2013.\n\n\nRESULTS\nEighty-three hand dermatitis charts were reviewed. Twenty-nine patients received systemic therapy, of which 17 (26.5%) were treated systemically with acitretin and/or methotrexate. Of these 17 patients, four patients received courses of both acitretin and methotrexate independently after failing the alternative treatment course. At 6 months, acitretin achieved clearance/almost clearance in 44% of patients, compared to 0% of those treated with methotrexate. At 12 months, 100% of patients treated with acitretin achieved clearance/almost clearance compared to 40% of patients treated with methotrexate. Adverse effects were minimal and as expected.\n\n\nCONCLUSIONS\nThis was a retrospective study, and the small sample size makes it difficult to generalize results.\n\n\nCONCLUSIONS\nSystemic retinoids are a good alternative for the treatment of chronic hand dermatitis.",
"affiliations": null,
"authors": "O'Shea|Patrick M|PM|;Lugo-Somolinos|Aída|A|",
"chemical_list": "D003879:Dermatologic Agents; D007641:Keratolytic Agents; D017255:Acitretin; D008727:Methotrexate",
"country": "United States",
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"issn_linking": "1545-9616",
"issue": "14(12)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D017255:Acitretin; D000328:Adult; D000368:Aged; D002908:Chronic Disease; D003879:Dermatologic Agents; D005260:Female; D006229:Hand Dermatoses; D006801:Humans; D007641:Keratolytic Agents; D008297:Male; D008727:Methotrexate; D008875:Middle Aged",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "1389-91",
"pmc": null,
"pmid": "26659930",
"pubdate": "2015-12",
"publication_types": "D003160:Comparative Study; D016421:Editorial",
"references": null,
"title": "Methotrexate versus Acitretin in the Treatment of Chronic Hand Dermatitis.",
"title_normalized": "methotrexate versus acitretin in the treatment of chronic hand dermatitis"
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"companynumb": "US-ANTARES PHARMA, INC.-2015-LIT-ME-0238",
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"abstract": "Pandoraea species are considered as emerging pathogens in people with cystic fibrosis (CF). The contribution of these organisms to disease progression in CF patients is not fully understood owing in large measure to the scant reports in clinical and research literature describing their colonization of CF patients and their associated virulence determinants. In an effort to increase awareness and evidence for Pandoraea spp. infection in people with CF, and to stimulate research aimed at unraveling the pathogenic properties of Pandoraea, we report a case of a 26-year-old Australian (Tasmanian) man with CF who was chronically infected with Pandoraea pnomenusa for at least one year prior to his death from respiratory failure. In addition, we describe for the first time evidence suggesting that this bacterium is a facultative anaerobe and report on the availability of a whole genome sequence for this organism. To the best of our knowledge, this report represents only the second clinical case study of P. pnomenusa infection in the world, and the first in an Australian CF patient.",
"affiliations": "School of Medicine, University of Tasmania Tasmania, TAS, Australia.;School of Medicine, University of TasmaniaTasmania, TAS, Australia; Department of Pathology, Royal Hobart HospitalTasmania, TAS, Australia.;Department of Microbiology and Infectious Diseases, Royal Hobart Hospital Tasmania, TAS, Australia.;School of Medicine, University of TasmaniaTasmania, TAS, Australia; Department of Paediatrics, Royal Hobart HospitalTasmania, TAS, Australia.;School of Medicine, University of Tasmania Tasmania, TAS, Australia.;Department of Microbiology and Infectious Diseases, Royal Hobart Hospital Tasmania, TAS, Australia.;Department of Respiratory and General Medicine, Royal Hobart Hospital Tasmania, TAS, Australia.;School of Medicine, University of Tasmania Tasmania, TAS, Australia.",
"authors": "Ambrose|Mark|M|;Malley|Roslyn C|RC|;Warren|Sanchia J C|SJ|;Beggs|Sean A|SA|;Swallow|Oliver F E|OF|;McEwan|Belinda|B|;Stock|David|D|;Roddam|Louise F|LF|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmicb.2016.00692",
"fulltext": "\n==== Front\nFront MicrobiolFront MicrobiolFront. Microbiol.Frontiers in Microbiology1664-302XFrontiers Media S.A. 10.3389/fmicb.2016.00692Public HealthCase ReportPandoraea pnomenusa Isolated from an Australian Patient with Cystic Fibrosis Ambrose Mark 1*Malley Roslyn C. 12Warren Sanchia J. C. 3Beggs Sean A. 14Swallow Oliver F. E. 1McEwan Belinda 3Stock David 5Roddam Louise F. 11School of Medicine, University of TasmaniaTasmania, TAS, Australia2Department of Pathology, Royal Hobart HospitalTasmania, TAS, Australia3Department of Microbiology and Infectious Diseases, Royal Hobart HospitalTasmania, TAS, Australia4Department of Paediatrics, Royal Hobart HospitalTasmania, TAS, Australia5Department of Respiratory and General Medicine, Royal Hobart HospitalTasmania, TAS, AustraliaEdited by: Yuji Morita, Aichi Gakuin University, Japan\n\nReviewed by: Haider Abdul-Lateef Mousa, University of Basrah, Iraq; Ines Schneider, MICOER, Germany\n\n*Correspondence: Mark Ambrose mark.ambrose@utas.edu.auThis article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology\n\n11 5 2016 2016 7 69211 12 2015 26 4 2016 Copyright © 2016 Ambrose, Malley, Warren, Beggs, Swallow, McEwan, Stock and Roddam.2016Ambrose, Malley, Warren, Beggs, Swallow, McEwan, Stock and RoddamThis 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) or licensor 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.Pandoraea species are considered as emerging pathogens in people with cystic fibrosis (CF). The contribution of these organisms to disease progression in CF patients is not fully understood owing in large measure to the scant reports in clinical and research literature describing their colonization of CF patients and their associated virulence determinants. In an effort to increase awareness and evidence for Pandoraea spp. infection in people with CF, and to stimulate research aimed at unraveling the pathogenic properties of Pandoraea, we report a case of a 26-year-old Australian (Tasmanian) man with CF who was chronically infected with Pandoraea pnomenusa for at least one year prior to his death from respiratory failure. In addition, we describe for the first time evidence suggesting that this bacterium is a facultative anaerobe and report on the availability of a whole genome sequence for this organism. To the best of our knowledge, this report represents only the second clinical case study of P. pnomenusa infection in the world, and the first in an Australian CF patient.\n\nPandoraeacystic fibrosisinfectionanaerobelung\n==== Body\nCase report\nIn January 2013, a 26-year-old man with cystic fibrosis (CF, genotype homozygous F508del) and a history of chronic mucoid Pseudomonas aeruginosa lung infection was admitted to the Royal Hobart Hospital (RHH), Tasmania, Australia, with increasing malaise and left-sided pleuritic chest pain. The patient was at the time on his eighth day of out-patient intravenous antibiotic therapy for a respiratory exacerbation, which consisted of once daily tobramycin (560 mg), piperacillin/tazobactam (12 g of piperacillin component/24 h) as a continuous infusion, in addition to his long-term azithromycin (500 mg, orally three times a week) therapy.\n\nOn the day of admission he was afebrile with an oxygen saturation of 97% on 4 L/min O2 via nasal cannulae, and his heart rate was 94 beats per minute with a blood pressure of 116/74 mm Hg. On physical examination, reduced breath sounds and inspiratory crackles were noted in the left lower zone. In addition, his white cell count was elevated (19.7 × 109/L [normal range 3.5–11.0 × 109/L]) with 80.2% neutrophils. A chest radiograph revealed a new and moderately large left pleural effusion. Computed tomography (CT) confirmed the multi-loculated left pleural effusion without contrast enhancement, as well as collapse/consolidation in the basal left upper and lower lobes (Figure 1). On the third day after admission a bronchoscopy and insertion of intercostal catheter (ICC) was performed in theater and serous fluid drained from the ICC. During the bronchoscopy copious purulent secretions were suctioned from the left bronchial tree and bronchial lavage performed. The bronchoscopy was complicated by respiratory failure, and consequently the patient was transferred to the intensive care unit (ICU) unit for mechanical ventilation. No bacteria or fungi were able to be recovered from the patient's pleural fluid samples collected at that time. In contrast, P. aeruginosa and Candida albicans were readily isolated from the bronchial pus. Moreover, P. aeruginosa, C. albicans, and what initially was determined to be a Pandoraea apista isolate, were all readily cultured from a sputum sample collected from the patient on the day of his admission to the RHH.\n\nFigure 1 A computed tomography (CT) scan showed a multi-loculated left pleural effusion.\n\nA repeat CT on the fourth day after the patient's admission showed a reduction in the volume of pleural fluid, but worryingly also the interval development of multiple bilateral foci of consolidation. His antibiotic regimen was altered to include imipenem (1 g IV, 6 hourly) and cotrimoxazole (1600/320 mg IV 6 hourly), extending the spectrum of antibiotic cover to include Pandoraea species. Due to the general lack of antibiotic susceptibility data available for Pandoraea species, the hospital recorded antibiotic susceptibility patterns of the recovered Pandoraea isolate were interpreted using EUCAST antibiotic breakpoint values that had previously been determined for other more common CF pathogens (imipenem susceptibility breakpoint for P. aeruginosa and cotrimoxazole susceptibility breakpoint for Stenotrophomonas maltophilia, for example).\n\nOn day five, video-assisted thoracoscopic surgery (VATS) was performed; exploration of the left pleural space revealed extensive fibrinopurulent material; and loculations were carefully divided and a decortication performed. Histology from the visceral pleural rind showed features of an organizing empyema. Despite the addition of empirical antimicrobials, namely vancomycin (1.5 g, 8 hourly) and caspofungin (70 mg loading dose, then 50 mg daily) there was no evident treatment response. Instead, the patient had persisting fevers and could not be weaned from ventilation.\n\nA repeat bronchoscopy on day seven showed a much-reduced volume of large airways secretions. A contemporaneous CT showed progressive consolidation and increasing prominence of widespread ground-glass opacities, suspicious for the development of adult respiratory distress syndrome (ARDS). Bronchial washings also showed persistence of mucoid P. aeruginosa, C. albicans, and Pandoraea. In keeping with an advanced directive, active treatment was withdrawn and palliative care commenced. On the 11th day after his admission to the RHH, the patient died.\n\nMicrobiology\nOn a previous (December 2011) presentation to the RHH, a multiple antibiotic resistant isolate was recovered from the patient's sputum sample that was streaked out on a Burkholderia cepacia-selective medium. The isolate was presumptively identified as a non-mucoid P. aeruginosa but was not stored. In February 2012, the patient presented to a local private hospital and a similar multi-resistant sputum isolate was recovered. This isolate was retrospectively identified as P. apista by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS, Bruker Daltonics GmbH, Leipzig, Germany) with a score of 2.049, which was indicative of a reliable identification. The isolate was also submitted to the Microbiological Diagnostic Unit Public Health Laboratory (University of Melbourne, Australia) but 16S rRNA gene sequencing and phenotypic testing collectively were only able to identify the isolate as belonging to the genus Pandoraea.\n\nIn January 2013, the patient's forced expiratory volume in 1 second (FEV1) was lower (55% predicted) than his previous measurement (of 60%, late 2012). Following this diagnosis, the out-patient treatment regimen with tobramycin, piperacillin/tazobactam, and azithromycin was continued. A sputum culture obtained from the patient eight days prior to his presentation and admission to the RHH (in January 2013) showed that he had a persistent poly-microbial airway infection, including P. aeruginosa, Staphylococcus aureus, Streptococcus milleri group, C. albicans, and P. apista; the identity of this P. apista isolate was confirmed by the MALDI-TOF MS, at the RHH. The P. apista isolate was subsequently demonstrated to be susceptible to the antibiotics imipenem (by RHH staff) and cotrimoxazole but resistant to ceftazidime, ciprofloxacin, gentamicin, tobramycin, piperacillin-tazobactam, ticarcillin/clavulanic acid (timentin), aztreonam, ceftriaxone, meropenem, colistin, and trimethoprim (Table 1). It is noteworthy that the antibiotic susceptibility profile of this P. apista isolate was similar to that obtained for the initial multi-drug resistant isolate recovered from the patient's sputum sample (December 2011).\n\nTable 1 P. pnomenusa antibiotic susceptibility testing by disk diffusion assay.\n\nAntibiotic\tDisc content (μg)\tZone diameter breakpoint for Resistance (mm)\tInhibition zone diameter (mm)\tResistant (R)/Susceptible (S)\t\nMeropenem\t10\ta18\t0\tR\t\nAmikacin\t30\ta15\t0\tR\t\nCiprofloxacin\t5\ta22\t0\tR\t\nCeftazidime\t10\ta16\t0\tR\t\nTicarcillin-clavulanic acid\t85\ta18\t8\tR\t\nGentamicin\t10\ta15\t0\tR\t\nTrimethoprim\t5\t–\t0\t–\t\nAztreonam\t30\ta16\t0\tR\t\nTobramycin\t10\ta16\t0\tR\t\nCefepime\t30\ta18\t0\tR\t\nPiperacillin-tazobactam\t36\ta18\t16\tR\t\nTrimethroprim-Sulphamethoxazole\t25\tb16\t28.5\tcS\t\na Pseudomonas spp. breakpoint.\n\nb Stenotrophomonas maltophilia breakpoint.\n\nc Minimum inhibitory concentration (MIC) of trimethoprim-sulfamethoxazole (cotrimoxazole, 12.5 μg/ml) determined by the broth dilution method.\n\nInterestingly, the CF lung environment is characterized by the presence of hypoxic micro-niches yet the ability of Pandoraea to colonize these niches is unknown. We demonstrated that the P. apista isolates were able to grow under anaerobic conditions. BHI agar plates supplemented with 1% potassium nitrate were inoculated with Pandoraea cultures and incubated in an anaerobic jar (containing an anaerobic sachet [AN0035; AnaeroGen, Oxoid, UK] and anaerobic indicator) at 37°C for five days. While growth of the Pandoraea cultures was scant under these conditions, it was nonetheless reproducible. Similarly, Daneshvar et al. (2001) also reported on the growth of nine Pandoraea isolates in a candle jar atmosphere. Collectively, these data would seem to indicate that at least some Pandoraea species might well be facultative anaerobes.\n\nTo gain an insight into the virulence mechanisms of Pandoraea species, it was decided to sequence the genomes of the two P. apista isolates recovered from this patient 11 months apart. Much to our surprise, the 16S rDNA sequence component of the genomes from both the February 2012 and January 2013 isolates identified them as Pandoraea pnomenusa (Ee et al., 2015). It is necessary to point out here that misidentification of Pandoraea species by MALDI-TOF MS alone is not uncommon because this method relies upon databases that are generated for microorganisms routinely recovered from clinical specimens. However, Pandoraea species are not routinely isolated or identified by the conventional microbiological methods available in many diagnostic laboratories; in turn, this makes creation of databases for these organisms that are necessary for accurate MALDI-TOF MS analyses somewhat problematic (Fernández-Olmos et al., 2012a). On review of the original MALDI-TOF MS identification scores, P. apista scored highest (2.090) followed by P. pulmonicola (1.817) and P. pnomenusa (1.614). The low score generated for P. pnomenusa (i.e., < 1.7) would likely have been interpreted as being unreliable for species determination. The results described in this case report further underscore the limitations of using MALDI-TOF MS for differentiating Pandoraea species and suggest that until such time comprehensive databases are available, accurate identification of Pandoraea species will be dependent upon molecular characterization (Coenye and LiPuma, 2002; Schneider and Bauernfeind, 2015).\n\nDiscussion\nCystic fibrosis (CF) is an autosomal recessive disease, which can be caused by any one of the over 2000 mutations known to affect the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on human chromosome 7. These mutations lead to an absent or dysfunctional chloride ion channel in respiratory epithelial cells, which in turn results in the accumulation of viscous respiratory secretions in the lungs of people with CF (Wilschanski et al., 1995). As a consequence, the airway of CF patients is intrinsically susceptible to colonization by a plethora of respiratory pathogens, and from very early on in life is colonized by bacterial pathogens including S. aureus and P. aeruginosa (Renders et al., 2001). These infections inevitably lead to pulmonary exacerbations and lung function decline. Despite aggressive antibiotic treatment, infection by P. aeruginosa eventually becomes chronic and is responsible for much of the morbidity and most of the mortality of people with CF (Hauser et al., 2011). Intriguingly, many “new” microorganisms are being isolated from and identified in respiratory secretions collected from CF patients due in part to improved laboratory diagnostic methods, although their contributions to disease progression are not yet known.\n\nOne group of bacteria currently considered to be emerging CF pathogens belongs to the genus Pandoraea. The genus Pandoraea was described by Coenye et al. (2000) to differentiate them from other already well-known CF pathogens, including Pseudomonas and two closely related Gram-negative rods, Burkholderia and Ralstonia species. In fact, phenotypic methods used by many microbiology laboratories commonly lead to the misidentification of Pandoraea species as either Burkholderia or Ralstonia species (Henry et al., 2001; Fernández-Olmos et al., 2012b). Different species of Pandoraea have been described, including P. apista, P. norimbergenesis, P. pnomenusa, P. pulmonicola, and P. sputorum. There is great genotypic and phenotypic diversity within species of Pandoraea but most have thus far been demonstrated to be aerobic, non-spore forming, non-nitrate-reducing, non-lactose-fermenting, Gram-negative rods with a single polar flagellum (Stryjewski et al., 2003). In addition, Pandoraea have been isolated from environmental samples (soil, water; Coenye et al., 2000), as well as from wound sites and variety of other clinical specimens including sputum, lung tissue, and urine (Daneshvar et al., 2001; LiPuma, 2010). Importantly, P. apista has been isolated from the lungs and blood cultures of CF patients (Stryjewski et al., 2003; Johnson et al., 2004), demonstrating the invasive potential of this Pandoraea species. However, there are few reports in the medical literature describing the contribution of Pandoraea to disease progression in CF patients. On this line, Jørgensen et al. (2003) and Fernández-Olmos et al. (2012a) independently showed that chronic bronchopulmonary colonization by either P. apista or P. sputorum was associated with frequent exacerbations and lung function decline in CF patients. Furthermore, Caraher et al. (2008) demonstrated in vitro that infection of lung cells by P. sputorum and other Pandoraea species induced a strong proinflammatory response, with elevated interleukin-6 (IL-6) and interleukin-8 (IL-8) production. However, the precise virulence mechanism(s) of Pandoraea responsible for provoking proinflammatory responses in cells and leading to chronic infection and disease in CF, as well as non-CF patients, remain to be fully determined.\n\nTo gain an insight into the potential virulence mechanisms of Pandoraea, our research group recently sequenced the whole genome of the two P. pnomenusa (initially identified as P. apista) isolates recovered 11 months apart from the patient being discussed in this case report. Sequencing results showed that the genomes of the two isolates were very similar, and differed only by one gene that apparently encodes a predicted phage tail protein (Ee et al., 2015). When we compared the genome sequence of these clinical isolates to that of the environmental P. pnomenusa strain RB38, we found that the clinical isolates possessed 152 unique genes (most of which were virulence genes) and were missing 87 genes unique to the P. pnomenusa strain RB38. Many of the 130 genes (~105 open reading frames [ORFs]) predicted to be associated with virulence and defense are indicated to be involved with resistance to antibiotics and toxic compounds (Ee et al., 2015), which is perhaps not too surprising given that the P. pnomenusa isolates were demonstrated to be resistant to multiple antibiotics. Major advances in our understanding of the role(s) of Pandoraea in disease progression in CF rest upon knowing the virulence properties of these organisms. In this context, the whole genome sequences for P. pnomenusa generated by our research group (Ee et al., 2015) and others (Lim et al., 2016) provide a valuable resource, that could be easily mined by researchers interested in forming a better understanding of Pandoraea colonization in people with CF and discovering potential therapeutic targets. In addition, our results demonstrating that P. pnomenusa is a facultative anaerobe are significant. It is well established that hypoxic micro-niches are present in the CF lung, and that oxygen gradients across the thick airway mucus (Worlitzsch et al., 2002; Tunney et al., 2008) and oxygen consumption by polymorphonuclear cells and bacteria (Kolpen et al., 2010) potentiate microaerophilic and even anaerobic growth. It is therefore of high clinical significance that P. pnomenusa seems to be able to grow under anaerobic conditions, given that anaerobic growth appears to be associated with increased persistence and antibiotic resistance in other facultative anaerobes that infect the CF lung (Schobert and Tielen, 2010).\n\nConcluding remarks\nThis case report further highlights the limitations associated with using MALDI-TOF MS and phenotypic-based testing for the identification of uncommon pathogens, and serves as an important caution for laboratories relying on these two methodologies for accurate identification of species of Pandoraea. Without consistent and reliable species level identification of multidrug-resistant Pandoraea, the clinical significance of these organisms will remain difficult to determine.\n\nAuthor contributions\nMA and LR substantially contributed to the conception of the work, the acquisition, analysis and interpretation of data and drafting and critically revising the work. MA and LR also have final approval of the version to be published and agree to be accountable for all aspects of the work. RM, SW, SB, OS, BM, DS substantially contributed to the acquisition, analysis and interpretation of data and in drafting and critically revising the work.\n\nFunding\nThis work was funded by a Royal Hobart Hospital Research Foundation (RHHRF) grant number R22664.\n\nConflict of interest statement\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\nCaraher E. Collins J. Herbert G. Murphy P. G. Gallagher C. G. Crowe M. J. . (2008 ). Evaluation of in vitro virulence characteristics of the genus Pandoraea in lung epithelial cells . J. Med. Microbiol. \n57(Pt 1) , 15 –20 . 10.1099/jmm.0.47544-0 18065662 \nCoenye T. Falsen E. Hoste B. Ohlén M. Goris J. Govan Jr. (2000 ). Description of Pandoraea gen. nov. with Pandoraea apista sp. nov., Pandoraea pulmonicola sp. nov., Pandoraea pnomenusa sp. nov., Pandoraea sputorum sp. nov. and Pandoraea norimbergensis comb. nov. \nInt. J. Syst. Microbiol. \n50(Pt 2) , 887 –899 . 10.1099/00207713-50-2-887 \nCoenye T. LiPuma J. J. (2002 ). Use of the gyrB gene for the identification of Pandoraea species . FEMS Microbiol. Lett. \n208 , 15 –19 . 10.1111/j.1574-6968.2002.tb11053.x 11934487 \nDaneshvar M. I. Hollis D. G. Steigerwalt A. G. Whitney A. M. Spangler L. Douglas M. P. . (2001 ). Assignment of CDC weak oxidizer group 2 (WO-2) to the genus Pandoraea and characterization of three new Pandoraea genomospecies . J. Clin. Microbiol. \n39 , 1819 –1826 . 10.1128/JCM.39.5.1819-1826.2001 11325997 \nEe R. Ambrose M. Lazenby J. Williams P. Chan K. G. Roddam L. (2015 ). Genome sequences of two Pandoraea pnomenusa isolates recovered 11 months apart from a cystic fibrosis patient . 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Vandamme P. Coenye T. Speert D. P. (2001 ). Phenotypic methods for determining genomovar status of the Burkholderia cepacia complex . J. Clin. Microbiol. \n39 , 1073 –1078 . 10.1128/JCM.39.3.1073-1078.2001 11230429 \nJohnson L. N. Han J. Y. Moskowitz S. M. Burns J. L. Qin X. Englund J. A. (2004 ). Pandoraea bacteremia in a cystic fibrosis patient with associated systemic illness . Pediatr. Infect. Dis. J. \n23 , 881 –882 . 10.1097/01.inf.0000136857.74561.3c 15361734 \nJørgensen I. M. Johansen H. K. Frederiksen B. Pressler T. Hansen A. Vandamme P. . (2003 ). Epidemic spread of Pandoraea apista, a new pathogen causing severe lung disease in cystic fibrosis patients . Pediatr. Pulmonol. \n36 , 439 –446 . 10.1002/ppul.10383 14520728 \nKolpen M. Hansen C. R. Bjarnsholt T. Moser C. Christensen L. D. van Gennip M. . (2010 ). Polymorphonuclear leucocytes consume oxygen in sputum from chronic Pseudomonas aeruginosa pneumonia in cystic fibrosis . Thorax \n65 , 57 –62 . 10.1136/thx.2009.114512 19846469 \nLim Y. L. Ee R. Yong D. Yu C. Y. Ang G. Y. Tee K. K. . (2016 ). Complete genome sequence analysis of Pandoraea pnomenusa type strain dsm 16536(T) isolated from a cystic fibrosis patient . Front. Microbiol. \n7 :109 . 10.3389/fmicb.2016.00109 26903988 \nLiPuma J. J. (2010 ). The changing microbial epidemiology in cystic fibrosis . Clin. Microbiol. Rev. \n23 , 299 –323 . 10.1128/CMR.00068-09 20375354 \nRenders N. Verbrugh H. Van Belkum A. (2001 ). Dynamics of bacterial colonisation in the respiratory tract of patients with cystic fibrosis . Infect. Genet. Evol. \n1 , 29 –39 . 10.1016/S1567-1348(01)00004-1 12798048 \nSchneider I. Bauernfeind A. (2015 ). Intrinsic carbapenem-hydrolyzing oxacillinases from members of the genus Pandoraea . Antimicrob. Agents Chemother. \n59 , 7136 –7141 . 10.1128/AAC.01112-15 26349828 \nSchobert M. Tielen P. (2010 ). Contribution of oxygen-limiting conditions to persistent infection of Pseudomonas aeruginosa . Future Microbiol. \n5 , 603 –621 . 10.2217/fmb.10.16 20353301 \nStryjewski M. E. LiPuma J. J. Messier R. H. Jr.Reller L. B. Alexander B. D. (2003 ). Sepsis, multiple organ failure, and death due to Pandoraea pnomenusa infection after lung transplantation . J. Clin. Microbiol. \n41 , 2255 –2257 . 10.1128/JCM.41.5.2255-2257 12734295 \nTunney M. M. Field T. R. Moriarty T. F. Patrick S. Doering G. Muhlebach M. S. . (2008 ). Detection of anaerobic bacteria in high numbers in sputum from patients with cystic fibrosis . Am. J. Respir. Crit. Care Med. \n177 , 995 –1001 . 10.1164/rccm.200708-1151OC 18263800 \nWilschanski M. Zielenski J. Markiewicz D. Tsui L. C. Corey M. Levison H. . (1995 ). Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations . J. Pediatr. \n127 , 705 –710 . 10.1016/S0022-3476(95)70157-5 7472820 \nWorlitzsch D. Tarran R. Ulrich M. Schwab U. Cekici A. Meyer K. C. . (2002 ). Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients . J. Clin. Invest. \n109 , 317 –325 . 10.1172/JCI13870 11827991\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-302X",
"issue": "7()",
"journal": "Frontiers in microbiology",
"keywords": "Pandoraea; anaerobe; cystic fibrosis; infection; lung",
"medline_ta": "Front Microbiol",
"mesh_terms": null,
"nlm_unique_id": "101548977",
"other_id": null,
"pages": "692",
"pmc": null,
"pmid": "27242717",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "25657265;20375354;12734295;19846469;22170922;11230429;11934487;26349828;18263800;7472820;21968086;15361734;14520728;20353301;18065662;11827991;21233507;11325997;12798048;26903988;10758901",
"title": "Pandoraea pnomenusa Isolated from an Australian Patient with Cystic Fibrosis.",
"title_normalized": "pandoraea pnomenusa isolated from an australian patient with cystic fibrosis"
} | [
{
"companynumb": "AU-BAUSCH-BL-2016-016175",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
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"activesubstancename": "TOBRAMYCIN"
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{
"abstract": "There is limited experience with facial retransplantation (fRT). We report on the management of facial retransplantation in a facial vascularized composite allotransplant recipient following irreversible allograft loss 88 months after the first transplant. Chronic antibody-mediated rejection and recurrent cellular rejection resulted in a deteriorated first allograft and the patient underwent retransplantation. We summarize the events between the two transplantations, focusing on the final rejection episode. We describe the surgical technique of facial retransplantation, the immunological and psychosocial management, and the 6-month postoperative outcomes. Removal of the old allograft and inset of the new transplant were done in one operation. The donor and recipient were a good immunological match. The procedure was technically complex, requiring more proximal arterial anastomoses and an interposition vein graft. During the first and second transplantation, the facial nerve was coapted at the level of the branches. There was no hyperacute rejection in the immediate postoperative phase. Outcomes 6 months postoperatively are promising. We provide proof-of-concept that facial retransplantation is a viable option for patients who suffer irreversible facial vascularized composite allograft loss.",
"affiliations": "Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Speech and Feeding Disorders Lab, MGH Institute of Health Professions, Charlestown, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Otolaryngology, Department of Surgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Schuster Transplantation Research Center, Renal Division, Boston, Massachusetts, USA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "Kauke|Martin|M|0000-0001-5399-4166;Panayi|Adriana C|AC|0000-0003-4053-9855;Safi|Ali-Farid|AF|0000-0002-8226-0572;Haug|Valentin|V|0000-0002-2964-979X;Perry|Bridget|B|0000-0002-4219-2552;Kollar|Branislav|B|0000-0001-6668-7798;Nizzi|Marie-Christine|MC|0000-0002-2062-8992;Broyles|Justin|J|0000-0003-0277-8046;Annino|Donald J|DJ|0000-0003-0525-0263;Marty|Francisco M|FM|0000-0002-3708-8734;Sinha|Indranil|I|0000-0001-9384-7347;Lian|Christine G|CG|0000-0003-4626-1612;Murphy|George F|GF|0000-0003-3464-793X;Chandraker|Anil|A|0000-0001-9729-7717;Pomahac|Bohdan|B|0000-0003-3703-8240",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16696",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(10)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; rejection: vascular; retransplantation; vascularized composite and reconstructive transplantation",
"medline_ta": "Am J Transplant",
"mesh_terms": "D064595:Composite Tissue Allografts; D005260:Female; D006084:Graft Rejection; D006801:Humans; D012086:Reoperation; D014184:Transplantation, Homologous",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3472-3480",
"pmc": null,
"pmid": "34033210",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Full facial retransplantation in a female patient-Technical, immunologic, and clinical considerations.",
"title_normalized": "full facial retransplantation in a female patient technical immunologic and clinical considerations"
} | [
{
"companynumb": "US-PFIZER INC-202101544047",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS"
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{
"abstract": "OBJECTIVE\nA randomized phase III study was designed to assess the efficacy and safety of second-line platinum-based chemotherapy with or without erlotinib in non-small cell lung cancer (NSCLC) with EGFR-activating mutation after secondary resistance to EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors).\n\n\nMETHODS\nWe report herein two of the first three patients who presented with major gastrointestinal toxicities in the experimental arm of the trial.\n\n\nCONCLUSIONS\nPending further data, it would seem safer to administer EGFR-TKIs and chemotherapy sequentially rather than concomitantly.",
"affiliations": "Department of Pharmacology, CHU de Caen, Caen, France.;Department of Clinical Research, Centre François Baclesse, Caen, France.;Department of Clinical Research, Centre François Baclesse, Caen, France.;Department of Clinical Research, Centre François Baclesse, Caen, France.;Department of Pharmacology, CHU de Caen, Caen, France.;Department of Pharmacology, CHU de Caen, Caen, France.;Department of Pharmacology, CHU de Caen, Caen, France.;Department of Pneumology, Meulan-Les Mureaux Intercommunal Hospital, Meulan en Yvelines, France.;Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France.;Department of Oncology, Centre François Baclesse, Caen, France.",
"authors": "Sassier|M|M|;Peyro-Saint-Paul|L|L|;Clarisse|B|B|;Leconte|A|A|;Coquerel|A|A|;Alexandre|J|J|;Fedrizzi|S|S|;Leroy-Terquem|E|E|;Madroszyk|A|A|;Gervais|R|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12406",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "41(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "chemotherapy; erlotinib; gastrointestinal toxicity; non-small cell lung cancer",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "447-448",
"pmc": null,
"pmid": "27306517",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Chemotherapy (platinum and pemetrexed) in combination with erlotinib in non-small cell lung cancer induces major gastrointestinal toxicity: two case reports from the FLARE/GFPC 03-2013 study.",
"title_normalized": "chemotherapy platinum and pemetrexed in combination with erlotinib in non small cell lung cancer induces major gastrointestinal toxicity two case reports from the flare gfpc 03 2013 study"
} | [
{
"companynumb": "FR-TEVA-690422ISR",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREPITANT"
},
"drugadditional": "3",
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{
"abstract": "To avoid the negative effects associated with pacing, pacemakers are designed to achieve a pacing cadence as close to physiological pacing as possible. In closed-loop stimulation (CLS; a type of rate-responsive functionality used in pacemakers), the changes in impedance (which correlates with the contractility of the myocardium around the lead tip electrode) are tracked, and the paced heart rate is adjusted accordingly. We herein report a case in which we implanted a pacemaker in a post-tricuspid valve replacement patient. A ventricular lead positioned in the coronary vein exhibited good CLS functionality, and the patient's dizziness and heart failure improved.",
"affiliations": "Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.;Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan.",
"authors": "Ikeya|Yukitoshi|Y|;Nakai|Toshiko|T|;Murata|Nobuhiro|N|;Monden|Masaki|M|;Ogaku|Akihito|A|;Hori|Koichiro|K|;Watanabe|Ryuta|R|;Arai|Masaru|M|;Okumura|Yasuo|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.4018-19",
"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32238662\n10.2169/internalmedicine.4018-19\nCase Report\nEffective Pacing Intervention by Closed-loop Stimulation Using a Coronary Vein Lead in a Post-tricuspid Valve Replacement Patient\nIkeya Yukitoshi 1 Nakai Toshiko 1 Murata Nobuhiro 1 Monden Masaki 1 Ogaku Akihito 1 Hori Koichiro 1 Watanabe Ryuta 1 Arai Masaru 1 Okumura Yasuo 1 \n1 Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Japan\nCorrespondence to Dr. Toshiko Nakai, nakai.toshiko@nihon-u.ac.jp\n\n\n1 4 2020 \n1 4 2020 \n59 7 963 966\n8 10 2019 29 10 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).To avoid the negative effects associated with pacing, pacemakers are designed to achieve a pacing cadence as close to physiological pacing as possible. In closed-loop stimulation (CLS; a type of rate-responsive functionality used in pacemakers), the changes in impedance (which correlates with the contractility of the myocardium around the lead tip electrode) are tracked, and the paced heart rate is adjusted accordingly. We herein report a case in which we implanted a pacemaker in a post-tricuspid valve replacement patient. A ventricular lead positioned in the coronary vein exhibited good CLS functionality, and the patient's dizziness and heart failure improved. \n\nclosed-loop stimulationCLScoronary vein leadleft ventricular pacing\n==== Body\nIntroduction\nThe design of pacemakers aims for pacing that is as physiological as possible in order to prevent the detrimental effects of pacing on the cardiac function and to improve the patient's exercise tolerance. BiotronikⓇ pacemakers use a unique closed-loop stimulation (CLS) technology as a form of rate-responsive functionality.\n\nCLS is a technology that extracts changes in impedance, which correlates with the contractility of the myocardium around the lead tip electrode, and converts the changes into a heart rate response in order to maintain the cardiac output, enabling more natural, physiological rate responsivity.\n\nWe herein report a case in which we placed the pacing lead and left ventricular (LV) lead [for cardiac resynchronization therapy (CRT)] of a pacemaker with CLS functionality in the patient's coronary vein when implanting a single-chamber ventricular (VVI) pacemaker in a post-tricuspid valve replacement (TVR) patient with chronic atrial fibrillation (AF) with bradycardia. The lead, which was positioned on the epicardial side of the LV, exhibited good CLS functionality.\n\nCase Report\nThe patient was a 79-year-old Japanese woman who visited the emergency room at our hospital for presyncope and nausea in June 2019. As the monitor showed bradycardia associated with chronic AF and because the patient's subjective symptoms were persisting, she was admitted to the hospital.\n\nThe patient had undergone pulmonary vein isolation (PVI) for paroxysmal AF in 2010, which progressed to chronic AF. In addition, TVR was performed in March 2016 for tricuspid valve insufficiency. In other systems, endoscopic polypectomy for early gastric cancer and stent placement for lower extremity arteriosclerosis obliterans (ASO) were both performed in 2016. The patient's medical history included chronic heart failure, chronic obstructive pulmonary disease, hypertension, chronic renal failure, pulmonary hypertension, and diabetes.\n\nThe physical findings at the initial visit included the following: body temperature 36.7 °C, blood pressure 182/80 mmHg, pulse rate 45 beats per minute (bpm), irregular; and no heart murmurs or abnormal respiratory sounds. Her blood test results showed chronic anemia (Hb 9.4 g/dL) and renal dysfunction [blood urea nitrogen (BUN) 27.7 mg/dL, Cr1 15 mg/dL]. Her thyroid function was within the normal range [thyroid-stimulating hormone (TSH), 2.32 μIU/mL; free triiodothyronine (FT) 3, 2.51 pg/mL; free thyroxine (FT) 4, 1.38 ng/dL]. There were no abnormalities in cardiac enzyme levels [creatine kinase (CK), CK-muscle brain (MB), troponin I] and no changes in markers of inflammation, and the results of liver function tests were normal. NT-proBNP was high at 8,464 pg/mL.\n\nElectrocardiography (ECG) revealed AF [heart rate (HR): 20-50 bpm] and complete right bundle branch block (QRS=144 ms). Inverted T waves were seen in leads II, III, aVF, and V1-4 (Fig. 1). Chest X-ray showed cardiomegaly (cardiothoracic ratio: 61%) and pulmonary congestion.\n\nFigure 1. The electrocardiography at the initial visit. The patient’s heart rate was 20 beat per minute, and complete right bundle branch block (QRS: 144 ms) was observed.\n\nEchocardiography did not exhibit clear asynergy in LV wall motion: the LV ejection fraction (LVEF) was 69%, the LV end-diastolic dimension (LVDd) was 54 mm, the LV end-systolic dimension (LVDs) was 33 mm, the interventricular septal thickness at end-diastole (IVSTd) was 10 mm, and the posterior LV wall thickness (PWTd) was 10 mm. The findings indicating valvular disease included trivial tricuspid regurgitation (TR) (post-TVR), mild to moderate pulmonary regurgitation (PR) [PR end-pressure gradient (PG): 3 mmHg], right atrial and ventricular (RA and RV) enlargement, and left atrial (LA) enlargement with a left atrial diameter (LAD) of 47 mm.\n\nAfter admission to the hospital, a β-blocker (bisoprolol fumarate, 0.625 mg) that the patient had been taking was withdrawn, and she was followed-up with diuretic dose adjustments. However, as the patient frequently had a heartbeat pause lasting 5-8 seconds associated with lightheadedness and since her bradycardia did not improve, permanent pacemaker implantation was performed. Because the patient's AF had become chronic, a VVI pacemaker was used. An LV lead for CRT - instead of an RV lead - was inserted in the coronary sinus (CS) and placed on the LV side (CS lateral branch), since the patient had previously undergone TVR, although a biological tissue valve had been used.\n\nAt the implantation, the R-wave sensing was 12.1 mV, the ventricular pacing threshold was 0.6 V at 0.4 ms, and the lead impedance was 526 Ω. All measurements were within the normal range. The pacemaker implanted this time was a model with a CLS function (Edora 8 SR-T; Biotronik, Berlin, Germany), and the settings of VVI-CLS were a lower rate of 60 ppm and sensor rate of 120 ppm. After the pacemaker implantation, the doses of the patient's oral medications, including the β-blocker and diuretics, were adjusted once more. Her lightheadedness and heart failure signs both improved, and the patient was discharged 10 days after the implantation.\n\nAn inspection of the pacemaker and ECG Holter monitoring after the patient's pacemaker implantation indicated that even though pacing was being performed by a lead placed on the epicardial side of the coronary vein, the CLS functionality was good, as indicated by an increased pacing rate (Fig. 2) and the following data: total heart beats (/day), 100,108; maximum HR (bpm), 121; minimum HR (bpm), 59; average HR (bpm), 70; and longest RR interval (sec), 1.22 (Table). Post-pacemaker implantation chest X-ray performed after the patient's discharge did not show pulmonary congestion (Fig. 3).\n\nFigure 2. The post-implantation electrocardiography at rest under pacing. The pacemaker settings were VVI-closed-loop stimulation (CLS) mode, basic rate of 60, and sensor rate of 120 ppm. The heart rate is 77 beat per minute, indicating that the CLS function is working.\n\nTable. Results of 24-hour Holter ECG Monitoring after Pacemaker Implantation.\n\nTotal heart beats (/day)\t\t100,108\t\nMaximum heart rate (bpm)\t\t121\t\nMinimum heart rate (bpm)\t\t59\t\nAverage heart rate (bpm)\t\t70\t\nLongest RR interval (sec)\t\t1.22\t\nECG: electrocardiography, bpm: beats per minute\n\nFigure 3. Post-implantation X-ray images taken at the outpatient clinic after discharge. Postero-anterior (left) and lateral (right) views. A pacing lead (arrow) placed in the coronary vein (lateral branch) is shown. No findings indicating pulmonary congestion or pleural effusion are seen.\n\nDiscussion\nWe implanted a VVI pacemaker in a post-TVR patient with AF and bradycardia. As the patient had previously undergone TVR, although a bioprosthetic valve was used, a V-lead was placed in her left ventricle using an LV lead for CRT. A pacemaker with a CLS function was selected, which worked with an LV lead.\n\nTo achieve a rate-responsive function, sensors other than the CLS were used in the present case, including an accelerometer that responds to body movements and has a superior rate response during exercise at a high activity level, and a minute ventilation sensor that monitors respiration and is suitable for responding to slow exercise and changes in mental activity.\n\nThe present patient had AF with bradycardia as her underlying heart condition; she had undergone TVR surgery and had a history of hospitalization for heart failure. The use of β-blockers for her heart failure treatment worsened the bradycardia, and the patient developed heart failure again. The pacemaker implantation stabilized the patient's heart rate, and the dose adjustments of oral drugs, including the β-blocker, alleviated her heart failure.\n\nAs noted above, in patients who have had bradycardia or develop bradycardia or chronotropic incompetence induced by a β-blocker, backup pacing at a physiological rate is important for preventing heart failure. CLS uses a sensing algorithm that can detect variations in cardiac contractility and respond to a decrease in the blood pressure by increasing the heart rate (1). Several research groups reported that CLS pacing is beneficial for patients with recurrent vasovagal syncope who demonstrate a cardio-inhibitory response on the head-up tilt table test (HUTT) (1-4). Another report showed that CLS is effective during states of emotional stress in patients with AF and chronotropic incompetence (5).\n\nFor these reasons, CLS was considered appropriate in this patient, who was 79 years old with an activity level that was not high and who had an unstable heartrate associated with AF and exhibited signs of heart failure. CLS is normally used with endocardial right ventricular leads, and whether or not the sensor functions well in epicardial pacing with a lead positioned in the coronary vein, as in our patient's case, was unclear. However, we selected Biotronik's Edora 8 SR-T model because previous reports noted that CLS was capable of heart rate modulation in pediatric patients when connected to an epicardial lead (6,7); in addition, we considered that, should CLS prove ineffective, the use of the rate response function of the accelerometer included in this model would be a useful contingency plan.\n\nThe CLS function was useful for LV pacing with an LV lead placed in the coronary vein of our adult patient. Our experience in this patient's case suggests the possibility of capitalizing on the advantages of CLS in postoperative dialysis patients and patients who require a surgically placed epicardial lead.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nToshiko Nakai: Honoraria, Abbott Medical, Biotronik Japan and Medtronic Japan.\n==== Refs\n1. \nRuzieh M , Grubb BP \nVasovagal syncope - role of closed loop stimulation pacing\n. Trends Cardiovasc Med \n28 : 534 -538\n, 2018 .29843961 \n2. \nRuzieh M , Ghahramani M , Nudy M , et al \nThe benefit of closed loop stimulation in patients with cardioinhibitory vasovagal syncope confirmed by head-up tilt table testing: a systematic review and meta-analysis\n. J Interv Card Electrophysiol \n55 : 105 -113\n, 2019 .30863907 \n3. \nPalmisano P , Dell'Era G , Russo V , et al \nEffects of closed-loop stimulation vs. DDD pacing on haemodynamic variations and occurrence of syncope induced by head-up tilt test in older patients with refractory cardioinhibitory vasovagal syncope: the tilt test-induced response in closed-loop stimulation multicentre, prospective, single blind, randomized study\n. Europace \n20 : 859 -866\n, 2018 .28407148 \n4. \nRusso V , Rago A , Papa AA , et al \nThe effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a prospective, randomised, single-blind, crossover study\n. Heart \n99 : 1609 -1613\n, 2013 .23723446 \n5. \nProietti R , Manzoni G , Di Biase L , et al \nClosed loop stimulation is effective in improving heart rate and blood pressure response to mental stress: report of a single-chamber pacemaker study in patients with chronotropic incompetent atrial fibrillation\n. Pacing Clin Electrophysiol \n35 : 990 -998\n, 2012 .22680238 \n6. \ndi Pino A , Agati S , Bianca I \nEfficacy of closed-loop stimulation with epicardial leads in an infant with congenital atrioventricular block\n. Europace \n10 : 334 -335\n, 2008 .18204100 \n7. \ndi Pino A , Caruso E , Censi F , Gaudenti G , Gargaro A , Calcagnini G \nPhysiological rate adaptation in a child with chronotropic incompetence through closed-loop stimulation using epicardial leads\n. Heart Rhythm Case Rep \n2 : 36 -39\n, 2015 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "CLS; closed-loop stimulation; coronary vein lead; left ventricular pacing",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D002304:Cardiac Pacing, Artificial; D003331:Coronary Vessels; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure; D006339:Heart Rate; D006350:Heart Valve Prosthesis; D006801:Humans; D010138:Pacemaker, Artificial; D011474:Prosthesis Design; D012804:Sick Sinus Syndrome; D014261:Tricuspid Valve",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "963-966",
"pmc": null,
"pmid": "32238662",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30863907;29843961;28407148;23723446;22680238;28491628;18204100",
"title": "Effective Pacing Intervention by Closed-loop Stimulation Using a Coronary Vein Lead in a Post-tricuspid Valve Replacement Patient.",
"title_normalized": "effective pacing intervention by closed loop stimulation using a coronary vein lead in a post tricuspid valve replacement patient"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1236689",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BISOPROLOL FUMARATE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAcute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia (AML) characterized by chromosomal translocations involving the retinoid acid receptor α (RARA) gene on chromosome 17. APL is a relatively rare blood disease that is highly curable with current treatment strategies; however, patient outcomes are heterogeneous in countries with limited resources. Promyelocytic leukemia accounts for 20-25% of all AML cases in Latin American countries.\n\n\nMETHODS\nWe conducted a study from July 2007 to July 2012 and applied the IC-APL2006 protocol. This case study reports the results from eleven patients with AML M3 (five males and six females). In all cases, the diagnoses were made by aspirating bone marrow and evaluating the t(15:17) or t(11:17) transcript. In eight cases, the molecular biology-based diagnostics for the PLM-RARa transcript were positive, and they were negative in two cases. One patient was positive for the PLZF-RARa transcript.\n\n\nRESULTS\nThe mean WBC at the time of diagnosis was 10.1 x 10(9)/L, and the mean platelet count was 17.1 x 10(9)/L. The mean percentage of abnormal promyelocytes in the bone marrow aspirates was 68%. Of the eleven patients, four presented with disseminated intravascular coagulation. All of the patients began treatment with transretinoic acid (ATRA) (45 mg/m(2)/day), which led to 4 cases of ATRA syndrome. There were 2 relapses, and the patient died in one case. The remaining ten patients were alive after the median follow-up period of 33.6 months (range from 11 to 60 months).\n\n\nCONCLUSIONS\nThe authors report on a series of cases involving pediatric patients with AML M3 seen at a single institution; the patients were stratified and treated with a standard protocol to obtain satisfactory results. Although the number of patients is limited, the health outcomes are relevant. To our knowledge, this is the first series of pediatric APL patients in Mexico who were treated with the IC-APL2006 protocol.",
"affiliations": "Departamento de Hemato-Oncología, Hospital Infantil de México Federico Gómez.",
"authors": "Dorantes-Acosta|Elisa|E|;Medina-Sanson|Aurora|A|;Jaimes-García|Yanet|Y|;López-Martínez|Briceida|B|",
"chemical_list": "D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D003561:Cytarabine; D014212:Tretinoin; D008942:Mitoxantrone; D015122:Mercaptopurine; D008727:Methotrexate; D003630:Daunorubicin",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-8376",
"issue": "65(5)",
"journal": "Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion",
"keywords": null,
"medline_ta": "Rev Invest Clin",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D060830:Consolidation Chemotherapy; D003561:Cytarabine; D003630:Daunorubicin; D004211:Disseminated Intravascular Coagulation; D005260:Female; D005500:Follow-Up Studies; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D015122:Mercaptopurine; D008727:Methotrexate; D008800:Mexico; D008942:Mitoxantrone; D015514:Oncogene Proteins, Fusion; D012008:Recurrence; D012074:Remission Induction; D016896:Treatment Outcome; D014212:Tretinoin",
"nlm_unique_id": "9421552",
"other_id": null,
"pages": "392-8",
"pmc": null,
"pmid": "24687338",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical features and treatment outcomes of pediatric acute promyelocytic leukemia in a Mexican pediatric hospital.",
"title_normalized": "clinical features and treatment outcomes of pediatric acute promyelocytic leukemia in a mexican pediatric hospital"
} | [
{
"companynumb": "MX-MYLANLABS-2015M1013360",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nChronic uveitis treated with immunosuppressive agents may have unfavorable outcomes due to delays in diagnosis. The aim of this study was to review initial data from clinical and ocular assessments and patient outcomes following specific treatments for atypical herpes virus ocular infections.\n\n\nMETHODS\nThe records of four consecutive patients with recurrent uveitis for at least five years treated in our department between 2001 and 2016 were retrospectively reviewed. They had atrophic retinal lesions resulting in an unfavorable outcome with lesion progression and vision loss under immunosuppressive treatment. Varicella zoster virus (1 case) and herpes simplex virus type 2 (3 cases) were detected in ocular samples.\n\n\nRESULTS\nUveitis was granulomatous and bilateral (3 cases) or unilateral (1 case). Immunosuppressive treatments worsened the clinical situation whereas antiherpetic treatments improved the control of intraocular inflammation.\n\n\nCONCLUSIONS\nThis description should be added to the broad repertoire of clinical polymorphisms associated with herpes virus infections. Recognizing these cases should be useful due to their sensitivity to antiherpetic treatments.",
"affiliations": "a Ophthalmology Department , Reference Centre for Rare Diseases, Pitié-Salpêtrière Hospital, University Paris VI , Paris , France.;a Ophthalmology Department , Reference Centre for Rare Diseases, Pitié-Salpêtrière Hospital, University Paris VI , Paris , France.;a Ophthalmology Department , Reference Centre for Rare Diseases, Pitié-Salpêtrière Hospital, University Paris VI , Paris , France.;b Laboratory of Virology, Cochin Hospital, University Paris V , Paris , France.;a Ophthalmology Department , Reference Centre for Rare Diseases, Pitié-Salpêtrière Hospital, University Paris VI , Paris , France.;a Ophthalmology Department , Reference Centre for Rare Diseases, Pitié-Salpêtrière Hospital, University Paris VI , Paris , France.",
"authors": "Souissi|Soufiane|S|;Fardeau|Christine|C|;Le|Hoang Mai|HM|;Rozenberg|Flore|F|;Bodaghi|Bahram|B|;Le Hoang|Phuc|P|",
"chemical_list": "D000914:Antibodies, Viral; D000998:Antiviral Agents; D004279:DNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2017.1327079",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "26(1)",
"journal": "Ocular immunology and inflammation",
"keywords": "Herpes virus; macular edema; retinitis; uveitis; vasculitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000328:Adult; D000914:Antibodies, Viral; D000998:Antiviral Agents; D001082:Aqueous Humor; D002908:Chronic Disease; D004279:DNA, Viral; D015828:Eye Infections, Viral; D005260:Female; D005500:Follow-Up Studies; D006561:Herpes Simplex; D006563:Herpes Zoster Ophthalmicus; D018258:Herpesvirus 2, Human; D014645:Herpesvirus 3, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012173:Retinitis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "94-103",
"pmc": null,
"pmid": "28628343",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic Herpetic Retinitis: Clinical Features and Long-Term Outcomes.",
"title_normalized": "chronic herpetic retinitis clinical features and long term outcomes"
} | [
{
"companynumb": "FR-PFIZER INC-2018076314",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Depression is known to be a risk factor for suicide. Currently, the most used antidepressants are selective serotonin reuptake inhibitors (SSRIs). Not all users, however, benefit from them. In such cases, treatment failure can be explained in part by genetic differences. In this study, we investigated the role of pharmacogenetic factors in citalopram-positive completed suicides (n = 349). Since citalopram is metabolized by CYP2C19 and CYP2D6 enzymes, the study population was genotyped for clinically relevant CYP2C19 and CYP2D6 polymorphisms and CYP2D6 copy number variation. To assess genetic differences between suicide cases and Finns in general, Finnish population samples (n = 855) were used as controls. Also, the role of drug interactions among suicide cases was evaluated. We found enrichment of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes (gMPs) of CYP2C19 among suicide victims compared to controls 0.356 [0.31-0.41] vs. 0.265 [0.24-0.30] (p = 0.0065). In CYP2D6 gMPs, there was no difference between cases and controls when the study population was analyzed as a whole. However, there were significantly more poor metabolizers among females who committed suicide by poisoning compared to female controls. In 8% of all drug poisoning deaths, lifetime drug-drug interaction was evaluated having a contribution to the fatal outcome. From clinical perspective, pharmacogenetic testing prior to initiation of SSRI drug could be beneficial. It may also be useful in medico-legal settings as it may elucidate obscure poisoning cases. Also, the possibility of unintentional drug interactions should be taken into account in drug poisoning deaths.",
"affiliations": "Department of Forensic Medicine, University of Helsinki, P.O.Box 40, Kytösuontie 11, 00014, Helsinki, Finland. anna-liina.rahikainen@helsinki.fi.;Forensic Medicine Unit, National Institute for Health and Welfare, P.O.Box 30, Mannerheimintie 166, 00271, Helsinki, Finland.;Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.;Department of Forensic Medicine, University of Helsinki, P.O.Box 40, Kytösuontie 11, 00014, Helsinki, Finland.;Department of Public Health, University of Helsinki, P.O.Box 20, Tukholmankatu 8B, 00014, Helsinki, Finland.;Department of Forensic Medicine, University of Helsinki, P.O.Box 40, Kytösuontie 11, 00014, Helsinki, Finland.;Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, P.O.Box 20, Tukholmankatu 8C, 00014, Helsinki, Finland.;Department of Forensic Medicine, University of Helsinki, P.O.Box 40, Kytösuontie 11, 00014, Helsinki, Finland. antti.sajantila@helsinki.fi.",
"authors": "Rahikainen|Anna-Liina|AL|http://orcid.org/0000-0002-8348-3639;Vauhkonen|P|P|;Pett|H|H|;Palo|J U|JU|;Haukka|J|J|;Ojanperä|I|I|;Niemi|M|M|;Sajantila|Antti|A|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00414-018-1927-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-9827",
"issue": "133(2)",
"journal": "International journal of legal medicine",
"keywords": "CYP2C19; CYP2D6; Citalopram; Drug interactions; Postmortem; Suicide",
"medline_ta": "Int J Legal Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D056915:DNA Copy Number Variations; D004347:Drug Interactions; D005260:Female; D005387:Finland; D053593:Forensic Toxicology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D017367:Serotonin Uptake Inhibitors; D013405:Suicide",
"nlm_unique_id": "9101456",
"other_id": null,
"pages": "353-363",
"pmc": null,
"pmid": "30173302",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": "19907421;12774892;27388693;18584194;29481489;12705964;26132657;28841781;19367325;8093319;29075918;8941024;29134625;17301689;21926427;25154506;27038154;17823102;28482932;21565059;25974703;14574440;17625515;28608626;21192344;23881890;29325448;21722691;10739177;8807658;28568523;8988065;8494072",
"title": "Completed suicides of citalopram users-the role of CYP genotypes and adverse drug interactions.",
"title_normalized": "completed suicides of citalopram users the role of cyp genotypes and adverse drug interactions"
} | [
{
"companynumb": "FI-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-291635",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drug... |
{
"abstract": "Anesthetic management of elderly patients requires numerous physiological considerations. With aging, degenerative changes occur in the structure and functional capacity of tissues and organs. Typically, these patients experience clinical effects with lower doses of medication. Important considerations for the geriatric populations following anesthesia include increased time to recovery and avoidance of functional decline. A case is reported in which an 83-year-old Caucasian female with a complex medical history presented for routine dental treatment under intravenous sedation via dexmedetomidine infusion.",
"affiliations": "Department of Dental Anesthesiology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania.;Department of Dental Anesthesiology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania.;Department of Dental Anesthesiology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania.",
"authors": "Young|Andrew S|AS|;Russell|Nicholas A|NA|;Giovannitti|Joseph A|JA|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "United States",
"delete": false,
"doi": "10.2344/anpr-64-02-08",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-3006",
"issue": "64(2)",
"journal": "Anesthesia progress",
"keywords": "Dexmedetomidine infusion; General anesthesia for elderly; Sedation for elderly",
"medline_ta": "Anesth Prog",
"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D000369:Aged, 80 and over; D000766:Anesthesia, Dental; D016292:Conscious Sedation; D020927:Dexmedetomidine; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D011300:Preoperative Care",
"nlm_unique_id": "0043533",
"other_id": null,
"pages": "88-96",
"pmc": null,
"pmid": "28604086",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20359259;8881629;17484705;21832859;25318569;21307770;19582189;16369581;25849473",
"title": "Dexmedetomidine Infusion for Routine Dental Management of an ASA IV Patient: A Case Report.",
"title_normalized": "dexmedetomidine infusion for routine dental management of an asa iv patient a case report"
} | [
{
"companynumb": "US-MYLANLABS-2018M1050664",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nChronic subdural hematoma (CSDH) is uncommon in the spine. Most spinal CSDHs occur as solitary lesions in the lumbosacral region. We report a rare case of multiple spinal CSDHs associated with hematomyelia. The diagnostic and therapeutic management of these complex spinal CSDHs is reviewed as well as the pertinent literature.\n\n\nMETHODS\nA 79-year-old woman on warfarin therapy presented with lower back pain and progressive lower extremity weakness that had developed in the previous 2 weeks. She subsequently developed paraplegia and urinary incontinence. Thoracolumbar magnetic resonance imaging showed a CSDH from T12-L3 compressing the cauda equina. Single-shot whole-spine magnetic resonance imaging showed another CSDH and hematomyelia at T2-3. She underwent L2-3 hemilaminectomy, which revealed a liquefied subdural hematoma. Delayed T2 laminectomy exposed an organized subdural hematoma and xanthochromic hematomyelia. After each surgery, the patient showed significant motor recovery. Finally, the patient could walk, and the urinary catheter was removed.\n\n\nCONCLUSIONS\nSpinal CSDH may occur in multiple regions and may be associated with hematomyelia. Whole-spine magnetic resonance imaging is useful to examine the entire spine for CSDH accurately and thoroughly. Comprehensive surgical exploration of all symptomatic hematomas may restore neurologic functions even with delayed surgery.",
"affiliations": "Department of Neurosurgery, Fukui Red Cross Hospital, Fukui, Japan.;Department of Neurosurgery, Fukui Red Cross Hospital, Fukui, Japan. Electronic address: htoda-nsu@umin.ac.jp.;Department of Rehabilitation, Fukui Red Cross Hospital, Fukui, Japan.;Department of Neurosurgery, Fukui Red Cross Hospital, Fukui, Japan.",
"authors": "Oichi|Yuki|Y|;Toda|Hiroki|H|;Yamagishi|Koji|K|;Tsujimoto|Yoshitaka|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.07.209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "131()",
"journal": "World neurosurgery",
"keywords": "Case report; Chronic subdural hematoma; Hematomyelia; Spinal subdural hematoma; Warfarin",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D005260:Female; D020200:Hematoma, Subdural, Chronic; D046649:Hematoma, Subdural, Spinal; D006801:Humans; D007796:Laminectomy; D008159:Lumbar Vertebrae; D008279:Magnetic Resonance Imaging; D010264:Paraplegia; D020758:Spinal Cord Vascular Diseases; D013904:Thoracic Vertebrae; D016055:Urinary Retention",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "95-103",
"pmc": null,
"pmid": "31394354",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Multiple Spinal Chronic Subdural Hematomas Associated with Thoracic Hematomyelia: A Case Report and Literature Review.",
"title_normalized": "multiple spinal chronic subdural hematomas associated with thoracic hematomyelia a case report and literature review"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1121765",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAVASTATIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Antidepressant-associated movement disorders are a well-described phenomenon. However, antidepressant-associated bruxism, jaw pain, or jaw spasm, while reported in dental literature, is less commonly recognized among neurologists. We summarize the clinical features and treatment of antidepressant-associated bruxism and associated jaw pain through a systematic review of case reports.\nAntidepressant-associated bruxism may occur in pediatric and adult patients, most commonly among female patients. Patients may develop symptoms with short-term and long-term antidepressant use. Fluoxetine, sertraline, and venlafaxine were the most commonly reported offending agents. Symptoms may begin within 3-4 weeks of medication initiation and may resolve within 3-4 weeks of drug discontinuation, addition of buspirone, or substitution with another pharmacologic agent. The incidence of this phenomenon is unknown.\nBruxism associated with antidepressant use is an underrecognized phenomenon among neurologists, and may be treated with the addition of buspirone, dose modification, or medication discontinuation.",
"affiliations": "Department of Neurology, Walter Reed National Military Medical Center, Bethesda, MD.;Department of Neurology, Walter Reed National Military Medical Center, Bethesda, MD.",
"authors": "Garrett|Andrew R|AR|;Hawley|Jason S|JS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/CPJ.0000000000000433",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2163-0402",
"issue": "8(2)",
"journal": "Neurology. Clinical practice",
"keywords": null,
"medline_ta": "Neurol Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101577149",
"other_id": null,
"pages": "135-141",
"pmc": null,
"pmid": "29708207",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "19740153;22490260;26536018;26039015;11110119;19512964;16753073;22888737;27141292;23037677;19165653;8913405;21886404;10665633;21768799;11157444;22358247;26922206;12400402;15383159;11847943;8270587;7249508;25969621;15291685;27315110;19264817;12972988;24206098;19910740;24987798;24743724;17308240",
"title": "SSRI-associated bruxism: A systematic review of published case reports.",
"title_normalized": "ssri associated bruxism a systematic review of published case reports"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0100606",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "BACKGROUND\nFor organ transplant recipients, cancer secondary to immunosuppressive therapy threatens long-term survival. The associated multiple comorbidities make major free flap reconstruction following cancer surgery a complicated event. This study evaluates the outcomes of free flap reconstruction in this population.\n\n\nMETHODS\nA retrospective chart review of all head and neck free flap cases in patients with a history of organ transplantation receiving systemic immunosuppressive therapy between 2005 and 2017 at a single-institution was conducted.\n\n\nRESULTS\nOf 57 organ transplant patients, 25 patients (28 flaps) were included. Flaps used included the anterolateral thigh (n = 17), radial forearm (n = 4), latissimus dorsi (n = 3), fibula (n = 2), lateral arm (n = 1), and thoracodorsal artery perforator (n = 1) flaps. The most common organ transplant was kidney, then lung, liver, and heart. Mean inpatient stay was 8.2 days (range, 4-28). Complications occurred in 15 patients, with no total or partial flap losses.\n\n\nCONCLUSIONS\nMajor head and neck free flap reconstructive surgery can be performed safely in organ transplant patients receiving immunosuppressive therapy. Meticulous multidisciplinary care is required to achieve consistently successful outcomes.",
"affiliations": "Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Schaverien|Mark V|MV|http://orcid.org/0000-0001-6345-2643;Dean|Riley A|RA|;Myers|Jeffrey N|JN|;Fang|Lin|L|;Largo|Rene D|RD|;Yu|Peirong|P|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/jso.25035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-4790",
"issue": "117(7)",
"journal": "Journal of surgical oncology",
"keywords": "free flap; head and neck; organ transplant; outcomes; systemic immunosuppression",
"medline_ta": "J Surg Oncol",
"mesh_terms": "D005260:Female; D005360:Fibula; D005500:Follow-Up Studies; D058752:Free Tissue Flaps; D006257:Head; D006258:Head and Neck Neoplasms; D006801:Humans; D007166:Immunosuppressive Agents; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009333:Neck; D016377:Organ Transplantation; D011183:Postoperative Complications; D011379:Prognosis; D019651:Reconstructive Surgical Procedures; D012189:Retrospective Studies; D013848:Thigh",
"nlm_unique_id": "0222643",
"other_id": null,
"pages": "1575-1583",
"pmc": null,
"pmid": "29723399",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of microvascular flap reconstruction of the head and neck in patients receiving systemic immunosuppressive therapy for organ transplantation.",
"title_normalized": "outcomes of microvascular flap reconstruction of the head and neck in patients receiving systemic immunosuppressive therapy for organ transplantation"
} | [
{
"companynumb": "PHHY2018US003671",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Cerebral vascular accidents are caused by vasospasm when induced by preeclampsia or by dopamine agonists. However, six arteries nourish the pituitary and prevent against vasospasm-induced damage, which up until now has not been thought to occur. Bromocriptine was used to arrest lactation in a 31-year-old with secondary amenorrhea following preeclampsia and fetal demise at 28 weeks gestation. Tests and history revealed panhypopituitarism not associated with hemorrhage or mass infarction but instead caused by vasospasm. The present study is the first report of pituitary damage from a non-hemorrhagic, vaso-occlusive event in the literature. In keeping with Sheehan's and Simon's syndromes, we have named pituitary damage resulting from vaso-occlusion as Dahan's syndrome, and a literature review suggests that it may be a common and previously overlooked disorder.\n\n\nCONCLUSIONS\nVasospasm can cause damage to the pituitary gland, although it was not previously believed to do so.Preeclampsia and the use of a dopamine agonist, particularly in the peripartum state, may trigger vasospasm.Vasospasm resulting from dopamine agonists may be a common cause of injury to the pituitary gland, and it may have been overlooked in the past.",
"affiliations": "Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology , McGill University Health Center , 687 Pine Avenue West F 6.58, Montreal, Quebec , Canada H3A 1A1.;Division of Endocrinology , McGill University Health Center , 687 Pine Avenue West F 6.58, Montreal, Quebec , Canada H3A 1A1.;Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology , McGill University Health Center , 687 Pine Avenue West F 6.58, Montreal, Quebec , Canada H3A 1A1.",
"authors": "Kuriya|Anita|A|;Morris|David V|DV|;Dahan|Michael H|MH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1530/EDM-15-0001",
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepedmEDM Case ReportsEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol EDM15000110.1530/EDM-15-0001New Disease or Syndrome: Presentations/Diagnosis/ManagementPituitary injury and persistent hypofunction resulting from a peripartum non-hemorrhagic, vaso-occlusive event Pituitary injury and persistent hypofunctionKuriya Anita 1Morris David V 2Dahan Michael H 11 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, McGill University Health Center, 687 Pine Avenue West F 6.58, Montreal, Quebec, Canada H3A 1A12 Division of Endocrinology, McGill University Health Center, 687 Pine Avenue West F 6.58, Montreal, Quebec, Canada H3A 1A1Correspondence should be addressed to M H Dahan Email: dahanhaim@hotmail.com1 6 2015 2015 2015 15000119 4 2015 23 4 2015 © 2015 The authors2015This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nCerebral vascular accidents are caused by vasospasm when induced by preeclampsia or by dopamine agonists. However, six arteries nourish the pituitary and prevent against vasospasm-induced damage, which up until now has not been thought to occur. Bromocriptine was used to arrest lactation in a 31-year-old with secondary amenorrhea following preeclampsia and fetal demise at 28 weeks gestation. Tests and history revealed panhypopituitarism not associated with hemorrhage or mass infarction but instead caused by vasospasm. The present study is the first report of pituitary damage from a non-hemorrhagic, vaso-occlusive event in the literature. In keeping with Sheehan's and Simon's syndromes, we have named pituitary damage resulting from vaso-occlusion as Dahan's syndrome, and a literature review suggests that it may be a common and previously overlooked disorder.\n\nLearning points\n\nVasospasm can cause damage to the pituitary gland, although it was not previously believed to do so.\n\nPreeclampsia and the use of a dopamine agonist, particularly in the peripartum state, may trigger vasospasm.\n\nVasospasm resulting from dopamine agonists may be a common cause of injury to the pituitary gland, and it may have been overlooked in the past.\n==== Body\nBackground\nDuring pregnancy, the pituitary gland undergoes hypertrophy and enlarges to compensate for increased hormone production during the intra-partum and postpartum periods. The circle of Willis is a physiologic compensatory mechanism to protect the pituitary gland from blood loss, which is a common phenomenon at delivery. Inflow to the circle occurs from the right and left anterior, middle, and posterior cerebral arteries. The fact that six arteries supply blood to the pituitary protects this gland from insufficiency when an artery or, in theory, even two arteries are occluded because of stroke, vasospasm, or significant postpartum hemorrhage. Having so many arteries feed the gland ensures that some blood flow continues during peripartum severe shock.\n\nPreeclampsia has been shown to result in cerebral vascular thrombosis during pregnancy (1)\n(2). One study showed that risk factors for postpartum cerebral vascular disease, including ischemic stroke, intracranial hemorrhage, cerebral venous sinus thrombosis, pituitary apoplexy, carotid/vertebral artery dissection, hypertensive encephalopathy, or other acute cardiovascular disease that occurred after hospital discharge but before 6 weeks after delivery, were eclampsia (odds ratio (OR) 10.1; 95% CI 3.09, 32.8) and preeclampsia (OR 2.1; 95% CI 1.6, 2.8), among other factors, including coagulation disorders and African origins (3). However, that study did not add to our understanding of the mechanisms that cause these disorders. The mechanism that underlies preeclampsia-caused vascular thrombosis is thought to be vasospasm, which also puts the patients at risk for eclamptic seizures (4). Dopamine agonists have also been noted to place patients at risk for postpartum vaso-occlusive episodes (2). The case in the present study is the first to report pituitary damage from a non-hemorrhagic vasospasmic event; it is thus a combination of severe preeclampsia and a postpartum dopamine agonist.\n\nCase presentation\nA 31-year-old African American G2P2L1 type 2 diabetic (DM2) presented with a 3-year history of secondary infertility and amenorrhea without any headaches. She had been diagnosed with DM2 6 years earlier after being tested for it because of her strong family history of DM2. Her condition was managed with short-acting insulin lispro: 14 units before breakfast, 14 units before lunch, and 14 units before dinner as s.c. injections. She also received an injection of 12 units of neutral protamine Hagedorn long-acting insulin at bedtime. Sliding scale lispro insulin was also used as needed. She demonstrated no evidence of organ injury.\n\nThe patient did not report any difficulty in conceiving her first two pregnancies. The amenorrhea presented in the immediate postpartum period, and she failed to have any menses after delivery. She had undergone a successful induction of labor at 28 weeks gestation for severe preeclampsia and fetal demise at another institution. There was no history of eclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, postpartum hemorrhage, infection, fever, or curettage. Her liver enzymes and platelet count were normal throughout her admission. However, she was given bromocriptine (5 mg daily for 30 days) postpartum to prevent lactation because of the fetal demise. Two days after delivery, she complained of severe headache and transient left-sided weakness. A computed tomography (CT) scan and CT arteriogram of the brain were ordered. The CT scan did not find any masses, lesions, vascular accidents, hemorrhages, or sinus thrombosis. The pituitary gland was normal size, and no adenomas or deviations were noted. The arteriogram did not detect any vascular occlusions. However, vascular flow was noted to be diffusely decreased, particularly at the distal ends of arteries, which is consistent with diffuse spasm. In spite of this finding, the bromocriptine was continued. No delivery of vasodilators was recorded.\n\nThe patient described her amenorrhea as dating from that period onward. She denied any history of bitemporal hemianopsia, diploplia, or any other vision problems during or after the pregnancy. Loss of consciousness, frequent urination, and polydipsia were also denied.\n\nInvestigation\nUpon physical examination, the patient had an elevated BMI (36 kg/m2). Her HbA1c level was 7.9%. Her initial ultrasound showed an anatomically normal uterus with an antral follicle count of 11. Random hormonal test results showed a serum with 3.0 IU/l follicle-stimulating hormone (FSH; follicular phase: 2–15 IU/l, mid-cycle: 5–20 IU/l, luteal phase: 2–10 IU/l, and menopause: 25–135 IU/l), 3.0 IU/l luteinizing hormone (LH; follicular phase: 2–10 IU/l, mid-cycle: 15–100 IU/l, luteal phase: 1–10 IU/l, and menopause: 10–60 IU/l), 41 pmol/l estradiol (E2; normal: non-pregnant 50–1800 pmol/l and menopausal <18–200 pmol/l), 1.52 mIU/l thyrotrophin (TSH; normal: 0.40–4.40 mIU/l), 17 pmol/l free thyroxine (normal: 10–23 pmol/l), 0.22 nmol/l total testosterone (normal: 0.35–2.70 nmol/l), and 3.0 μg/l prolactin (normal: 3.3–26.7 μg/l). Repeat random analysis showed a serum with 3.7 IU/l FSH, 2.2 IU/l LH, 147 pmol/l E2, 4 pmol/l early morning fasting adrenocorticotropin (ACTH; normal: ≤10 pmol/l), 127 nmol/l random cortisol (normal: 120–535 nmol/l), 11.4 nmol/l insulin-like growth factor 1 (normal: 13.3–42.6 nmol/l), and 2.5 μg/l prolactin (normal: 3.3–26.7 μg/l). Serum sodium, potassium, and chloride levels were normal. A clomiphene challenge test was administered, wherein 100 mg of clomiphene was given for 5 days. Five days after completing the clomiphene, serum FSH and E2 levels were 3.7 IU/l and <73.4 pmol/l respectively, which confirmed a pituitary gonadotropin production dysfunction. An insulin-induced hypoglycemic stress test of the adrenal gland resulted in the serum levels that are shown in Table 1. Cortisol levels did not increase with induced hypoglycemia, as would normally occur. The patient did become symptomatic; however, adequate hypoglycemia was not obtained. A magnetic resonance imaging (MRI) exam showed a small, partially degenerated pituitary gland consistent with an empty sella as well as a thin hypothalamic stalk.\n\nTable 1 Insulin bolus-induced hypoglycaemic changes in serum cortisol levels\n\n\t\nTime (min)\t\n\n−15\n\t\n15\n\t\n30\n\t\n45\n\t\n60\n\t\n90\n\t\n120\n\t\nSerum cortisol levels (nmol/l)\t221\t189\t173\t162\t182\t178\t180\t\nSerum insulin levels (pmol/l)\t120\t\t965\t\t992\t1057\t335\t\nSerum glucose levels (mmol/l)\t12.5\t14.2\t10.4\t9.2\t7.4\t5.9\t4.8\t\nTreatment\nAlthough doing so was debatable, oral glucocorticoid therapy was initiated in the form of 12.5 mg Cortizone to be taken orally twice daily, because all other attempts to alter in any way the patient's endogenous cortisol levels failed. Diabetic control was augmented.\n\nOutcome and follow-up\nIn order to explain the present patient's pituitary dysfunction, we hypothesized that she had a cerebrovascular accident at the level of the circle of Willis that had resulted from the vaso-occlusive effects of severe preeclampsia and the intake of a postpartum dopamine agonist.\n\nDiscussion\nBromocriptine acts as a dopamine agonist, and its side effects, which are mostly minor, include orthostatic hypotension, nausea, and headaches. Although it is rare, vasospasm has been described as being related to the use of bromocriptine, particularly in the postpartum period (2). Katz et al. (5) reported two cases of cerebrovascular accidents that presented several days after the use of bromocriptine. They concluded that the exact mechanism of the events that led to the cerebral accidents remained unclear, but they questioned the safety of bromocriptine use for lactation suppression. Kim et al. (4) reported a similar case of postpartum reversible cerebral vasoconstriction syndrome in a patient following bromocriptine use in the peripartum period. The postpartum period has been associated with an elevated risk for thromboembolic events (1). Postpartum cerebral vascular thrombosis has also been associated with severe preeclampsia (2). One case documented pituitary apoplexy (intra-pituitary hemorrhage) as a result of severe preeclampsia and HELLP syndrome with a resultant low platelet count and a risk for spontaneous bleeding (6). But to date there have been no cases described in the literature of hypopituitarism that resulted from a non-hemorrhagic, vaso-occlusive event, regardless of whether they occurred in the peripartum period or in a non-pregnancy state. In none of the cases in the literature has there been a report of pituitary damage related to preeclampsia without hemorrhage.\n\nThe present patient not only presented with secondary amenorrhea in the absence of other puerperal risk factors, but she also had radiologic imaging suggestive of injury at the pituitary level (7). The pituitary undergoes many anatomic and physiologic changes during pregnancy, mainly to accommodate enlarging lactotrophs, which makes it vulnerable to many pregnancy-related disorders (7). Defects at the level of the hypophysis are best visualized on MRI. A partially empty sella can signify a primary defect in the pituitary that is related to a defect in cerebrospinal fluid pressure or a secondary defect that is related to the removal or treatment of a mass, mass infarct, or pituitary apoplexy. A partially empty sella can also be seen in Sheehan's syndrome or lymphocytic hypophysitis (8)\n(9). According to the MRI report in the present study, the pituitary was found to have a thin, not thickened, pituitary stalk, which makes the differential of lymphocytic hypophysitis less likely. Moreover, the lack of a history of postpartum hemorrhage invalidates Sheehan's syndrome. The occurrence of amenorrhea was temporally associated with severe preeclampsia combined with the use of a postpartum dopamine agonist. The CT scan at the time of the incident confirmed a normal pituitary gland, which ruled out hemorrhage into a pituitary macroadenoma apoplexy. Vasospasm was diffusely present, which supported the conclusion of peripartum vasospasm at the pituitary level to explain our patient's symptomatology. However, the fact that the patient did not have an MRI exam in the peripartum period is a limitation. There has been a suggestion in the literature that the sensitivity of MRI, particularly in non-hemorrhage pituitary apoplexy, appears to be superior to that of CT scans (10)\n(11).\n\nHypopituitarism can have a variety of presentations. Symptoms vary according to the degree of hormonal deficiency and can be partial or total and acute or chronic. As a general rule, gonadotropins and growth hormones (GH) are more likely to be affected than ACTH and TSH are. Prolactin deficiency, which was present in our patient, is usually a rare manifestation and appears after global pituitary dysfunction (8). GH production was also suppressed in the present case. In spite of the symptomatology, the ACTH stimulation in this patient did not increase in response to insulin-induced hypoglycemia. However, the level of the hypoglycemia was insufficient to confirm a diagnosis of ACTH production failure. It is fascinating that the patient's serum cortisol levels remained unchanged in spite of the symptomatology, though. The symptomatology was likely caused by poorly controlled diabetes mellitus type 2.\n\nA combination of low FSH, LH, and E2 will prompt a diagnosis of hypogonadotropic hypogonadism (HH). The clomiphene challenge test is a commonly used test to confirm HH. When this test was administered to the present patient, she failed to produce gonadotropins, which once again confirmed a lesion at the pituitary level.\n\nInfarction of a pituitary macroadenoma with a resultant pituitary hemorrhage can result in pituitary injury (12). No macro- or microadenomas of the pituitary gland were present in our patient. Traditionally, empty sella syndrome resulting from macroadenoma infarction and the resultant herniation of the meninges into the sella turcica and compression of the pituitary results in maintained pituitary function or a minimal loss of hormone production (12). Although panhypopituitarism can occur with empty sella syndrome, the macroadenoma that would have been required to initiate the event was not present (12). Lastly, up to 80% of patients with empty sella syndrome report chronic headaches, which were lacking in the present case (12). Although diabetes mellitus is associated with increased vascular disease, it has not been described as a cause of severe pituitary hypofunction because of the protection provided by the many vessels that feed the circle of Willis. Rarely, infiltrative diseases, such as sarcoidosis or lymphoma, or radiation therapy have been shown to damage the pituitary gland, although evidence of these diseases was lacking in the present case.\n\nIn the medical literature, pituitary injury resulting from a hemorrhagic peripartum event is called Shehan's syndrome, whereas a hemorrhagic non-pregnancy event (usually a car accident or other severe trauma) is called Simon's syndrome. To maintain continuity, we propose that pituitary injury resulting from a non-hemorrhagic vaso-occlusive event be called Dahan's syndrome.\n\nIt cannot be known if the damage caused to the pituitary resulted from preeclampsia, the use of a dopamine agonist postpartum, or a combination of both. The literature lists the use of dopamine agonists as being more common in patients who present with pituitary hypofunction (apoplexy) and a history of pituitary masses (13). However, the mechanism of pituitary injury was thought to be the result of tumor infarct, and the present case suggests that it may be a result of vascular spasm (13). Spasms are more likely to cause injury at the pituitary gland level in people with small microadenomas of 1–3 mm in size when they are on dopamine agonists than infarction is. Pituitary injury in these situations has been previously noted (13). It should be recognized that that the six vessels supply the circle of Willis from their most distal points. It could be hypothesized that uniform vasospasm of all of these vessels caused by a pathologic condition or medication could spare the brain but provide inadequate blood flow to the pituitary gland.\n\nIn short, many endocrine disorders can lead to amenorrhea. The differential diagnosis of secondary amenorrhea can be vast. In the present case, the investigation led to a hypothesis of postpartum pituitary hypofunction and damage secondary to vasospasm that was caused by a combination of severe preeclampsia or the use of a postpartum dopamine agonist. This makes the present case the first of its kind in the literature, and it has resulted in the coining of the term Dahan's syndrome.\n\nPatient consent\nWritten informed consent was obtained from the patient for the publication of this case report.\n\nAuthor contribution statement\nAll three authors were involved in the investigation and work up of this patient. All three authors participated in the writing of this case report. Dr M H Dahan was the primary physician, Dr D V Morris was the referral endocrinologist from Dr M H Dahan, and Dr A Kuriya was the resident on the case.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n==== Refs\nReferences\n1 \n\nKamel \nH \n, \nNavi \nBB \n, \nSriram \nN \n, \nHovsepian \nDA \n, \nDevereux \nRB \n & \nElkind \nMSV \n. 2014 \nRisk of thrombotic event after the 6-week postpartum period . New England Journal of Medicine \n370 \n1307 –1315 . 10.1056/NEJMoa1311485 \n24524551 \n2 \n\nWitlin \nAG \n, \nMattar \nF \n & \nSibai \nB \n. 2000 \n\nPostpartum stroke: a twenty-year experience . American Journal of Obstetrics and Gynecology \n183 \n83 –88 . 10.1016/S0002-9378(00)70397-8 \n10920313 \n3 \n\nHovsepian \nDA \n, \nSriram \nN \n, \nKamel \nH \n, \nFink \nME \n & \nNavi \nBB \n. 2014 \nAcute cerebrovascular disease occurring after hospital discharge for labor and delivery . Stroke \n45 \n1947 –1950 . 10.1161/STROKEAHA.114.005129 \n24903986 \n4 \n\nKim \nYS \n, \nBaek \nW \n, \nKim \nJ \n, \nKim \nHY \n & \nLee \nYJ \n. 2012 \nDelayed ischemic stroke associated with bromocriptine-induced reversible cerebral vasoconstriction syndrome . Neurological Sciences \n34 \n409 –411 . 10.1007/s10072-012-1015-z \n22419017 \n5 \n\nKatz \nM \n, \nKroll \nD \n, \nPak \nI \n, \nOsimoni \nA \n & \nHirsch \nM \n. 1985 \nPuerperal hypertension, stroke, and seizures after suppression of lactation with bromocriptine . 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Endocrine Research \n34 \n10 –17 . 10.1080/07435800902841306 \n19557587 \n9 \n\nGlezer \nA \n & \nBronstein \nMD \n. 2012 \nPituitary autoimmune disease: nuances in clinical presentation . Endocrine \n42 \n72 –74 . 10.1007/s12020-012-9654-7 \n\n10 \n\nBoellis \nA \n, \ndi Napoli \nA \n, \nRomano \nA \n & \nBozzao \nA \n. 2014 \nPituitary apoplexy: an update on clinical and imaging features . Insights into Imaging \n5 \n753 –762 . 10.1007/s13244-014-0362-0 \n25315035 \n11 \n\nRandeva \nHS \n, \nSchoebel \nJ \n, \nByrne \nJ \n, \nEsiri \nM \n, \nAdams \nCB \n & \nWass \nJA \n. 1999 \nClassical pituitary apoplexy: clinical features, management and outcome . Clinical Endocrinology \n51 \n181 –188 . 10.1046/j.1365-2265.1999.00754.x \n10468988 \n12 \n\nGuitelman \nM \n, \nGarcia Basavilbaso \nN \n, \nVitale \nM \n, \nChervin \nA \n, \nKatz \nD \n, \nMiragaya \nK \n, \nHerrera \nJ \n, \nCornalo \nD \n, \nServidio \nM \n, \nBoero \nL \n\n\n2013 \nPrimary empty sella (PES): a review of 175 cases . Pituitary \n2 \n270 –274 . 10.1007/s11102-012-0416-6 \n22875743 \n13 \n\nVargas \nG \n, \nGonzalez \nB \n, \nGuinto \nG \n, \nMendoza \nV \n, \nLópez-Félix \nB \n, \nZepeda \nE \n & \nMercado \nM \n. 2014 \nPituitary apoplexy in nonfunctioning pituitary macroadenomas: a case–control study . Endocrine Practice \n20 \n1274 –1280 . 10.4158/EP14120.OR \n25100377\n\n",
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"medline_ta": "Endocrinol Diabetes Metab Case Rep",
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"pmid": "26038692",
"pubdate": "2015",
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"references": "3840873;21601847;24524551;22419017;22583510;10920313;24903986;22875743;25315035;22426958;19557587;25100377;10468988",
"title": "Pituitary injury and persistent hypofunction resulting from a peripartum non-hemorrhagic, vaso-occlusive event.",
"title_normalized": "pituitary injury and persistent hypofunction resulting from a peripartum non hemorrhagic vaso occlusive event"
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{
"abstract": "This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma.\n\n\n\nEligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.\n\n\n\n141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]).\n\n\n\nEryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.",
"affiliations": "Digestive and Medical Oncology Unit, Hôpital Beaujon, Assistance Publique - Hôpitaux de Paris, University Denis Diderot Paris VII, 92110 Clichy, France. Electronic address: pascal.hammel@aphp.fr.;Parc Euromedecine, 208 Rue Des Apothicaires, 34070 Montpellier, France.;Institut Sainte Catherine, Gastrointestinal and Liver Cancer Unit, Chemin de Baigne Pieds, 84000 Avignon, France.;CHRU de Brest - Hôpital Morvan, 2 Avenue Foch, 29609 Brest, France.;Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, and Sorbonne Universités, France.;Medical Oncology Department, Centre Leon Berard, Lyon, France.;Department of Medical Oncology, Institut Mutualiste Montsouris, 42 Boulevard Jourdan, 75014 Paris, France.;Centre Oscar Lambret, 3 Rue Frédéric Combemale, 59000 Lille, France.;Les Oudairies, Hospital La Roche-Sur-Yon, Boulevard Stephane Moreau, 85000 La Roche Sur Yon, France.;Institut Universitaire du Cancer, Avenue Hubert Curien, 31100 Toulouse, France.;Gastroenterology Department and Medical Oncology Department, Poitiers University Hospital, Faculty of Medicine of Poitiers, 86000 Poitiers, France.;Service Oncologie Digestive, CHU Reims, Avenue Général Koenig, 51092 Reims Cede, France.;Department of Hepatogastroenterology and Digestive Oncology, CHU de Tours, 37044 Tours Cedex, France.;Groupe Hospitalier Mutualiste de Grenoble, 8 Rue Docteur Calmette, 38100 Grenoble, France.;Service d'Oncologie médicale, Hôpital Henri Mondor, AP-HP, Université Paris-Est, 94010 Créteil, France.;Beaujon University Hospital, Department of Pathology-INSERM U1149, 100 Bvd Gal Lerclerc, 92110 Clichy, France.;RK Statistics Ltd, St Giles View, Main Street, Great Longstone, Bakewell, DE45 1TZ, UK.;Cytel Inc., 675 Massachusetts Ave Cambridge, MA 02139, USA.;ERYTECH, One Main Street, Suite 1150, Cambridge, MA 02142, USA.;Sorbonne Universités, UPMC Université, Gastroenterology and Digestive Oncology Department, Pitié Salpêtrière Hospital, 75013 Paris, France.;ERYTECH, One Main Street, Suite 1150, Cambridge, MA 02142, USA.",
"authors": "Hammel|Pascal|P|;Fabienne|Portales|P|;Mineur|Laurent|L|;Metges|Jean-Philippe|JP|;Andre|Thierry|T|;De La Fouchardiere|Christelle|C|;Louvet|Christophe|C|;El Hajbi|Farid|F|;Faroux|Roger|R|;Guimbaud|Rosine|R|;Tougeron|David|D|;Bouche|Olivier|O|;Lecomte|Thierry|T|;Rebischung|Christine|C|;Tournigand|Christophe|C|;Cros|Jerome|J|;Kay|Richard|R|;Hamm|Adam|A|;Gupta|Anu|A|;Bachet|Jean-Baptiste|JB|;El Hariry|Iman|I|",
"chemical_list": "D009944:Organoplatinum Compounds; D003841:Deoxycytidine; C056507:gemcitabine; D001215:Asparaginase; C000708079:eryaspase; D019733:Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; C000629889:ASNS protein, human; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2019.10.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "124()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Asparaginase; Asparagine synthetase; Erythrocyte; Pancreatic adenocarcinoma; Survival",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D001706:Biopsy; D019733:Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia; D009944:Organoplatinum Compounds; D010179:Pancreas; D010190:Pancreatic Neoplasms; D000077982:Progression-Free Survival; D066066:Response Evaluation Criteria in Solid Tumors",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "91-101",
"pmc": null,
"pmid": "31760314",
"pubdate": "2020-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial.",
"title_normalized": "erythrocyte encapsulated asparaginase eryaspase combined with chemotherapy in second line treatment of advanced pancreatic cancer an open label randomized phase iib trial"
} | [
{
"companynumb": "FR-PFIZER INC-2020042133",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "The second-generation proteasome inhibitor carfilzomib produces superior outcomes in relapsed or refractory multiple myeloma (MM). We conducted a single-arm trial of twice-weekly carfilzomib (27 mg/m2)-dexamethasone (Kd27) for relapsed and refractory MM in China. Kd27 was administered in 28-day cycles to 123 patients previously treated with ≥ 2 other regimens, including treatment with bortezomib and an immunomodulatory drug, and refractory to their most recent therapy. Overall response rate (ORR) was the primary endpoint; progression-free survival (PFS) and overall survival (OS) were key secondary endpoints. Primary analysis was conducted when all patients received ≥ 6 cycles of Kd27 or discontinued Kd27. Median age was 60 years; median number of prior regimens was 4; 74% were refractory to proteasome inhibitors and immunomodulatory drugs. ORR was 35.8% (95% CI 27.3-44.9), median PFS was 5.6 (95% CI 4.6-6.5) months, and median OS was 16.6 (95% CI 12.2-NE) months. Grade ≥ 3 adverse events (AEs) occurred in 76.4% of patients. Grade ≥ 3 AEs of interest included hypertension (13.8%), acute renal failure (3.3%), cardiac failure (0.8%), ischemic heart disease (0.0%), and peripheral neuropathy (0.0%); 5.7% of patients discontinued carfilzomib due to AEs. Carfilzomib-dexamethasone produced a clinically meaningful response without new safety findings in Chinese patients with previously treated MM.Trial registration: NCT03029234.",
"affiliations": "Department of Hematology, Shanghai Changzheng Hospital, Shanghai, China.;Department of Hematology, Henan Cancer Hospital, Zhengzhou, Henan, China.;Department of Hematology, Peking Union Medical College Hospital, Beijing, China.;Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China.;Department of Hematology, Guangzhou First People's Hospital, Guangzhou, Guangdong, China.;Department of Lymphoma and Myeloma, Institute of Hematology and Hospital of Blood Disease, Tianjin, China.;Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China.;Department of Hematology, Central Hospital of Wuhan, Wuhan, Hubei, China.;Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.;Department of Hematology, The First Hospital of Jilin University, Changchun , Jilin, China.;Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.;Department of Hematology and Oncology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Hematology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.;Department of Hematology, Zhongshan Hospital Fudan University, Shanghai, China.;Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.;Global Biometric Data Science, Amgen Inc., Shanghai, China.;Global Development, Amgen Inc, Thousand Oaks, CA, USA.;Department of Hematology, Shanghai Renji Hospital, 160 Pujian Road, Pudong New District, Shanghai, China. houjian@medmail.com.cn.;Department of Hematology, Beijing Chao Yang Hospital, Capital Medical University, 8 Gongti South Road, Beijing, 100020, China. 13910107759@163.com.",
"authors": "Du|Juan|J|;Fang|Baijun|B|;Li|Jian|J|;Jin|Jie|J|;Wang|Shunqing|S|;Zou|Dehui|D|;Cai|Zhen|Z|;Wang|Hongxiang|H|;Hu|Jianda|J|;Li|Wei|W|;Fu|Chengcheng|C|;Shao|Zonghong|Z|;Xia|Zhongjun|Z|;Liu|Peng|P|;Niu|Ting|T|;Tang|En-Tzu|ET|;Kimball|Amy S|AS|;Hou|Jian|J|;Chen|Wenming|W|",
"chemical_list": "D009842:Oligopeptides; C524865:carfilzomib; D003907:Dexamethasone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-020-03044-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "113(3)",
"journal": "International journal of hematology",
"keywords": "Carfilzomib; China; Proteasome inhibitor; Relapsed and refractory multiple myeloma; Single-arm",
"medline_ta": "Int J Hematol",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002681:China; D003131:Combined Modality Therapy; D003907:Dexamethasone; D019008:Drug Resistance, Neoplasm; D005260:Female; D006331:Heart Diseases; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D006973:Hypertension; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D010523:Peripheral Nervous System Diseases; D000077982:Progression-Free Survival; D012008:Recurrence; D016879:Salvage Therapy",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "422-429",
"pmc": null,
"pmid": "33389656",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A study of carfilzomib and dexamethasone in patients with relapsed and refractory multiple myeloma in China.",
"title_normalized": "a study of carfilzomib and dexamethasone in patients with relapsed and refractory multiple myeloma in china"
} | [
{
"companynumb": "CN-TAKEDA-2021TUS078946",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in a recipient of a solid organ, bone marrow or stem cell allograft. The development of PTLDs is usually associated with Epstein-Barr virus (EBV) and the disorder is also termed EBV-associated lymphoproliferative disorder (LPD). The development of PTLD is a rare complication in autologous bone marrow/peripheral blood stem cell transplantation. In the present study, we report a case of EBV-associated LPD which developed following autologous peripheral blood stem cell transplantation for relapsing Hodgkin's lymphoma. A 51-year-old male presented with swelling of the left cervical lymph nodes. A biopsy revealed nodular sclerosis classical Hodgkin's lymphoma. Following four courses of ABVd (adriamycin, bleomycin, vinblastine, dacarbazine) therapy, the Hodgkin's lymphoma relapsed. CHASE (cyclophosphamide, etoposide, cytarabine, dexamethasone) therapy and autologous peripheral blood stem cell transplantation were performed. In the 128 days following the transplantation, lymph node swelling was noted and a biopsy specimen demonstrated EBV-associated LPD. The serum copy number of EBV-DNA was 2.7×10(3) copies/ml. The occurrence of EBV-associated LPD may be on the rise due to the increased number of patients undergoing immunosuppression therapy. The measurement of the serum EBV-DNA copy number and the detection of EBV-infected atypical lymphocytes using in situ hybridization are significant in establishing an early accurate diagnosis and initiating the correct treatment for EBV-associated LPD in patients with immunosuppression.",
"affiliations": "Department of Hematology, Shiga University of Medical Science, Otsu, Shiga, Japan.",
"authors": "Izumiya|Sakura|S|;Ishida|Mitsuaki|M|;Hodohara|Keiko|K|;Yoshida|Takashi|T|;Okabe|Hidetoshi|H|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2012.670",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "3(6)",
"journal": "Oncology letters",
"keywords": null,
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1203-1206",
"pmc": null,
"pmid": "22783418",
"pubdate": "2012-06",
"publication_types": "D016428:Journal Article",
"references": "15877793;14506660;9674863;2821199;9720750;11998794;21739449;17049061;14730339;11100284;14974943;18832928;20874650;11223975",
"title": "Epstein-Barr virus-associated lymphoproliferative disorder developed following autologous peripheral blood stem cell transplantation for relapsing Hodgkin's lymphoma.",
"title_normalized": "epstein barr virus associated lymphoproliferative disorder developed following autologous peripheral blood stem cell transplantation for relapsing hodgkin s lymphoma"
} | [
{
"companynumb": "JP-PFIZER INC-2019096360",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
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