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"abstract": "The addition of NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (Peg-IFN)-α and ribavirin for the treatment of hepatitis C virus (HCV) genotype 1-infected patients has led to higher rates of virological response and adverse events. Among the several side effects of interferon, neuropsychiatric symptoms have been described, particularly depression and anxiety, occurring in about 25% of patients. Although seizures have been reported in interferon-treated patients with multiple sclerosis and in a variety of malignancies, the epileptogenic potential of interferon-α in the treatment of HCV infection is considered minimal. In this report we present a new onset of seizures occurring in 2 patients during anti-HCV therapy in association with Peg-IFN, ribavirin and HCV protease inhibitors.",
"affiliations": "Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy.",
"authors": "Milazzo|Laura|L|;Falvella|Felicia Stefania|FS|;Magni|Carlo|C|;Gervasoni|Cristina|C|;Peri|Anna Maria|AM|;Cattaneo|Dario|D|;Antinori|Spinello|S|;Vidale|Simone|S|",
"chemical_list": "D000998:Antiviral Agents; D002352:Carrier Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; C084422:NS3 protein, hepatitis C virus; C455041:NS4A cofactor peptide, Hepatitis C virus; D009842:Oligopeptides; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000355836",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-7012",
"issue": "92(5-6)",
"journal": "Pharmacology",
"keywords": null,
"medline_ta": "Pharmacology",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D002352:Carrier Proteins; D004347:Drug Interactions; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011392:Proline; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012254:Ribavirin; D012640:Seizures; D017361:Viral Nonstructural Proteins",
"nlm_unique_id": "0152016",
"other_id": null,
"pages": "235-7",
"pmc": null,
"pmid": "24192929",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures in patients with chronic hepatitis C treated with NS3/4A protease inhibitors: does pharmacological interaction play a role?",
"title_normalized": "seizures in patients with chronic hepatitis c treated with ns3 4a protease inhibitors does pharmacological interaction play a role"
} | [
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"companynumb": "IT-TEVA-515090ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
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"drugadditional": null,
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{
"abstract": "Advances in therapies and management of conditions encountered by paediatric respiratory specialists have led to improved outcomes and improved survival rates dramatically in chronic diseases such as cystic fibrosis. However, this has also meant an increase in treatment burden. A variety of inhaled treatments are crucial in managing paediatric respiratory diseases, but these patients also have to take many oral medications. It is widely recognised that developing oral formulations appropriate for the paediatric population can affect how well a product is received by patients and their families. Consideration should be given to palatability and the number of medicines to be administered as these can all contribute to treatment adherence. Polypharmacy specifically in the context of management of patients with cystic fibrosis is not a new concept, but the recently introduced cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and their potential for interactions and adverse reactions create novel challenges. There are some strategies that families and healthcare professionals can implement to reduce treatment burden. This review will also provide some insight into the life of a teenager with cystic fibrosis and the relative complexities of her treatment and the impacts on daily life.\nTo describe the difficulties faced by children with long-term respiratory conditions having to take oral medication.To discuss oral drug interactions that may exist within paediatric respiratory medicine and to consider issues with polypharmacy.To highlight strategies that may be used to reduce the burden of care for children on oral medication.",
"affiliations": "Pharmacy Dept, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK.;Paediatric Respiratory Medicine, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK.;Paediatric Respiratory Medicine, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK.",
"authors": "Sareen|Anneka|A|;Ramphul|Manisha|M|https://orcid.org/0000-0002-6209-3869;Bhatt|Jayesh Mahendra|JM|https://orcid.org/0000-0003-0083-7460",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1183/20734735.0005-2021",
"fulltext": "\n==== Front\nBreathe (Sheff)\nBreathe (Sheff)\nBREATHE\nbreathe\nBreathe\n1810-6838\n2073-4735\nEuropean Respiratory Society\n\n10.1183/20734735.0005-2021\nEDU-0005-2021\nVersion of Record\nReviews\n9\n14\nIt's not all about inhaled treatment: challenges with oral therapy in paediatric respiratory medicine\nChallenges with oral therapy in paediatric respiratory medicine\nSareen Anneka 1\nhttps://orcid.org/0000-0002-6209-3869\nRamphul Manisha 2\nhttps://orcid.org/0000-0003-0083-7460\nBhatt Jayesh Mahendra 2\n1 Pharmacy Dept, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK\n2 Paediatric Respiratory Medicine, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK\nE-mail: jayesh.bhatt@nuh.nhs.uk\n3 2021\n17 1 2100055 1 2021\n30 3 2021\nCopyright ©ERS 2021\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Breathe articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.\nAdvances in therapies and management of conditions encountered by paediatric respiratory specialists have led to improved outcomes and improved survival rates dramatically in chronic diseases such as cystic fibrosis. However, this has also meant an increase in treatment burden. A variety of inhaled treatments are crucial in managing paediatric respiratory diseases, but these patients also have to take many oral medications. It is widely recognised that developing oral formulations appropriate for the paediatric population can affect how well a product is received by patients and their families. Consideration should be given to palatability and the number of medicines to be administered as these can all contribute to treatment adherence.\n\nPolypharmacy specifically in the context of management of patients with cystic fibrosis is not a new concept, but the recently introduced cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and their potential for interactions and adverse reactions create novel challenges. There are some strategies that families and healthcare professionals can implement to reduce treatment burden. This review will also provide some insight into the life of a teenager with cystic fibrosis and the relative complexities of her treatment and the impacts on daily life.\n\nEducational aims\n\nTo describe the difficulties faced by children with long-term respiratory conditions having to take oral medication.\n\nTo discuss oral drug interactions that may exist within paediatric respiratory medicine and to consider issues with polypharmacy.\n\nTo highlight strategies that may be used to reduce the burden of care for children on oral medication.\n\nIn children, medications given by the oral route can be challenging to administer, add to the burden of care and contribute to poor adherence. Additionally, polypharmacy increases the chances of interactions between oral medications. https://bit.ly/3fxgXQU\n==== Body\nCase vignette\n\nA typical day in the life of a 16-year-old with cystic fibrosis (CF) and persistent nontuberculous mycobacterial (NTM) infection is described by her parent in box 1.\n\nBox 1 The parent's view\n\nAs the carer of a teenager with CF, I live with the constant feeling that I have forgotten something. When I started to write a list of all her treatments, I had this feeling (that I had forgotten something) so strongly that I decided to go through her daily routine for an average school day instead to give an idea of what goes on.\n\nOn waking Disconnect feed.\n\nGive percutaneous endoscopic gastrostomy (PEG) meds (co-trimoxazole, ursodeoxycholic acid, multivitamins).\n\nCheck blood sugar and give oral meds (Kaftrio, azithromycin, minocycline, clofazimine).\n\nSet up nebulised amikacin.\n\nNag about NovoRapid and creon if breakfast is on the cards and remember to check she has her BM machine in her schoolbag (not that she remembers to use it at school!).\n\nDad stands over her whilst she does physio and the nebuliser as compliance is not great if left to her own devices. This has become one of dad's jobs as I got fed up with the eye-rolling and attitude that daughters seem to give their mums and not their dads!\n\nAt school (in theory)\n\nBlood sugar before lunch and before leaving school.\n\nCreon and NovoRapid with lunch (I suspect not often).\n\nThis morning I had a few CF admin jobs after the school run: call to Nutricia as no extension sets came with yesterday's feed delivery, call to Pari as we need a new plug and nebuliser head for the eFlow, returned a call from DWP as our daughter was 16 the other day and DLA turns into PIP at age 16.\n\nOn return from school\n\nBlood sugar and food as usually starving!\n\nMore nagging about creon and NovoRapid.\n\nDornase via iNeb (again usually with supervision as can be a bit crafty with it, at least you can see whether she's done it from the number on the disc).\n\nAbout 9pm\n\nPhysio and then nebulised amikacin via the eFlow (again dad in attendance!)\n\nBedtime (usually overseen by me)\n\nSet up feed.\n\nGive meds (Lantus, Kalydeco, creon, co-trimoxazole and iron supplement via the PEG.) Three nights a week she has an injection of interferon-γ.\n\nOnce a week we change the water in the balloon (more eye-rolling!). Every 3–4 months we change the button. One of our trusty nurses comes once a month to flush the port.\n\nOther admin tasks include ordering meds from three different sources: general practitioner (GP), hospital and the homecare company. We also need to source needles and syringes for the interferon and for the amikacin (unusually from Amazon!).\n\nThen there's the psychological stuff.\n\nMy daughter usually seems pretty accepting, but she does get cheesed off especially with me. Mainly I suspect she gets fed up with me being in and out of her room, which is her teenage sanctuary. I have to make sure I knock these days!\n\nFrom my point of view, I frequently feel guilty I've forgotten a treatment or inadequate if we've run out of something and I haven't ordered it in time. Packing to go on holiday stresses me out entirely: I'm terrified of forgetting a nebuliser or the insulin, etc. (I write lots of lists!).\n\nAll in all, it's a full-time job but she's worth it!\n\nHer daily routine includes several inhalers, nebulisers and airway clearance twice daily. This is not the end of it: the routine gets even more challenging as she has to endure taking multiple oral medications (tablets, capsules and oral suspensions) (figure 1). These are all to be taken at different times of the day, and many of them do not taste very nice at all. Adherence with oral treatment is difficult; she feels nauseated with some of her treatment, which is then managed though the introduction of new oral medicines in the form of anti-emetics. Additionally, she has to have overnight feeds via the gastrostomy and have regular admissions to the hospital for intravenous antibiotics.\n\nFigure 1 Treatments taken each day (including oral, subcutaneous and nebulised medication and medicines/feeds via the gastrostomy).\n\nAfter discussion with her doctors and pharmacist, changes to her medication are made to help with the treatment burden. For example, rather than taking ursodeoxycholic acid in tablet form at 450 mg twice daily, she started taking 1 g once daily as a liquid. In view of the nausea with moxifloxacin being used to treat NTM, she is changed to minocycline.\n\nShe has a gastrostomy to optimise her nutrition and the gastrostomy also alleviates some of the discomfort with swallowing tablets; this involves changing a few of the medicines to liquid formulations.\n\nHer list of oral medications remains extensive: Creon 25 000 capsules, up to 5 per day\n\nOmeprazole MUPS 20 mg, once daily\n\nMultivitamin liquid 0.5 mL, alternate days\n\nUrsodeoxycholic acid liquid 1 g, once daily\n\nIron supplements 1 sachet, once daily\n\nAzithromycin liquid 250 mg, once daily\n\nMinocycline tablets 75 mg, once daily\n\nClofazimine tablets 50 mg, once daily\n\nMetoclopramide liquid, as needed\n\nOndansetron liquid, as needed\n\nParacetamol liquid, as needed\n\nIvacaftor 75 mg, Tezacaftor 50 mg and Elexacaftor 100 mg (Kaftrio) 2 tablets in the morning with 1 tablet of Ivacaftor 150 mg (Kalydeko®) in the evening\n\nInhaled/nebulised and injectable treatments: Dornase alfa 2.5 mg, once daily\n\nInterferon-γ 1B 60 μg, three times weekly\n\nSalbutamol 100 μg per dose metered-dose inhaler 2 puffs, twice daily\n\nInsulin administered as directed with meals\n\nIntroduction\n\nSwallowing tablets can be a challenge for young children who are yet to develop oro-motor oral skills, as well as for teenagers who dislike the sensation of swallowing medication. This may be a particular problem in paediatric respiratory medicine, for example in CF, where children may be on multiple oral medications. Alternative preparations, such as liquid formulations may be employed, but other issues such as palatability and side-effects (e.g. nausea) may also be contributing factors leading to poor adherence. The burden of care with oral medication is substantial for children and their families.\n\nWhat is adherence?\n\nThe World Health Organization defines adherence as “the extent to which a person's behaviour – taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider.” [1]. There are three stages where adherence to oral medication can falter in children with respiratory disease [2]. 1) Failure to initiate prescribed treatment. Initiation of treatment refers to the first time the child takes the treatment and this is a binary event, with patients either starting to take their oral medication or not.\n\n2) Failure to implement treatment as prescribed. Children may skip their medication at certain times or on certain days, due to personal factors or side-effects of the medication such as nausea.\n\n3) Non-persistence with treatment. Persistence relates to the extent to which patients take medication for the duration intended by the medical team, as paediatric patients may opt to stop taking the medication earlier than directed.\n\nOne study involving 100 paediatric patients aimed to identify levels of adherence to specific treatments used in the management of CF. Low adherers were defined as those who had <80% of their medicines dispensed against the quantity prescribed during the studied period. It identified that “72% of patients were classed as low adherers to enzyme supplements; 59% were low-adherers to vitamins and 49% were low adherers to chest physiotherapy” [3]. While this study focused on some (and not all) treatments used in the management of CF, it can help to provide a general indicator of adherence levels within the paediatric CF population.\n\nAdherence to oral medication in paediatric respiratory medicine is influenced by a variety of factors which will be explored below.\n\nTypes of formulations\n\nCF is a multi-system disease, whose treatment requires polypharmacy. It is widely recognised that the survival rates for people with CF have dramatically improved [4], due to improvement in management and development of new treatments [5, 6]. Management includes not only inhaled or nebulised medication, but also a wide array of oral medication such as: prophylactic and/or maintenance oral antibiotic therapies; pancreatic enzyme replacement therapy; fat-soluble vitamins; and other nutritional therapies.\n\nIn addition to the burden of oral and inhaled maintenance treatment, intravenous antibiotics may also be needed depending on the clinical status.\n\nThe oral therapies that are used are available in a variety of formulations and all licensed preparations can be found in the British National Formulary for Children (BNFc) and/or summary of product characteristics (SPCs) on the electronic medicines compendium (EMC) [7, 8]. It is worth noting that although licensed preparations exist, a number of medicines will not be licensed for use in certain respiratory conditions (e.g. azithromycin is often used for prophylactic and treatment purposes in CF and azoles, such as itraconazole, voriconazole and posaconazole, are used in the treatment of allergic bronchopulmonary aspergillosis (ABPA) but are not recognised in their license for these indications) [7, 9].\n\nNon-interchangeable oral formulations\n\nWhile a medicine may be available in a variety of formulations, there are some instances where formulations are not interchangeable.\n\nPosaconazole is also used for the treatment of ABPA and there is some research to indicate that it is superior compared with other azoles in terms of treatment success [10]. Posaconazole tablets and posaconazole liquid are not interchangeable and so the same formulation should be used throughout a treatment course [11, 12]. A retrospective study assessing clinical effectiveness of posaconazole tablets versus posaconazole liquid in lung transplant patients with Aspergillus identified that posaconazole tablets could be better relied upon for consistent posaconazole levels [13].\n\nBy contrast, serum concentrations of itraconazole are higher when the oral solution is used instead of the capsules (despite the same dose of drug being administered) [14, 15].\n\nIvacaftor (Kalydeko), lumacaftor/ivacaftor (Orkambi), tezacaftor/ivacaftor (Symkevi) and elexacaftor/tezacaftor/ivacaftor (Kaftrio) are all cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies that will potentiate or correct the CFTR pathway caused by defective variants within the CFTR gene [16, 17]. Ivacaftor (Kalydeko) and lumacaftor/ivacaftor (Orkambi) are available as granules and tablets and the remaining CFTR modulators are all available as tablets only [7]. Ivacaftor (Kalydeko) and lumacaftor/ivacaftor (Orkambi) are licensed for use in younger patients (4 months and 2 years of age, respectively), and are available in a variety of formulations including granules. The license for tezacaftor/ivacaftor (Symkevi) is for patients aged over 6 years and elexacaftor/tezacaftor/ivacaftor (Kaftrio) at the time of writing is for patients aged 12 years and over, and both are only currently available as tablet formulations.\n\nGiven previously identified variable levels of adherence to certain treatments used within CF [3], it remains to be seen whether these rates will be transferrable and applicable to CFTR modulators (and how these will balance against the relative cost of these drugs) [7].\n\nIssues around palatability, swallowing of medication or lack of suitable formulations\n\nGuidance published by the European Medicines Agency (EMA) recognises that it is of great importance to develop medication for use within paediatrics that is age-appropriate and to a consistently high standard without impacting unnecessarily on patients and their families in terms of treatment burden [18]. It also identified that patient acceptance of a particular product will affect whether patients are adherent and hence determine how effective and safe a treatment is. Issues such as palatability, appearance, the volume/number of doses (for liquids and tablets, respectively) and dosing frequency can have a significant impact on how well a product is received.\n\nThe Smart Paediatric Drug Development UK Project (SpaeDD-UK project) [19] worked to develop a theoretical algorithm to determine and describe what will be considered an acceptable medicine form for different age groups based on their own review of the limited information available. The project itself recognised the lack of primary research to indicate the size and number of tablets appropriate for each age group, which may support the somewhat surprising suggestions in table 1. It is thought that the suggestions may help in guiding decisions about the design and development of paediatric formulations that will probably be considered acceptable by different age groups.\n\nTable 1 Algorithm on acceptable medicine forms for different age groups\n\n\tLiquid#\tConventional or minitablet\tMulti-particulate\tOrodispersible tablet\tChewable tablet\t\nNeonates\t<0.5 mL volume\nNeutral taste\t2 mm minitablet acceptable\tX\tX\tX\t\nInfants\t<2.5 mL volume\nNeutral taste\t<3 mm tablet\nUp to 3 tablets per dose\tNeutral taste\t<6.5 mm tablet\nNeutral taste\tX\t\nChildren aged 2–5 years\t<2.5 mL volume\nNeutral taste\tUp to 10 minitablets acceptable\n<4 mm tablet\nUp to 3 tablets per dose\tNeutral taste\t<9.5 mm tablet\nNeutral taste\t<9.5 mm tablet\nNeutral taste\t\nChildren aged 6–12 years\t<10 mL volume\nNeutral taste\t<7 mm tablet\nUp to 3 tablets per dose\tNeutral taste\t<9.5 mm tablet\nNeutral taste\t<14.7 mm tablet\nNeutral taste\t\n#: including dispersible tablet or granules for reconstitution. Information from [19].\n\nFactors influencing starting to take tablets\n\nThere are a number of factors that will influence when a paediatric patient will be able to safely swallow tablets, but it is generally considered appropriate for individuals aged 6 years and upwards. For paediatric patients with chronic respiratory disease, it is thought that those aged as young as 3 years old may be able to swallow tablets following appropriate training and support from the multidisciplinary team and family (particularly where the alternative is a liquid formulation not tolerated due to taste) [18]. To further add to this, a feasibility study identified that tablets could be a possibility for patients aged 4 years and upwards, and that for younger patients, larger tablets may be easier to swallow (although an average of 8 mm diameter were tolerated across the studied age group of 4–12 years old) [20].\n\nA variety of methods can be adopted to support children in successfully swallowing tablets including behavioural techniques and changing head positions (as this can impact on swallowing) [21–23].\n\n“Pill schools” entail well-designed services, where children are seen by psychologists and play therapists for an initial assessment, followed by subsequent visits to set the scene, allow children to practice, allow parents to explore and tackle their individual child's worries and preferences, and reward the child with praise for their attempts. Families are also taught the techniques of positive reinforcement to help their children. This has been shown to be effective in children as young as 6 years old [24–26].\n\nPill schools have won the favour of both children and families who report that taking tablets is less stressful than taking liquids, and also of professionals who recognise that tablets are cheaper, have fewer excipients, may have modified-release mechanisms, and have a better safety profile in terms of ensuring the correct dose is administered.\n\nMedicines for Children have also developed an informative leaflet that can be downloaded or printed that provides practical information to help children swallow tablets or capsules [27].\n\nAlternatives to tablets: liquid formulations\n\nConsidering the appropriateness of excipients particularly in liquid formulations for paediatric patients can also provide challenges [18]. Excipients within a medicine will exist to serve a specific purpose, for example acting as a diluent or preservative [28]. It is well recognised that liquid formulations will need to be preserved (to support an appropriate shelf life of the product) whereas tablets will generally not require this [18].\n\nExcipients such as benzyl alcohol, ethanol, sorbitol and propylene glycol may be of detriment to paediatric patients if present in sufficient quantities [29].\n\nA variety of natural and artificial sweeteners are used in drug formulations to augment the sweetness and thereby palatability of the product. One or more sweeteners (for example aspartame, a phenylalanine-containing synthetic sweetener) can be found in up to 50% of medications including commonly prescribed antibiotics [30]. Omission and inaccuracy of drug labelling information on pharmaceutical excipients may expose susceptible individuals to adverse reactions caused by these agents [31]. Complications of inadvertent intake of sugar-containing medicines are not only a growing concern among dentists [32], but can also cause problems for children with diabetes, or patients with phenylketonuria due to the intake of aspartame [31]. The choice of an oral antibiotic is very restricted for a preschool-age child with phenylketonuria, who cannot swallow tablets and requires oral antibiotics for community-acquired pneumonia.\n\nWhile the risk of under- or over-dosing with liquid formulations is a possibility, the EMA specifies that the relative “ease and accuracy of administration” should form part of the pharmaceutical development of a product. Measuring devices such as syringes or cups should always be provided (unless specifically justified not to) [18]. With oral suspensions, there may be some separation of active ingredient from the vehicle in which it has been suspended. Consideration to appropriate patient counselling is required, as the risk of under- or over-dosing in this case can be resolved by shaking the oral suspension prior to use [18].\n\nIn November 2019, Merck announced that manufacture of theophylline capsules (Slo-Phyllin) would be discontinued with immediate effect once supplies in circulation had been used [33]. Theophylline is indicated in the treatment of asthma for patients aged 2 years and over [7, 34–36], but the only licensed formulation now available are the prolonged release tablets (Uniphyllin Continus) [33]. There is also an unlicensed special liquid formulation available. Theophylline capsules (Slo-Phyllin) were usually administered twice daily and for patients unable to swallow the capsules whole, there was the option of opening and emptying the contents of capsules onto a spoonful of soft food [34–36]. While the prolonged release tablets (Uniphyllin Continus) are also dosed at twice daily, the tablets themselves cannot be split, crushed or chewed as this may result in unreliable release of theophylline and potential toxicity (especially as theophylline is a drug with a narrow therapeutic window) [33–36]. Whilst the unlicensed liquid can be used in patients unable to swallow the prolonged release tablets whole, dosing frequency would increase to four times daily. The change to the liquid formulation would obviously increase the treatment burden, but with a lack of other suitable formulations available, would be a necessary addition.\n\nAzithromycin is a macrolide antibiotic that is commonly used as prophylactic treatment against lower respiratory tract infections in children who are at increased risk. There is a variation in azithromycin regimes prescribed, but one survey of paediatric departments in Eastern England found that the most common regime prescribed is three times weekly: Monday, Wednesday and Friday [37].\n\nThe branded azithromycin powder for suspension, Zithromax, has a shelf life of 5 days once reconstituted potentially resulting in frequent trips to the community pharmacy for families to collect this product or the reliance on families to correctly reconstitute the product at home [38]. The generic azithromycin suspension offers a slightly longer shelf of 10 days once reconstituted [39]. While tablets and capsules are an option, the lowest strength available is 250 mg, which may not always be feasible to prescribe [7].\n\nIncreasing amounts of evidence have linked paediatric respiratory disease to gastro-oesophageal reflux disease, but the exact underlying mechanisms are not known [40]. It therefore comes as no surprise that anti-reflux medications are commonly prescribed in children with respiratory disease. A supply disruption alert issued by the Medicines and Healthcare products Regulatory Agency (MHRA) and updated in December 2019 stated that ranitidine tablets, effervescent tablets and oral solution would be unavailable for prescribing until further notice [41]. This has meant reliance on other H2 receptor antagonists or proton pump inhibitors (PPIs) if children still need anti-reflux medication [41]. This has undoubtedly presented some challenges for Trusts and clinical teams to carefully consider other agents for use. To take omeprazole as an example of a commonly used PPI, capsules, tablets and dispersible tablets and a relatively recently available licensed liquid are all available for prescribing [7]. Consideration would need to be given if enteral feeding tubes are to be used for medication administration, as the omeprazole dispersible tablets, in particular, can block fine-bore feeding tubes [41]. While the recently licensed liquid may seem an obvious choice for use, the relative cost of this product against the other formulations would also need to be considered [7], especially if continued use of anti-reflux medication is required. Both the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPHAGAN) and National Institute for Health and Care Excellence (NICE) guidelines recommend PPIs should be started and trialled for an 8-week period, then a trial off medication is recommended [42, 43].\n\nPrednisolone, amongst other indications, is used for the treatment of acute asthma episodes in children [44]. Doses given are dependent on age and treatment courses of 3 days are considered appropriate, but longer courses may be required. It is well recognised that administration of crushed prednisolone tablets is difficult in children due to their bitter taste in those who are unable to swallow tablets whole [45]. Whilst it is reported that prednisolone oral solution is generally better tolerated in children compared with crushed tablets [46], the relative cost of the solution compared with the tablets does mean that in practice, the practice of using crushed tablets is generally preferred [7, 47]. The tablets themselves, when crushed, can be mixed with a small amount of soft food such as yoghurt or jam to disguise the bitter taste [47].\n\nGenerally, most medicines used within the treatment of CF are available as licensed preparations: tablets, capsules or liquid formulations. On some occasions, due to palatability or volume of solution required, for example, licensed available formulations may not be appropriate. Where there are not licensed preparations available, some centres do manufacture unlicensed preparations for use locally and nationally. Resources such as The NEWT guidelines for administration of medication to patients with enteral feeding tubes or swallowing difficulties or unpublished advice obtained from manufacturers can guide as to whether tablets can be crushed, the contents of capsules opened and emptied or whether i.v. preparations can be used orally [48]. In these situations, however, there should always be an appreciation that the pharmaceutical properties of the product may be altered and will not have been included as part of the original trial data prior to receiving a product license [18].\n\nDifficulties with administration of certain CF treatments have been acknowledged and recognised.\n\nAs part of the “Prevent and treat” arm of the CF START trial [49], patients may be randomised to receive flucloxacillin twice daily. It was widely reported whilst preparing for the trial that the taste of flucloxacillin liquid had been a barrier to continuing with treatment. Research was conducted by the University of Birmingham where some solutions were identified to the issue around palatability [50, 51]: Persistence with administration;\n\nSwitching the brand of flucloxacillin provided by the pharmacy;\n\nSwitching to the more concentrated solution of 250 mg/5 mL instead of 125 mg/5 mL;\n\nUsing the oral syringe generally provided with the solution to dispense instead of a spoon;\n\nLots of positive reinforcement provided to the child; and\n\nConsidering use of capsules if the child is old enough to swallow these whole.\n\nCreon is available as both gastro-resistant capsules and gastro-resistant granules [7]. The manufacturers [52] advise that, if necessary, the capsules can be opened and taken with fruit juices or soft food but must not be chewed. One study found that in a patient cohort aged 6–36 months, parents found it easier to use the measure provided with the gastro-resistant granules rather than opening the capsules and using the contents, particularly where small doses were required [53].\n\nThese are only a few examples that highlight the importance of tailoring medicine formulations to the patient and particularly in patients with chronic disease.\n\nPolypharmacy\n\nPolypharmacy can be broadly defined as the use of a number of medicines in any given individual [54]. While there is great debate about the numerical value of polypharmacy, a systematic review [55] found that the most commonly reported numerical definition of polypharmacy was if an individual took five or more medicines each day.\n\nManaging patients with CF, a multi-organ disease, inevitably entails that polypharmacy is always a factor to consider in this condition [56]. Whilst polypharmacy within the management of CF is not a new concept, the much-welcomed availability of CFTR modulators for CF patients has introduced a new consideration for multi-disciplinary teams in terms of further different formulations, possible adverse reactions and drug–drug interactions with other concurrent therapies. Additionally, metabolic food–drug interactions can occur when the consumption of a particular food modulates the activity of a drug-metabolising enzyme system, resulting in an alteration to the pharmacokinetics of drugs metabolised by that system. Foods that contain complex mixtures of phytochemicals, such as fruits, vegetables, herbs, spices and teas, have the greatest potential to induce or inhibit the activity of drug-metabolising enzymes, although dietary macroconstituents (i.e. total protein, fat and carbohydrate ratios, and total energy intake) can also have effects. Particularly large interactions may result from the consumption of herbal dietary supplements. Cytochrome P450 (CYP) 3A4 appears to be especially sensitive to dietary effects [57].\n\nThe CFTR modulator therapies all influence cytochrome P450 pathways [58]. Names of cytochrome P450 pathways are derived from gene sequences and are allocated according to family and sub-family names and the specific enzyme in question. Drug interactions occur when medicines “share a common P450 pathway,” and while this will be a common pathway for a large proportion of interactions, other mechanisms and pathways do exist [58–60].\n\nEnzyme induction generally results in reduced levels of the drug substrate (due to an increase in metabolism of the substrate), unless the substrate is a prodrug that usually undergoes metabolism to its active metabolite. In this situation, there may be potential toxicity. Enzyme inhibition generally results in increased levels of the drug substrate [60, 61].\n\nCareful consideration to potential interactions between the CFTR modulators and concomitant therapies is required (Supplementary table S1). The individual product SPCs can be referred to for more information [62–70].\n\nLumacaftor/ivacaftor (Orkambi), tezacaftor/ivacaftor (Symkevi) and elexacaftor/tezacaftor/ivacaftor (Kaftrio) are all considered “black triangle drugs” by the MHRA as they have only become available widely in the UK in the past year [62–71]. Due to their recent availability, there is relatively limited safety data available and so it is encouraged that any suspected adverse reactions are reported using the Yellow Card Scheme so that this data can be utilised in future to guide treatment decisions [72]. The MHRA are keen to monitor all suspected adverse reactions to medicines, but are particularly interested in those that occur in new drugs to the market (e.g. the CFTR modulators) and in children [73]. Whilst reporting this data nationally is key for providing continued medicines safety, it is also important to encourage individuals to report any adverse effects to their GP or clinical teams, as these will sadly contribute towards treatment burden.\n\nCardiac side-effects of respiratory drugs\n\nQT prolongation in patients can be drug-induced and is clearly more likely to happen in patients with polypharmacy. Information summarised by the UK Medicines Information service stated that this could be primarily due to one of three reasons [74–77]. 1) Pharmacodynamic reactions: if more than one drug that can cause QT prolongation is used in a patient, the risk is additive.\n\n2) Pharmacokinetic reactions: whilst a drug itself may not cause QT prolongation, it may change the metabolism of a different agent that can cause QT prolongation. An example of this is where azoles, such as voriconazole, as a CYP3A inhibitor, will inhibit the metabolism of tacrolimus. Both of these agents have the potential to prolong the QT interval in their own right but the combination of both would require a dose reduction of tacrolimus and careful monitoring [78].\n\n3) Electrolyte derangement: drugs affecting electrolyte balance (primarily by causing low potassium or magnesium) can cause QT prolongation. Examples include diuretics, which are known to cause electrolyte disturbances.\n\nDrugs specifically used within paediatric respiratory medicine that may cause QT prolongation include azithromycin, ciprofloxacin, clarithromycin, azole therapy and anti-emetics such as domperidone and ondansetron. This list is by no means exhaustive [77].\n\nWhile drug interactions will be a key consideration with polypharmacy, it is also worth noting that often to counteract adverse effects of one medicine, another medicine may be prescribed.\n\nDiet and oral medication\n\nDietary regimens (e.g. a ketogenic diet for treatment of epilepsy), or diet as a treatment (e.g. special formula in phenylketonuria) or dietary choices (e.g. grapefruit juice), can occasionally further contribute to the complex interactions (not only via the cytochrome P450 pathway) between things consumed orally. Whilst a rare occurrence, for children with complex respiratory problems, who are on a ketogenic diet for treatment of epilepsy, avoidance of carbohydrates in medication is incredibly important [79]. While it may not be possible to completely eliminate carbohydrate contributions from medication, avoiding liquid formulations and opting for tablets is usually considered more appropriate [79].\n\nWhile a variety of resources are available to support parents with medication administration in children, one particular study focused on “tried and tested” techniques discussed in 10 internet forums and three main strategies were found: one included involving the child in the process of medication administration whilst openly changing the palatability using food or drink; another involved hiding medication in food and administering it unknown to the child; and the third involved forced administration. The study did not provide any information about the participants (like the number of children or their age ranges) and there is no specific focus on any particular medicines. Despite these limitations, the concluding statements of this study were to highlight some of the unique techniques used by parents with the aim of successfully administering medication to their children and that awareness by healthcare professionals of techniques used can help with future shared decision making with families about treatment choices [80].\n\nAlthough food can be used to disguise medication, it is important to recognise that not all medications can be taken with food. Montelukast itself is available in a variety of formulations and is indicated in the treatment of asthma in those aged 2 years and older. For individuals aged between 6 months and 5 years old, both granules and chewable tablets are available for prescribing. For those aged between 6 and 14 years old, chewable tablets are available, and tablets alone are available for individuals over 15 years of age [7, 44]. The chewable tablets should be taken on an empty stomach (1 h before or 2 h after food). The manufacturers advise that the mean oral bioavailability is 73% in individuals in the fasted state and is reduced to 63% when taken with food. To make the chewable tablets more palatable, they are generally available with cherry flavouring [81].\n\nThe granules, which are generally used in children under 5 years old, can be given directly or mixed with a spoonful of cold or room temperature soft food such as apple sauce or ice cream [82].\n\nGastrointestinal side-effects with all formulations of montelukast are common; however, the manufacturers report that studies have shown abdominal pain to be more common in individuals over 2 years of age taking the tablets or chewable tablets, whereas diarrhoea was reportedly more common with the granules in children aged 6 months up to 2 years old. Other notable differences reported are headaches in older patients (age 6 years and over), and hyperkinesia and rash as possible issues in children taking the granules [81, 82].\n\nThe MHRA issued a safety alert in 2019 highlighting and reminding all prescribers of the risk of neuropsychiatric reactions with montelukast that could vary from sleep disturbances and agitation (affecting possibly one in 100 individuals) to hallucinations and suicidal ideations (affecting possibly one in 10 000 people) [83]. It is reported that, between 2014 and 2018, there were 219 reports of possible neuropsychiatric reactions against 14 million prescriptions. While the MHRA did not comment on differences in adverse reactions between formulations, it has been reported that nightmares, aggression and behavioural changes were more prevalent in children than in adults [83].\n\nWhat can healthcare professionals do to support patients with taking oral medication?\n\nConsider the use of commercial medication flavouring products. These are available, but no data supports the long-term stability of medications when mixed with these; they are best added just prior to administration.\n\nConsider the use of chewable tablets, quick dissolve, or “melting” dosage forms.\n\nConsidering the use of higher strength liquids (if liquid formulations are deemed the most appropriate formulation for the patient).\n\nAlternative medications that require fewer daily doses or “trial and error” with patients to identify those that are considered more palatable.\n\nInvolvement of clinical psychologists and “pill schools” to support children and their families in administration of tablets.\n\nWhat can parents do to maximise compliance with oral medication?\n\nMask the taste of medication using food if appropriate.\n\nTeach children to swallow tablets.\n\nTry administering medication into different areas of the mouth to assess patient preference (e.g. into cheek, onto back of tongue).\n\nExplain the benefits/rationale for using the medication, and allow children to choose administration modality (syringe, cup, straw, spoon).\n\nPositive reinforcement: praise and/or reward for successful medication administration.\n\nConclusion\n\nTaking medications orally may be a very important component of the treatment plan for a variety of childhood respiratory conditions. Clinicians must recognise that this places an enormous burden of care on patients and their families. Polypharmacy should be minimised as much as possible, and interactions between oral medications should be considered. There are measures that healthcare professionals and families can put into practice to help with adherence to oral medication.\n\nKey points\n\nThere is a large burden of care with oral medication for children and their families.\n\nThe challenges with oral medication administration can lead to poor adherence with treatment in long-term respiratory conditions.\n\nPolypharmacy increases the chances of interactions between oral medications and these should be considered.\n\nHealthcare professionals and parents can devise strategies that may help with adherence to oral medication.\n\nSelf-evaluation questions\n\nWhich of the following CFTR modulators can be administered as granules? a) Orkambi\n\nb) Symkevi\n\nc) Kaftrio\n\nd) None of the above\n\nWhich one of the following drugs will most likely cause QT prolongation? a) Domperidone\n\nb) Orkambi\n\nc) Creon\n\nd) Lansoprazole\n\nWhich one of the following drugs is a CYP3A inducer? a) Rifampicin\n\nb) Clarithromycin\n\nc) Posaconazole\n\nd) Erythromycin\n\nWhich of the following does not help to promote adherence to oral medication in children? a) Mixing the liquid medication with food to mask the taste\n\nb) Praising children when they take the medication\n\nc) Telling children off when they refuse medication\n\nd) Using a formulation that requires fewer daily doses\n\nSuggested answers\n\na.\n\na.\n\na.\n\nc.\n\nSupplementary material\n\n10.1183/20734735.0005-2021.Supp1 Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.\n\nSupplementary table S1 EDU-0005-2021.supplement\n\nThis article has supplementary material available from breathe.ersjournals.com\n==== Refs\nReferences\n\n1 Sabaté E, ed. 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Date last accessed: November 22, 2020.\n67 Vertex Pharmaceuticals (Europe) Limited. Summary of product characteristics – Kalydeco 150 mg Film-coated Tablets. www.medicines.org.uk/emc/product/3040/smpc Date last updated: November 23, 2020. Date last accessed: November 23, 2020.\n68 Vertex Pharmaceuticals (Europe) Limited. Kalydeco 25 mg granules in sachet. www.medicines.org.uk/emc/product/10982/smpc Date last updated: November 23, 2020. Date last accessed: November 23, 2020.\n69 Vertex Pharmaceuticals (Europe) Limited. Kalydeco 50 mg granules in sachet. www.medicines.org.uk/emc/product/1954/smpc Date last updated: November 23, 2020. Date last accessed: November 23, 2020.\n70 Vertex Pharmaceuticals (Europe) Limited. Kalydeco 75 mg granules in sachet. www.medicines.org.uk/emc/product/10150/smpc Date last updated: November 23, 2020. Date last accessed: November 23, 2020.\n71 Medicines and Healthcare products Regulatory Agency. The Black Triangle Scheme: continued monitoring of medicines with a black triangle status. Drug Safety Update 2009. www.gov.uk/drug-safety-update/the-black-triangle-scheme-or Date last updated: December 11, 2014. Date last accessed: November 22, 2020.\n72 Medicines and Healthcare products Regulatory Agency. Yellow Card scheme. yellowcard.mhra.gov.uk/ Date last accessed: November 22, 2020.\n73 Medicines and Healthcare products Regulatory Agency. Yellow Card: Specific areas of interest for reporting suspected adverse drug reactions. assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/403078/Specific_areas_of_interest_for_adverse_drug_reaction_reporting.pdf Date last accessed: November 22, 2020.\n74 UK Medicines Information. Medicines Q&As: What issues should be considered regarding drug induced QT prolongation? www.sps.nhs.uk/wp-content/uploads/2017/09/QA237_2_DruginducedQTprolongation-2017-update.pdf Date last updated: August 24, 2017. Date last accessed: November 22, 2020.\n75 Baxter K, Preston CL, eds, Stockley's Drug Interactions. Drugs that prolong the QT interval+Other drugs that prolong the QT interval. www.medicinescomplete.com Date last updated: June 1, 2020. Date last accessed: November 22, 2020.\n76 Kannankeril PJ, Roden DM. Drug-induced long QT and torsade de pointes: recent advances. Curr Opin Cardiol 2007; 22 : 39–43. doi:10.1097/HCO.0b013e32801129eb 17143043\n77 CredibleMeds. Combined list of drugs that prolong QT and/or cause Tosades de pointes (TDP). www.crediblemeds.org/index.php/tools/pdfdownload?f=cql_en Date last updated: September 10, 2020. Date last accessed: November 22, 2020.\n78 Pfizer Limited. Summary of product characteristics – VFEND 200 mg film-coated tablets. www.medicines.org.uk/emc/product/8408/smpc Date last updated: 2020 September. Date last accessed: November 27, 2020.\n79 Kossoff EH, Zupec-Kania BA, Auvin S, et al. The Charlie Foundation, Matthew's Friends and the Practice Committee of the Child Neurology Society. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open 2018; 3 :175–192. doi:10.1002/epi4.12225 29881797\n80 Bergene EH, Tostein Baade R, Steinsbekk A. Strategies parents use to give children oral medicine: a qualitative study of online discussion forums. Scand J Prim Health Care 2017; 35 : 221–228. doi:10.1080/02813432.2017.1333308 28581890\n81 Organon Pharma (UK) Limited. Summary of product characteristics – Singulair Paediatric 4 mg chewable tablets. www.medicines.org.uk/emc/product/6500/smpc Date last updated: August 25, 2007. Date last accessed: March 8, 2021.\n82 Organon Pharma (UK) Limited. Summary of product characteristics – Singulair Paediatric 4 mg Granules. www.medicines.org.uk/emc/product/45/smpc Date last updated: August 25, 2007. Date last accessed: March 8, 2021.\n83 Medicines and Healthcare products Regulatory Agency. Montelukast (Singulair): reminder of the risk of neuropsychiatric reactions. 2019. www.gov.uk/drug-safety-update/montelukast-singulair-reminder-of-the-risk-of-neuropsychiatric-reactions Date last accessed: March 8, 2021.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1810-6838",
"issue": "17(1)",
"journal": "Breathe (Sheffield, England)",
"keywords": null,
"medline_ta": "Breathe (Sheff)",
"mesh_terms": null,
"nlm_unique_id": "101231007",
"other_id": null,
"pages": "210005",
"pmc": null,
"pmid": "34295409",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "19846397;14531721;19951895;33039988;21532781;25927329;30805605;18718819;9378812;29881797;27524471;25032007;27540213;17143043;2802957;29110351;28031875;9557771;10694286;17119779;11259239;27662106;16968958;29470322;29311001;17353298;19840958;29017448;29896075;28581890;32198220;27587314;29506920;27633317;12271287",
"title": "It's not all about inhaled treatment: challenges with oral therapy in paediatric respiratory medicine.",
"title_normalized": "it s not all about inhaled treatment challenges with oral therapy in paediatric respiratory medicine"
} | [
{
"companynumb": "GB-VERTEX PHARMACEUTICALS-2021-010335",
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"activesubstancename": "AZITHROMYCIN ANHYDROUS"
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"abstract": "Viral hepatitis is a serious problem worldwide that was under-recognized till recently. The prevalence of chronic hepatitis C virus (HCV) is estimated to be 180 million people worldwide. Treatment of chronic HCV using combined pegylated interferon and ribavirin (PEG/RIBA) has long been the standard of care with modest response. In our study, we will report the real-life experience of serious adverse events (SAEs) that were reported by the National Committee for Control of Viral Hepatitis (NCCVH, Cairo, Egypt) program while treating chronic HCV using the triple therapy, sofosbuvir combined with pegylated interferon and ribavirin (PEG/RIBA/SOF), which led to premature discontinuation of treatment. This retrospective analysis included a total of 6,989 chronic HCV patients who were treated by the NCCVH. They received the triple antiviral therapy in 26 treatment centers in Egypt using PEG/RIBA/SOF for 12 weeks. Among 6,989 patients who were treated in 26 treatment centers related to NCCVH, 406 cases (5.9%) reported SAEs and prematurely stopped their treatment. Triple therapy PEG/RIBA/SOF was an important intermediate milestone between interferon-based therapy and the interferon-free all-oral direct acting antiviral agents (DAAs). Results of this study were the leading cause of discontinuation of interferon-based therapy and introduction of interferon-free all-oral treatment protocols, incorporating DAAs from different classes as soon as they gain approval.",
"affiliations": "1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;2 Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute , Cairo, Egypt .;2 Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;3 National Liver Institute, Menoufiya University , Shebeen EL Kom, Egypt .;4 Faculty of Medicine, Pediatric Department, Ain Shams University , Cairo, Egypt .;5 Faculty of Medicine, Tropical Medicine Department, Ain Shams University , Cairo, Egypt .;6 Faculty of Medicine, Internal Medicine Department, Ain Shams University , Cairo, Egypt .;7 Internal Medicine Department, Cairo University , Cairo, Egypt .;7 Internal Medicine Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .;1 Faculty of Medicine, Endemic Medicine and Hepatology Department, Cairo University , Cairo, Egypt .",
"authors": "Elbaz|Tamer|T|;Elserafy|Magdy|M|;Elakel|Wafaa|W|;Mohey|Mohammad A|MA|;Abdo|Mahmoud|M|;Hassany|Mohamed|M|;Mehrez|Mai|M|;Abouelkhair|Mahmoud|M|;Yosry|Ayman|A|;Omar|Ashraf|A|;Waked|Imam|I|;Elsayed|Manal Hamdy|MH|;Mahran|Zakaria|Z|;Elshazly|Yahia|Y|;Elgarem|Noman|N|;Gaballa|Aly|A|;Doss|Wahid|W|;Esmat|Gamal|G|",
"chemical_list": "D016898:Interferon-alpha; D012254:Ribavirin; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1089/jir.2016.0131",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-9907",
"issue": "37(8)",
"journal": "Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research",
"keywords": "HCV; genotype 4; interferon; serious adverse events; sofosbuvir",
"medline_ta": "J Interferon Cytokine Res",
"mesh_terms": "D004359:Drug Therapy, Combination; D004534:Egypt; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D012254:Ribavirin; D000069474:Sofosbuvir; D028761:Withholding Treatment",
"nlm_unique_id": "9507088",
"other_id": null,
"pages": "348-353",
"pmc": null,
"pmid": "28777714",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Serious Adverse Events with Sofosbuvir Combined with Interferon and Ribavirin: Real-Life Egyptian Experience.",
"title_normalized": "serious adverse events with sofosbuvir combined with interferon and ribavirin real life egyptian experience"
} | [
{
"companynumb": "EG-GILEAD-2017-0288739",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
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"activesubstancename": "RIBAVIRIN"
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... |
{
"abstract": "Myeloid-derived suppressor cells (MDSC) play a significant role in tumor-induced immune suppression. Targeting their function could improve antitumor therapies. Previously, we demonstrated that phosphodiesterase 5 (PDE5) inhibition in MDSCs augmented antitumor immunity in murine models. Here, we show how the addition of the PDE5 inhibitor, tadalafil, in a patient with end-stage relapsed/refractory multiple myeloma reduced MDSC function and generated a dramatic and durable antimyeloma immune and clinical response. Strategies targeting MDSC function with PDE5 inhibitors represent a novel approach that can augment the efficacy of tumor-directed therapies.",
"affiliations": "The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland; and.;The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland; and.;The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland; and.;H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida.;The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland; and iborrell@jhmi.edu.",
"authors": "Noonan|Kimberly A|KA|;Ghosh|Nilanjan|N|;Rudraraju|Lakshmi|L|;Bui|Marilyn|M|;Borrello|Ivan|I|",
"chemical_list": "D002243:Carbolines; C504000:IL4R protein, human; D007155:Immunologic Factors; D053662:Interleukin-4 Receptor alpha Subunit; D058986:Phosphodiesterase 5 Inhibitors; D013792:Thalidomide; D000068581:Tadalafil; D003907:Dexamethasone; D000077269:Lenalidomide; D017291:Clarithromycin",
"country": "United States",
"delete": false,
"doi": "10.1158/2326-6066.CIR-13-0213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-6066",
"issue": "2(8)",
"journal": "Cancer immunology research",
"keywords": null,
"medline_ta": "Cancer Immunol Res",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002243:Carbolines; D017291:Clarithromycin; D003907:Dexamethasone; D006801:Humans; D007108:Immune Tolerance; D007155:Immunologic Factors; D053662:Interleukin-4 Receptor alpha Subunit; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D022423:Myeloid Cells; D058986:Phosphodiesterase 5 Inhibitors; D013601:T-Lymphocytes; D000068581:Tadalafil; D013792:Thalidomide",
"nlm_unique_id": "101614637",
"other_id": null,
"pages": "725-31",
"pmc": null,
"pmid": "24878583",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "10092790;17101732;17989313;17603493;19197294;21477210;15824085;19380816;15922712;10605607;18593947;16168663;16982917;20028852;12393651;17016559;14707072",
"title": "Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma.",
"title_normalized": "targeting immune suppression with pde5 inhibition in end stage multiple myeloma"
} | [
{
"companynumb": "US-CELGENEUS-163-21880-14091740",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": nul... |
{
"abstract": "Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non-Hodgkin's lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach being generally ineffective. The most employed first-line treatment is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which still results in high rates of relapses. Denileukin diftitox is a fusion protein combining the cytotoxic portion of the diphtheria toxin and the receptor-binding domain of the interleukin-2 (IL-2) molecule, thereby targeting cells expressing the IL-2 receptor, including both T-cell and B-cell lymphomas. It has been approved for the treatment of cutaneous T-cell lymphomas, and it has documented activity in PTCL both as a single agent and as part of combination therapy. This report documents three cases of PTCL where denileukin diftitox has been used as long-term maintenance therapy after complete remission was achieved. While the overall survival rate of patients with advanced stage, refractory PTCL is generally poor (with median overall survival of 5.5 months), the three patients described in this report are all experiencing an ongoing complete remission for more than four years.",
"affiliations": "Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;Florida Cancer Specialists and Research Institute, Leesburg, FL 34748, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.",
"authors": "Fuentes|Alejandra C|AC|;Szwed|Ellen|E|;Spears|Cathy D|CD|;Thaper|Sandeep|S|;Dang|Long H|LH|;Dang|Nam H|NH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/123756",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2015/123756Case ReportDenileukin Diftitox (Ontak) as Maintenance Therapy for Peripheral T-Cell Lymphomas: Three Cases with Sustained Remission Fuentes Alejandra C. \n1\nSzwed Ellen \n2\nSpears Cathy D. \n2\nThaper Sandeep \n3\nDang Long H. \n2\nDang Nam H. \n2\n\n*\n1Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA2Division of Hematology/Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA3Florida Cancer Specialists and Research Institute, Leesburg, FL 34748, USA*Nam H. Dang: nam.dang@medicine.ufl.eduAcademic Editor: Guido Fadda\n\n2015 9 7 2015 2015 12375631 3 2015 25 6 2015 5 7 2015 Copyright © 2015 Alejandra C. Fuentes et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non-Hodgkin's lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach being generally ineffective. The most employed first-line treatment is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which still results in high rates of relapses. Denileukin diftitox is a fusion protein combining the cytotoxic portion of the diphtheria toxin and the receptor-binding domain of the interleukin-2 (IL-2) molecule, thereby targeting cells expressing the IL-2 receptor, including both T-cell and B-cell lymphomas. It has been approved for the treatment of cutaneous T-cell lymphomas, and it has documented activity in PTCL both as a single agent and as part of combination therapy. This report documents three cases of PTCL where denileukin diftitox has been used as long-term maintenance therapy after complete remission was achieved. While the overall survival rate of patients with advanced stage, refractory PTCL is generally poor (with median overall survival of 5.5 months), the three patients described in this report are all experiencing an ongoing complete remission for more than four years.\n==== Body\n1. Introduction\nNon-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders. Approximately 71,850 new cases of NHL and 19,790 deaths are projected for 2015, accounting for 4% of new cases and 3% of cancer deaths [1]. Although only about 15–20% of NHL cases originate from the T-cell lineage, T-cell non-Hodgkin's lymphomas are generally more aggressive and have a poorer prognosis than their B-cell counterpart, with decreased short-term survival and frequent relapses.\n\nPeripheral T-cell lymphomas (PTCL) comprise most of the cases of T-cell NHL. The classification and treatment options for PTCL have advanced since the REAL Classification recognized PTCL as a specific entity independent from the B-Cell lineage in 1994 [2]. Due to the rarity of PTCL and lack of randomized controlled trials, there is no consensus on first-line therapy. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been widely used, largely based on results extrapolated from studies on aggressive B-cell lymphomas. However, CHOP has failed to improve survival and often culminates with frequent relapses, with a 5-year overall survival rates ranging around 32–35% [3, 4]. Studies comparing intensive therapies to CHOP have not demonstrated improved overall survival [5]. These findings highlight the crucial need for improved treatment strategies. In the past few years, advances in molecular biology have identified different cell surface molecular markers, leading to promising novel therapies that are currently under ongoing investigation and are being used as salvage therapy for relapsed disease [3, 4].\n\nDenileukin diftitox (DD) is a recombinant cytotoxic fusion protein that binds the enzymatically active portion of the diphtheria toxin to the receptor-binding domain of the interleukin-2 molecule, thereby targeting cells producing the IL-2 receptor. These cells can derive from multiple lineages, including B and T lymphocytes, macrophages, and natural killer cells. Previous work has demonstrated that DD exhibited significant single-agent activity and was well tolerated in both T-cell and B-cell malignancies, as well as CD25+ and CD25− tumors [6–8].\n\nIn 2008 we reported the first case of prolonged remission with long-term maintenance therapy with DD in a patient with advanced stage, relapsed/refractory PTCL [9]. This patient is presently experiencing an ongoing complete remission of more than 9 years (ND, personal communications). To date, no other such cases had been described. This current report describes three additional cases of patients with advanced stage PTCL in which DD was used successfully as long-term maintenance therapy to maintain ongoing remission, hence illustrating the exciting potential of this novel drug as an agent that can be used as maintenance therapy in selected cases of PTCL.\n\n2. Case 1\nThe patient is a 51-year-old African-American female with past medical history significant for Hepatitis B and with relapsed/refractory Stage IVB subcutaneous panniculitis gamma delta T-cell lymphoma. In November 2004 she first came to local medical attention with a firm, nontender 4 × 2 cm growth in her forehead and a smaller one in her left anterior shoulder. Biopsy of the forehead nodule revealed atypical T-cell proliferation with necrosis, and flow cytometry studies demonstrated the presence of a population of CD3+, CD4+, CD8+, CD5+, and CD56− cells.\n\nHer complete blood count at that time revealed WBC 4,200 per mm3 (normal differential), Hgb. 10.5 g/dL, Hct. 32.2%, and platelets 297 K/mm3. Bone marrow studies showed normal aspirate and core biopsy, with no evidence of abnormal cells. She was diagnosed with an inflammatory reaction of unclear etiology and was placed on a prednisone taper for 6 months, which resulted in clinical improvement and resolution of her nodules by April 2005. Her local dermatologist prescribed Plaquenil after the prednisone taper, based on a presumed diagnosis of lymphoid dermatitis.\n\nIn November 2006, she experienced a recurrence of subcutaneous nodules in her right eye, left forearm, and left chest area, each measuring approximately 1 cm in size. Her WBC was 4,900 per mm3 with predominant lymphocytosis at 41%, Hgb. 12.2 g/dL, Hct. 36.9%, and platelets 349 K/mm3. Computed tomography (CT) scan also revealed a new subcutaneous soft tissue density measuring 3.8 × 2.3 cm in the left anterior abdomen. Biopsy of the abdominal mass showed morphologically atypical lymphocytes that appeared to rim adipocytes in a manner described for panniculitis-like T-cell lymphoproliferative disorders, with Ki-67 proliferation marker expressed in many of the cells. Immunohistochemical stains showed a predominance of CD3+/CD5+ T-cells, comprised of a mixture of CD4+ and CD8+ cells, with a few background CD20+ B-cells. CD56, CD57, CD30, ALK-1, and CD10 markers were negative. CD25 was not tested. However, a clonal population was not identified by flow cytometry and T-cell gene rearrangement analysis was negative. By January 2007, her nodules were increasing in size and in light of her clinical picture she was treated for presumed lymphoma with 6 cycles of CVP (cytoxan, vincristine, and prednisone) every 3 weeks. She tolerated the treatment well and her nodules resolved. Follow-up PET scan in July 2007 showed abnormal FDG activity in the head of the pancreas, and all labs were otherwise normal. Patient was thereafter lost to follow-up.\n\nIn May 2010, she presented to the emergency department with bilateral lower extremity swelling, upper extremity nodules, fevers, night sweats, abdominal pain, vomiting, and diarrhea for one month. CT imaging revealed recurrent multiple indurated lesions in the left flank. Biopsy of a right arm nodule showed lobular panniculitis and focal fat necrosis with involvement by an atypical T-cell infiltrate. Molecular studies were positive for a monoclonal rearranged band of T-cell receptor gamma gene and flow cytometry revealed increased level of gamma/delta T-cells at approximately 40%, consistent with subcutaneous panniculitis-like T-cell lymphoma. Bone marrow biopsy showed normal cellularity (80–90%) with multilinear hematopoiesis and no evidence of lymphoma. She received 3 cycles of ICE (ifosfamide, carboplatin, and etoposide) combination therapy, but her disease continued to progress with increasing number of subcutaneous nodules and continuing constitutional symptoms. She then received two cycles of ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) with mixed response based on CT scan with no evidence of adenopathy but increase in nodularity and size of the anterior abdomen subcutaneous nodule. She was evaluated for stem cell transplantation, but she needed to attain at least partial remission before being a candidate.\n\nSince she had multiple relapses despite treatment with CVP, ICE, and ESHAP combination therapies, she was started on treatment with DD in December 2010. The treatment was administered intravenously at 18 μg/kg daily for 5 days every 4 weeks, with steroid premedication. After a total of 8 cycles, CT imaging confirmed resolution of her subcutaneous nodules (Figure 1). Due to the clinical and radiological response, she then received an additional 8 cycles of DD as maintenance therapy, given at 18 μg/kg daily for 5 days every 8 weeks, which she continued to tolerate well without side effects. Her performance status remained zero throughout the entirety of her disease course and treatment, and the patient has now achieved ongoing complete remission of more than 4 years, as documented by periodic surveillance scans, physical exams, and routine blood tests.\n\n3. Case 2\nThe patient is a 71-year-old Caucasian male with past medical history of type-2 diabetes mellitus, deep vein thrombosis with inferior vena cava filter placement in 2010, and newly diagnosed stage IVB peripheral T-cell lymphoma.\n\nHe first presented to an outside institution in April 2010 with complaints of progressive groin adenopathy, leg swelling, and fatigue for several months. His CBC at that time revealed WBC 6,300 per mm3 (with 77.0% neutrophils and 9.6% lymphocytes), Hgb. 13.8 g/dL, Hct. 44.3%, and platelets 252 K/mm3. CT imaging demonstrated disease on both sides of the diaphragm with a 1.5 cm left axillary node and subcarinal node, as well as diffuse lymphadenopathy in the retroperitoneum, pelvis, and left groin. A lymph node biopsy was positive for peripheral T-cell lymphoma, NOS. Bone marrow biopsy did not show definitive morphologic involvement with a T-cell lymphoproliferative disorder, but T-cell clonality analysis was positive for a clonal T-cell receptor beta gene rearrangement. Flow cytometric analysis of the bone marrow detected a small population of T-cells (5%), which had an inverted CD4 : CD8 ratio at 0.3 : 1; otherwise no aberrant antigen expression was detected. CD25 was not tested.\n\nHe was started on treatment with CHOP combination chemotherapy and achieved complete remission after 6 cycles by August 2010, as documented by end-of-treatment CT scans showing complete resolution of adenopathy and repeat bone marrow biopsy indicating complete clearance of tumor cells. CBC at this time revealed WBC 3,000 per mm3 (with 70.3% neutrophils and 15.5% lymphocytes), Hgb. 14.9 g/dL, Hct. 43.6%, and platelets 138 K/mm3.\n\nHe was not a candidate for consolidation with stem cell transplantation due to his age. In view of the high risk of relapse and poor prognosis associated with stage IVB PTCL, the patient opted for maintenance therapy with DD, starting with the first cycle in December 2010. DD was administered intravenously at 18 μg/kg daily for 5 days every 4 weeks, for the first eight cycles, and then additional 8 cycles were given at 18 μg/kg daily for 5 days every 8 weeks. He completed a total of 16 cycles without any side effects. He experienced decreased fatigue and improved performance status from 1 to 0. The patient has now maintained an ongoing complete remission of greater than 4 years as documented by periodic surveillance scans, bone marrow biopsies, physical exams, and routine blood tests.\n\n4. Case 3\nThe patient is a 27-year-old Hispanic female with past medical history of coarctation of the aorta, with Stage IIIA CD30+ anaplastic large cell lymphoma, null type, positive for ALK-1 (anaplastic lymphoma kinase-1).\n\nShe first presented in August 2010 to an outside institution with fevers, night sweats, paresthesias, 15 lb weight loss, and bilateral supraclavicular adenopathy with mild swelling in her groin. CT scans revealed extensive mediastinal, pelvic, and retroperitoneal lymphadenopathy with accompanying ascites and mild splenomegaly. The largest nodes were a mesenteric lymph node measured 2.3 cm and a right inguinal lymph node 3 cm. Right inguinal lymph node biopsy revealed anaplastic large cell lymphoma of null type, ALK-1 positive. Immunohistochemical stain was strongly positive for ALK-1, CD4, CD30, CD25, and epithelial membrane antigen (EMA) at 60%, mildly positive for CD45, and negative for CD3, CD20, and CD8. The pattern of ALK-1 immunostain was diffuse cytoplasmic with peripheral intensification, suggesting ALK partner with TPM3 (t(1; 2)(q25; p23)). Bone marrow studies showed a normal aspirate and core biopsy, without evidence of abnormal cells. Her WBC was 9,700/mm3, Hgb. 11.2 g/dL, Hct. 33.4%, and platelets 285 K/mm3.\n\nShe received CHOP combination chemotherapy with initial response and resolution of palpable lymphadenopathy after three cycles. However, two weeks after her third cycle in October 2010, she noted increasing cervical adenopathy. A repeat CT scan revealed left cervical, left supraclavicular and right inguinal lymphadenopathy, with the largest inguinal node measuring 1.7 cm with heterogenous appearance. Cervical lymph node biopsy revealed persistent anaplastic large cell lymphoma with the same immunophenotype. Her CBC showed WBC 3,400/mm3, Hgb. 11.5 g/dL, Hct. 35.9%, and platelets 218 K/mm3. She was referred to our institution in November 2010, where she received four cycles of ICE (ifosfamide, carboplatin, and etoposide) salvage chemotherapy, finishing in December 2010. Follow-up CBC in January 2011 showed WBC 3,900/mm3, Hgb. 9.1 g/dL, Hct. 25.5%, and platelets 72 K/mm3, and CT scan at that time demonstrated remission with no evidence of nodal disease.\n\nShe declined consolidation with stem cell transplantation and opted for maintenance therapy with DD, which was initiated in February 2011. She received 6 cycles administered intravenously at 18 μg/kg daily for 5 days every 4 weeks, and then additional 4 cycles were administered intravenously at 18 μg/kg daily for 5 days every 8 weeks. She received a total of 10 cycles by March 2012 and was then lost to follow-up. CT imaging after cycles 3, 6, and 10 were negative for recurrence of disease. Associated side effects included fatigue and weight gain after the first cycle and bilateral leg swelling after the fifth cycle (improved with furosemide administration), as well as anasarca and lower extremity deep vein thrombosis (DVT) after the tenth cycle.\n\nShe returned in January 2013 to reestablish care and has continued to show no recurrence of disease. The patient has now maintained an ongoing complete remission of greater than 4 years as documented by periodic surveillance scans, physical exams, and routine blood tests.\n\n5. Discussion\nAlthough PTCL only account for 6% of NHLs and are relatively rare when compared to their B-cell counterparts, they tend to be aggressive and are associated with higher international prognostic index (IPI) scores. Relapses after treatment with CHOP, the most employed therapy, are common, leading to poor prognosis and short-term survival, with 5-year overall survival (OS) rates ranging around 32–35% [3, 4]. Patients with relapsed or refractory PTCL have a reported median progression-free survival of 3.1 months and a median OS of 5.5 months [10]. In contrast, after using DD as maintenance therapy, the cases presented in this report have achieved ongoing sustained remission for over 4 years. DD as maintenance therapy has only been reported in one prior case [9], and this patient is presently experiencing sustained remission for 9+ years (ND, personal communications). To our knowledge, these are the only four patients who have received DD as maintenance therapy, and all four of them have achieved remarkable results. As exemplified in these cases, this novel targeted therapy may provide an alternative to stem cell transplantation (SCT), whose role as consolidation therapy in PTCL remains controversial, with some studies supporting its efficacy and others suggesting lack of improved outcomes [11–14]. Additionally, as evidenced in this report, not all patients meet criteria for SCT.\n\nThe efficacy of DD as salvage therapy in otherwise refractory PTCL has already been well documented in a phase II trial [6]. It has also been demonstrated that combination therapy with DD and CHOP is effective, with OS rate of 63.3% and median duration of response of 30 months, as opposed to historical data of 32–35% and 12 months, respectively, with CHOP alone [15]. However, it is important to note that previous publications on DD have studied its activity with limited cycles of treatment (a maximum of 8 cycles), with disease eventually recurring. In contrast, the cases presented here demonstrate the efficacy of DD when it is used as maintenance therapy (over a span of 1-2 years), which can result in long-term remission, even long after DD has been discontinued.\n\nIn our first case, although stage IVB subcutaneous panniculitis gamma delta T-cell lymphoma typically results in poor survival, DD was successful as salvage therapy after the disease had relapsed with CVP, ICE, and ESHAP and subsequently served as maintenance therapy, resulting in sustained remission. Maintenance therapy in our second case also resulted in sustained remission, despite the fact that the patient had stage IVB PTCL, NOS, which is typically associated with poor prognosis. Although ALK-1 positive anaplastic large cell lymphoma is generally associated with improved prognosis due to superior response rates to CHOP-like regimens [5, 16], our patient in the third case had stage III disease that was refractory to CHOP, rendering a poor prognosis. However, she also has experienced continuing sustained remission for more than four years following long-term therapy with DD. Our first two cases tolerated the drug exceedingly well and case 3 exhibited some adverse events (anasarca and DVT). While DD can be associated with adverse reactions including capillary leak syndrome, infusion reactions, and visual changes, among others, it is not associated with cumulative toxicity or clinically significant myelosuppression [6].\n\nAlthough a specific mechanism remains unclear, it is our hypothesis that the activity of DD as long-term maintenance therapy involves its ability to potentially regulate the immune system. Specifically, T-regulatory cell population is CD25+ and long-term DD therapy may depress the level of CD25+ T regulatory cell populations, resulting in increased immune activity against the cancer cells and long-term remission. Such immune-surveillance activity by anti-CD25 agents has been described in prior studies [17–20]. This may explain how DD is effective against a heterogeneous group of lineages, including T-cell and B-cell malignancies, and both CD25+ and CD25− tumors [6–8].\n\nGiven the demonstrated efficacy of DD as maintenance therapy and its general tolerability in advanced stage PTCL with generally poor prognosis, our findings can have significant implications. Additional studies would need to be conducted in a formal clinical trial setting to firmly establish the role of DD as potential maintenance therapy in PTCL.\n\nAcknowledgment\nThe authors would like their patients for their willingness to share their experiences with their medical community.\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.\n\nConflict of Interests\nThe authors declare that they have no conflict of interests or disclosures regarding the publication of this paper.\n\nAuthors' Contribution\nAll authors contributed, read, and approved the final paper.\n\nFigure 1 Case 1: CTs of the abdomen illustrating (a) subcutaneous nodules prior to initiation of denileukin diftitox and (b) resolution of the subcutaneous nodules after treatment with denileukin diftitox.\n==== Refs\n1 American Cancer Society Cancer Facts and Figures 2015 2015 Atlanta, Ga, USA American Cancer Society http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/index \n2 Harris N. L. Jaffe E. S. Stein H. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group Blood 1994 84 5 1361 1392 2-s2.0-0028064764 8068936 \n3 Karlin L. Coiffier B. The changing landscape of peripheral T-cell lymphoma in the era of novel therapies Seminars in Hematology 2014 51 1 25 34 10.1053/j.seminhematol.2013.11.001 2-s2.0-84892945819 24468313 \n4 Reddy N. M. Evens A. M. Chemotherapeutic advancements in peripheral T-cell lymphoma Seminars in Hematology 2014 51 1 17 24 10.1053/j.seminhematol.2013.11.006 2-s2.0-84892854428 24468312 \n5 Escalón M. P. Liu N. S. Yang Y. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience Cancer 2005 103 10 2091 2098 10.1002/cncr.20999 2-s2.0-18044383718 15816054 \n6 Dang N. H. Pro B. Hagemeister F. B. Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma British Journal of Haematology 2007 136 3 439 447 10.1111/j.1365-2141.2006.06457.x 2-s2.0-33846010137 17233846 \n7 Wong B. Y. Gregory S. A. Dang N. H. Denileukin diftitox as novel targeted therapy for lymphoid malignancies Cancer Investigation 2007 25 6 495 501 10.1080/07357900701360096 2-s2.0-34548839667 17882663 \n8 Dang N. H. Hagemeister F. B. Pro B. Phase II study of denileukin diftitox for relapsed/refractory B-cell non-Hodgkin's lymphoma Journal of Clinical Oncology 2004 22 20 4095 4102 10.1200/jco.2004.03.071 2-s2.0-7044254964 15353540 \n9 Wong B. Y. Ma Y. Fitzwilson R. Dang N. H. De novo maintenance therapy with denileukin diftitox (Ontak) in a patient with peripheral T-cell lymphoma is associated with prolonged remission American Journal of Hematology 2008 83 7 596 598 10.1002/ajh.21177 2-s2.0-45749120841 18383317 \n10 Mak V. Hamm J. Chhanabhai M. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors Journal of Clinical Oncology 2013 31 16 1970 1976 10.1200/jco.2012.44.7524 2-s2.0-84880687533 23610113 \n11 Dearden C. E. Foss F. M. Peripheral T-cell lymphomas: diagnosis and management Hematology/Oncology Clinics of North America 2003 17 6 1351 1366 10.1016/s0889-8588(03)00119-9 2-s2.0-0346367060 14710889 \n12 Jagasia M. Morgan D. Goodman S. Histology impacts the outcome of peripheral T-cell lymphomas after high dose chemotherapy and stem cell transplant Leukemia and Lymphoma 2004 45 11 2261 2267 10.1080/10428190412331272749 2-s2.0-8644231731 15512815 \n13 Mounier N. Gisselbrecht C. Briere J. All aggressive lymphoma subtypes do not share similar outcome after front-line autotransplantation: A matched-control analysis by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Annals of Oncology 2004 15 12 1790 1797 15550584 \n14 Zamkoff K. W. Matulis M. D. Mehta A. C. Beaty M. W. Hutchison R. E. Gentile T. C. High-dose therapy and autologous stem cell transplant does not result in long-term disease-free survival in patients with recurrent chemotherapy-sensitive ALK-negative anaplastic large-cell lymphoma Bone Marrow Transplantation 2004 33 6 635 638 10.1038/sj.bmt.1704392 2-s2.0-1842483136 15004538 \n15 Foss F. M. Sjak-Shie N. Goy A. A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study Leukemia and Lymphoma 2013 54 7 1373 1379 10.3109/10428194.2012.742521 2-s2.0-84879338660 23278639 \n16 Armitage J. O. The aggressive peripheral T-cell lymphomas: 2013 American Journal of Hematology 2013 88 10 910 918 10.1002/ajh.23536 2-s2.0-84884727679 24078271 \n17 Spranger S. Gajewski T. Rational combinations of immunotherapeutics that target discrete pathways Journal for ImmunoTherapy of Cancer 2013 1, article 16 10.1186/2051-1426-1-16 \n18 Kline J. Brown I. E. Zha Y.-Y. Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma Clinical Cancer Research 2008 14 10 3156 3167 10.1158/1078-0432.CCR-07-4696 2-s2.0-49649121241 18483384 \n19 Rech A. J. Vonderheide R. H. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells Annals of the New York Academy of Sciences 2009 1174 99 106 10.1111/j.1749-6632.2009.04939.x 2-s2.0-70350496784 19769742 \n20 Sutmuller R. P. M. van Duivenvoorde L. M. van Elsas A. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses The Journal of Experimental Medicine 2001 194 6 823 832 10.1084/jem.194.6.823 2-s2.0-0035903324 11560997\n\n",
"fulltext_license": "CC BY",
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"issue": "2015()",
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"medline_ta": "Case Rep Oncol Med",
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"other_id": null,
"pages": "123756",
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"pmid": "26240767",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "23278639;17233846;18383317;24468313;23610113;18483384;24468312;8068936;15816054;15353540;15004538;14710889;19769742;24829752;15512815;17882663;11560997;15550584;24078271",
"title": "Denileukin Diftitox (Ontak) as Maintenance Therapy for Peripheral T-Cell Lymphomas: Three Cases with Sustained Remission.",
"title_normalized": "denileukin diftitox ontak as maintenance therapy for peripheral t cell lymphomas three cases with sustained remission"
} | [
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"companynumb": "US-JNJFOC-20150808335",
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{
"abstract": "BACKGROUND\nStudies investigating the aripiprazole augmentation treatment of serotonin reuptake inhibitor (SRI)-resistant obsessive-compulsive disorder (OCD) are insufficient. The aim of the present pilot study was to investigate the efficacy and tolerability of flexible doses of aripiprazole as an augmenting agent in SRI-resistant OCD patients.\n\n\nMETHODS\nOCD patients who met the criteria of this study were followed up with flexible doses of aripiprazole augmentation over a 10-week period. Effectiveness of treatment was evaluated via the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. At the end of the 10-week follow-up period, patients who showed an improvement of ≥30% for the Y-BOCS total score from baseline were considered responders.\n\n\nRESULTS\nThirty patients met the study inclusion criteria; three patients did not agree to participate, and four patients dropped out of the study. The differences between baseline and scores at 10 weeks for the parameters studied were as follows: Y-BOCS scores: 32.0±6.3-24.0±8.1 (Z=4.2, P<0.05); Y-BOCS compulsion subscore: 15.0±4.2-11.5±4.3 (Z=4.01, P<0.05); Y-BOCS obsession subscore: 17.0±2.6-12.4±4.0 (Z=4.1, P<0.05); and CGI-S scores: 4.8±0.8-3.1±1.2 (Z=3.9, P<0.05). Patients showed a significant improvement over the 10-week study period; however, only seven of 23 patients (30.4%) who completed the study met the criteria determined for treatment response.\n\n\nCONCLUSIONS\nDespite the limited number of cases and open-label design of this study, results support the notion that adding aripiprazole to SRIs could be a valid strategy for treatment-resistant OCD patients.",
"affiliations": "Gulhane School of Medicine, Etlik-Ankara, Turkey. drmehmetak@gmail.com",
"authors": "Ak|Mehmet|M|;Bulut|Suheyla Dogan|SD|;Bozkurt|Ali|A|;Ozsahin|Aytekin|A|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D017367:Serotonin Uptake Inhibitors; D000068180:Aripiprazole",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-011-0011-7",
"fulltext": null,
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"issn_linking": "0741-238X",
"issue": "28(4)",
"journal": "Advances in therapy",
"keywords": null,
"medline_ta": "Adv Ther",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003192:Compulsive Behavior; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004351:Drug Resistance; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009770:Obsessive Behavior; D009771:Obsessive-Compulsive Disorder; D010879:Piperazines; D011569:Psychiatric Status Rating Scales; D015363:Quinolones; D017367:Serotonin Uptake Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "8611864",
"other_id": null,
"pages": "341-8",
"pmc": null,
"pmid": "21437763",
"pubdate": "2011-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Aripiprazole augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a 10-week open-label study.",
"title_normalized": "aripiprazole augmentation of serotonin reuptake inhibitors in treatment resistant obsessive compulsive disorder a 10 week open label study"
} | [
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"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-96298",
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"abstract": "Cutaneous metastases of endometrial carcinoma are rare. We report a case of a 54-year-old woman who developed cutaneous metastases from an endometrial carcinoma, and review the related literature to offer insight into this rare and serious condition.\n\n\n\nThe clinical and pathological data and therapy delivered to a patient from Peking University People's Hospital, were retrieved from her medical records. A systematic literature search regarding this unusual disease progression was conducted through PubMed/MEDLINE.\n\n\n\nA postmenopausal patient diagnosed with stage IB endometrioid carcinoma rapidly developed cutaneous metastases. 10 months postoperatively, the patient developed multiple lymph node metastases, and 22 months later, cutaneous metastases appeared on both breasts. She was then treated with chemotherapy, immunotherapy and hormone therapy. The skin lesions eased temporarily but deteriorated quickly. Ultimately, she died in 7 months subsequent to the appearance of cutaneous lesions.\n\n\n\nCutaneous metastases from endometrial carcinoma have usually been incurable and associated with a limited prognosis.",
"affiliations": "Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China.;Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China.;Reproductive Medical Center, Peking University People's Hospital, Beijing, China.;Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China. wangjianliu@pkuph.edu.cn.",
"authors": "Fan|Yuan|Y|0000-0003-3598-9253;Deng|Hao|H|;Tian|Li|L|;Wang|Jianliu|J|0000-0001-9323-0566",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00404-021-06165-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0932-0067",
"issue": "304(5)",
"journal": "Archives of gynecology and obstetrics",
"keywords": "Cutaneous metastases; Endometrial cancer; Endometrial carcinoma; Skin metastases",
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D018269:Carcinoma, Endometrioid; D016889:Endometrial Neoplasms; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D017698:Postmenopause; D011379:Prognosis; D012878:Skin Neoplasms",
"nlm_unique_id": "8710213",
"other_id": null,
"pages": "1127-1133",
"pmc": null,
"pmid": "34338831",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "22853962;4336632;8335743;24708772;4007502;10410889;8721599;3351974;17415118;22617133;16648864;21993268;19623034;7417946;13678747;8404015;8056889;9190989;11426989;12877741;16148416;16122207;19743722;27672676;31116808",
"title": "Cutaneous metastases of endometrial carcinoma: report of an unusual case and literature review.",
"title_normalized": "cutaneous metastases of endometrial carcinoma report of an unusual case and literature review"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-337730",
"fulfillexpeditecriteria": "1",
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"drug": [
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"actiondrug": "5",
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"activesubstancename": "CARBOPLATIN"
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{
"abstract": "We present a patient who had two allogeneic bone marrow transplantations for acute lymphocytic leukemia. She developed slowly progressive limb-girdle weakness in the context of other symptoms of graft-vs.-host disease (GVHD). Her myopathy symptoms had been initially attributed to GVHD, but when she progressed despite immunotherapy, genetic testing was requested. Initial testing was performed on a blood sample, identifying a variant of unknown significance in DMD. Subsequent testing of DNA from the patient's muscle tissue identified two pathogenic variants in CAPN3, with absence of the DMD variant (this latter variant presumed to have been received from the donor). Allele-specific digital droplet qPCR permitted the quantification of the donor variant in various tissues from the patient (whole skin, isolated fibroblasts, whole blood, saliva, buccal cells, urine sediment, and two muscle biopsies taken at a 2 year interval). This report emphasizes that genetic disease should still be considered in the context of presumably acquired disease, and also demonstrates the extent of transdifferentiation of donor cells into other tissues.",
"affiliations": "Department of Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.;Department of Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.;Division of Neurology, Department of Medicine, Kelowna General Hospital, Kelowna, BC, Canada.;Department of Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.;Department of Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.;Department of Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.",
"authors": "Martens|Kristina|K|;Leckie|Jamie|J|;Fok|Daniel|D|;Wells|Robyn A|RA|;Chhibber|Sameer|S|;Pfeffer|Gerald|G|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2020.604547",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.604547\nNeurology\nCase Report\nCase Report: Calpainopathy Presenting After Bone Marrow Transplantation, With Studies of Donor Genetic Content in Various Tissue Types\nMartens Kristina 1 Leckie Jamie 1 Fok Daniel 2 Wells Robyn A. 1 Chhibber Sameer 1 Pfeffer Gerald 13* 1Department of Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada\n2Division of Neurology, Department of Medicine, Kelowna General Hospital, Kelowna, BC, Canada\n3Department of Medical Genetics, Alberta Child Health Research Institute, University of Calgary, Calgary, AB, Canada\nEdited by: Edoardo Malfatti, INSERM U1179 Handicap neuromusculaire: Physiopathologie, Biothérapie et Pharmacologie appliquées (END-ICAP), France\n\nReviewed by: Zhiyv Neal Niu, Mayo Clinic, United States; Raghav Govindarajan, University of Missouri, United States\n\n*Correspondence: Gerald Pfeffer gerald.pfeffer@ucalgary.caThis article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology\n\n\n11 1 2021 \n2020 \n11 60454709 9 2020 02 12 2020 Copyright © 2021 Martens, Leckie, Fok, Wells, Chhibber and Pfeffer.2021Martens, Leckie, Fok, Wells, Chhibber and PfefferThis 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.We present a patient who had two allogeneic bone marrow transplantations for acute lymphocytic leukemia. She developed slowly progressive limb-girdle weakness in the context of other symptoms of graft-vs.-host disease (GVHD). Her myopathy symptoms had been initially attributed to GVHD, but when she progressed despite immunotherapy, genetic testing was requested. Initial testing was performed on a blood sample, identifying a variant of unknown significance in DMD. Subsequent testing of DNA from the patient's muscle tissue identified two pathogenic variants in CAPN3, with absence of the DMD variant (this latter variant presumed to have been received from the donor). Allele-specific digital droplet qPCR permitted the quantification of the donor variant in various tissues from the patient (whole skin, isolated fibroblasts, whole blood, saliva, buccal cells, urine sediment, and two muscle biopsies taken at a 2 year interval). This report emphasizes that genetic disease should still be considered in the context of presumably acquired disease, and also demonstrates the extent of transdifferentiation of donor cells into other tissues.\n\nmyopathycalpain 3LGMD2Alate onsettransdifferentiationbone marrow transplantationdigital droplet pcrdystrophin\n==== Body\nIntroduction\nGenetic myopathies and muscular dystrophies can be difficult to diagnose on account of genetic and/or clinical heterogeneity, poor genotype-phenotype correlation, and variability in onset age. A compounding factor in late-onset muscle disease is the fact that patients may have coexistent acquired diseases that complicate the clinical picture and present additional diagnostic challenges. In general, medical diagnosis attempts to attribute symptoms to a unifying diagnosis, but in the modern era of genomic sequencing it is increasingly well-known that coincident rare disease diagnoses are common rather than being exceptional, either as being a case of dual genetic diagnoses (1), gene modifier effects (2), genetic disorders having very late onset (3), or combinations of genetic and acquired disease (4).\n\nWe present a case of a patient who was diagnosed with acute lymphocytic leukemia (ALL) and received two bone marrow transplants (BMT). She developed slowly progressive limb-girdle weakness which was initially attributed to graft-vs.-host disease (GVHD), however she did not respond to immunotherapy. We describe her genetic investigations (using DNA isolated from blood and muscle tissue) as well as genetic studies identifying donor DNA in various fractions in different tissues. The case emphasizes the need to consider genetic disease even in the context of other acquired diseases. This report also provides quantification of donor DNA within various tissue types.\n\nMethods\nEthics Statement\nWritten informed consent was obtained from the patient for these studies and for publication of this case report. Ethical approval was obtained from the University of Calgary Conjoint Health Research Ethics Board.\n\nClinical Chart Review\nRetrospective chart review was conducted to report the evolution of the clinical history, therapies, and investigations, including two separate muscle biopsy procedures.\n\nDNA Extraction Protocols\nWhole blood collected in EDTA tubes was isolated using a MagMAX DNA Multi-Sample Ultra 2.0 Kit (cat#A36570) on the KingFisher Duo Prime Purification System by ThermoFisher. Two skeletal muscle biopsies (collected in 2013 and 2016) were flash frozen in liquid nitrogen and stored at −80 until processed. A partial depth skin punch biopsy was collected and stored in Ham's F12 media (supplemented with 20% FBS, 1% pen/strep, 1% Glutamax, and 1% Fungizone) and kept at 4 degrees until processed. A portion of the skin biopsy was used for fibroblast isolation using a standard derivation of Primary Human Fibroblasts protocol. After collection, urine was centrifuged, washed with PBS and stored at −20 until processed. Muscle, skin, fibroblast and urine samples were isolated using the Qiagen All Prep DNA/RNA Mini Kit (Cat. 80204). Saliva and Buccal samples were collected with Oragene DNA kits, and gDNA isolated using prepIT L2P reagent by DNA Genotek.\n\nExome Sequencing and Bioinformatics\nDetailed methods are provided in Supplement. To summarize, library preparation used the Agilent SureSelect XT2 Target Enrichment System for Illumina Paired-End Multiplexed Sequencing. This protocol used reagents from the #G9621B SureSelect XT2 Reagent Kit and exome capture probes from the #5190-9501 SureSelect XT2 Clinical Research Exome V2 Capture Library. Sequencing was performed on an Illumina NextSeq 500 sequencer and 300 cycle (2 × 150 bp) high-output sequencing kits to produce ~10 Gb of sequence data (≥Q30) per sample. Variant calls were generated based upon the detailed protocol described in Supplement. The variant list was filtered to identify coding variants with MAF <0.005 from genes associated with neuromuscular diseases.\n\nPCR and Sanger Sequencing\nEndpoint PCR and Sanger sequencing was used to screen for the patient's Calpain 3 germline mutations CAPN3 c.550delA p.Thr184fs (rs80338800), and c.865C > T p.Arg289Trp (rs528417986), as well as DMD c.3028G > GC p.Ala1010Pro (rs766325631). We used custom primers for each variant (all primer sequences available on request). PCR was performed using Qiagen Taq polymerase, 400nM primer, 1ul of gDNA, 56°C annealing and 39 cycles. Amplified products were purified using ExoI/SAP, and Sanger Sequencing was performed using BigDye (Applied Biosystems) on an ABI 3730XL sequencer (Applied Biosystems). Chromatographs were interpreted using Mutation Surveyor software (Applied Biosystems).\n\nAllele-Specific Digital Droplet PCR (ddPCR)\nTo determine the proportion of genomes containing the DMDc.3028G > GC variant in different tissues, we performed allele-specific ddPCR using primers specific to the variant and reference sequences at the 3′ end. ddPCR reactions consisted of 12.5 ul EvaGreen Supermix (Bio-Rad cat#1864034), 400 nM primer, 50 ng gDNA, and nuclease free water up to 25 ul volume. Reactions were prepared in 96 well plates and transferred to an Automated Droplet Generator (Bio-rad) to create 20,000 droplets or individual PCR reactions. PCR Cycling conditions were carried on Bio-Rad C1000 Touch Thermal Cycler as follows: 95°C for 10 min, 45 cycles of 95°C for 30 s, 63°C for 1 min and a final extension of 98° for 10 min.\n\nDroplet counts were analyzed using QX200 Droplet Reader (Bio-Rad) and QuantaSoft Analysis Pro. The relative proportion of genomes containing the variant was approximated by direct comparison of positive droplets in the variant specific reaction compared to the reference sequence specific reaction.\n\nResults\nCase Report\nAt time of referral the patient was a 38 year old woman with slowly progressive symmetric proximal weakness and muscle cramps. She had no prior history of neuromuscular disease. Four years prior, she was diagnosed with acute lymphocytic leukemia (ALL), and received two allogeneic BMTs (four and 2 years prior to presentation) from different donors. Following the second transplant she was in remission from ALL but developed eruptions affecting her skin and oral mucosa that were attributed to graft-vs.-host disease (GVHD). She originally received treatment with prednisone and tacrolimus for 1 month, and due to lack of effect tacrolimus was changed to cyclosporine. Prednisone was discontinued after another 9 months following which her GVHD symptoms remained well-controlled on cyclosporine.\n\nFour months after stopping prednisone, she developed weakness when trying to rise from a chair, lifting arms over her head, and had symmetric muscle cramps. She was not reporting other neurological symptoms, namely no facial weakness, bulbar symptoms, contractures, cardiac or respiratory symptoms. Since she had not developed other GVHD symptoms, it was not clear whether these symptoms were a manifestation of GVHD or another condition. On family history, there were no family members known to have any neuromuscular condition. Her parents were non-consanguineous, and healthy in their 60′s. She had no siblings, and one son aged 12 who was healthy with normal development.\n\nHer initial neurologic examination indicated normal cranial nerves, normal motor tone, bulk, and reflexes, and grade 4 MRC weakness in neck flexors, deltoid, biceps, triceps, hip flexors and abductors bilaterally, with normal strength in other muscle groups. Coordination and sensory examinations were normal. A myositis antibody panel including HMG-CoA-R and SRP antibodies were negative. EMG and nerve conduction studies were normal. Muscle biopsy of vastus lateralis was largely non-specific and unremarkable, with no inflammatory cell infiltrates, but possible rare regenerating myofibres.\n\nOn speculation that the patient may still have an immune-mediated myopathy, she received a trial of therapy with intravenous immunoglobulins and prednisone, followed by a trial of rituximab, which did not result in any improvement. Her cyclosporine was switched to tacrolimus which similarly did not provide any improvement.\n\nShe was followed clinically and 2 years later her exam had deteriorated. She had developed scapular winging bilaterally and had atrophy developing in limb girdle musculature. Weakness had become MRC grade 4 in shoulder abduction, elbow flexion/extension, and knee flexion; MRC grade 2 strength was present in hip abductors/extensors. Given this change and a lack of clear diagnosis she was re-investigated, including a second muscle biopsy which was again inconclusive, with minimal myofibre size variation and occasional atrophic fibers. Dystrophin immunohistochemistry was normal. MRI of the upper legs showed fatty infiltration of posterior hamstring muscles with relative sparing of anterior leg compartment, iliopsoas, hip flexors (Figure 1).\n\nFigure 1 Muscle MRI of upper legs. In this representative transverse axial T1 weighted image from the patient, increased signal intensity is seen in the bilateral adductor magnus, semitendinosus, and semimembranosus muscles.\n\nA review of prior records identified an elevated CK of 890 U/L from prior to her onset of muscle symptoms, raising the question of a possible pre-existing genetic muscle disease. That CK elevation was recorded when she presented for investigation of chest pain, although ultimately her cardiac workup (troponin, ECG, and echocardiogram) had returned normal. A repeat CK level 2 days later had decreased to 510, but was still elevated (reference range <190U/L). At her initial presentation with myopathy symptoms, her CK level was 813 U/L, and subsequent measurements fluctuated from 834 to 1,522 U/L in her first year of these symptoms. In her second year of myopathy symptoms, the CK enzyme level ranged from 720 to 2,571 U/L. In both years she had received the above-mentioned immunosuppressive therapies, which did not result in clinical improvement or reliable reductions on CK levels. After discontinuation of these therapies her CK enzyme levels did not significantly change, and her most recent CK levels ranged from 672 to 1,835 U/L.\n\nTesting with a genetic sequencing panel for 78 genes (5) associated with myopathy identified a heterozygous variant of unknown significance in DMD [c.3028G > GC, predicted to cause p.(Ala1010Pro), and listed in dbSNP as rs766325631], although testing had been performed on DNA isolated from blood, due to a test ordering error. Chimerism studies in the patient's blood revealed 100% chimerism for the second BMT donor, indicating that this variant actually originated from the second donor.\n\nExome Sequencing of DNA Isolated From Muscle\nBased on our variant prioritization approach we identified eight candidate variants. Compound heterozygous variants in CAPN3 were identified [c.865C > T, predicted to cause p.(Arg289Trp), rs528417986 in dbSNP; and c.550delA, predicted to cause p.(Thr184fs), rs80338800 in dbSNP]. Both variants are listed as pathogenic in ClinVar. This was considered to be the explanation for the patient's condition given the characteristics of the variants, and the strong consistency of the clinical phenotype and muscle MRI with calpainopathy. However, we could not formally confirm that the variants are in trans because other family members were not available for testing.\n\nThe other variants identified from exome sequencing included six single heterozygous variants in AGL, ATL1, MAP3K20, PDK3, TOR1AIP1, and TRAPPC11. None of these were deemed as explanations for the patient's condition due to the inheritance pattern (recessive disease for AGL, AMP3K20, TOR1AIP1, and TRAPPC11) and/or phenotype associated with these genes (ATL1 associated with dominant sensory neuropathy or spastic paraplegia; PDK3 associated with X-linked dominant sensorimotor neuropathy).\n\nAs a matter of research interest we sought to identify any reads containing the DMD variant from testing from blood, but there were only three reads at this position and the variant was not present.\n\nAllele-Specific Digital Droplet PCR\nIn order to identify the extent to which the DMD variant may have transdifferentiated into other tissues, we performed allele-specific ddPCR on DNA from available tissue types including both muscle biopsies, a skin biopsy, urine sediment, buccal cells, and saliva. The results are presented in Figure 2, and demonstrate that the variant is present in a fairly large proportion of genomes isolated from buccal, blood, and urine sediment DNA sources. Skin and muscle tissue had detectable levels of the DMD variant but this was <10% in these tissues.\n\nFigure 2 Allele fractions of the DMD variant in various tissue types. This figure shows the Sanger sequencing chromatographs at the position of the DMD variant (outlined with red box) in various tissue types, which is quantified using the described allele specific ddPCR assay. Blood predictably demonstrated an allele fraction that was approaching 50%. For tissue types that do not contain significant numbers of white blood cells, such as skin, fibroblasts, and muscle, the allele fractions were below 10%. For other tissues that contain a high proportion of white blood cells such as saliva, urine sediment and buccal cells, the allele fractions were intermediate.\n\nDiscussion\nWe describe a case of calpainopathy with late onset, that was a diagnostic challenge on account of the patient's diagnosis of ALL, two BMTs, and prior history of GVHD. In retrospect, the clinical phenotype is typical for calpainopathy, but this was difficult to recognize given that acquired disease was initially suspected in this context.\n\nThe c.550delA mutation is one of the common pathogenic mutations in CAPN3 and has been associated with a range of phenotypes including LGMD as well as hyperCKaemia (6). The deleterious effect of this variant is presumably due to the frameshift and presumed loss of function. The c.865C > T mutation is located within the first insertion sequence (in the second protease core domain of CAPN3) (7). The insertion sequence contains two autolysis sites and we speculate that this mutation may affect autoproteolysis of CAPN3, which is a described mechanism for the pathogenicity of some CAPN3 mutations. For purposes of genotype-phenotype correlation, we are not aware of this combination of mutations in previously reported patients with calpainopathy.\n\nThis case provides several interesting learning points, the most important being that genetic disease should be considered in the differential diagnosis even when presenting with late onset disease and in the context of other medical comorbidities. In this particular case, it is possible that the medical comorbidities and medical therapy (particularly the long term steroid treatment) may have accelerated the course of this patient's genetic myopathy, which had previously been asymptomatic. There is no means to be certain whether an interaction could have occurred, though CAPN3-related disease covers a broad clinical spectrum ranging from asymptomatic hyper-CKaemia (8) to severe limb girdle weakness presenting in childhood (9), and in rare cases cardiomyopathy (10). The fact that wide phenotypic variability exists even within families with the same mutations (11) suggests that environmental or other circumstantial factors may play a role in the eventual outcome of the disease. Therefore, the steroid therapy, or the coexistent medical stressors (ALL and two BMTs) could have contributed to this patient's disease course, although her development of myopathy symptoms at the same time as her BMT treatments and GVHD could also have been coincidental.\n\nDonor cells from BMT may transdifferentiate into other host tissues (12, 13), to varying extents up to 10% of the cell population (14). Given this, we speculated that if substantial transdifferentiation occurred, this would introduce the VUS in DMD from the donor, which could have a damaging effect on the recipient's muscle if this variant is pathogenic. Alternatively, transdifferentiation of donor cells could potentially have a beneficial effect, given the host's original cell population contains compound heterozygous mutations causing muscular dystrophy. In this case study, we demonstrate the extent of donor DNA in various tissue types, which is smaller in tissues such as muscle and skin, and higher in tissues which will have a contribution from white blood cells, such as saliva, buccal cells, and urine sediment. Our study demonstrates that these latter tissue sources may not be reliable for testing of genetic disease in individuals who have had BMT, which is useful information because DNA from saliva is increasingly used in clinical testing, and urine sediment is a highly useful source of DNA for particular genetic diagnoses (15).\n\nWe are aware of two prior examples in which a bone marrow transplant occurred in a patient with a genetic disease. In one case, the patient had dual genetic diagnoses of dystrophinopathy as well as X-linked severe combined immunodeficiency (16). BMT was used to treat the immune deficiency, and subsequent studies of muscle biopsies up to 13 years later revealed persistence of transdifferentiated donor cells, in the range of 0.5–0.9%. The second report was a dual genetic diagnosis of dystrophinopathy and Diamond-Blackfan anemia (17). Subsequent muscle biopsies on days 730 and 1,250 post-BMT revealed 8 and 10.4% chimerism, respectively, in the recipient's muscle tissue. Results from our study are similar to that present in the second report, if one considers that the allele fraction of the DMD variant constitutes only 50% of the donor DNA (given that the variant was heterozygous in the donor). We have summarized these findings in Table 1.\n\nTable 1 Comparison of bone marrow donor genetic material in muscle tissues compared with prior literature.\n\nPublication\tDonor genetic content (%)\tTime from BMT to muscle biopsy (years)\t\nCurrent report\t3.4\t2\t\n\t10.4\t5\t\nGussoni et al. (16)\t0.5–0.9\t13\t\nNair et al. (17)\t8\t2\t\n\t10.4\t3\t\nThis table summarizes the extent of donor genetic content within muscle biopsy tissues in prior reports compared to this study. Each of the reports applied different methods, although the findings in the current study are similar to that reported in one of the prior studies. Note that the donor genetic content was multiplied by two compared to the result from Figure 2, because our ddPCR assay was specific for a variant that was heterozygous in the donor.\n\nIn conclusion, this study emphasizes the importance of considering genetic disease in the differential diagnosis of late-onset presentations even in the presence of medical comorbidities, suggests possible environmental factors which could be explored in future studies of calpainopathy, emphasizes the preferred tissue sources for genetic testing, and contributes to the highly limited literature about the transdifferentiation of BMT cells into tissues such as muscle.\n\nData Availability Statement\nThe datasets generated in this article are not openly available because of ethical concerns which could potentially allow the participant to be identified. Requests to access the datasets should be directed to the corresponding author.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by University of Calgary Conjoint Health Research Ethics Board. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nKM analysis of laboratory data and authored manuscript. JL, DF, and SC collection of clinical data and drafted sections on clinical data. RW analysis of laboratory data. GP conceptualization of study, supervision of laboratory studies, and authored manuscript. All authors approved the final version of the manuscript for submission.\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\nWe thank to Paul Gordon for assistance with bioinformatic analysis.\n\nFunding. Exome sequencing was performed at the University of Calgary Center for Health Genomics and Informatics (CHGI). CHGI was supported by the University of Calgary. Infrastructure used in this study was supported by a Canada Foundation for Innovation Grant to GP. Funding for this study was provided from internal funds by the Department of Clinical Neurosciences and Hotchkiss Brain Institute.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2020.604547/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Posey JE Harel T Liu P Rosenfeld JA James RA Coban Akdemir ZH \nResolution of disease phenotypes resulting from multilocus genomic variation\n. N Engl J Med . (2017 ) 376 :21 –31\n. 10.1056/NEJMoa1516767 27959697 \n2. Niu Z Pontifex CS Berini S Hamilton LE Naddaf E Wieben E . Myopathy with SQSTM1 and TIA1 variants: clinical and pathological features\n. Front Neurol . (2018 ) 9 :147 . 10.3389/fneur.2018.00147 29599744 \n3. Almomen M Martens K Quadir A Pontifex CS Hanson A Korngut L . High diagnostic yield and novel variants in very late-onset spasticity\n. J Neurogenet . (2019 ) 33 :27 –32\n. 10.1080/01677063.2019.1566326 30747022 \n4. Ginsberg L Malik O Kenton AR Sharp D Muddle JR Davis MB . Coexistent hereditary and inflammatory neuropathy\n. Brain . (2004 ) 127 :193 –202\n. 10.1093/brain/awh017 14607795 \n5. Levesque S Auray-Blais C Gravel E Boutin M Dempsey-Nunez L Jacques PE . Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing\n. Orphanet J Rare Dis . (2016 ) 11 :8 . 10.1186/s13023-016-0390-6 26809617 \n6. Hanisch F Muller CR Grimm D Xue L Traufeller K Merkenschlager A . Frequency of calpain-3 c.550delA mutation in limb girdle muscular dystrophy type 2 and isolated hyperCKemia in German patients\n. Clin Neuropathol . (2007 ) 26 :157 –63\n. 10.5414/NPP26157 17702496 \n7. Ye Q Campbell RL Davies PL . Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation\n. J Biol Chem . (2018 ) 293 :4056 –70\n. 10.1074/jbc.RA117.001097 29382717 \n8. Kyriakides T Angelini C Schaefer J Sacconi S Siciliano G Vilchez JJ \nEFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia\n. Eur J Neurol . (2010 ) 17 :767 –73\n. 10.1111/j.1468-1331.2010.03012.x 20402744 \n9. Angelini C Fanin M \nCalpainopathy\n. In: Adam MP Ardinger HH Pagon RA Wallace SE Bean LJH Stephens K Amemiya A editors. Genereviews . Seattle, WA : University of Washington, Seattle (2005 ).\n10. Okere A Reddy SS Gupta S Shinnar M . A cardiomyopathy in a patient with limb girdle muscular dystrophy type 2A\n. Circ Heart Fail . (2013 ) 6 :e12 –3\n. 10.1161/CIRCHEARTFAILURE.112.971424 23322878 \n11. Schessl J Walter MC Schreiber G Schara U Muller CR Lochmuller H . Phenotypic variability in siblings with calpainopathy (LGMD2A)\n. Acta Myol . (2008 ) 27 :54 –8\n.19364062 \n12. Mezey E Chandross KJ Harta G Maki RA McKercher SR . Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow\n. Science . (2000 ) 290 :1779 –82\n. 10.1126/science.290.5497.1779 11099419 \n13. Orlic D Kajstura J Chimenti S Bodine DM Leri A Anversa P \nBone marrow stem cells regenerate infarcted myocardium\n. Pediatr Transplant . (2003 ) 7 (Suppl. 3 ):86 –8\n. 10.1034/j.1399-3046.7.s3.13.x \n14. Hong YC Liu HM Chen PS Chen YJ Lyou JY Hu HY . Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation\n. Bone Marrow Transplant . (2007 ) 40 :871 –4\n. 10.1038/sj.bmt.1705823 17704789 \n15. de Laat P Koene S van den Heuvel LP Rodenburg RJ Janssen MC Smeitink JA . Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation\n. J Inherit Metab Dis . (2012 ) 35 :1059 –69\n. 10.1007/s10545-012-9465-2 22403016 \n16. Gussoni E Bennett RR Muskiewicz KR Meyerrose T Nolta JA Gilgoff I \nLong-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation\n. J Clin Invest . (2002 ) 110 :807 –14\n. 10.1172/JCI0216098 12235112 \n17. Nair V Das S Sharma A Sharma S Kaur J Mishra D . Successful bone marrow transplantation in a patient with Diamond-Blackfan anemia with co-existing Duchenne muscular dystrophy: a case report\n. J Med Case Rep . (2011 ) 5 :216 . 10.1186/1752-1947-5-216 21639928\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "11()",
"journal": "Frontiers in neurology",
"keywords": "LGMD2A; bone marrow transplantation; calpain 3; digital droplet pcr; dystrophin; late onset; myopathy; transdifferentiation",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "604547",
"pmc": null,
"pmid": "33505349",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "19364062;23322878;12235112;21639928;29599744;12603699;17704789;30747022;26809617;29382717;20402744;27959697;11099419;14607795;17702496;22403016",
"title": "Case Report: Calpainopathy Presenting After Bone Marrow Transplantation, With Studies of Donor Genetic Content in Various Tissue Types.",
"title_normalized": "case report calpainopathy presenting after bone marrow transplantation with studies of donor genetic content in various tissue types"
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"companynumb": "CA-TEVA-2021-CA-1927364",
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"abstract": "OBJECTIVE\nTo preliminarily study the feasibility of oocyte cryopreservation in postpubertal girls aged between 13 and 15 years who were at risk for premature ovarian failure due to the accelerated follicle loss associated with Turner syndrome or cancer treatments.\n\n\nMETHODS\nRetrospective cohort and review of literature.\n\n\nMETHODS\nAcademic fertility preservation unit.\n\n\nMETHODS\nThree girls diagnosed with Turner syndrome, 1 girl diagnosed with germ-cell tumor. and 1 girl diagnosed with lymphoblastic leukemia.\n\n\nMETHODS\nAssessment of ovarian reserve, ovarian stimulation, oocyte retrieval, in vitro maturation, and mature oocyte cryopreservation.\n\n\nMETHODS\nResponse to ovarian stimulation, number of mature oocytes cryopreserved and complications, if any.\n\n\nRESULTS\nMean anti-müllerian hormone, baseline follical stimulating hormone, estradiol, and antral follicle counts were 1.30 ± 0.39, 6.08 ± 2.63, 41.39 ± 24.68, 8.0 ± 3.2; respectively. In Turner girls the ovarian reserve assessment indicated already diminished ovarian reserve. Ovarian stimulation and oocyte cryopreservation was successfully performed in all female children referred for fertility preservation. A range of 4-11 mature oocytes (mean 8.1 ± 3.4) was cryopreserved without any complications. All girls tolerated the procedure well.\n\n\nCONCLUSIONS\nOocyte cryopreservation is a feasible technique in selected female children at risk for premature ovarian failure. Further studies would be beneficial to test the success of oocyte cryopreservation in young girls.",
"affiliations": "Innovation Institute for Fertility Preservation and IVF, New York, NY; Laboratory of Molecular Reproduction and Fertility Preservation, Obstetrics and Gynecology, New York Medical College, Valhalla, NY. Electronic address: koktay@fertilitypreservation.org.;Innovation Institute for Fertility Preservation and IVF, New York, NY; Laboratory of Molecular Reproduction and Fertility Preservation, Obstetrics and Gynecology, New York Medical College, Valhalla, NY.",
"authors": "Oktay|K|K|;Bedoschi|G|G|",
"chemical_list": "D004958:Estradiol; D054304:Anti-Mullerian Hormone; D005640:Follicle Stimulating Hormone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1083-3188",
"issue": "27(6)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Fertility preservation; Germ cell tumor; Lymphocytic leukemia; Oocyte cryopreservation; Ovarian stimulation; Turner syndrome",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000293:Adolescent; D054304:Anti-Mullerian Hormone; D002648:Child; D015925:Cryopreservation; D004958:Estradiol; D005260:Female; D059247:Fertility Preservation; D005640:Follicle Stimulating Hormone; D006801:Humans; D009369:Neoplasms; D009865:Oocytes; D006080:Ovarian Follicle; D010062:Ovulation Induction; D016649:Primary Ovarian Insufficiency; D012189:Retrospective Studies; D014424:Turner Syndrome",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "342-6",
"pmc": null,
"pmid": "25214440",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": "17543957;21496813;22993032;21734500;17932880;18930221;9457923;16882268;15140872;23715580;18957497;23083924;23020910;20462941;19192353;22884018;8671490;22018453;23050166;22946282;20502358;20188362;20097335;17974956;19458318;23706339",
"title": "Oocyte cryopreservation for fertility preservation in postpubertal female children at risk for premature ovarian failure due to accelerated follicle loss in Turner syndrome or cancer treatments.",
"title_normalized": "oocyte cryopreservation for fertility preservation in postpubertal female children at risk for premature ovarian failure due to accelerated follicle loss in turner syndrome or cancer treatments"
} | [
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"companynumb": "US-FRESENIUS KABI-FK201705235",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
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"abstract": "OBJECTIVE\nProthrombin complex concentrate (PCC) is a plasma-derived concentrate used to replenish clotting factors. There are limited recommendations for treating coagulopathy induced by direct oral anticoagulants (DOAC). Data are limited regarding both total dose and repeated dosing with this population.\n\n\nMETHODS\nWe describe a case of an adult patient anticoagulated with apixaban who received two 35 unit/kg doses of PCC resulting in suspected pulmonary embolism.\n\n\nCONCLUSIONS\nTreatment of DOAC-induced bleeding remains an \"off-label\" indication for PCC. Additional doses should be given with caution if given at all and patients monitored closely.",
"affiliations": "Department of Pharmacy Services, Saint Joseph Hospital, Lexington, KY, USA.;Department of Pharmacy Services, Saint Joseph Hospital, Lexington, KY, USA.;Department of Pharmacy Services, Saint Joseph Hospital, Lexington, KY, USA.;Department of Pharmacy Services, Saint Joseph Hospital, Lexington, KY, USA.",
"authors": "King|G S|GS|;Cottingham|L G|LG|;Hughes|R E|RE|;Ratliff|P D|PD|",
"chemical_list": "D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C025667:prothrombin complex concentrates; C522181:apixaban",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "anticoagulation; prothrombin complex concentrate; pulmonary embolism; repeat dosing; reversal",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000368:Aged; D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D006470:Hemorrhage; D006801:Humans; D008297:Male; D056687:Off-Label Use; D011655:Pulmonary Embolism; D011720:Pyrazoles; D011728:Pyridones",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "903-905",
"pmc": null,
"pmid": "29885249",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Probable pulmonary embolism with repeat administration of prothrombin complex concentrate in a factor Xa inhibitor patient.",
"title_normalized": "probable pulmonary embolism with repeat administration of prothrombin complex concentrate in a factor xa inhibitor patient"
} | [
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"companynumb": "US-BAYER-2018-214698",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
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"drugadditional": null,
"dr... |
{
"abstract": "To explore the feasibility and reliability of Clinical Coding Surveillance (CCS) for the routine monitoring of Adverse Drug Events (ADE) and describe the characteristics of harm identified through this approach in a large district health board (DHB).\n\n\n\nAll hospital admissions at Waitemata DHB from 2015 to 2016 with an ADE-related ICD10-AM code of Y40-Y59, X40-X49 or T36-T50 were extracted from clinical coded data. The data was analysed using descriptive statistics, statistical process control and Pareto charts. Two clinicians assessed a random sample of 140 ADEs for their accuracy against what was clinically documented in medical records.\n\n\n\nA total of 11,999 ADEs were identified in 244,992 admissions (4.9 ADEs per 100 admissions). ADEs were more prevalent in older adults and associated with longer average length of stays and medicines such as analgesics, antibiotics, anticoagulants and diuretics. Only 2,164 (18%) of ADEs were classified as originating within hospital. Of ADEs originating outside of the hospital, the main causes were poisoning by psychotropics, anti-epileptics and anti-parkinsonism agents and non-opioid analgesics. Clinicians agreed that 91% of ADE positive admissions were accurately classified as per clinical documentation.\n\n\n\nCCS is a feasible and reliable approach for the routine monitoring of ADEs in hospitals.",
"affiliations": "Lead Advisor, Improvement, Research & Informatics, Institute for Innovation and Improvement (i3), Waitemata DHB, Auckland.;Director, Institute for Innovation and Improvement (i3), Waitemata DHB, Auckland.;Medical Fellow, Planning, Funding and Outcomes, Waitemata DHB, Auckland.;Information Analyst, Institute for Innovation and Improvement (i3), Waitemata DHB, Auckland.;Clinical Coding Auditor, Health Information Group, Waitemata DHB, Auckland.;Clinical Coding Team Leader, Health Information Group, Waitemata DHB, Auckland.;Senior Lecturer, Department of Population Health, University of Otago, Christchurch.;Professor, Centre of Methods and Policy Application in the Social Sciences (COMPASS), University of Auckland, Auckland.;Independent Consultant, Seddon Healthcare Quality, Auckland.;Senior Lecturer, School of Management, Massey University, Auckland.;Associate Professor, School of Pharmacy, University of Auckland, Auckland.;Chief Advisor for Asian International Collaboration, Waitemata District Health Board, Auckland.;Senior Lecturer, School of Population Health, University of Auckland, Auckland.;Public Health Physician (Surgical), Institute for Innovation and Improvement (i3), Waitemata DHB, Auckland.;Public Health Physician (Maternity), Child, Women and Family, Waitemata DHB, Auckland.;Senior Research Fellow, Department of Geriatric Medicine, University of Auckland, Auckland.;Chief Pharmacist, Pharmacy Department, Waitemata DHB, Auckland.;Medication Safety Pharmacist, Pharmacy Department, Waitemata DHB, Auckland (Died 24 April 2018).;Clinical Director for Safety and Quality in Primary Care, Waitemata DHB, Auckland.;Executive Director-Allied Health, Scientific & Technical Professions, Waitemata DHB, Auckland.;Information Systems Change Manager, Health Information Group, Waitemata DHB, Auckland.;Director of Nursing and Midwifery, Waitemata DHB, Auckland.;Chief Medical Officer, Waitemata DHB, Auckland.;Chief Executive Officer, Waitemata DHB, Auckland.",
"authors": "Ng|Jerome|J|;Andrew|Penny|P|;Muir|Paul|P|;Greene|Monique|M|;Mohan|Sabitha|S|;Knight|Jacqui|J|;Hider|Phil|P|;Davis|Peter|P|;Seddon|Mary|M|;Scahill|Shane|S|;Harrison|Jeff|J|;Zhou|Lifeng|L|;Selak|Vanessa|V|;Lawes|Carlene|C|;Galgali|Geetha|G|;Broad|Joanna|J|;Crawley|Marilyn|M|;Pevreal|Wynn|W|;Houston|Neil|N|;Brott|Tamzin|T|;Ryan|David|D|;Peach|Jocelyn|J|;Brant|Andrew|A|;Bramley|Dale|D|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-8446",
"issue": "131(1484)",
"journal": "The New Zealand medical journal",
"keywords": null,
"medline_ta": "N Z Med J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D059019:Clinical Coding; D005240:Feasibility Studies; D005260:Female; D006760:Hospitalization; D006761:Hospitals; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D015203:Reproducibility of Results; D055815:Young Adult",
"nlm_unique_id": "0401067",
"other_id": null,
"pages": "46-60",
"pmc": null,
"pmid": "30359356",
"pubdate": "2018-10-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Feasibility and reliability of clinical coding surveillance for the routine monitoring of adverse drug events in New Zealand hospitals.",
"title_normalized": "feasibility and reliability of clinical coding surveillance for the routine monitoring of adverse drug events in new zealand hospitals"
} | [
{
"companynumb": "NZ-GLAXOSMITHKLINE-NZ2019GSK062590",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
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"actiondrug": "5",
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"activesubstancename": "CEFUROXIME SODIUM"
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"abstract": "This study identified tracheobronchial cartilage calcification in children with congenital heart disease. Calcification of the tracheobronchial airways has been found previously in adults receiving warfarin and in children receiving warfarin after mitral valve replacement. A 9-year-old girl who had received a Fontan repair 6 years previously underwent a cardiac computed tomography (CT) scan to evaluate pulmonary artery size. The result was an incidental finding of extensive tracheobronchial cartilage calcification. A retrospective review of all pediatric Fontan patients who had undergone cardiac CT was conducted to search for calcification of the tracheobronchial cartilage. The study investigated ten pediatric Fontan patients who had undergone cardiac CT scanning. Two patients with extensive calcification of the tracheobronchial airways were identified. The index case had hypoplastic left heart syndrome, and the patient had undergone a staged repair with the Fontan at the age of 3 years. A 16-year-old boy with tricuspid atresia had undergone staged repair and Fontan at the age of 3.5 years. These two patients had received continuous warfarin therapy for 6 and 13 years, respectively. Other common causes of airway calcification were excluded from the study. This report describes warfarin-induced tracheobronchial calcification in patients after the Fontan procedure. This finding has possible implications for airway growth and vascular calcification.",
"affiliations": "Green Lane Paediatric and Congenital Cardiology Services, Starship Hospital, Victoria Street West, Private Bag 92024, Auckland, 1142, New Zealand.",
"authors": "Eckersley|Luke|L|;Stirling|John|J|;Occleshaw|Christopher|C|;Wilson|Nigel|N|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-014-0880-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-0643",
"issue": "35(6)",
"journal": "Pediatric cardiology",
"keywords": null,
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D000293:Adolescent; D000925:Anticoagulants; D001980:Bronchi; D002114:Calcinosis; D002648:Child; D002675:Child, Preschool; D005260:Female; D018729:Fontan Procedure; D006330:Heart Defects, Congenital; D006801:Humans; D008297:Male; D011184:Postoperative Period; D013995:Time; D014057:Tomography, X-Ray Computed; D014132:Trachea; D014859:Warfarin",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "954-8",
"pmc": null,
"pmid": "24584210",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10954513;22952653;21798429;23117658;18071068;22843202;14924689;22513267;2389031;21298649;6704660;20374330;22537354;23246393;13571496;23606286;12821256;4434061;1620843;23223575;13706477",
"title": "Two cases of warfarin-induced tracheobronchial calcification after Fontan surgery.",
"title_normalized": "two cases of warfarin induced tracheobronchial calcification after fontan surgery"
} | [
{
"companynumb": "PHHY2014NZ101949",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
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"drugadditional": null,
"drugad... |
{
"abstract": "OBJECTIVE\nTo determine the efficacy and safety of Curcuma domestica extracts in pain reduction and functional improvement.\n\n\nMETHODS\n367 primary knee osteoarthritis patients with a pain score of 5 or higher were randomized to receive ibuprofen 1,200 mg/day or C. domestica extracts 1,500 mg/day for 4 weeks. The main outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, WOMAC pain, WOMAC stiffness, and WOMAC function scores. Adverse events (AEs) were also recorded.\n\n\nRESULTS\n185 and 182 patients were randomly assigned into C. domestica extracts and ibuprofen groups, respectively. The baseline characteristics were no different between groups. The mean of all WOMAC scores at weeks 0, 2, and 4 showed significant improvement when compared with the baseline in both groups. After using the noninferiority test, the mean difference (95% confidence interval) of WOMAC total, WOMAC pain, and WOMAC function scores at week 4 adjusted by values at week 0 of C. domestica extracts were noninferior to those for the ibuprofen group (P=0.010, P=0.018, and P=0.010, respectively), except for the WOMAC stiffness subscale, which showed a trend toward significance (P=0.060). The number of patients who developed AEs was no different between groups. However, the number of events of abdominal pain/discomfort was significantly higher in the ibuprofen group than that in the C. domestica extracts group (P=0.046). Most subjects (96%-97%) were satisfied with the treatment, and two-thirds rated themselves as improved in a global assessment.\n\n\nCONCLUSIONS\nC. domestica extracts are as effective as ibuprofen for the treatment of knee osteoarthritis. The side effect profile was similar but with fewer gastrointestinal AE reports in the C. domestica extracts group.",
"affiliations": "Department of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Department of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Sirindhorn National Medical Rehabilitation Center, Ministry of Public Health, Nonthaburi, Thailand.;Department of Rehabilitation Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.;Department of Rehabilitation Medicine, Ratchaburi Hospital, Ministry of Public Health, Ratchaburi, Thailand.;Department of Rehabilitation Medicine, Songkhla Hospital, Ministry of Public Health, Songkhla, Thailand.;Department of Rehabilitation Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;Department of Rehabilitation Medicine, Rajvithi Hospital, Ministry of Public Health, Bangkok, Thailand.;Department of Rehabilitation Medicine, Vachira Phuket Hospital, Ministry of Public Health, Phuket, Thailand.",
"authors": "Kuptniratsaikul|Vilai|V|;Dajpratham|Piyapat|P|;Taechaarpornkul|Wirat|W|;Buntragulpoontawee|Montana|M|;Lukkanapichonchut|Pranee|P|;Chootip|Chirawan|C|;Saengsuwan|Jittima|J|;Tantayakom|Kesthamrong|K|;Laongpech|Supphalak|S|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D010936:Plant Extracts; D007052:Ibuprofen",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CIA.S58535",
"fulltext": "\n==== Front\nClin Interv AgingClin Interv AgingClinical Interventions in Aging1176-90921178-1998Dove Medical Press 10.2147/CIA.S58535cia-9-451Original ResearchEfficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study Kuptniratsaikul Vilai 1Dajpratham Piyapat 1Taechaarpornkul Wirat 2Buntragulpoontawee Montana 3Lukkanapichonchut Pranee 4Chootip Chirawan 5Saengsuwan Jittima 6Tantayakom Kesthamrong 7Laongpech Supphalak 81 Department of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand2 Sirindhorn National Medical Rehabilitation Center, Ministry of Public Health, Nonthaburi, Thailand3 Department of Rehabilitation Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand4 Department of Rehabilitation Medicine, Ratchaburi Hospital, Ministry of Public Health, Ratchaburi, Thailand5 Department of Rehabilitation Medicine, Songkhla Hospital, Ministry of Public Health, Songkhla, Thailand6 Department of Rehabilitation Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand7 Department of Rehabilitation Medicine, Rajvithi Hospital, Ministry of Public Health, Bangkok, Thailand8 Department of Rehabilitation Medicine, Vachira Phuket Hospital, Ministry of Public Health, Phuket, ThailandCorrespondence: Vilai Kuptniratsaikul, Department of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Rd, Bangkok 10700, Thailand, Tel +66 2 419 7511, Fax +66 2 411 4813, Email vilai.kup@mahidol.ac.th2014 20 3 2014 9 451 458 © 2014 Kuptniratsaikul et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objective\nTo determine the efficacy and safety of Curcuma domestica extracts in pain reduction and functional improvement.\n\nMethods\n367 primary knee osteoarthritis patients with a pain score of 5 or higher were randomized to receive ibuprofen 1,200 mg/day or C. domestica extracts 1,500 mg/day for 4 weeks. The main outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, WOMAC pain, WOMAC stiffness, and WOMAC function scores. Adverse events (AEs) were also recorded.\n\nResults\n185 and 182 patients were randomly assigned into C. domestica extracts and ibuprofen groups, respectively. The baseline characteristics were no different between groups. The mean of all WOMAC scores at weeks 0, 2, and 4 showed significant improvement when compared with the baseline in both groups. After using the noninferiority test, the mean difference (95% confidence interval) of WOMAC total, WOMAC pain, and WOMAC function scores at week 4 adjusted by values at week 0 of C. domestica extracts were noninferior to those for the ibuprofen group (P=0.010, P=0.018, and P=0.010, respectively), except for the WOMAC stiffness subscale, which showed a trend toward significance (P=0.060). The number of patients who developed AEs was no different between groups. However, the number of events of abdominal pain/discomfort was significantly higher in the ibuprofen group than that in the C. domestica extracts group (P=0.046). Most subjects (96%–97%) were satisfied with the treatment, and two-thirds rated themselves as improved in a global assessment.\n\nConclusion\nC. domestica extracts are as effective as ibuprofen for the treatment of knee osteoarthritis. The side effect profile was similar but with fewer gastrointestinal AE reports in the C. domestica extracts group.\n\nKeywords\nCurcuma domesticacurcuminefficacyibuprofenknee osteoarthritissafety\n==== Body\nIntroduction\nKnee osteoarthritis (OA) is the most common degenerative joint disorder in the elderly and a major public health problem throughout the world. It is the leading cause of pain and is estimated to be the fourth leading cause of disability among the aging population.1 It increases the risks of morbidity because of loss of functional capacity, including difficulty in walking, inability to perform self-care, transferring, and going up and down stairs. Knee OA not only impairs physical functions but also reduces quality of life.2 In addition, it is the third leading cause of life-years lost due to disability.3\n\nThe prevalence of OA is increasing rapidly.4 Its prevalence among Asian countries ranges from 38.1% to 46.8%.5–7 In Thailand, there was a survey among elderly in the community aged more than 50 years using history of knee pain and X-ray finding. It was found that the prevalence of knee OA ranged from 34.5% to 45.6%.8 Concerning pharmacologic treatment, nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common prescription for pain relief in OA.9 Unfortunately, some patients cannot use NSAIDs due to their adverse effects (AEs) on the gastrointestinal (GI) system, including dyspepsia, ulceration, upper GI bleeding, and perforation of the stomach or duodenum.10–12\n\nCurcumin is a spice commonly used for a long time as a coloring agent (yellow) in many kinds of curry powder in Thai food. Evidence from in vitro studies revealed that curcumin has an inhibitory effect on substances involved in the inflammatory pathway, including lipoxygenase, cyclooxygenase (COX), phospholipase, collagenase, elastase, and hyaluronidase.13–16 Furthermore, curcumin was found to inhibit the activation of free radical activated transcription factors such as nuclear factor kappa B and nitric oxide synthase.13 It also reduces the proinflammatory cytokines: eg, tumor necrosis factor alpha, interleukin (IL)-1 beta, IL-8, and matrix metalloproteinase-13.17,18 All of these substances have a major role in the inflammatory joint process. Jackson et al19 reported that curcumin strongly inhibited collagenase and stromelysin expression, suggesting its therapeutic potential for the treatment of arthritis. Concerning safety profiles, curcumin was demonstrated to be safe, even after high-dose ingestion of up to 8,000 mg/day for 3 months.20,21\n\nNowadays, there is scarce information from clinical trials of curcumin in patients with knee OA. In 2009, we performed a single-blind randomized controlled trial to evaluate the efficacy of 2,000 mg/day of Curcuma domestica extracts compared with 800 mg/day of ibuprofen in 107 knee OA patients for 6 weeks.22 There were some limitations in that study, including inadequate sample size, subtherapeutic dosage of ibuprofen (800 mg per day), a single-blinded assessor, and the unequal frequency of drug intake between the two groups. We decided to conduct this multicenter study with better design: ie, double-blind randomized controlled trial using a lower dosage of curcumin with a shortened duration to 4 weeks, in order to determine the efficacy and safety of 1,500 mg/day of C. domestica extracts in pain reduction and functional improvement compared with 1,200 mg/day of ibuprofen.\n\nMaterials and methods\nThis study was registered at ClinicalTrials.gov (NCT00792818). The study protocol was conducted in accordance with the ethical principles stated in the most recent version of the Declaration of Helsinki. After receiving approval from the Institutional Review Board of eight tertiary hospitals in Thailand, including four hospitals in the central, one in the northern, one in the northeastern, and two in the southern regions of Thailand, we started to recruit knee OA patients from July 2010 to March 2012. The inclusion criteria were primary knee OA patients according to the American Rheumatism Association criteria23 who had a numerical rating scale of knee pain of ≥5 out of 10 and age ≥50 years. Patients who had abnormal liver function or renal function, history of peptic ulcer, allergy to curcumin or ibuprofen, or were unable to walk were excluded.\n\nThe randomization number was generated by computerized method, and the allocation codes were serially concealed in opaque envelops. After being recruited into the study, every subject received a knee X-ray, which indicated severity according to Kellgren–Lawrence criteria.24 Then, all participants were randomly allocated to receive either 1,200 mg/day of ibuprofen or 1,500 mg/day of C. domestica extracts. For blinding patients and assessors, both medications were manufactured by the Department of Pharmacy, Siriraj Hospital, Bangkok, Thailand, in the form of a capsule, to make them identical in appearance. The treatment codes were kept by a pharmacist who was not involved in the study process. The patients were asked to take the medication in the form of two capsules after meals three times a day for 4 weeks and not to use other medications during the study. If they had severe pain, they could take tramadol as a rescue medication and were asked to record the amount of drug intake.\n\nThe outcomes were evaluated at week 2 and week 4 by the same assessor at each site. The principal outcomes were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), modified Thai version,25 and a 6-minute walk distance. The WOMAC scores were composed of three subscales: ie, WOMAC pain, WOMAC stiffness, and WOMAC function. Each scale ranged from 0 to 10. The higher score represented more pain, more stiffness, or worse knee functions. For safety concerns, the AEs were recorded if the patients developed new symptoms during the study. Compliance of treatment was assessed using pill count at each visit. At the end of the study, the patients’ global assessment and satisfaction were evaluated.\n\nThis study was designed as a noninferiority trial under the assumption of significant difference in WOMAC pain score after treatment of ±0.5 point. We calculated the sample size by using the nQuery Advisor program, Release 6.0, 2005 (Statistical Solutions, Boston, MA, USA), based on mean change from baseline of our previous study22 of a score of 1.9 with 5% type I error and 20% type II error, so the sample size of each group would be 180. In case of a 10% dropout rate, the sample size would be 198 per group. Repeated-measures analysis of variance was used to analyze the change over time of the main outcomes. The mean score, mean differences of WOMAC scores, and 6-minute walk distance at week 4 were compared between groups using analysis of covariance and the unpaired t-test for noninferiority and equality. The AE and satisfaction levels were analyzed using the chi-square test. The compliance of drug intake was compared using the t-test for equality. Per protocol analysis was applied for noninferiority study design.26\n\nPreparation of C. domestica\nDried rhizomes of C. domestica were ground into powder. The turmeric powder was extracted with ethanol and then evaporated at low pressure to obtain ethanol extract in the form of a semisolid containing oleoresin and curcuminoids. The oleoresin was removed to yield curcuminoids extract (total curcuminoids content between 75% and 85%). The peak ratio of curcumin to demethoxycurcumin and bisdemethoxycurcumin in the extract was determined by high-performance thin-layer chromatography. The peak ratio of curcumin to demethoxycurcumin to bisdemethoxycurcumin was 1:0.59:0.23. The extract (calculated for 250 mg of curcuminoids) was filled into a capsule under Good Manufacturing Practices standards.\n\nResults\nA total of 524 knee OA patients were screened, but only 367 could be recruited. One hundred and eighty-two and 185 subjects were randomized to ibuprofen and C. domestica extracts groups, respectively. Only 160 patients in the ibuprofen and 171 in the C. domestica extracts groups completed the study. The reasons for those subjects being lost to follow-up are presented in Figure 1. There were seven patients in the ibuprofen group and one patient in the C. domestica extracts group who were lost to follow-up due to AEs.\n\nThe baseline characteristics of participants were no different between the two groups (Table 1). The study population had a mean age of 60 years, a female predominance (approximately 90%), and a body mass index of 26 kg/m2. Nearly 60% of them had unilateral knee OA. Few patients (7%) used walking aids. Only one-third used knee support and took pain relief medication. Three-quarters of them performed knee exercise (one to seven times/week). The WOMAC total, WOMAC pain, WOMAC stiffness, and WOMAC function at baseline scores were higher than 5 out of 10 and were no different between groups. The 6-minute walk distance was 304 meters and 310 meters in the ibuprofen and C. domestica extracts groups. The numbers of knee X-rays with II–IV grading classified by Kellgren–Lawrence criteria were 138 (86.8%) versus (vs) 150 (87.7%) in the ibuprofen and C. domestica extracts groups, respectively, with no difference.\n\nFigure 2 presents the changes over time of the mean (standard deviation) of WOMAC total, WOMAC pain, WOMAC stiffness, and WOMAC function subscales at week 0, week 2, and week 4 of both groups using repeated-measures analysis of variance. A within-group comparison of WOMAC scores showed decreased scores in both groups, which meant significant improvement from baseline (P<0.001). However, the between-group comparison showed no differences in WOMAC scores (P=0.326, P=0.531, P=0.522, and P=0.278 for WOMAC total, WOMAC pain, WOMAC stiffness, and WOMAC function subscales, respectively).\n\nConcerning the effectiveness of C. domestica extracts in this study, we compared the primary outcomes at week 4 adjusted by week 0. The mean, standard deviation, and difference values (95% confidence interval [CI]) of WOMAC total score, WOMAC pain, WOMAC stiffness, and WOMAC function subscales at week 4 are presented in Table 2. All of the WOMAC scores in the C. domestica extracts group seemed to be more than those in the ibuprofen group. However, after using the noninferiority test, the mean difference (95% CI) of the WOMAC total, WOMAC pain, and WOMAC function subscales at week 4 adjusted by week 0 of the C. domestica extracts group was within 0.5 point, which means that the C. domestica extracts group was noninferior to the ibuprofen group (P=0.010, P=0.018, and P=0.010, respectively), whereas the WOMAC stiffness subscale showed a trend toward significance (P=0.060). In addition, the 6-minute walk distance at week 4 was approximately 350 meters, which was no different between the groups (mean difference and 95% CI were 7.18 meters and −7.01 to 21.38 meters).\n\nIn addition, the number of subjects with AE occurring during the study was no different between the two groups (35.7% in ibuprofen vs 29.7% in the C. domestica extracts group, P=0.222, Table 3). Common AEs were dyspepsia, abdominal pain/distension, nausea, loose stool, and pitting edema. For the numbers of events that occurred, the rate of abdominal pain/distension was significantly lower in the C. domestica extracts group than in the ibuprofen group (10.8% vs 18.1%, P=0.046). However, the rates of dyspepsia, nausea, and pitting edema were higher in the ibuprofen group than in the C. domestica extracts group (15.9% vs 11.4% for dyspepsia, 8.2% vs 4.9% for nausea, and 7.1% vs 3.8% for pitting edema), but none of these events reached statistical significance. Only the symptom of loose stool was higher in the C. domestica extracts group than in the ibuprofen group, also with no difference (11.9% vs 8.8%, P=0.330). There were two patients in the ibuprofen group who had melena.\n\nThere was no difference in drug compliance between the groups (93.8% vs 92.6% in the ibuprofen and C. domestica extracts groups, respectively, P=0.202). Concerning the rescue drug, two (1.1%) and five (2.7%) patients in the ibuprofen group and the C. domestica extracts group used tramadol, but no significant difference was found (P=0.449). The patients’ global assessment and satisfaction at week 4 also was no different between groups (P=0.665 and P=0.707, respectively). Most subjects (96%–97%) were satisfied with the treatment, and two-thirds of them rated themselves as improved in a global assessment (Table 4).\n\nDiscussion\nIn the past decade, evidence in vitro has revealed the efficacy of curcumin in many aspects, including anti-inflammatory,20,27 antioxidant,28 and anticarcinogenic.29–31 We were interested in its anti-inflammatory effect because some patients with knee OA are unable to use NSAIDs due to their gastrointestinal AEs.10–12 The mechanism of anti-inflammatory activity of curcumin extracts was demonstrated by the inhibition of many different substances that play a major role in inflammation, including phospholipase, lipoxygenase, COX-2, leukotrienes, thromboxane, prostaglandins, collagenase, elastase, hyaluronidase, tumor necrosis factor-α, IL-1, IL-8, and IL-12.13–17 In addition, Henrotin et al32 found that diferuloylmethane (the active ingredient of curcumin) protects chondrocytes by inhibiting IL-1β, activator protein-1/nuclear factor kappa B, and matrix metalloproteinase-3 and preventing chondrocyte apoptosis. Lev-Ari et al33 reported an in vitro study of curcumin with COX-2 anti-inflammatory agents that showed that it can inhibit COX by reducing prostaglandin E2 level. However, studies of the efficacy of curcumin in knee OA patients are scarce.\n\nThere are some clinical studies concerning the efficacy of curcumin. Belcaro et al34 studied the effect of Meriva® (Indena S.p.A., Milan, Italy) 1,000 mg per day (containing curcumin 200 mg/day) combined with NSAIDs or analgesic drugs for 8 months in 100 knee OA patients with Kellgren–Lawrence grade I–II severity. They found that it could significantly improve WOMAC scores and walking distance only in the study group. However, their study used a low dose of curcumin in combination with NSAIDs, not a head-to-head comparison between curcumin and NSAIDs as in our study. The duration of drug intake was 8 months. In addition, subjects in their study were young with a mean age of 44 years and mild severity of knee OA (X-ray grading I–II). These may be the reasons why their outcomes seem to be good. The compliance of drug intake among the groups was not reported.\n\nAnother study from India reported a comparative trial concerning the efficacy of RA-11 (Artrex, Mendar ; Bioved Pharmaceuticals, Inc., Pune, India), the multiplant Ayuravej drug that is composed of Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa, in 90 patients with knee OA.35 Subjects were randomized to have RA-11 or placebo for 32 weeks. Their results were that knee pain score and WOMAC score significantly decreased (P,0.05, P,0.01) only in the study group. However, there were 28 subjects who withdrew before the end of the study. This study was different from ours because it used a mixture of drugs and compared with placebo, whereas we chose curcuminoid extracts and compared with an active controlled drug (ibuprofen).\n\nA study from Thailand carried out by Pinsornsak and Niempoog36 in 2012 performed a randomized control trial of the efficacy of 1,000 mg/day of C. longa extract as an adjuvant therapy of diclofenac (75 mg/day) for 3 months in 88 primary knees with OA. They found no statistical significance between groups in visual analog scale for pain and functions evaluated by Knee Injury and Osteoarthritis Outcome Score.37 That means that C. longa extract does not add more benefit for subjects than those receiving only diclofenac.\n\nFrom our previous study in 2009, even though there was a trend toward a greater effect in patients receiving C. domestica extracts, we could not definitely conclude that C. domestica extracts were as effective as ibuprofen, because the upper limit of the 95% CI of mean difference in the pain score exceeded the prespecified equivalence limit (one point). This study adjusted some of the methodology to correct those flaws: ie, the frequency and dosage of C. domestica extracts and ibuprofen (1,500 mg/d vs 1,200 mg/d, respectively, divided into three times per day), the double-blinded controlled trial, and shortening the duration of drug intake from 6 weeks to 4 weeks due to the better trend of outcomes at week 4 from our previous study.22 In addition, for precision of outcomes, we chose the narrow range of difference (±0.5 point) in main outcome after treatment, and we used the t-test for noninferiority to determine effect between groups.\n\nOne thing that we have concern about is the dosage of ibuprofen used in the active controlled group. Even though ibuprofen at a higher dosage of 1,800 mg per day can be expected to have higher tissue distribution, decrease proinflammatory synovial fluid cytokine levels, and provide better control of knee symptoms, as reported by Gallelli et al,38,39 we still chose a daily dose of 1,200 mg ibuprofen in this study. The reasons were that Thai people have a lower average body weight compared with Caucasians, and our rheumatologist suggested a daily dosage of 800–1,200 mg of ibuprofen in daily practice. Moreover, a higher dosage would increase risk of GI AE, especially melena, as presented in this study.\n\nFinally, our results show that the mean differences of all WOMAC scores of the C. domestica group (except stiffness subscale) were noninferior to the ibuprofen group, and those values were within a prespecified range of noninferiority limit (0.5 point). The 6-minute walk distance was also no different between groups. Therefore, we can conclude that C. domestica extracts were as efficacious as ibuprofen in pain reduction and functional improvement. For safety concerns, C. domestica extracts showed safety profiles better than ibuprofen in terms of abdominal pain/distension. In addition, seven patients in the ibuprofen group were lost to follow-up due to AEs, as compared with one patient in the C. domestica extracts group. This evidence supports the safety profile of the C. domestica extracts group. Cheng et al21 reported that C. domestica extracts can be provided at 2,000 mg/d for 6 weeks or an even higher dose of up to 8,000 mg/d for 3 months without any serious AEs. Moreover, the compliance rate of both drugs in this study was more than 90%. Patients’ global assessment of improvement was approximately 64% in both groups, and more than 95% of both groups were satisfied with the treatment outcomes. All these documented results confirm the efficacy and safety of C. domestica extracts.\n\nConclusion\nC. domestica extracts are noninferior to ibuprofen for the treatment of knee OA. The AE profile was similar but with fewer GI AE reports in the C. domestica extracts group.\n\nAcknowledgments\nThe authors would like to thank Mr Suthiphol Udompunturuk and Ms Julaporn Poolium for statistical analyses, and Professor Manee Rattanachaiyanont for reviewing the manuscript. This study was supported by the National Research Council of Thailand (NRCT), the Clinical Research and Collaborative Network (CRCN), and the Thai Government Pharmaceutical Organization (GPO).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Flow of participants through stages of a randomized trial.\n\nFigure 2 The changes over time of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, WOMAC pain, WOMAC stiffness, and WOMAC function scores at weeks 0, 2, and 4 of both groups using repeated-measures analysis of variance.\n\nTable 1 Baseline characteristics of 331 participants\n\nBaseline characteristics\tIbuprofen\n(n=160)\tCurcuma domestica extracts\n(n=171)\tP-valuea\t\nMean age ± SD (years)\t60.9±6.9\t60.3±6.8\t0.452\t\nSex:female\t139 (86.9%)\t157 (91.8%)\t0.144\t\nMean BMI ± SD (kg/m2)\t26.6±4.0\t26.5±3.7\t0.918\t\nMean duration of pain ± SD (months)\t52.0±51.7\t51.3±53.4\t0.898\t\nKnee pain\t\n Unilateral\t92 (57.5%)\t93 (54.4%)\t0.569\t\n Bilateral\t68 (42.5%)\t78 (45.6%)\t\t\nUsing walking aids\t11 (6.9%)\t12 (7.0%)\t0.959\t\nUsing knee support (one to seven times/week)\t64 (40.0%)\t60 (35.1%)\t0.356\t\nRoutinely taking pain medicine (three to seven times/week)\t48 (30.0%)\t42 (24.6%)\t0.266\t\nExercising knee (one to seven times/week)\t122 (76.3%)\t127 (74.3%)\t0.677\t\nWOMAC total ± SD\t5.2±1.7\t5.3±1.8\t0.611\t\nWOMAC pain ± SD\t5.4±1.7\t5.3±1.8\t0.899\t\nWOMAC stiffness ± SD\t5.2±2.6\t5.1±2.6\t0.847\t\nWOMAC functions ± SD\t5.1±1.8\t5.3±2.0\t0.440\t\n6-minute walk distance ± SD (meters)\t304.5±83.8\t310.9±84.8\t0.489\t\nX-ray gradingb\t\n Grade I\t21 (13.2%)\t21 (12.3%)\t0.543\t\n Grade II\t57 (35.8%)\t74 (43.3%)\t\t\n Grade III\t54 (34.0%)\t48 (28.1%)\t\t\n Grade IV\t27 (17.0%)\t28 (16.3%)\t\t\nNotes:\n\na Unpaired t-test or chi-square test;\n\nb Kellgren–Lawrence grading: 0= normal radiograph; I= doubtful pathology; II= minimal osteophytes, possible narrowing, cysts, and sclerosis; III= moderate, as in definite osteophytes with moderate joint space narrowing; IV= severe, with large osteophytes and definite joint space narrowing.\n\nAbbreviations: BMI, body mass index; SD, standard deviation; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.\n\nTable 2 Mean, SD, and difference (95% CI) of WOMAC total, WOMAC pain, WOMAC stiffness, and WOMAC function scores and 6-minute walk distance at week 4 adjusted by week 0 in ibuprofen and Curcuma domestica groups\n\nMean score at week 4 adjusted by week 0 ± SD\tIbuprofen\n(n=160)\tC. domestica extracts\n(n=171)\tMean differencea\n(95% CI)\tP-value\t\nWOMAC total score\t3.23±1.97\t3.36±2.04\t−0.07 (−0.43, 0.29)\t0.010b\t\nWOMAC pain subscale\t3.17±1.98\t3.25±2.11\t−0.09 (−0.47, 0.29)\t0.018b\t\nWOMAC stiffness subscale\t3.16±2.36\t3.28±2.38\t−0.15 (−0.59, 0.29)\t0.060b\t\nWOMAC function subscale\t3.26±2.05\t3.41±2.09\t0.06 (−0.43, 0.32)\t0.010b\t\n6-minute walk (meters)\t347.99±86.60\t345.43±91.66\t7.18 (−7.01, 21.38)\t0.320c\t\nNotes:\n\na Estimated marginal means week 4 adjusted by week 0 of ibuprofen group minus C. domestica extracts group;\n\nb analysis of covariance and unpaired t-test for noninferiority test;\n\nc analysis of covariance for equality.\n\nAbbreviations: CI, confidence interval; SD, standard deviation; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.\n\nTable 3 Adverse events (AEs) occurring during study compared between two groups\n\nAdverse events\tIbuprofen\n(n=182)\tCurcuma domestica extracts\n(n=185)\tP-valuea\t\nNumber of patients with AE\t65 (35.7%)\t55 (29.7%)\t0.222\t\nNumber of events\t\n Abdominal pain/distension\t33 (18.1%)\t20 (10.8%)\t0.046b\t\n Dyspepsia\t29 (15.9%)\t21 (11.4%)\t0.201\t\n Nausea\t15 (8.2%)\t9 (4.9%)\t0.191\t\n Loose stool\t16 (8.8%)\t22 (11.9%)\t0.330\t\n Melena\t2 (1.1%)\t–\t0.245\t\n Pitting edema\t13 (7.1%)\t7 (3.8%)\t0.156\t\nNotes:\n\na Chi-square test, Fisher’s exact test;\n\nb statistical significance.\n\nTable 4 Patients’ global assessment and satisfaction at week 4\n\nVariables\tIbuprofen\n(n=160)\tCurcuma domestica extracts\n(n=171)\tP-valuea\t\nGlobal assessment\t\t\t0.665\t\n Improved\t102 (63.8%)\t110 (64.3%)\t\t\n Indifferent\t52 (32.5%)\t58 (33.9%)\t\t\n Deteriorated\t6 (3.7%)\t3 (1.8%)\t\t\nSatisfaction index\t\t\t0.707\t\n Satisfied\t153 (95.6%)\t166 (97.1%)\t\t\n Indifferent\t7 (4.4%)\t4 (2.3%)\t\t\n Unsatisfied\t–\t1 (0.6%)\t\t\nNote:\n\na Chi-square test for trend.\n==== Refs\nReferences\n1 Fransen M Bridgett L March L Hoy D Penserga E Brooks P The epidemiology of osteoarthritis in Asia Int J Rheum Dis 2011 14 2 113 121 21518309 \n2 Kim IJ Kim HA Seo YI Prevalence of knee pain and its influence on quality of life and physical function in the Korean elderly population: a community based cross-sectional study J Korean Med Sci 2011 26 9 1140 1146 21935267 \n3 March LM Bagga H Epidemiology of osteoarthritis in Australia Med J Aust 2004 180 Suppl 5 S6 S10 14984356 \n4 Suri P Morgenroth DC Hunter DJ Epidemiology of osteoarthritis and associated comorbidities PM R 2012 4 Suppl 5 S10 S19 22632687 \n5 Du H Chen SL Bao CD Prevalence and risk factors of knee osteoarthritis in Huang-Pu District, Shanghai, China Rheumatol Int 2005 25 8 585 590 15309503 \n6 Yoshida S Aoyagi K Felson DT Aliabadi P Shindo H Takemoto T Comparison of the prevalence of radiographic osteoarthritis of the knee and hand between Japan and the United States J Rheumatol 2002 29 7 1454 1458 12136905 \n7 Cho HJ Chang CB Kim KW Gender and prevalence of knee osteoarthritis types in elderly Koreans J Arthroplasty 2011 26 7 994 999 21414750 \n8 Kuptniratsaikul V Tosayanonda O Nilkanuwong S Thamlikitkul V The epidemiology of knee osteoarthritis patients J Med Assoc Thai 2002 85 2 154 161 12081113 \n9 Seed SM Dunican KC Lynch AM Osteoarthritis: a review of treatment options Geriatrics 2009 64 10 20 29 20726384 \n10 Gumbrevicius G Milasius A Sveikata A Nonsteroidal anti-inflammatory agents: choice between disturbances of gastrointestinal tract and cardiovascular toxicity Medicina (Kaunas) 2006 42 5 429 439 16778472 \n11 Gallelli L Colosimo M Pirritano D Retrospective evaluation of adverse drug reactions induced by nonsteroidal anti-inflammatory drugs Clin Drug Investig 2007 27 2 115 122 \n12 Turajane T Wongbunnak R Patcharatrakul T Ratansumawong K Poigampetch Y Songpatanasilp T Gastrointestinal and cardiovascular risk of non-selective NSAIDs and COX-2 inhibitors in elderly patients with knee osteoarthritis J Med Assoc Thai 2009 92 Suppl 6 S19 S26 20128070 \n13 Bengmark S Curcumin, an atoxic antioxidant and natural NF kappa B, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases J Parenter Enteral Nutr 2006 30 1 45 51 \n14 Oyagbemi AA Saba AB Ibraheem AO Curcumin: from food spice to cancer prevention Asian Pac J Cancer Prev 2009 10 6 963 967 20192567 \n15 Khanna D Sethi G Ahn KS Natural products as a gold mine for arthritis treatment Curr Opin Pharmacol 2007 7 3 344 351 17475558 \n16 Saja K Babu MS Karunagaran D Sudhakaran PR Anti-inflammatory effect of curcumin involves downregulation of MMP-9 in blood mononuclear cells Int Immunopharmacol 2007 7 13 1659 1667 17996675 \n17 Kim KH Lee EN Park JK Curcumin attenuates TNF-α-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and proinflammatory cytokines in human endometriotic stromal cells Phytother Res 2012 26 7 1037 1047 22183741 \n18 Yang Q Wu S Mao X Wang W Tai H Inhibition effect of curcumin on TNF-α and MMP-13 expression induced by advanced glycation end products in chondrocytes Pharmacology 2013 91 1–2 77 85 23183190 \n19 Jackson JK Higo T Hunter WL Burt HM The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis Inflam Res 2006 55 4 168 175 \n20 Chainani-Wu N Safety and anti-inflammatory activity of curcumin: a component of tumuric (Curcuma longa ) J Altern Complement Med 2003 9 1 161 168 12676044 \n21 Cheng AL Hsu CH Lin JK Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions Anticancer Res 2001 21 4B 2895 2900 11712783 \n22 Kuptniratsaikul V Thanakhumtorn S Chinswangwatanakul P Wattanamongkonsil L Thamlikitkul V Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis J Altern Comple Med 2009 15 8 891 897 \n23 Altman R Asch E Bloch D Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association Arthritis Rheum 1986 29 8 1039 1049 3741515 \n24 Kellgren JH Lawrence JS Radiological assessment of osteoarthrosis Ann Rheum Dis 1957 16 4 494 502 13498604 \n25 Kuptniratsaikul V Rattanachaiyanont M Validation of a modified Thai version of the Western Ontario and McMaster (WOMAC) osteoarthritis index for knee osteoarthritis Clin Rheumatol 2007 26 10 1641 1645 17310271 \n26 Hauck WW Anderson S Some issues in the design and analysis of equivalence trials Drug Inf J 1999 33 109 118 \n27 Banerjee M Tripathi LM Srivastava VM Puri A Shukla R Modulation of inflammatory mediators by ibuprofen and curcumin treatment during chronic inflammation in rat Immunopharmacol Immunotoxicol 2003 25 2 213 224 12784914 \n28 Ringman JM Frautschy SA Cole GM Masterman DL Cummings JL A potential role of the curry spice curcumin in Alzheimer’s disease Curr Alzheimer Res 2005 2 2 131 136 15974909 \n29 Bar-Sela G Epelbaum R Schaffer M Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications Curr Med Chem 2010 17 3 190 197 20214562 \n30 Johnson JJ Mukhtar H Curcumin for chemoprevention of colon cancer Cancer Lett 2007 255 2 170 181 17448598 \n31 Karunagaran D Rashmi R Kumar TR Induction of apoptosis by curcumin and its implications for cancer therapy Curr Cancer Drug Targets 2005 5 2 117 129 15810876 \n32 Henrotin Y Clutterbuck AL Allaway D Biological actions of curcumin on articular chondrocytes Osteoarthritis Cartilage 2010 18 2 141 149 19836480 \n33 Lev-Ari S Strier L Kazanov D Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells Rheumatology (Oxford) 2006 45 2 171 177 16249246 \n34 Belcaro G Cesarone MR Dugall M Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients Altern Med Rev 2010 15 4 337 344 21194249 \n35 Chopra A Lavin P Patwardhan B Chitre D A 32-week randomized, placebo-controlled clinical evaluation of RA-11, an Ayurvedic drug, on osteoarthritis of the knees J Clin Rheumatol 2004 10 5 236 245 17043520 \n36 Pinsornsak P Niempoog S The efficacy of Curcuma Longa L . extract as an adjuvant therapy in primary knee osteoarthritis: a randomized control trial J Med Assoc Thai 2012 95 Suppl 1 S51 S58 23964444 \n37 Roos EM Roos HP Lohmander LS Ekdahl C Beynnon BD Knee Injury and Osteoarthritis Outcome Score (KOOS)-development of a self-administered outcome measure J Orthop Sports Phys Ther 1998 28 2 88 96 9699158 \n38 Gallelli L Galasso O Urzino A Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis Clin Drug Investig 2012 32 12 827 833 \n39 Gallelli L Galasso O Falcone D The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial Osteoarthritis Cartilage 2013 21 9 1400 1408 23973155\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-9092",
"issue": "9()",
"journal": "Clinical interventions in aging",
"keywords": "Curcuma domestica; curcumin; efficacy; ibuprofen; knee osteoarthritis; safety",
"medline_ta": "Clin Interv Aging",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D030024:Curcuma; D005260:Female; D006801:Humans; D007052:Ibuprofen; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee; D008517:Phytotherapy; D010936:Plant Extracts; D016896:Treatment Outcome",
"nlm_unique_id": "101273480",
"other_id": null,
"pages": "451-8",
"pmc": null,
"pmid": "24672232",
"pubdate": "2014",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "21518309;20128070;23973155;22183741;13498604;20214562;17310271;17475558;16387899;15974909;15810876;17448598;21194249;20726384;20192567;23086696;23183190;19836480;17043520;3741515;16807698;9699158;21414750;17217316;12081113;14984356;23964444;16778472;21935267;22632687;17996675;11712783;16249246;12136905;12784914;19678780;15309503;12676044",
"title": "Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study.",
"title_normalized": "efficacy and safety of curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis a multicenter study"
} | [
{
"companynumb": "US-JNJFOC-20150219214",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nThe role of flow-diversion in acute sub-arachnoid haemorrhage (SAH) is controversial. Many of the published data warns of high rates of procedure-related complications and aneurysmal rebleed. This study evaluates the safety, efficacy, clinical and angiographic outcomes of acute flow-diversion at our institute.\n\n\nMETHODS\nThe institutional database from June 2015 to June 2020 was retrospectively reviewed for aneurysmal SAH (aSAH) treated with flow diversion. Clinical presentation, procedural details, complications, anti-platelet usage, rebleeding and aneurysm occlusion rates and outcomes were recorded.\n\n\nRESULTS\n22 (59% females; median age 56 years) consecutive patients were identified. None of them were on regular antiplatelets/anticoagulation in the 15-days preceding the treatment. The mean aneurysm diameter was 5.4 mm and the median delay to flow-diversion was 2 days. Almost 73% (16/22) of patients had adjunctive coiling in the same session. There was no aneurysmal rebleed at a median follow up of 8.5 months and 86.3% (19/22 patients) had good clinical outcomes (3-month MRS 0-2). Adverse events related to the flow diversion procedure were seen in 3 patients; none of them had a medium to long-term clinical consequence. Three patients died from complications of SAH, unrelated to the procedure. Vascular imaging follow-up was available for 20 patients and the complete aneurysm occlusion rate was 95%.\n\n\nCONCLUSIONS\nFlow-diversion could be a reasonably safe and effective technique for treating ruptured aneurysms in appropriately selected patients when conventional options of surgical clipping and coiling are considered challenging.",
"affiliations": "Division of Interventional Radiology, Department of Diagnostic Imaging, National University Health System, Singapore. Electronic address: anil_gopinathan@nuhs.edu.sg.;Division of Neurosurgery, University Surgical Cluster, National University Health System, Singapore. Electronic address: swati_jain@nuhs.edu.sg.;Division of Neurosurgery, University Surgical Cluster, National University Health System, Singapore. Electronic address: sein_lwin@nuhs.edu.sg.;Division of Neurosurgery, University Surgical Cluster, National University Health System, Singapore. Electronic address: kejia_teo@nuhs.edu.sg.;Division of Interventional Radiology, Department of Diagnostic Imaging, National University Health System, Singapore. Electronic address: cunli_yang@nuhs.edu.sg.;Division of Interventional Radiology, Department of Diagnostic Imaging, National University Health System, Singapore. Electronic address: Vincent_nga@nuhs.edu.sg.;Division of Neurosurgery, University Surgical Cluster, National University Health System, Singapore. Electronic address: tseng_tsai_yeo@nuhs.edu.sg.",
"authors": "Gopinathan|Anil|A|;Jain|Swati|S|;Lwin|Sein|S|;Teo|Kejia|K|;Yang|Cunli|C|;Nga|Vincent|V|;Yeo|Tseng Tsai|TT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2021.105910",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "30(8)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Acute flow diversion; Blister aneurysms; Dissecting aneurysms; Telescoping-stents",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000784:Aneurysm, Dissecting; D017541:Aneurysm, False; D017542:Aneurysm, Ruptured; D002560:Cerebrovascular Circulation; D016208:Databases, Factual; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D012039:Regional Blood Flow; D012189:Retrospective Studies; D013345:Subarachnoid Hemorrhage; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "105910",
"pmc": null,
"pmid": "34119748",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Flow Diversion in Acute Sub Arachnoid Haemorrhage: A Single Centre Five Year Experience.",
"title_normalized": "flow diversion in acute sub arachnoid haemorrhage a single centre five year experience"
} | [
{
"companynumb": "SG-DSJP-DSJ-2021-130123",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
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... |
{
"abstract": "BACKGROUND\nThoracic outlet decompression (TOD) is associated with significant postoperative pain often leading to hospital length of stay out of proportion to the risk profile of the operation. We seek to describe the improvement in hospital length of stay and patient pain control with an improved multiagent pain management regimen.\n\n\nMETHODS\nWe retrospectively reviewed the hospital length of stay, medication regimen/usage, operative details, and operative indications for all patients undergoing TOD from January 2012 through June 2015. During early experience, single-agent narcotic therapy was the mainstay of postoperatively pain control. Since 2014, we have adopted a regimen consisting of narcotic patient controlled analgesia, oral narcotics, and scheduled ibuprofen and valium, which is transitioned to oral narcotics/valium upon discharge. Operative approach (supraclavicular, infraclavicular, transaxial, or paraclavicular) was determined by patient anatomy and indication for procedure (neurogenic/arterial thoracic outlet syndrome or arteriovenous access dysfunction).\n\n\nRESULTS\nSeventy-four patients were treated with TOD over the study period: 36 (49.3%) for neurogenic thoracic outlet syndrome, 23 (31.5%) for venous thoracic outlet syndrome, and 15 (19.2%) for arteriovenous access dysfunction. Prior to 2014, the mean length of stay was 4 days with a median pain score of 6. Since 2014, the mean length of stay was 2.6 (P = 0.04) with a median pain score of 4 (P = 0.005). There was no statistically significant difference in the indication for operation or operative approach between the two periods.\n\n\nCONCLUSIONS\nSince adoption of a multiagent pain management regimen to include scheduled NSAIDs and benzodiazepines, we have reduced the mean pain score experienced by our patients as well as the hospital length of stay.",
"affiliations": "Division of Vascular and Cardiothoracic Surgery, College of Medicine, University of South Florida, Tampa, FL. Electronic address: mwooster@health.usf.edu.;Division of Vascular and Cardiothoracic Surgery, College of Medicine, University of South Florida, Tampa, FL.;Division of Vascular and Cardiothoracic Surgery, College of Medicine, University of South Florida, Tampa, FL.;Division of Vascular and Cardiothoracic Surgery, College of Medicine, University of South Florida, Tampa, FL.",
"authors": "Wooster|Mathew|M|;Reed|Dana|D|;Tanious|Adam|A|;Illig|Karl|K|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D009292:Narcotic Antagonists; D003975:Diazepam; D007052:Ibuprofen",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2017.03.175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": "44()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic; D019299:Decompression, Surgical; D003975:Diazepam; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists; D059408:Pain Management; D010147:Pain Measurement; D010149:Pain, Postoperative; D011182:Postoperative Care; D012189:Retrospective Studies; D013901:Thoracic Outlet Syndrome; D019616:Thoracic Surgical Procedures; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "241-244",
"pmc": null,
"pmid": "28479443",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postoperative Pain Management following Thoracic Outlet Decompression.",
"title_normalized": "postoperative pain management following thoracic outlet decompression"
} | [
{
"companynumb": "US-JNJFOC-20171112390",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
"d... |
{
"abstract": "Chronic pain in the region of varicocele embolization is not well described and can be a challenging symptom to manage, with limited options for treatment after failing conservative measures. It is important to counsel patients of this potential complication when determining the best option for varicocele repair. To our knowledge, there are no reported cases of gonadal vein excision for chronic abdominal pain after coil embolization. A 63-year-old Caucasian male presented to our urology clinic after coil embolization. His testicular pain resolved but he reported new left-sided abdominal pain after coil embolization for a large left varicocele. After failing conservative measures including nonsteroidal anti-inflammatory drugs, antibiotics, and prednisone, he was referred for further work-up and to discuss treatment options. On presentation, the patient reported pain on the left side of his abdomen consistent with the location of gonadal vein. After extensive counseling that surgical removal may not alleviate his pain, robotic gonadal vein excision was offered, and the patient elected to proceed. Intraoperatively, the coils were easily seen through the wall of the vessel. This segment of the gonadal vein containing the coil was excised in its entirety. The patient was discharged on postoperative day 1 with only nonsteroidal pain medications. Six weeks postoperatively, the patient reported no complications, and almost complete resolution of his preoperative pain. To our knowledge, this is the first case report demonstrating the surgical removal of the gonadal vein for treatment of chronic abdominal pain after varicocele embolization. After failing conservative measures, this may present another viable treatment option to address this difficult complication in a select group of patients.",
"affiliations": "Cleveland Clinic, Cleveland, Ohio, USA.;Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.",
"authors": "Doolittle|Johnathan|J|;Maniar|Viraj|V|;Dietrich|Peter|P|;Sandlow|Jay|J|;Johnson|Scott|S|;Kansal|Jagan|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/cren.2020.0171",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2379-9889",
"issue": "6(4)",
"journal": "Journal of endourology case reports",
"keywords": "chronic pain; coil embolization; minimally invasive surgery; robotics; varicocele",
"medline_ta": "J Endourol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101684114",
"other_id": null,
"pages": "533-535",
"pmc": null,
"pmid": "33457722",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Resolution of Abdominal Pain After Coil Embolization of Varicocele with Robotic Resection of Gonadal Vein.",
"title_normalized": "resolution of abdominal pain after coil embolization of varicocele with robotic resection of gonadal vein"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP001971",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
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{
"abstract": "BACKGROUND\nKaposi sarcoma-associated herpesvirus (KSHV), or human herpesvirus type 8 (HHV8), is consistently identified in 2 human immunodeficiency virus (HIV)-associated lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease. Rarely, KSHV/HHV8-positive extracavitary solid tissue lymphomas occur, often at extranodal sites, which are not associated with an effusion. These solid variants of PEL are similar morphologically, immunophenotypically, clinically and genetically to classic PEL.\n\n\nMETHODS\nHere we report a case of a 46-year-old HIV-positive patient with lymphadenopathy and Kaposi sarcoma of the skin. The lymph node biopsy shows a KSHV/HHV8-positive high-grade B-cell lymphoma with co-infection with Epstein-Barr virus, which supports the diagnosis of a solid variant of PEL. The same lymph node is also multifocally involved in Kaposi sarcoma.\n\n\nCONCLUSIONS\nAnalysis of viral infection is of primary importance to define this solid variant of PEL. The exact oncogenic mechanisms of HHV8 are not clearly defined. It is believed that it is related to a few latent viral gene products including ORF73, ORF72, and ORF71 which increase proliferation and impair apoptosis through variant regulatory processes. To the best of our knowledge, this is the first reported case of solid tissue PEL along with Kaposi sarcoma involving the same anatomic site.",
"affiliations": "Department of Pathology, Hackensack University Medical Center, NJ, USA.",
"authors": "Zhang|Hailing|H|;Yang|Xiao Yan|XY|;Hong|Tao|T|;Feldman|Tatyana|T|;Bhattacharyya|Pritish K|PK|",
"chemical_list": "D014764:Viral Proteins",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000314347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "123(4)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D020031:Epstein-Barr Virus Infections; D006679:HIV Seropositivity; D004854:Herpesvirus 4, Human; D019288:Herpesvirus 8, Human; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D014764:Viral Proteins",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "237-41",
"pmc": null,
"pmid": "20484888",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Kaposi sarcoma-associated herpesvirus (human herpesvirus type 8)-associated extracavitary lymphoma: Report of a case in an HIV-positive patient with simultaneous kaposi sarcoma and a review of the literature.",
"title_normalized": "kaposi sarcoma associated herpesvirus human herpesvirus type 8 associated extracavitary lymphoma report of a case in an hiv positive patient with simultaneous kaposi sarcoma and a review of the literature"
} | [
{
"companynumb": "US-ROCHE-1790244",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\n\"Phantom bite syndrome,\" a persistent complaint of an uncomfortable bite sensation with no obvious occlusal abnormal finding, recently was suggested to be related with central nervous system dysfunction. Here, we report a case of phantom bite syndrome in which the occlusal discomfort was improved with mirtazapine and aripiprazole combination parallel with regional cerebral blood flow change.\n\n\nMETHODS\nA 60-year-old-female patient came to our clinic with the chief complaint of a \"loosely bite\" after dental treatment and various uncomfortable sensations of body sites. One year after the medication therapy, the prosthodontic retreatment was carried out successfully, and a good outcome was obtained for over 24 months so far. In addition, a subsequent change of regional cerebral blood flow was observed in single-photon emission computed tomography: the right and left asymmetry of cerebral blood flow in the frontal lobe has disappeared along with the improvement to the symptoms improvement.\n\n\nCONCLUSIONS\nThis case suggests that some central nervous system dysfunction involving dopaminergic system might be related to the pathophysiology of phantom bite syndrome.",
"affiliations": "Department of Psychosomatic Dentistry and.;Diagnostic Radiology and Nuclear Medicine, Graduate School of Medical and Dental Sciences, and.;Department of Gerodontology, Graduate School of Tokyo Medical and Dental University, Tokyo Medical and Dental University, Tokyo, Japan.;Section of Geriatric Dentistry, Department of General Dentistry, Fukuoka Dental College, Fukuoka.;Department of Psychosomatic Dentistry and.",
"authors": "Umezaki|Yojiro|Y|;Tu|Trang T H|TTH|;Toriihara|Akira|A|;Sato|Yusuke|Y|;Naito|Toru|T|;Toyofuku|Akira|A|",
"chemical_list": "D000928:Antidepressive Agents; D000068180:Aripiprazole; D000078785:Mirtazapine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000328",
"fulltext": "\n==== Front\nClin NeuropharmacolClin NeuropharmacolWNFClinical Neuropharmacology0362-56641537-162XLippincott Williams & Wilkins WNF5024510.1097/WNF.000000000000032800006Case ReportsChange of Cerebral Blood Flow After a Successful Pharmacological Treatment of Phantom Bite Syndrome: A Case Report Umezaki Yojiro DDS, PhD*†Tu Trang T. H. DDS†Toriihara Akira MD, PhD‡Sato Yusuke DDS, PhD§Naito Toru DDS, PhD*Toyofuku Akira DDS, PhD†* Section of Geriatric Dentistry, Department of General Dentistry, Fukuoka Dental College, Fukuoka; and† Department of Psychosomatic Dentistry and‡ Diagnostic Radiology and Nuclear Medicine, Graduate School of Medical and Dental Sciences, and§ Department of Gerodontology, Graduate School of Tokyo Medical and Dental University, Tokyo Medical and Dental University, Tokyo, Japan.Address correspondence and reprint requests to Yojiro Umezaki, DDS, PhD, Section of Geriatric Dentistry, Department of General Dentistry, Fukuoka Dental College, 2-15-1, Tamura, Sawara-ku, Fukuoka-shi, Fukuoka, Japan; E-mail: yume.ompm@tmd.ac.jpMar-Apr 2019 15 2 2019 42 2 49 51 Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.2019Wolters Kluwer Health, Inc. All rights reserved.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Background\n“Phantom bite syndrome,” a persistent complaint of an uncomfortable bite sensation with no obvious occlusal abnormal finding, recently was suggested to be related with central nervous system dysfunction. Here, we report a case of phantom bite syndrome in which the occlusal discomfort was improved with mirtazapine and aripiprazole combination parallel with regional cerebral blood flow change.\n\nCase report\nA 60-year-old-female patient came to our clinic with the chief complaint of a “loosely bite” after dental treatment and various uncomfortable sensations of body sites. One year after the medication therapy, the prosthodontic retreatment was carried out successfully, and a good outcome was obtained for over 24 months so far. In addition, a subsequent change of regional cerebral blood flow was observed in single-photon emission computed tomography: the right and left asymmetry of cerebral blood flow in the frontal lobe has disappeared along with the improvement to the symptoms improvement.\n\nConclusions\nThis case suggests that some central nervous system dysfunction involving dopaminergic system might be related to the pathophysiology of phantom bite syndrome.\n\nKey Words\naripiprazolemirtazapineocclusal dysesthesiaphantom bite syndromesingle-photon emission computed tomography (SPECT) OPEN-ACCESSTRUE\n==== Body\n“Phantom bite syndrome” (PBS), which was first described by Marbach1–3 in the year 1976, is a persistent complaint of uncomfortable bite sensation with no obvious occlusal abnormal findings. Conventional dental treatments were repeated again and again to adjust patients' occlusion, but only worsened the symptoms.\n\nPrevious studies suggested that PBS was mostly developed after dental treatment (eg, prosthodontic, restoration, orthodontic, etc). While most patients could adapt quickly to the restored occlusion, some of them were hardly and slowly to adapt and keep complaining of their discomfort.4 Although PBS has been considered to be associated with paranoia, personality problems, or some other mental diseases,1 not all the cases of PBS have psychiatric symptoms. Several researches have suggested a relationship between PBS and some dysfunction in the central nervous system.5,6 In particular, a decreased blood flow of the dorsolateral prefrontal and frontopolar cortex was reported with reproduced occlusal discomfort in healthy participants using near-infrared spectroscopy.7 Supporting the hypothesis about a relationship between PBS and central nervous system, antidepressants and antipsychotics were used for PBS management.8 However, there is no investigation involving patients with PBS focusing on the change of cerebral blood flow before and after treatment has been reported.\n\nCASE REPORT\nA 60-year-old housewife complaining about her occlusal discomfort visited our clinic. She felt a pressure sensation on the maxillary anterior fixed prosthetic and numbness of her right face. She had no remarkable incidents in medical/psychiatric history and was living with her husband in a good relationship.\n\nFifteen months before the initial visit to our clinic, after placing a porcelain fused zirconia crown on the maxillary left incisor, the patient started to feel an occlusal discomfort, which she described as “bite is loose,” “heavy” sensation in her back, “twisting” sensation in her waist, and general lethargy. Even though the crown was immediately replaced by a temporary one and adjusted many times, her symptoms did not improve. Then, the dentist suggested a consult with a psychiatrist, but she refused that proposal. She believed strongly that what she needed was “correcting bite,” not mental health care.\n\nAt the first visit to our clinic, she brought along her own illustration to demonstrate the occlusal abnormality and blamed her “lousy bite” to the prior dentist. There she was in a presentable appearance, and a polite attitude was kept through our interview. No overreaction, manic episodes, hallucination, or any sight of delusional complaints were seen.\n\nExtraoral examination found symmetrical face and pleasant countenance. Hypertonia or tenderness of masticatory muscle, clicking, crepitus, and trismus were not observed. However, the patient kept complaining about being unable to find the “correct bite” and unstable “tapping point.” No abnormalities in intraoral examination as well as in the radiographs were found. In accordance with the criteria suggested by Melis and Zawawi,9 we diagnosed the patient as having PBS. Then a head magnetic resonance imaging and 99mTc ethyl cysteinate dimer single-photon emission computed tomography (SPECT) were performed. The head magnetic resonance imaging showed no obvious organic change (eg, bleeding of the brain parenchyma, infarction, expansion of cerebral ventricles, etc). On the other hand, the SPECT imaging showed the asymmetrical cerebral blood flow patterns between the right and left with right-sided dominance in the frontal lobe (Fig. 1A). The assessment was carried out by a physician specialized in the field of nuclear medicine.\n\nFIGURE 1 A, The SPECT images showed the rCBF was asymmetrical between the right and left with right-sided dominance in the frontal lobe (white arrow). B, After the treatment, the asymmetrical rCBF pattern disappeared.\n\nAfter explaining that the symptoms might come from the central nervous system, so that any conventional dental treatment could not be mitigated, we obtained her consent for medication therapy. The patient was initially prescribed amitriptyline 10 mg/d, but she complained about many adverse effects such as “stagger,” “strong nausea,” or “cannot do anything.” On day 7, she was switched to mirtazapine 15 mg/d. After 1 week, her appetite returned, and she felt slightly better. The staggering remained so she refused to increase the dosage of the mirtazapine. Instead, aripiprazole 1 mg/d was added on. One month after initiation of medications, the patient was aware of the improvement of “twisted body” feeling. Three months later, the occlusal discomfort improved but remained slightly. The same prescription was continued, and the symptoms stabilized until the prosthodontic retreatment was carried out one year after the initial visit. During the dental treatment, her oral complaints such as “bite was loose” and “the crown did not fit me” recurred; however, it calmed down quickly a week later with the same prescription. The crown was successfully delivered. After the symptom relief, we checked the SPECT image again and observed the previous asymmetrical regional cerebral blood flow (rCBF) pattern disappeared (Fig. 1B). At 41 months' follow-up visits, the patient remained in stable condition with the same prescription. No sight of recurrence has been observed.\n\nDISCUSSION\nThe persistence of occlusal discomfort even after many repeated dental treatment is diagnosed as PBS1–3 or occlusal dysesthesia.9,10 A study revealed more than 30% of the temporomandibular disorders patients suffer from bite discomfort.9 In our opinion, PBS might be included in such patients, although the precise prevalence is still unclear. In another study, 70% of PBS patients developed their symptoms after conventional dental treatment.8 The exact pathophysiological mechanism of PBS remained unknown, but previous research suggested the hypothesis of biochemical abnormalities related to neurotransmitter in the brain and higher brain dysfunction correlated with the cognitive processes.11 In this report, in order to clarify those hypotheses, the treatment course and the change in rCBF were assessed.\n\nBefore the treatment, SPECT image showed the asymmetrical rCBF pattern between the right and left frontal lobe with dominance in the right side. After prescribed mirtazapine and aripiprazole combination, the cerebral blood flow pattern has been changed. From the view of drugs reaction: mirtazapine is classified as a noradrenergic and specific serotonergic antidepressant and acts like an antagonist of presynaptic α2-adrenergic autoreceptors while enhancing serotonin neurotransmission at the 5-HT1 receptor.12 On the other hand, aripiprazole is a partial agonist on dopamine D2, D3, and serotonin 1A and antagonist on serotonin A2.13 In this case, the monotherapy of mirtazapine did not show sufficient effects, but adding on aripiprazole resulted in a good course. This suggests the occlusal discomfort might relate to dysfunction of complex neurotransmissions involving the dopaminergic system.\n\nA remarkable phenomenon in this case is the recurrence of occlusal discomfort after restarting the prosthodontic treatment. Although the sensation existed in only a very short time, then obtained improvement without additional prescription, the prosthodontic treatment likely provoked PBS symptoms. A possible explanation here would be the alteration of sensorimotor functions following modifying dental occlusion. That study also reported that the ability to adapt new altered occlusal in rats related to asymmetrical neuroplasticity between the right and left side of the primary motor cortex of the face in the frontal lobe.4 Therefore, the spontaneous recovery of adaptation capacity after retreatment and the asymmetrical rCBF change in the frontal lobe in this case might reflect the alternation of this condition.\n\nCONCLUSIONS\nWe reported a case of PBS in which the occlusal discomfort was improved by mirtazapine and aripiprazole combination therapy. In the 99mTc ethyl cysteinate dimer SPECT images taken after treatment, the right and left asymmetry of the cerebral blood flow in the frontal lobe has disappeared along with the improvement of the symptoms. It was inferred that the neurotransmitter dysfunction involving dopamine system might have contributed to PBS.\n\nConflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare.\n\nThis work was supported by the Japan Society for the Promotion of Science KAKENHI (Grant-in-Aid for Scientific Research) grant JP18K17306.\n==== Refs\nREFERENCES\n1 Marbach JJ \nPhantom bite . Am J Orthod \n1976 ;70 :190 –199 .1066055 \n2 Marbach JJ Varoscak JR Blank RT \n“Phantom bite”: classification and treatment . J Prosthet Dent \n1983 ;49 :556 –559 .6221095 \n3 Marbach JJ \nPhantom bite syndrome . Am J Psychiatry \n1978 ;135 :476 –479 .637145 \n4 Avivi-Arber L Lee J-C Sessle BJ \nDental occlusal changes induce motor cortex neuroplasticity . J Dent Res \n2015 ;94 :1757 –1764 .26310722 \n5 Leon-Salazar V Morrow L Schiffman EL \nPain and persistent occlusal awareness: what should dentists do? \nJ Am Dent Assoc \n2012 ;143 :989 –991 .22942145 \n6 IL A \nIdiopathic orofacial pain: a review . Internet J Pain \n2009 ;2 :1 –8 .\n7 Ono Y Kobayashi G Hayama R \nPrefrontal hemodynamic changes associated with subjective sense of occlusal discomfort . Biomed Res Int \n2015 ;2015 :395705 .26090407 \n8 Watanabe M Umezaki Y Suzuki S \nPsychiatric comorbidities and psychopharmacological outcomes of phantom bite syndrome . J Psychosom Res \n2015 ;78 :255 –259 .25477300 \n9 Melis M Zawawi KH \nOcclusal dysesthesia: a topical narrative review . J Oral Rehabil \n2015 ;42 :779 –785 .25994945 \n10 Hara ES Matsuka Y Minakuchi H \nOcclusal dysesthesia: a qualitative systematic review of the epidemiology, aetiology and management . J Oral Rehabil \n2012 ;39 :630 –638 .22506934 \n11 Toyofuku A \nA clinical study on psychosomatic approaches in the treatment of serious oral psychosomatic disorders during hospitalization—evaluation of “‘behavior restriction therapy’” for oral psychosomatic disorders and consideration of its pathophysiology [in Japanese] . J Psychosom Dent \n2000 ;15 :41 –71 .\n12 Stimmel GL Dopheide JA Stahl SM \nMirtazapine: an antidepressant with noradrenergic and specific serotonergic effects . Pharmacotherapy \n1997 ;17 :10 –21 .9017762 \n13 Mamo D Graff A Mizrahi R \nDifferential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study . Am J Psychiatry \n2007 ;164 :1411 –1417 .17728427\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0362-5664",
"issue": "42(2)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000928:Antidepressive Agents; D000068180:Aripiprazole; D001732:Bite Force; D002560:Cerebrovascular Circulation; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008875:Middle Aged; D000078785:Mirtazapine; D013577:Syndrome; D013705:Temporomandibular Joint Disorders; D016896:Treatment Outcome",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "49-51",
"pmc": null,
"pmid": "30789368",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1066055;17728427;22506934;22942145;25477300;25994945;26090407;26310722;6221095;637145;9017762",
"title": "Change of Cerebral Blood Flow After a Successful Pharmacological Treatment of Phantom Bite Syndrome: A Case Report.",
"title_normalized": "change of cerebral blood flow after a successful pharmacological treatment of phantom bite syndrome a case report"
} | [
{
"companynumb": "JP-ACCORD-110996",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "This is the first case of follicular T-cell lymphoma (FTCL) presenting as methotrexate-associated lymphoproliferative disorders (MTX-LPDs). A 69-year-old man treated rheumatoid arthritis with methotrexate presented with cervical swelling, hoarseness and fever. Imaging studies revealed multiple lymphadenopathy and lymphoma was suspected. Lymph node biopsy was performed to confirm the diagnosis. Pathologically, the lymph node was composed of atypical lymphocytes with a follicular growth pattern and area of necrosis. Immunohistochemical examination showed the atypical lymphocytes were positive for CD3, CD4, programmed cell death protein 1, and inducible T-cell co-stimulator. These findings are consistent with FTCL. During hospitalization, the patient's fever subsided and cervical lymphadenopathy improved, probably due to discontinuation of MTX. Here we presented the first case of FTCL presenting as MTX-LPDs. The T-cell phenotype MTX-LPDs are relatively rare and accounts for only 3.4%-6.3% of all MTX-LPD cases. Therefore, detailed clinicopathological features have not been clarified sufficiently. It is hoped that similar cases should be accumulated and studied to better understand the clinical and pathological features of this condition.",
"affiliations": "Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan.;Department of Hematology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan.;Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.;Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.;Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.;Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.;Department of Pathology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan.",
"authors": "Muto|Reiji|R|http://orcid.org/0000-0001-5251-5258;Kawakita|Toshiro|T|;Miyoshi|Hiroaki|H|http://orcid.org/0000-0002-2356-3725;Arakawa|Fumiko|F|;Nakashima|Kazutaka|K|;Ohshima|Koichi|K|;Murayama|Toshihiko|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/pin.13155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5463",
"issue": "71(11)",
"journal": "Pathology international",
"keywords": "T-cell lymphoma; follicular T-cell lymphoma; lymphoproliferative disorders; malignant lymphoma; methotrexate",
"medline_ta": "Pathol Int",
"mesh_terms": null,
"nlm_unique_id": "9431380",
"other_id": null,
"pages": "765-770",
"pmc": null,
"pmid": "34473863",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "The first case of methotrexate-associated lymphoproliferative disorder presenting as follicular T-cell lymphoma.",
"title_normalized": "the first case of methotrexate associated lymphoproliferative disorder presenting as follicular t cell lymphoma"
} | [
{
"companynumb": "JP-MEDEXUS PHARMA, INC.-2021MED00231",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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{
"abstract": "Mutations in the Sterile alpha motif domain containing 9 (SAMD9) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in SAMD9 (c.2471 G>A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel SAMD9 mutation was confirmed experimentally. Expression of mutant SAMD9 caused a significant decrease in proliferation and increase in cell death of the transfected cells. Conclusion: We describe a novel SAMD9 mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with SAMD9 mutations and multisystem involvement.",
"affiliations": "Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Molecular Genetics Laboratory, Center of Cardiovascular Surgery and Transplantation, Brno, Czechia.;Molecular Genetics Laboratory, Center of Cardiovascular Surgery and Transplantation, Brno, Czechia.;Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia.;Faculty of Medicine, Masaryk University, Brno, Czechia.;Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;CEITEC, Masaryk University, Brno, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Faculty of Medicine, Masaryk University, Brno, Czechia.;Department of Pediatric Hematology, University Hospital Brno, Brno, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.;Faculty of Medicine, Masaryk University, Brno, Czechia.;Faculty of Medicine, Masaryk University, Brno, Czechia.;Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.",
"authors": "Formankova|Renata|R|;Kanderova|Veronika|V|;Rackova|Marketa|M|;Svaton|Michael|M|;Brdicka|Tomas|T|;Riha|Petr|P|;Keslova|Petra|P|;Mejstrikova|Ester|E|;Zaliova|Marketa|M|;Freiberger|Tomas|T|;Grombirikova|Hana|H|;Zemanova|Zuzana|Z|;Vlkova|Marcela|M|;Fencl|Filip|F|;Copova|Ivana|I|;Bronsky|Jiri|J|;Jabandziev|Petr|P|;Sedlacek|Petr|P|;Soukalova|Jana|J|;Zapletal|Ondrej|O|;Stary|Jan|J|;Trka|Jan|J|;Kalina|Tomas|T|;Skvarova Kramarzova|Karolina|K|;Hlavackova|Eva|E|;Litzman|Jiri|J|;Fronkova|Eva|E|",
"chemical_list": "C107514:SMAD9 protein, human; D051904:Smad8 Protein",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2019.02194",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2019.02194ImmunologyCase ReportNovel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement Formankova Renata 1†Kanderova Veronika 1†Rackova Marketa 1Svaton Michael 1Brdicka Tomas 2Riha Petr 1Keslova Petra 1Mejstrikova Ester 1Zaliova Marketa 1Freiberger Tomas 345Grombirikova Hana 35Zemanova Zuzana 6Vlkova Marcela 57Fencl Filip 8Copova Ivana 8Bronsky Jiri 8Jabandziev Petr 459Sedlacek Petr 1Soukalova Jana 510Zapletal Ondrej 11Stary Jan 1Trka Jan 1Kalina Tomas 1Skvarova Kramarzova Karolina 1Hlavackova Eva 57Litzman Jiri 57Fronkova Eva 1*†1Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia2Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia3Molecular Genetics Laboratory, Center of Cardiovascular Surgery and Transplantation, Brno, Czechia4CEITEC, Masaryk University, Brno, Czechia5Faculty of Medicine, Masaryk University, Brno, Czechia6Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia7Department of Clinical Immunology and Allergology, St. Anne's University Hospital Brno, Brno, Czechia8Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia9Department of Paediatrics, University Hospital Brno, Brno, Czechia10Department of Medical Genetics, University Hospital Brno, Brno, Czechia11Department of Pediatric Hematology, University Hospital Brno, Brno, CzechiaEdited by: Yenan Bryceson, Karolinska Institute (KI), Sweden\n\nReviewed by: Kimberly Gilmour, Great Ormond Street Hospital, United Kingdom; Silvia Clara Giliani, University of Brescia, Italy\n\n*Correspondence: Eva Fronkova eva.fronkova@lfmotol.cuni.czThis 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\n18 9 2019 2019 10 219423 1 2019 30 8 2019 Copyright © 2019 Formankova, Kanderova, Rackova, Svaton, Brdicka, Riha, Keslova, Mejstrikova, Zaliova, Freiberger, Grombirikova, Zemanova, Vlkova, Fencl, Copova, Bronsky, Jabandziev, Sedlacek, Soukalova, Zapletal, Stary, Trka, Kalina, Skvarova Kramarzova, Hlavackova, Litzman and Fronkova.2019Formankova, Kanderova, Rackova, Svaton, Brdicka, Riha, Keslova, Mejstrikova, Zaliova, Freiberger, Grombirikova, Zemanova, Vlkova, Fencl, Copova, Bronsky, Jabandziev, Sedlacek, Soukalova, Zapletal, Stary, Trka, Kalina, Skvarova Kramarzova, Hlavackova, Litzman and FronkovaThis 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.Mutations in the Sterile alpha motif domain containing 9 (SAMD9) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in SAMD9 (c.2471 G>A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel SAMD9 mutation was confirmed experimentally. Expression of mutant SAMD9 caused a significant decrease in proliferation and increase in cell death of the transfected cells.\n\nConclusion: We describe a novel SAMD9 mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with SAMD9 mutations and multisystem involvement.\n\nSAMD9MIRAGEimmunodeficiencyneutropeniacytomegalovirus infectiondysphagiahematopoietic stem cell transplantationgastrointestinal disorderUniverzita Karlova v Praze10.13039/100007397Ministerstvo Zdravotnictví Ceské Republiky10.13039/501100003243Ministerstvo Školství, Mládeže a Tělovýchovy10.13039/501100001823\n==== Body\nBackground\nIn 2016, Narumi et al. (1) reported mutations in Sterile alpha motif domain-containing protein 9 (SAMD9) in 11 patients examined primarily for adrenal hypoplasia. Most of the patients shared strikingly similar phenotypes, and thus, a novel multisystem disorder, MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome, was defined. Two patients from the cohort developed myelodysplastic syndrome (MDS) accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. In 2017, Buonocore et al. (2) found similar de-novo, heterozygous SAMD9 mutations in 8 children with a complex multisystem growth restriction phenotype. Adrenal insufficiency was frequently but not constantly present.\n\nThe appropriate treatment of the patients with SAMD9 mutations is not currently known. Fourteen of 19 patients from the first two studies died, mostly due to severe infections, in first 2 years of age. Two patients from the surviving group developed MDS with monosomy 7 and received hematopoietic stem cell transplantation (HSCT). Monosomy 7, deletions of 7q or secondary somatic loss of function mutation in SAMD9 frequently developed as a compensatory mechanism for the mutated allele, which rescued the growth-restricting effect of the SAMD9 mutation, but it could lead to MDS in some of the patients. Schwarz reported a germline SAMD9 mutation in three siblings with MDS and monosomy 7. Interestingly, the patients had an otherwise mild phenotype with no signs of MIRAGE syndrome except for hypospadia and bifid scrotum in one boy, and even had an asymptomatic mother carrying the same mutation (3). Bluteau et al. found 6 patients with mutated SAMD9 and 10 patients with a mutation in SAMD9 counterpart SAMD9L (4) in a cohort of 86 patients with BM failure of suspected inherited origin (5). The patients presented with mild BM failure and monosomy 7, and only one presented typical signs of MIRAGE syndrome.\n\nCase Presentation\nWe describe the case of a Caucasian boy from the 4th gravidity of healthy, non-consanguineous parents. In the first month after a preterm birth (32 weeks and 3 days of pregnancy, weight 1,450 g), he manifested with bilateral bronchopneumonia and hepatopathy that progressed to septicemia with bradycardia and respiratory failure requiring ventilation support. Generalized primary cytomegalus virus (CMV) infection was confirmed at the age of 3 months. His health status was complicated by bilateral pneumonia followed by respiratory distress that demanded ventilation support complicated by disseminated intravascular coagulation and septic shock. A 6-week treatment with ganciclovir was introduced. Antimycotic treatment was introduced for suspected aspergillus infection. A huge persisting cutaneous defect in the gluteal region with uretroscrotal fistula was present from the second month of age complicated by scrotal abscess at the age of 5 months.\n\nHe suffered from recurrent upper respiratory tract infections but also sepsis of unknown origin with high fever, and high C-reactive protein (CRP) responding to antibiotic treatment. From the age of 14 months, he had recurring pneumonia with respiratory distress and septicemia at the age of 18 months. Recurrent oral, nasal and urethral candidiasis were confirmed.\n\nGastrointestinal Involvement\nBecause of hypoproteinic malnutrition, failure to thrive and inability to swallow presumably caused by frequent vomiting, percutaneous endoscopic gastrostomy (PEG) was introduced at the age of 5 months. PEG tube management was complicated by extensive leakage. He suffered from sublingual erosions, diarrhea, recurrent proctocolitis with intestinal bleeding, and chronic perianal erosions. Hemorrhagic proctocolitis caused by Pseudomonas aeuruginosa with septicemia manifested at the age of 13 months. Severe Clostridium difficile gastroenteritis demanding intensive care manifested at the age of 23 months. Gastroscopy and colonoscopy at 18 months of age did not reveal any significant disturbances. Histologic evaluation of the duodenal mucosa showed a mild deficit of disaccharides and other enzymes of the brush-border and mild chronic non-active enteritis.\n\nHematopoietic System Involvement\nImmediately after birth, the patient presented with transient thrombocytopenia and anemia (Figure 1A). From 6 months of age, he had significant neutropenia with absolute neutrophil count (ANC) <0.5 × 109/l. Granulocyte colony stimulating factor G-CSF was introduced at the age of 19 months. BM evaluation at 18 months of age revealed normocellularity with reduced myeloid lineage (31%) with gradual maturation and increased erythroid lineage (48%); megakaryocytes were in the normal range, and atypical cells were not documented.\n\nFigure 1 (A) The results of hematological testing and infectious diseases during the course of the disease. (B) The results of immunological testing during the course of the disease. BM, bone marrow; CMV, cytomegalovirus; IFNg, interferon gamma; SCT, hematopoietic stem cell transplantation.\n\nOther Symptoms\nHypospadia, micropenis, central hypotonic syndrome, pseudobulbar syndrome, psychomotor retardation, and mild orofacial stigmatization with macroglossia and hypomimia were documented.\n\nHSCT\nThe patient was indicated for HSCT for unspecified primary immunodeficiency with severe infections, neutropenia and lack of B-cells at the age of 26 months. Conditioning regimen included busulfan targeted to plasma concentrations of 500–700 ng/mL from days−5 to−2, fludarabine 40 mg/m2/day from days−6 to−3 and alemtuzumab in total dose 1 mg/kg from days−8 to−6. Graft-vs.-host (GVHD) prophylaxis administered from day−1 consisted of cyclosporine A (CsA) and mycophenolate mofetil (MMF). Plasmapheresis was performed for high titers of anti-A antibodies in the situation of ABO incompatibility on days −10, −9, −8, and on day 0. He received a BM graft from his HLA identical older brother (2.6 × 108 nucleated cells/kg, 5.6 × 106 of CD34pos cells). Neutrophil engraftment defined as the first of 3 days with ANC above 0.5 × 109/l was achieved on day +18, thrombocyte engraftment (the thrombocytes count above 20 × 106/l without transfusion in previous 7 days) on day +33, respectively. Complete donor chimerism (>98% donor cells) in non-separated peripheral blood (PB) evaluated by PCR amplification of the microsatellite markers was documented from day +21. The early post-transplant period was complicated by mucositis grade III, febrile neutropenia and CMV reactivation on day +20 with good response to ganciclovir therapy. He was discharged on day +42, without signs of acute GVHD, with diarrhea, vomiting and inability to swallow, persisting from the pre-transplant period.\n\nMMF was stopped on day +60, CsA on day +164. Recurrent febrile states with elevation of inflammatory markers, vomiting and abdominal pain started again from day +270. Gastroduodenoscopy and colonoscopy performed for suspicion of pseudo obstruction showed no pathology. In contrast with an unsatisfactory clinical condition, absolute numbers of CD3+ T cells, CD19+ B cells and CD3+CD16+56+ NK cells and proliferative response to phytohemagglutinin were comparable to controls 1 year after SCT. Serum concentrations of IgG, IgA, IgM were in the normal ranges on continuous treatment with IVIG, and BM evaluation showed normocellular trilineage hematopoiesis. On day +440, he developed sepsis with hemoculture positive for Streptococcus salivarius and rapid progression to septic shock and despite antibacterial treatment and intensive care he died from multiple organ failure.\n\nClinical and Laboratory Investigations\nGenetic Analysis\nThe cytogenetic evaluation performed from PB at 5 months of age did not reveal any structural or numerical abnormality, and retrospective FISH evaluation using CEP7 probe did not reveal monosomy 7. Whole-genome SNP array and FISH analysis from BM sample taken at 18 months of age found monosomy 7 in 78.5% of interphase nuclei.\n\nWhole-exome sequencing analysis was performed at 18 months of age. Mutations in the genes causing congenital neutropenia were excluded, as well as variants in genes causing dyskeratosis congenita, because Hoyeraal Hreidarsson syndrome was considered. No other potentially causative variants were found using the virtual panel of genes associated with bone marrow failure or immunodeficiency. After publication of the SAMD9 patient cohort in 2016, the data were reanalyzed, and a novel, previously unreported de-novo heterozygous mutation in the SAMD9 gene (c.2471 G>A, p.R824Q) was reported. Although this change is predicted as tolerated by SIFT (6) and benign by PolyPhen2 (7), with a CADD (8) score of 15.2, the residue is located near previously reported mutations p.K821M (9) and p.N834Y (1), and the mutation was not found in the ExAC or gnomAD population databases (10).\n\nImmunological Evaluation and Functional Testing\nThe results of immunological testing during the course of the disease are summarized in Figure 1B. Flow cytometry (FC) determination (first performed at the age of 5 months) of major lymphocyte subsets did not provide conclusive results. CD3 cells were overrepresented; their percentages fluctuated from 87 to 96% (ref. range 39–77%), absolute CD3 cell numbers from 2.99 to 9.88 109/l (ref. range 2.4–6.9 109/l). CD4 cell numbers were normal: 21–42% (ref. range 25–50%), absolute number 1.34–2.28 109/l (ref. range 1.04–5.10 109/l). CD8+ cells were abundant: 47–69% (ref. range 13–26%), absolute number 1.62–7.49 109/l (ref. range 0.6–2.2 109/l). CD19+ cells were markedly decreased with repeatedly estimated representation of 2% (ref. range 13–35%), absolute number 0.07–0.22 109/l (ref. range 0.7–2.5 109/l). CD4/C8 ratio varied between 0.30 to 0.83 (ref 0.7–3.08) NK cell (CD16/56+CD3-) numbers were normal: from 7 to 11% (ref. range 2–13%), abs number 0.76–0.38 (ref range 0.7–1.0 109/l).\n\nLevels of immunoglobulins were elevated (IgG 10.6 g/l, IgM 7.1 g/l, IgA level was within ref. range: 0.204 g/l). Thereafter, IgG and IgA levels remained within normal levels, IgM decreased to 3.25 g/l. IgE: was repeatedly <17 UI/ml. Total hemolytic complement (CH 50) and granulocyte function test (“burst test) results were normal.\n\nDetailed FC evaluation at 7 months of age revealed increased proportion of T cells, with profound activation of CD8 T cells (HLA-DR+ 72%) and shift from naive (6%) to effector memory phenotype (77%). This was presumably in response to persistently present CMV viremia. However, no functionally responding CMV specific T cells were detected. Minor response restricted to CD8+ IFNg+ producing cell was detected at 8.5 months of age that did not lead to CMV control. CMV reactivation control was restored only at one year of age (PCR CMV negativity). Retrospective analysis of neonatal dry blood spot did not reveal any presence of CMV.\n\nLymphocyte proliferation in response to phytohemagglutinin (PHA) using 3H-Thymidine incorporation was repeatedly found reduced between 5 and 14 months of age. At 7 months of age, activated T-cell cultures were established by stimulating PBMCs with immobilized anti-CD3ε antibody followed by propagation in the presence of IL-2. These cultures displayed reduced viability, accompanied by the lack of anti-apoptotic Bcl-2 protein expression (Figures 2A,B). Upon CD3 re-stimulation, they showed slightly decreased calcium flux (Figure 2C), while no difference in overall tyrosine phosphorylation after TCR stimulation was observed (data not shown). However, examination of activated T-cell cultures newly established 6 months later (coincident with CMV control) revealed normal level of apoptosis, normal cell proliferation and Bcl-2 expression comparable to controls (data not shown).\n\nFigure 2 (A) T-cell culture viability determined by flow cytometry. Live cells were gated based on propidium iodide and forward scatter signals. (B) Western blot analysis of Bcl-2 and Bcl-xL expression in T cells after 2, 3, and 5 weeks of culture. Ctrl, control, Pt, patient. (C) Flow cytometry analysis of T-cell calcium response to activation with 1 and 100 μg/ml anti-CD3ε antibody. The arrow indicates the time point when antibody was added to the sample.\n\nNeither T-cell receptor excision (TREC) nor kappa-deleting element excision (KREC) circle levels were decreased at 5 months of age in PB, but at 17 months of age, the KREC numbers were decreased to the levels observed in SCID patients, and TREC levels were reduced below the 3rd percentile of age-matched controls.\n\nFunctional Evaluation of SAMD9 Mutation\nTransient ectopic expression of wt SAMD9 resulted in a significant decrease in proliferation of the transfected cells. The impact of mutant SAMD9 was even more profound resulting in a dramatic drop in the number of proliferating cells (Figure 3A). Expression of SAMD9 (both wt and mutant) also caused an increase in apoptosis. Interestingly, mutant SAMD9 induced primary necrosis of the cultured cells further demonstrating the gain-of-function impact of p.R824Q on SAMD9 (Figure 3B).\n\nFigure 3 Analysis of proliferation (A), cell death (B) of HEK293T cells transfected with wt SAMD9-GFP, mutant SAMD9-GFP or empty GFP-positive control expression vector. Representative data are shown with results depicted as a fraction of GFP+ cells. Statistical significance: (*P ≤ 0.05; **P ≤ 0.001; ***P ≤ 0.0001).\n\nDiscussion\nIn concordance with previously published cases (1, 2), our patient was delivered preterm and seriously ill in the neonatal period and needed intensive care. He showed genital anomalies, and he suffered from recurrent infections and chronic diarrhea. Thus, his phenotype was consistent with MIRAGE syndrome apart from the adrenal insufficiency, the sign that defined the original published cohort. Buonocore et al. reported severe adrenal insufficiency in 6 patients, while mild and no adrenal involvement were reported in the remaining two patients (2). Our patient repeatedly suffered from hyponatremia, but hyperpigmentation of the skin was not observed, and cortisol levels were only found decreased in one of three evaluations.\n\nOne of the two dominant clinical features in our patient were the inability to swallow, requiring PEG feeding, and chronic vomiting, symptoms which have not been highlighted as diagnostic signs so far. However, case presentations in the cohort of Narumi et al. reveal that at least four of 11 patients required feeding tubes, and one had a gastrostomy tube due to aspiration pneumonias, esophageal stricture, or achalasia. Also the two patients reported recently by Sarthy et al. had enteral feeding intolerance (9). Thus, SAMD9 mutations should be considered in cases of unexplained disturbances of the upper gastrointestinal tract. His other gastrointestinal symptoms included chronic diarrhea, which is a common symptom in MIRAGE syndrome [reported in 9 of 11 patients in the original cohort (1)].\n\nThe second dominant clinical feature was severe neutropenia requiring the administration of G-CSF. One of the three siblings reported by Schwartz et al. manifested with severe neutropenia, but it was associated with macrocytosis, thrombocytopenia and hypocellularity and trilineage dysplasia with 1% blasts in the BM. In our patient, BM aspiration performed at 18 months was without signs of myelodysplasia, only with reduction in the myeloid lineage. Thus, congenital neutropenia was primarily considered at that time. Monosomy 7 was revealed incidentally by SNP array, and retrospective evaluation of BM by FISH revealed monosomy 7 in the 78.5% of nuclei.\n\nThe complex immunodeficiency complications in our patient are in good accordance with manifestation of patients described by Narumi et al. where all 7 described patients were prone to complicated or recurrent infections, including episodes of pneumonia; one described patient suffered from severe CMV infection as well. In another patient, recurrent fever with high CRP was reported. Bluteau et al. reported severe recurrent infections in 4/6 patients with SAMD9 mutation (5). Despite clinically manifested immunodeficiency since birth, the laboratory immunological investigation did not show any gross abnormality. Examination of the lymphocyte subsets revealed decreased B lymphocytes, and the lymphocyte proliferation test showed decreased response after PHA stimulation. This finding is consistent with the previous observation by Narumi et al. that showed decreased numbers of B lymphocytes and decreased NK activity in several patients. Bluteau et al. reported immunoglobulin deficiency in 2/6 patients (5). The most prominent sign of immunodeficiency in our patient was non-responsiveness of T lymphocytes to CMV despite severe CMV infection in the early infancy period.\n\nSAMD9 acts as a growth repressor, and SAMD9 mutations are considered gain-of function mutations, thus, further intensifying the growth suppression. The p.R824Q mutation present in our patient was predicted as benign by two prediction tools. However, neither PolyPhen2 (7) nor SIFT (6) tools are adjusted for gain-of-function predictions and, thus, should be used with caution (11). Growth of HEK293 cells transfected with SAMD9 mutants was profoundly restricted in several studies (1, 9, 12). The cells transfected with the p.R824Q mutant showed a significant growth restriction as well. Interestingly, we also observed an increase in cell death of the cultured cells. The involvement of SAMD9 in cell death has already been predicted (13). During the initial evaluation of our patient, we observed a reduced growth, higher rate of apoptosis of cultured T lymphocytes together with the lack of Bcl-2 expression. However, this observation was not confirmed during repeated evaluation after 6 months. We can speculate that the renewal of the proliferation capacity could have been caused by the gradual emergence of cells with compensatory loss of chromosome 7, as observed in other studies (2).\n\nThe role of HSCT in the management of patients with SAMD9 mutations is not entirely clear. To our knowledge, 14 transplanted patients with SAMD9 mutation have been reported so far, including our patient. One patient from the cohort of Narumi et al. (1) was transplanted due to MDS, but died due to Epstein-Barr virus-related post-transplant lymphoproliferative disorder. The only 2 surviving patients from the cohort described by Buonocore et al. (2) were also transplanted due to MDS. However, these patients had the mildest phenotype, with only fewer syndromic features, compared to the rest of the patients. This was also the case of three other reported patients (3, 14) who survived after HSCT. Wilson et al. retrospectively identified a SAMD9 mutation in a patient with MIRAGE phenotype after HSCT due to MDS. The patient survived more than 10 years after transplant but suffered from multiple other medical issues related to syndromic features (12). Bluteau et al. reported four transplanted patients, of whom three survived without major complication, while the only one patient with MIRAGE phenotype died. Interestingly, 11 of 13 patients with SAMD9 or SAMD9L mutations, who were not transplanted immediately, showed spontaneous improvement in blood cell counts, and HSCT was even canceled in 5 of them with no impact on survival (5). Recently, Sarthy et al. reported two patients with SAMD9 mutations and severe MIRAGE phenotype transplanted due to BM failure, who both died after HSCT due to multiorgan complications connected with the syndrome (9). This was also the case of our patient, who tolerated relatively well the transplantation procedure and successfully restored hematopoiesis, but died 14 months after HSCT due to worsening of his other symptoms. Taken together, 5 of 6 reported patients with the MIRAGE phenotype died after SCT, while all 9 reported patients without severe syndromic features survived. These results show that in patients with the MIRAGE phenotype, the transplantation management is rarely successful due to accompanying multiorgan issues. BM disturbances can show spontaneous improvement, including the disappearance of monosomy 7. Thus, a watch and wait strategy should be an option for both syndromic and non-syndromic patients. However, their treatment must be managed by primary immunodeficiency centers with access to intensive care units with multidisciplinary teams.\n\nIn conclusion, we report the case of a patient with novel mutation in SAMD9 with severe gastrointestinal involvement, neutropenia and immunodeficiency, underscoring the role of SAMD9 in the differential diagnosis of patients with these symptoms. We further question the role of HSCT in the management of the disease.\n\nMethods\nThe detailed descriptions of CMV response detection (15), activated T-cell culture (16), cell viability, BCL-2 expression, calcium response (16), TREC/KREC analysis, and of the functional assessment of SAMD9 mutation in-vitro are available in the Supplementary File (17–19).\n\nEthics Statement\nThis study was carried out in accordance with the recommendations of the 2nd Medical Faculty Ethics Committee Guidelines. The parents of the patient gave written informed consent with the study in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the 2nd Medical Faculty, Charles University Prague. Written informed consent was obtained from the parents of the participant for the publication of this case report.\n\nAuthor Contributions\nRF, EF, TK, VK, MS, and TB analysis and interpretation of data for the study and drafting the manuscript. MR, KS, VK, MS, TB, EH, and HG functional experiments. PR, MZ, EM, TF, ZZ, EH, JB, PJ, PS, JSo, JSt, MV, JL, JT, IC, FF, PK, and OZ analysis and interpretation of data.\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\nWe would like to thank the family of the patient for their kind cooperation and permission to publish this paper.\n\nFunding. This project was supported by NV18-07-00430 (to EM and JSt), NV19-05-00332 (to EF and VK) projects of the Czech Ministry of Health and by 17-04941Y from the Czech Science Foundation. The research facilities were supported by the project for the conceptual development of research organization 00064203 and LO1604, the infrastructure was supported by CZ.2.16/3.1.00/24505. EF and MS were supported by PRIMUS/17/MED/11. KS and MR were supported by PRIMUS/19/MED/04. ZZ was supported by the project for the conceptual development of research organization RVO-VFN64165.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2019.02194/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Narumi S Amano N Ishii T Katsumata N Muroya K Adachi M . SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome and are associated with loss of chromosome 7 . Nat Genet. (2016 ) 48 :792 –7 . 10.1038/ng.3569 27182967 \n2. Buonocore F Kühnen P Suntharalingham JP Del Valle I Digweed M Stachelscheid H . Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans . J Clin Invest. (2017 ) 127 :1700 –13 . 10.1172/JCI91913 28346228 \n3. Schwartz JR Wang S Ma J Lamprecht T Walsh M Song G . Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome . Leukemia. (2017 ) 31 :1827 –30 . 10.1038/leu.2017.142 28487541 \n4. Chen DH Below JE Shimamura A Keel SB Matsushita M Wolff J . Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L . Am J Hum Genet. (2016 ) 98 :1146 –58 . 10.1016/j.ajhg.2016.04.009 27259050 \n5. Bluteau O Sebert M Leblanc T Peffault de Latour R Quentin S Lainey E . A landscape of germ line mutations in a cohort of inherited bone marrow failure patients . Blood. (2018 ) 131 :717 –32 . 10.1182/blood-2017-09-806489 29146883 \n6. Kumar P Henikoff S Ng PC . Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm . Nat Protoc. (2009 ) 4 :1073 –81 . 10.1038/nprot.2009.86 19561590 \n7. Adzhubei I Jordan DM Sunyaev SR . Predicting functional effect of human missense mutations using PolyPhen-2 . Curr Protoc Hum Genet. (2013 ) Chapter 7:Unit7.20. 10.1002/0471142905.hg0720s76 23315928 \n8. Kircher M Witten DM Jain P O'Roak BJ Cooper GM Shendure J . A general framework for estimating the relative pathogenicity of human genetic variants . Nat Genet. (2014 ) 46 :310 –5 . 10.1038/ng.2892 24487276 \n9. Sarthy J Zha J Babushok D Shenoy A Fan JM Wertheim G . Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype . (2018 ) 2 :3 –8 . 10.1182/bloodadvances.2017012682 29365320 \n10. Lek M Karczewski KJ Minikel EV Samocha KE Banks E Fennell T . Analysis of protein-coding genetic variation in 60,706 humans . Nature. (2016 ) 536 :285 –91 . 10.1038/nature19057 27535533 \n11. Flanagan SE Patch AM Ellard S . Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations . Genet Test Mol Biomark. (2010 ) 14 :533 –7 . 10.1089/gtmb.2010.0036 20642364 \n12. Wilson DB Bessler M Ferkol TW Shenoy S Amano N Ishii T . Comment on: acquired monosomy 7 myelodysplastic syndrome in a child with clinical features of dyskeratosis congenita and IMAGe association . Pediatr. Blood Cancer. (2018 ) 65 :e26747 . 10.1002/pbc.26747 28834235 \n13. Mekhedov SL Makarova KS Koonin EV . The complex domain architecture of SAMD9 family proteins, predicted STAND-like NTPases, suggests new links to inflammation and apoptosis . Biol Direct. (2017 ) 12 :13 . 10.1186/s13062-017-0185-2 28545555 \n14. Wong JC Bryant V Lamprecht T Ma J Walsh M Schwartz J . Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes . JCI Insight. (2018 ) 3 :121086 . 10.1172/jci.insight.121086 30046003 \n15. Pelák O Stuchlý J Król L Hubáček P Keslová P Sedláček P . Appearance of cytomegalovirus-specific T-cells predicts fast resolution of viremia post hematopoietic stem cell transplantation . Cytom. Part B Clin. Cytom. (2017 ) 92 :380 –8 . 10.1002/cyto.b.21348 26647177 \n16. Horejsí V Angelisová P Bazil V Kristofová H Stoyanov S Stefanová I . Monoclonal antibodies against human leucocyte antigens. II. Antibodies against CD45 (T200), CD3 (T3), CD43, CD10 (CALLA), transferrin receptor (T9), a novel broadly expressed 18-kDa antigen (MEM-43) and a novel antigen of restricted expression (MEM-74) . Folia Biol. (1988 ) 34 :23 –34 .2968928 \n17. Knapp W \nLeucocyte Typing IV : White Cell Differentiation Antigens. \nNew York, NY : Oxford University Press (1989 ).\n18. Fronková E Klocperk A Svaton M Nováková M Kotrová M Kayserová J . The TREC/KREC assay for the diagnosis and monitoring of patients with DiGeorge syndrome . PLoS ONE. (2014 ) 9 :e114514 . 10.1371/journal.pone.0114514 25485546 \n19. Sottini A Ghidini C Zanotti C Chiarini M Caimi L Lanfranchi A . Simultaneous quantification of recent thymic T-cell and bone marrow B-cell emigrants in patients with primary immunodeficiency undergone to stem cell transplantation . Clin Immunol. (2010 ) 136 :217 –27 . 10.1016/j.clim.2010.04.005 20452829\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "10()",
"journal": "Frontiers in immunology",
"keywords": "MIRAGE; SAMD9; cytomegalovirus infection; dysphagia; gastrointestinal disorder; hematopoietic stem cell transplantation; immunodeficiency; neutropenia",
"medline_ta": "Front Immunol",
"mesh_terms": "D002675:Child, Preschool; D003586:Cytomegalovirus Infections; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D007223:Infant; D008297:Male; D009154:Mutation; D009503:Neutropenia; D051904:Smad8 Protein",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "2194",
"pmc": null,
"pmid": "31620126",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "20452829;26647177;2968928;25485546;27182967;27535533;20642364;28545555;29146883;28346228;24487276;29365320;27259050;23315928;28487541;28834235;19561590;30046003",
"title": "Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement.",
"title_normalized": "novel samd9 mutation in a patient with immunodeficiency neutropenia impaired anti cmv response and severe gastrointestinal involvement"
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"abstract": "To describe Gd-EOB-DTPA-enhanced liver MR imaging findings in colon and rectal cancer patients who received Oxaliplatin.\n\n\n\nSpectrum of hepatobiliary phase imaging findings include diffuse heterogeneous dysfunction, macronodular and micronodular FNH-like lesions, and coexistence of periportal increased liver function with FNH-like lesions. Differentiation of these benign lesions from metastasis is crucial to avoid biopsy in patients with colorectal cancers and may allow better understanding of sinusoidal obstruction syndrome pathophysiology and regenerative response of liver.",
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"authors": "Ünal|Emre|E|;Karaosmanoğlu|Ali Devrim|AD|;Ozmen|Mustafa Nasuh|MN|;Akata|Deniz|D|;Karcaaltincaba|Musturay|M|",
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"keywords": "Colorectal cancer; FNH-like lesion; Gd-EOB-DTPA; Hepatobiliary phase; Liver MRI; Oxaliplatin; Sinusoidal obstruction syndrome",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D056486:Chemical and Drug Induced Liver Injury; D015179:Colorectal Neoplasms; D003287:Contrast Media; D005260:Female; D005472:Fluorouracil; D019786:Gadolinium DTPA; D006801:Humans; D002955:Leucovorin; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
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"title": "Hepatobiliary phase liver MR imaging findings after Oxaliplatin-based chemotherapy in cancer patients.",
"title_normalized": "hepatobiliary phase liver mr imaging findings after oxaliplatin based chemotherapy in cancer patients"
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"abstract": "Surgeons frequently deal with small bowel obstruction. However, small bowel obstruction caused by non-steroidal anti-inflammatory drug (NSAID)-induced diaphragm disease is very rare. The diagnosis is challenging, as symptoms are often non-specific and radiological studies remain inconclusive. We present a case of a 63-year-old man who, after an extensive diagnostic work-up and small bowel resection for obstructive symptoms, was finally diagnosed with NSAID-induced diaphragm disease as confirmed by histology. An unusual aspect of this case is that the patient stopped using NSAIDs after he was diagnosed with a gastric ulcer 2-years previously. This suggests that NSAID-induced diaphragms of the small bowel take some time to develop and underlines the importance of careful history taking.",
"affiliations": "Department of Colorectal Surgery, Churchill Hospital, Oxford University Hospitals , UK.;Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford , UK.;Department of Colorectal Surgery, Churchill Hospital, Oxford University Hospitals , UK.",
"authors": "Coolsen|Mme|M|;Leedham|S J|SJ|;Guy|R J|RJ|",
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"title": "Non-steroidal anti-inflammatory drug-induced diaphragm disease: an uncommon cause of small bowel obstruction.",
"title_normalized": "non steroidal anti inflammatory drug induced diaphragm disease an uncommon cause of small bowel obstruction"
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"abstract": "We report two cases of cutaneous granuloma induced by anti-TNF-alpha therapy: a 47-year-old man suffering from psoriatic arthritis treated with infliximab and a 56-year-old woman treated with adalimumab for polyarticular juvenile rheumatoid arthritis. The biospies confirmed the diagnosis of a 'sarcoidosis-like' reaction. No systemic involvement was observed. Such cases of noninfectious granulomatous diseases occurring during anti-TNF-alpha therapy are becoming increasingly frequent.",
"affiliations": "Department of Dermatology, Amiens University Medical Centre, South Hospital, Amiens, France. Florie.Dhaille @ orange.fr",
"authors": "Dhaille|F|F|;Viseux|V|V|;Caudron|A|A|;Dadban|A|A|;Tribout|C|C|;Boumier|P|P|;Clabaut|A|A|;Lok|C|C|",
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"title": "Cutaneous sarcoidosis occurring during anti-TNF-alpha treatment: report of two cases.",
"title_normalized": "cutaneous sarcoidosis occurring during anti tnf alpha treatment report of two cases"
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"companynumb": "FR-CELLTRION INC.-2017FR002493",
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"abstract": "A 28-year-old male, 10 years post live-related renal transplant with stable graft function of 1.4 mg/dL, presented with complaints of loss of appetite and vomiting for three days. On evaluation, he was found to have significant graft dysfunction with a creatinine of 10.3 mg/dL. He was initiated on hemodialysis in view of uremic gastrointestinal symptoms. Graft biopsy done revealed acute cell-mediated rejection BANFF IIB and diffuse C4d-positive antibody-mediated rejection. He was treated with intravenous methylprednisolone, therapeutic plasma exchange, and intravenous immunoglobulin therapy, following which his graft function improved gradually. He received multiple injections of bortezomib as a part of anti-rejection treatment protocol and developed peripheral neuropathy, leukocytoclastic vasculitis, and varicellosis. This case report is to highlight the unusual phenomenon of leukocytoclastic vasculitis in a post renal transplant setting secondary to bortezomib therapy.",
"affiliations": "Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India.;Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India.;Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India.;Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India.;Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India.;Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India.",
"authors": "Yashwanth|Thiagarajan Raj|TR|;Vairakkani|Raveendran|R|;Srinivasaprasad|Nagalakshmi Dhanapal|ND|;Sujith|Suren|S|;Thirumalvalavan|Kaliaperumal|K|;Fernando|Mervin Edwin|ME|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D000069286:Bortezomib",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/1319-2442.301178",
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"issue": "31(5)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000328:Adult; D000069286:Bortezomib; D006084:Graft Rejection; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D010951:Plasma Exchange; D012867:Skin; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
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"pmid": "33229776",
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"title": "Leukocytoclastic Vasculitis Associated with Bortezomib Therapy.",
"title_normalized": "leukocytoclastic vasculitis associated with bortezomib therapy"
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"activesubstancename": "BORTEZOMIB"
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{
"abstract": "Seizures can be difficult to distinguish from other causes of transient cerebral hypoxia in the emergency department. We present a case of seizure activity in a woman in whom EKG led to a diagnosis of intermittent monomorphic and polymorphic ventricular tachycardia (torsades de pointes), highlighting the need for careful consideration of alternative causes of seizures, even in patients with known epilepsy.",
"affiliations": "Division of Emergency Medicine, University of Washington, United States.;Division of Emergency Medicine, University of Washington, United States. Electronic address: stephenmorrismd@gmail.com.;Division of Emergency Medicine, University of Washington, United States.",
"authors": "Wentlandt|Max|M|;Morris|Stephen C|SC|;Mitchell|Steven H|SH|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D004232:Diuretics; D008278:Magnesium Sulfate; D008012:Lidocaine; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2016.11.051",
"fulltext": null,
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"issn_linking": "0735-6757",
"issue": "35(5)",
"journal": "The American journal of emergency medicine",
"keywords": "Dysrhythmia; Seizure; Torsades de pointes",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D000437:Alcoholism; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D004232:Diuretics; D004562:Electrocardiography; D004632:Emergency Medical Services; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008012:Lidocaine; D008133:Long QT Syndrome; D008278:Magnesium Sulfate; D008691:Methadone; D012640:Seizures; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome; D014882:Water-Electrolyte Balance",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "804.e5-804.e6",
"pmc": null,
"pmid": "27914889",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ventricular tachycardia and prolonged QT interval presenting as seizure-like activity.",
"title_normalized": "ventricular tachycardia and prolonged qt interval presenting as seizure like activity"
} | [
{
"companynumb": "US-ORION CORPORATION ORION PHARMA-SPIR2017-0017",
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"occurcountry": "US",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
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{
"abstract": "BACKGROUND\nImmune agents including anti-programmed death receptor-1 and anti-cytotoxic T-lymphocyte antigen-4 have been associated with numerous immune-related complications. Pembrolizumab, a programmed death-1 inhibitor, has been associated with a number of immune-related adverse events such as pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and type 1 diabetes.\n\n\nMETHODS\nWe present a rare case of an elderly male on pembrolizumab who suffered from four autoimmune toxicities including type 1 diabetes, pneumonitis, hypothyroidism, and polymyalgia rheumatica likely catalyzed by age-related immune activation.Management and outcome: Immunotherapy was indefinitely stopped, and patient was started on steroids for the immune-related adverse events with complete resolution of polymyalgia rheumatica. Thyroid dysfunction resolved once he started thyroid replacement therapy. His diabetes is well controlled with insulin and is followed by endocrinology. He continues on prednisone for immune-mediated pneumonitis with a good response with regular monitoring via computed tomography scans and pulmonary consultation.\n\n\nCONCLUSIONS\nFew cases wherein multiple toxicities are seen within one patient are reported. Aging appears to be a risk factor for immune-related adverse events. Aging is associated with an increased incidence of autoimmunity as programmed death-1 ligand expression represents an important mechanism that tissues use to protect from self-reactive effector T cells. Programmed death-1 blockade breaks this protective mechanism and enhances autoimmune diseases. Therefore, close monitoring and extreme vigilance is warranted while using immune checkpoint inhibitors including pembrolizumab as multiple toxicities can occur within a short span of infusion, especially in elderly individuals. Prompt discontinuation and the use of a multidisciplinary team are prudent to prevent further morbidity and mortality.",
"affiliations": "Department of Internal Medicine, University of Connecticut, CT, USA.;Department of Internal Medicine, University of Connecticut, CT, USA.;Department of Internal Medicine, University of Connecticut, CT, USA.;Department of Internal Medicine, University of Connecticut, CT, USA.;Department of Hematology/Oncology, University of Connecticut, CT, USA.",
"authors": "Kethireddy|Nikhila|N|https://orcid.org/0000-0001-8664-4891;Thomas|Steffi|S|https://orcid.org/0000-0001-7791-6648;Bindal|Poorva|P|https://orcid.org/0000-0003-3459-0099;Shukla|Prateek|P|;Hegde|Upendra|U|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000082082:Immune Checkpoint Inhibitors; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220921543",
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"issue": "27(1)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Anti-PD-1 therapy; immune-related adverse events; irAEs; melanoma; pembrolizumab",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008297:Male; D008545:Melanoma",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "207-211",
"pmc": null,
"pmid": "32390537",
"pubdate": "2021-01",
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"title": "Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab.",
"title_normalized": "multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab"
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"abstract": "High-dose of methotrexate chemotherapy is used in the treatment of some tumors. It presents several side effects that required therapeutic drug monitoring, which is commonly performed on 24, 48 and 72h after the beginning of the methotrexate infusion. Treatment of overexposure to methotrexate is based on injection of carboxypeptidase G2, which specifically degrades methotrexate into inactive metabolite: DAMPA. FPIA immunoassay on TDx automated analyzer (Abbott™) was used for therapeutic drug monitoring of methotrexate. This immunoassay presented a significant cross-reactivity between methotrexate and DAMPA, which widely overestimate the residual concentration compared to the gold standard HPLC/MS. TDx automated analyzer was substituted by a new immunoassay on Architect automated analyzer (Abbott™). However, this immunoassay has the same cross-reactivity, which needs to be careful when monitoring methotrexate after an injection of carboxypeptidase G2. In order to determine the most suitable assay for the therapeutic drug monitoring of methotrexate, the knowledge of injection of carboxypeptidase G2 remains essential.",
"affiliations": "Laboratoire central de biochimie, Hôpital Robert Debré, CHU de Reims, Reims, France, Laboratoire de biochimie médicale et de biologie moléculaire, UMR CNRS 7369, Faculté de médecine, Reims, France.;Laboratoire central de biochimie, Hôpital Robert Debré, CHU de Reims, Reims, France.;Laboratoire de pharmacologie et toxicologie, Hôpital Maison Blanche, CHU de Reims, Reims, France, SFR Cap-Santé-EA3801-Université de Reims, Laboratoire de pharmacologie médicale, Faculté de médecine, Reims, France.;Laboratoire de pharmacologie et toxicologie, Hôpital Maison Blanche, CHU de Reims, Reims, France.;Laboratoire de pharmacologie et toxicologie, Hôpital Maison Blanche, CHU de Reims, Reims, France, SFR Cap-Santé-EA3801-Université de Reims, Laboratoire de pharmacologie médicale, Faculté de médecine, Reims, France.;Laboratoire de pharmacologie et toxicologie, Hôpital Maison Blanche, CHU de Reims, Reims, France, SFR Cap-Santé-EA3801-Université de Reims, Laboratoire de pharmacologie médicale, Faculté de médecine, Reims, France.",
"authors": "Oudart|Jean-Baptiste|JB|;Marquet|Benjamin|B|;Feliu|Catherine|C|;Gozalo|Claire|C|;Djerada|Zoubir|Z|;Millart|Hervé|H|",
"chemical_list": "D008727:Methotrexate",
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"issue": "74(3)",
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"keywords": "carboxypeptidase G2; cross reactivity; methotrexate; osteosarcoma",
"medline_ta": "Ann Biol Clin (Paris)",
"mesh_terms": "D000293:Adolescent; D001859:Bone Neoplasms; D000075202:Contraindications; D003429:Cross Reactions; D016903:Drug Monitoring; D057915:Drug Substitution; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D007674:Kidney Diseases; D008297:Male; D008727:Methotrexate; D012516:Osteosarcoma",
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"pubdate": "2016-06-01",
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"references": null,
"title": "Analytical interference in the therapeutic drug monitoring of methotrexate.",
"title_normalized": "analytical interference in the therapeutic drug monitoring of methotrexate"
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"abstract": "Because the embryopathy associated with maternal warfarin use seems dose-dependent, some physicians advocate low-dose warfarin for pregnant women requiring anticoagulation. The current case, however, highlights that optic nerve dysfunction (as well as other signs of warfarin embryopathy) can occur after low-dose maternal warfarin exposure.",
"affiliations": "Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. arif.khan@mssm.edu",
"authors": "Khan|Arif O|AO|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
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"issue": "28(3)",
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"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000925:Anticoagulants; D004305:Dose-Response Relationship, Drug; D005145:Face; D005260:Female; D006801:Humans; D007223:Infant; D009264:Nails, Malformed; D009901:Optic Nerve Diseases; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011261:Pregnancy Trimester, First; D011297:Prenatal Exposure Delayed Effects; D020246:Venous Thrombosis; D014859:Warfarin",
"nlm_unique_id": "9436057",
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"title": "Optic nerve dysfunction in a child following low-dose maternal warfarin exposure.",
"title_normalized": "optic nerve dysfunction in a child following low dose maternal warfarin exposure"
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"abstract": "Epstein-Barr-virus- (EBV-) associated lymphoproliferative disorder (LPD) after immunosuppressive therapy for aplastic anemia (AA), in a nontransplant setting, has not been well described. We report one case of colonic EBV-LPD after a single course of immunosuppressive therapy for AA. The patient developed multiple colonic tumors 3 months after receiving immunosuppressive therapy, which consisted of rabbit antithymocyte globulin (ATG), cyclosporine, and methyl-predonisolone. The histological findings of biopsy specimens revealed that atypical lymphocytes had infiltrated colonic glands. Immunohistochemical staining for CD20 was positive, and in situ hybridization for EBV-encoded small RNAs was also positive. The EBV viral load in peripheral blood was slightly increased to 140/10(6) white blood cells. After the cessation of immunosuppressant, the colonic tumors spontaneously regressed, and the EBV viral load decreased to undetectable levels. This is the first report of the single use of rabbit ATG inducing colonic EBV-LPD. Because a single use of immunosuppressive therapy containing rabbit ATG can cause EBV-LPD, we should carefully observe patients receiving rabbit ATG for AA.",
"affiliations": "Department of Hematology/Oncology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8606, Japan.",
"authors": "Sugimoto-Sekiguchi|Hiroko|H|;Tashiro|Haruko|H|;Shirasaki|Ryosuke|R|;Arai|Tomio|T|;Yamamoto|Tadashi|T|;Oka|Yoko|Y|;Akiyama|Nobu|N|;Kawasugi|Kazuo|K|;Shirafuji|Naoki|N|",
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"doi": "10.1155/2012/395801",
"fulltext": "\n==== Front\nCase Rep Gastrointest MedCase Rep Gastrointest MedCRIM.GMCase Reports in Gastrointestinal Medicine2090-65282090-6536Hindawi Publishing Corporation 10.1155/2012/395801Case ReportColonic EBV-Associated Lymphoproliferative Disorder in a Patient Treated with Rabbit Antithymocyte Globulin for Aplastic Anemia Sugimoto-Sekiguchi Hiroko \n1\nTashiro Haruko \n1\n*Shirasaki Ryosuke \n1\nArai Tomio \n2\n\n3\nYamamoto Tadashi \n1\nOka Yoko \n1\nAkiyama Nobu \n1\nKawasugi Kazuo \n1\nShirafuji Naoki \n1\n1Department of Hematology/Oncology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8606, Japan2Division of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8606, Japan3Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan*Haruko Tashiro: haruko-t@med.teikyo-u.ac.jpAcademic Editors: E. Altintas and S. Chokhavatia\n\n2012 23 9 2012 2012 3958018 7 2012 28 8 2012 Copyright © 2012 Hiroko Sugimoto-Sekiguchi et al.2012This 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.Epstein-Barr-virus- (EBV-) associated lymphoproliferative disorder (LPD) after immunosuppressive therapy for aplastic anemia (AA), in a nontransplant setting, has not been well described. We report one case of colonic EBV-LPD after a single course of immunosuppressive therapy for AA. The patient developed multiple colonic tumors 3 months after receiving immunosuppressive therapy, which consisted of rabbit antithymocyte globulin (ATG), cyclosporine, and methyl-predonisolone. The histological findings of biopsy specimens revealed that atypical lymphocytes had infiltrated colonic glands. Immunohistochemical staining for CD20 was positive, and in situ hybridization for EBV-encoded small RNAs was also positive. The EBV viral load in peripheral blood was slightly increased to 140/106 white blood cells. After the cessation of immunosuppressant, the colonic tumors spontaneously regressed, and the EBV viral load decreased to undetectable levels. This is the first report of the single use of rabbit ATG inducing colonic EBV-LPD. Because a single use of immunosuppressive therapy containing rabbit ATG can cause EBV-LPD, we should carefully observe patients receiving rabbit ATG for AA.\n==== Body\n1. Introduction\nEpstein-Barr virus (EBV) is one of the oncogenic viruses, and primary infection usually occurs in childhood. After primary infection, EBV remains latent in the bone marrow and other tissues under immunosurveillance by virus-specific CD8+ cytotoxic T cells and virus-specific CD4+ T cells. EBV reactivation and EBV-associated lymphoproliferative disorder (EBV-LPD) have been increasingly observed in immunodeficient hosts such as patients who received allogeneic hematopoietic stem cell transplantation [1] or solid organ transplantation [2]. EBV-LPD after allogeneic hematopoietic stem cell transplantation (HSCT) is a rare complication; however, it sometimes becomes serious and lethal [3]. The major risk factor for EBV-LPD in a transplant setting is the use of in vivo T-cell depletion with antithymocyte globulin (ATG) for the prophylaxis of acute graft versus host disease (GVHD) [1, 4], or a reduced intensity conditioning regimen [5]. In addition, alternative donor stem cell transplantation, that is, an unrelated donor or at least a 2 locus human leukocyte antigen-mismatched-related donor, is associated with an increased risk of EBV-LPD [3]. \n\nATG is widely used for the treatment of aplastic anemia (AA) in patients without a suitable donor [6], besides being used for the prevention of acute GVHD in allogeneic HSCT. Whether the use of ATG for AA increases EBV-LPD has not been well established. There are a few reports about EBV-related disease occurring after ATG for AA, in nontransplant setting [7–10]. Here, we report a patient who developed colonic EBV-LPD after immunosuppressive therapy using rabbit ATG, cyclosporine (CSP) and methyl-predonisolone for AA. Furthermore, the lesion disappeared only by the cessation of CSP. \n\n2. Case Presentation\nIn February 2010, a 55-year-old Japanese man was referred to our hospital due to a bleeding tendency. His blood cell count was hemoglobin (Hb) 10.0 g/dL, platelets 1.5 × 104/μL, white blood cells (WBC) 2.9 × 103/μL with 46% neutrophils and 49% lymphocytes, and absolute reticulocyte number 33,330/μL. Bone marrow examination revealed severe hypocellular marrow without any dysplasia. Chromosomal analysis showed a normal karyotype. A whole-body CT scan showed no abnormal findings. Thus, we diagnosed him with AA (stage 3). Serological studies for human immunodeficiency virus, hepatitis B and C virus, and cytomegalovirus (CMV) were all negative. Anti-EBV antibody titers at diagnosis were viral capsid antigen (VCA) IgG-positive, VCA IgM-negative, and EBV nuclear antigen- (EBNA-) positive. The quantities of EBV-DNA viral load in peripheral blood using the RT-PCR method were not measured at diagnosis. He depended on regulatory red blood cell and platelet transfusions. \n\nBecause he had no related HLA-identical donor, he was treated with immunosuppressive therapy consisted of methyl-predonisolone (125 mg/day days 1–5, then tapered), CSP (6 mg/kg/day, orally), and rabbit ATG (3.75 mg/kg/day, days 1–5) in May 2010. The dose of rabbit ATG was decided according to the guideline for the diagnosis and management of AA of the British Society of Haematology [11]. On day +9 after immunosuppressive therapy, his lymphocyte count decreased to 0/μL. Although, after day +13, his lymphocyte count increased gradually, it was maintained on the level below 100/μL. He developed no documented infection, and he was discharged with a regulatory blood transfusion dependency. In August 2010, he developed severe anemia and needed frequent red blood cell transfusions. Moreover, the serum LDH gradually increased to 358 IU/L from a normal range (119–229 IU/L). He developed general malaise and appetite loss. He was afebrile and did not develop superficial lymphadenopathy. Because occult blood tests in stools were positive, he underwent a colonoscopy, which revealed multiple tumors of the ascending, transverse, and descending colons (Figure 1(a)). All biopsy specimens from colonic tumors showed the proliferation of atypical lymphocytes (Figure 2(a)). Immunostaining revealed that the atypical lymphocytes were CD20+ (Figure 2(b)), CD79a+, CD3−, and CD5−. Immunocytochemistry studies for EBV encoded small RNAs (EBER) involving in situ hybridization were positive (Figure 2(c)). The PET/CT showed no lymphadenopathy other than the colonic tumors. On day +84 after immunosuppressive therapy, the EBV viral load was slightly increased to 140/106 WBC. He was diagnosed with EBV-LPD. He received only CSP as immunosuppressive therapy at day +84. The serum concentration of CSP was 333 ng/mL on day +90. We stopped the administration of CSP on day +97. After cessation, his symptoms gradually improved, and the serum LDH level decreased to the normal range. His lymphocyte counts gradually increased to 300/μL. One month after the cessation of CSP, he underwent colonoscopy again, which showed regression of the tumors (Figure 1(b)). Two months after the cessation of CSP, the EBV viral load was below the detectable level. In February 2011, he had achieved a partial hematological response and was independent of blood transfusion. At this moment, 2 years later, no EBV-LPD occurred. \n\n3. Discussion\nEBV-LPD in patients undergoing allogeneic HSCT is increasing, because pre- and posttransplantation settings have diversified. The risk factors associated with the development of EBV-LPD after allogeneic HSCT have yet to be a higher degree of immunosuppression, including ATG. However, it is not determined whether the therapeutic use of ATG for AA, in a nontransplant setting, is a risk factor for EBV-LPD.\n\nThere are a few reports concerning EBV-related [7–10] or EBV-nonrelated [12, 13] LPD after immunosuppressive therapy for AA. A brief summary of EBV-LPD in a nontransplant setting is shown in Table 1. Wondergem et al. [10] reported EBV-associated diffuse large B-cell lymphoma in a patient with severe AA who was treated with rabbit ATG as a second course of immunosuppression. They suggested the feasibility of monitoring EBV reactivation in patients being treated with rabbit ATG as a second course of immunosuppression. In addition, Calistri et al. [7] reported the case of a patient who developed infectious mononucleosis, after immunosuppressive therapy with CSP and two courses of ATG (first course was rabbit ATG, and second was equine) for AA. These two cases were administered both rabbit and equine ATG. The second course of ATG may be a risk factor for EBV-LPD after immunosuppressive therapy for AA. Rabbit ATG is considered to be more immunosuppressive than equine ATG. In a study comparing rabbit with equine ATG, lymphocytopenia was more prolonged and the median peak EBV copy number was higher in the rabbit ATG than in the equine ATG group [14, 15].\n\nHere, we report a patient who developed colonic EBV-LPD after rabbit ATG as the first course of immunosuppressive therapy consisted of rabbit ATG, CSP, and methyl predonisolone for AA. Due to the fact that we did not perform colonoscopy before immunosuppressive therapy, there is a possibility that his tumors existed before immunosuppressive therapy. However, his colonic tumors were diminished, and the EBV viral load was decreased only by the discontinuation of CSP. These findings suggested that his EBV-LPD may have occurred due to the suppression of his cellular immunity. To our knowledge, this is the first report of EBV-LPD caused by one course of rabbit ATG for AA, and, moreover, that it could be diminished only by the cessation of CSP. In contrast to other reported cases, in our patient, the EBV viral load was relatively low and his clinical symptoms were mild. This may reflect the lighter degree of immunosuppression by single course of ATG. On the other hand, the optimal given dose of ATG has not become settled yet. Although we administered 3.75 mg/kg of rabbit ATG for 5 days according to the British guideline, there are several reports of lower doses of rabbit ATG for immunosuppressive therapy [16–18]. The dose of 3.75 mg/kg for 5 days may have been too strong for immune suppression. Further investigation is needed to explore the optimal doses of rabbit ATG for AA. \n\nEBV-LPD in allogeneic HSCT is sometimes lethal [19] and is needed for early intervention. To treat early frequent monitoring of the EBV-DNA load by quantitative real-time PCR has been suggested [2]. However, Wakabayashi et al. [20] reported that weekly monitoring for EBV-DNA could not prevent the development of EBV-LPD after allogeneic bone marrow transplantation for severe AA. Furthermore, in nontransplant setting, Scheinberg et al. [14] reported their findings on CMV and EBV reactivation following immunosuppressive therapy for AA, in which they state that although EBV reactivation was observed, in the majority of patients no EBV-related disease occurred. Thus, the authors concluded that routine monitoring of the viral load is not necessary for AA patients who have received immunosuppressive therapy. However, as mentioned above, EBV-LPD, including our case, was demonstrated also after immunosuppressive therapy for AA. It remains controversial whether routine monitoring of the EBV-DNA viral load is necessary or not.\n\nAlthough, in our case, the EBV-LPD disappeared only by the cessation of CSP, EBV-LPD cannot usually be effectively controlled by the dose reduction or discontinuation of immunosuppressants alone, in an allogeneic HSCT setting. And EBV-specific cytotoxic T cells with donor lymphocyte infusion and rituximab are available as a therapeutic option [21]. Furthermore, adoptive immunotherapy with EBV-specific T cells has been investigated for EBV-LPD in transplant settings [2]. \n\nIn conclusion, EBV-related disease may occur after a single course of rabbit ATG for AA. We should observe patients carefully not only during but also after immunosuppressive therapy for AA. Once EBV-LPD occurs, cessation of the immunosuppressant may be an effective treatment option in a nontransplant setting. \n\nFigure 1 (a) Colonoscopic findings at diagnosis. Multiple tumors at the ascending colon are observed. (b) Colonoscopic findings one month after the cessation of CSP. No tumors are observed.\n\nFigure 2 Histologic findings of biopsy specimens. (a) Atypical lymphocytes, lymphocytes, and neutrophils infiltrate the colonic lamina propria. Mildly atrophied crypts with goblet cell depletion are also observed (H&E, original magnification ×10). (b) Immunohistochemical staining with anti-CD20 antibody shows a diffuse reaction (original magnification ×25). (c) In situ hybridization for EBER reveals positive staining (original magnification ×25).\n\nTable 1 Summary of EBV-LPD after ATG for aplastic anemia in a nontransplant setting.\n\nAge, gender\t\nType of ATG\tDose of ATG\tOther drugs\tMonths to diagnosis from ATG\tEBV viral load\tType of LPD\tPrevious treatment for AA\tTreatment for LPD\tOutcome\tReference\t\n38, M\tEquine\t3.5 mg/kg NR\tmPSL, CSP\t1>\t30,000/150,000 cells\tIM\trATG \tRit\tCR\t[7]\t\n36, M\tEquine\t0.75 mL/kg 8 days\tCSP\t1>\tNR\tEBV-LPD\tNR\tNR\tDead\t[8]\t\n55, M\tEquine\tNR\tNone\t1 \t60,060/mL\tEBV-LPD\tATG*\tGCV**, FCV** Rit\tNR\t[9]\t\n42, F\tRabbit\t12.5 mg/kg 4 days\tCSP\t1>\t4 × 106/mL\tDLBCL\teATG\tRit, CPA\tCR\t[10]\t\n55, M\tRabbit\t3.75 mg/kg 5 days\tmPSL, CSP\t3 \t140/106 WBC\tEBV-LPD\tNone\tCessation of CSP\tCR\tOur case\t\nNR: not reported, IM: infectious monocytosis, rATG: rabbit ATG, eATG: equine ATG, Rit: rituximab, CR: complete remission, EBV-LPD: Epstein-Barr-virus-associated lymphoproliferative disorder, GCV: ganciclovir, FCV: foscarnet, DLBCL: diffuse large B-cell lymphoma, CPA: cyclophosphamide, and CSP: cyclosporine.\n\n*This patient received autologous peripheral blood stem cell transplantation for Burkitt lymphoma before development of aplastic anemia.\n\n**For concurrence of cytomegalovirus reactivation.\n==== Refs\n1 Van Esser JWJ Van Der Holt B Meijer E Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT Blood 2001 98 4 972 978 2-s2.0-0035883085 11493441 \n2 Shaffer DR Rooney CM Gottschalk S Immunotherapeutic options for Epstein-Barr virus-associated lymphoproliferative disease following transplantation Immunotherapy 2010 2 5 663 671 2-s2.0-77957552572 20874650 \n3 Meijer E Cornelissen JJ Epstein-Barr virus-associated lymphoproliferative disease after allogeneic haematopoietic stem cell transplantation: molecular monitoring and early treatment of high-risk patients Current Opinion in Hematology 2008 15 6 576 585 2-s2.0-55149097217 18832928 \n4 Bacigalupo A Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects Bone Marrow Transplantation 2005 35 3 225 231 2-s2.0-13944258549 15558041 \n5 Cohen J Gandhi M Naik P Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning British Journal of Haematology 2005 129 2 229 239 2-s2.0-20244382569 15813851 \n6 Rosenfeld S Follmann D Nunez O Young NS Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome Journal of the American Medical Association 2003 289 9 1130 1135 2-s2.0-0037420270 12622583 \n7 Calistri E Tiribelli M Battista M Epstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia American Journal of Hematology 2006 81 5 355 357 2-s2.0-33646475755 16628717 \n8 Raghavachar A Ganser A Freund M Heimpel H Herrmann F Schrezenmeier H Long-term interleukin-3 and intensive immunosuppression in the treatment of aplastic anemia Cytokines and Molecular Therapy 1996 2 2 215 223 2-s2.0-0030502943 9384707 \n9 Viola GM Zu Y Baker KR Aslam S Epstein-Barr virus-related lymphoproliferative disorder induced by equine anti-thymocyte globulin therapy Medical Oncology 2010 1 5 2-s2.0-77955040344 \n10 Wondergem MJ Stevens SJC Janssen JJWM Monitoring of EBV reactivation is justified in patients with aplastic anemia treated with rabbit ATG as a second course of immunosuppression Blood 2008 111 3 p. 1739 2-s2.0-38949192914 \n11 Marsh JCW Ball SE Cavenagh J Guidelines for the diagnosis and management of aplastic anaemia British Journal of Haematology 2009 147 1 43 70 2-s2.0-70349213313 19673883 \n12 Dorr V Doolittle G Woodroof J First report of a B cell lymphoproliterative disorder arising in a patient treated with immune suppressants for severe aplastic anemia American Journal of Hematology 1996 52 2 108 113 2-s2.0-0029991766 8638630 \n13 Suzuki Y Niitsu N Hayama M Lymphoproliferative disorders after immunosuppressive therapy for aplastic anemia: a case report and literature review Acta Haematologica 2009 121 1 21 26 2-s2.0-62349130222 19295190 \n14 Scheinberg P Fischer SH Li L Distinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia Blood 2007 109 8 3219 3224 2-s2.0-34147220089 17148582 \n15 Scheinberg P Nunez O Weinstein B Horse versus rabbit antithymocyte globulin in acquired aplastic anemia New England Journal of Medicine 2011 365 5 430 438 2-s2.0-79961116424 21812672 \n16 Afable MG II Shaik M Sugimoto Y Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia Haematologica 2011 96 9 1269 1275 21606164 \n17 Di Bona E Rodeghiero F Bruno B Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO) British Journal of Haematology 1999 102 2 330 334 2-s2.0-0034060620 \n18 Garg R Faderl S Garcia-Manero G Phase II study of rabbit anti-thymocyte globulin, cyclosporine and granulocyte colony-stimulating factor in patients with aplastic anemia and myelodysplastic syndrome Leukemia 2009 23 7 1297 1302 2-s2.0-67650921718 19242494 \n19 Peres E Savasan S Klein J Abidi M Dansey R Abella E High fatality rate of Epstein-Barr virus-associated lymphoproliferative disorder occurring after bone marrow transplantation with rabbit antithymocyte globulin conditioning regimens Journal of Clinical Microbiology 2005 43 7 3540 3543 2-s2.0-22144475134 16000501 \n20 Wakabayashi S Ohashi K Hanajiri R Rapidly progressive Epstein-Barr virus-associated lymphoproliferative disorder unpredictable by weekly viral load monitoring Internal Medicine 2010 49 10 931 935 2-s2.0-77952928085 20467179 \n21 McGuirk JP Seropian S Howe G Smith B Stoddart L Cooper DL Use of rituximab and irradiated donor-derived lymphocytes to control Epstein-Barr virus-associated lymphoproliferation in patients undergoing related haplo-identical stem cell transplantation Bone Marrow Transplantation 1999 24 11 1253 1258 2-s2.0-0033371889 10642818\n\n",
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"title": "Colonic EBV-Associated Lymphoproliferative Disorder in a Patient Treated with Rabbit Antithymocyte Globulin for Aplastic Anemia.",
"title_normalized": "colonic ebv associated lymphoproliferative disorder in a patient treated with rabbit antithymocyte globulin for aplastic anemia"
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... |
{
"abstract": "Burn patients with large burn surface area involvement are at increased risk of infection due to the presence of large wounds, multiple surgeries, prolonged intensive care unit admission, and immunosuppression. Pseudomonas aeruginosa is the most commonly isolated organism in this population. Even with frequent infections in the burn population, meningitis and encephalitis are rare, and ventriculitis is exceptional. We report the case of a 66-year-old woman who developed P. aeruginosa bacteremia during her hospital course, causing secondary meningoencephalitis with ventriculitis. She was admitted for partial- and full-thickness burns affecting the neck, chest, abdomen, upper medial arms, and bilateral anteromedial thighs for an estimated 20% total body surface area burn. She met sepsis criteria and broad-spectrum antimicrobial coverage was initiated. Magnetic resonance imaging of the brain, performed for altered mental status, revealed meningitis and ventriculitis. Cerebrospinal fluid analysis demonstrated findings consistent with bacterial meningitis, with cultures positive for P. aeruginosa. Serial neuroimaging with computerized tomography revealed new areas of ischemia concerning for septic emboli. In the presence of altered mental status and fever of unknown origin, workup should remain broad. Even in the presence of another source, it is important to keep an open mind for the rarer intracerebral infection as it requires different management, including urgent evaluation of antibiotic selection and dosing to ensure central nervous system penetration, and neurosurgical evaluation.",
"affiliations": "Division of Critical Care Medicine, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, USA.;Department of Surgery, University of Florida College of Medicine, Gainesville, USA.;Department of Surgery, University of Florida College of Medicine, Gainesville, USA.;Division of Infectious Disease and Global Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, USA.;Department of Surgery, University of Florida College of Medicine, Gainesville, USA.;Division of Critical Care Medicine, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, USA.",
"authors": "Segal|Nicolas|N|0000-0002-0715-9730;Polcz|Valerie E|VE|;McKean|Jordan A|JA|;Kariyawasam|Vidhu|V|;Carson|Joshua S|JS|;Fahy|Brenda G|BG|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jbcr/irab016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1559-047X",
"issue": "42(4)",
"journal": "Journal of burn care & research : official publication of the American Burn Association",
"keywords": null,
"medline_ta": "J Burn Care Res",
"mesh_terms": null,
"nlm_unique_id": "101262774",
"other_id": null,
"pages": "832-835",
"pmc": null,
"pmid": "33484564",
"pubdate": "2021-08-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pseudomonal Meningoencephalitis With Ventriculitis Secondary to Bacteremia in a Burn Patient: A Novel Case.",
"title_normalized": "pseudomonal meningoencephalitis with ventriculitis secondary to bacteremia in a burn patient a novel case"
} | [
{
"companynumb": "US-BAUSCH-BL-2021-031835",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSerous papillary peritoneal carcinoma (SPPC) is a rare clinical entity. Based on the understanding of the pattern of spread, its multifocality, polyclonality and the high frequency of diffuse, widespread peritoneal metastasis, a robust rationale for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for SPPC exists. Herein we report the clinical outcomes of SPPC patients treated with neoadjuvant systemic chemotherapy (NACT) followed by CRS including total parietal peritonectomy and HIPEC.\n\n\nMETHODS\nClinico-pathological data of 22 patients of serous papillary peritoneal carcinoma (SPPC) was retrospectively analyzed from a prospectively maintained database from June 2000 to July 2017. Patients were treated with CRS, total parietal peritonectomy and HIPEC with cisplatin (42 mg/L of perfusate) and doxorubicin (15 mg/L of perfusate) after NACT. Survival curves were calculated from the date of surgery.\n\n\nRESULTS\n22 patients underwent CRS, total parietal peritonectomy and HIPEC. The median age was 62 years (Range 47-72). On histological evaluation, 18/30 (60%) parietal peritonectomy specimens showed microscopic disease, when no disease was evident macroscopically at surgical exploration. Grade III-IV surgical complications were recorded in 4/22 (18%) patients. There was no postoperative mortality. At a median follow up of 12 months, the five-year overall survival (OS) was 64.9%. The median OS was not reached. Median progression-free survival was 32.9 months and progression-free survival at 5 years was 33.2%.\n\n\nCONCLUSIONS\nCRS with total peritonectomy + HIPEC after NACT, presents as a promising treatment modality for SPPC, and could be associated with good survival results in patients with SPPC.",
"affiliations": "Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, via Venezian 1, Milan, MI, CAP 20133, Italy. Electronic address: marcello.deraco@istitutotumori.mi.it.;Department of Surgical Oncology, Jehangir Hospital, Sassoon Road, Pune, 411001, Maharashtra, India. Electronic address: snitanag@gmail.com.;Department of Gynecologic Oncology, National Cancer Institute of Mexico, Mexico city, CP14080, Mexico. Electronic address: rosasalher@gmail.com.;Department of Surgical oncology, All India Insitute of medical sciences, Ansari Nagar, New Delhi, Delhi, 110029, India. Electronic address: jrvk85@gmail.com.;Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, via Venezian 1, Milan, MI, CAP 20133, Italy. Electronic address: dario.baratti@istitutotumori.mi.it.;Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, via Venezian 1, Milan, MI, CAP 20133, Italy. Electronic address: xguagli@gmail.com.;Department of Surgery A, Tel-Aviv Sourasky Medical Center and Sackler Fcaulty of Medicine, Tel Aviv, Israel. Electronic address: eran.nizri@gmail.huji.ac.il.;Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, via Venezian 1, Milan, MI, CAP 20133, Italy. Electronic address: shigeki.kusamura@istitutotumori.mi.it.",
"authors": "Deraco|Marcello|M|;Sinukumar|Snita|S|;Salcedo-Hernández|Rosa Angélica|RA|;Rajendra|Vinayakumar J|VJ|;Baratti|Dario|D|;Guaglio|Marcello|M|;Nizri|Eran|E|;Kusamura|Shigeki|S|",
"chemical_list": "D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejso.2019.06.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0748-7983",
"issue": "45(11)",
"journal": "European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology",
"keywords": "Cytoreductive surgery and HIPEC; Epithelial ovarian carcinoma; Serous papillary peritoneal carcinoma; Total peritonectomy",
"medline_ta": "Eur J Surg Oncol",
"mesh_terms": "D000231:Adenocarcinoma, Papillary; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002945:Cisplatin; D065426:Cytoreduction Surgical Procedures; D004317:Doxorubicin; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007263:Infusions, Parenteral; D007902:Length of Stay; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018297:Neoplasms, Cystic, Mucinous, and Serous; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D010537:Peritoneum; D011183:Postoperative Complications; D000077982:Progression-Free Survival; D012189:Retrospective Studies",
"nlm_unique_id": "8504356",
"other_id": null,
"pages": "2103-2108",
"pmc": null,
"pmid": "31230982",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinico-pathological outcomes after total parietal peritonectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced serous papillary peritoneal carcinoma submitted to neoadjuvant systemic chemotherapy- largest single institute experience.",
"title_normalized": "clinico pathological outcomes after total parietal peritonectomy cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced serous papillary peritoneal carcinoma submitted to neoadjuvant systemic chemotherapy largest single institute experience"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1109215",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a newly described hematologic disorder, which presents as acute thrombocytopenia and thrombosis after administration of the ChAdOx1 nCov-19 (AstraZeneca) and Ad26.COV2.S (Johnson & Johnson) adenovirus-based vaccines against COVID-19. Due to positive assays for antibodies against platelet factor 4 (PF4), VITT is managed similarly to autoimmune heparin-induced thrombocytopenia (HIT) with intravenous immunoglobulin (IVIG) and non-heparin anticoagulation. We describe a case of VITT in a 50-year-old man with antecedent alcoholic cirrhosis who presented with platelets of 7 × 103 /μL and portal vein thrombosis 21 days following administration of the Ad26.COV2.S COVID-19 vaccine. The patient developed progressive thrombosis and persistent severe thrombocytopenia despite IVIG, rituximab and high-dose steroids and had persistent anti-PF4 antibodies over 30 days after his initial presentation. As such, delayed therapeutic plasma exchange (TPE) was pursued on day 32 of admission as salvage therapy, with a sustained improvement in his platelet count. Our case serves as proof-of-concept of the efficacy of TPE in VITT.",
"affiliations": "Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA.;Department of Pathology, The University of Chicago, Chicago, Illinois, USA.;Department of Pathology, The University of Chicago, Chicago, Illinois, USA.;Department of Pathology, The University of Chicago, Chicago, Illinois, USA.;Department of Pathology, The University of Chicago, Chicago, Illinois, USA.;Department of Pathology, The University of Chicago, Chicago, Illinois, USA.;Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA.",
"authors": "Major|Ajay|A|https://orcid.org/0000-0001-7261-1335;Carll|Timothy|T|;Chan|Clarence W|CW|;Christenson|Chancey|C|;Aldarweesh|Fatima|F|;Wool|Geoffrey D|GD|https://orcid.org/0000-0002-3335-2905;Cohen|Kenneth S|KS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21945",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": null,
"journal": "Journal of clinical apheresis",
"keywords": "coronavirus; platelet factor; thrombocytopenia; thrombosis; vaccines",
"medline_ta": "J Clin Apher",
"mesh_terms": null,
"nlm_unique_id": "8216305",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34672380",
"pubdate": "2021-10-21",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Refractory vaccine-induced immune thrombotic thrombocytopenia (VITT) managed with delayed therapeutic plasma exchange (TPE).",
"title_normalized": "refractory vaccine induced immune thrombotic thrombocytopenia vitt managed with delayed therapeutic plasma exchange tpe"
} | [
{
"companynumb": "US-CELLTRION INC.-2021US014687",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nIxekizumab is a recently developed biopharmaceutical used since 2016 in the US and Europe for the treatment of plaque psoriasis. Few adverse effects have been reported in the literature and ixekizumab is not known to increase the risk of viral reactivation. Herein we report the case of an immunocompetent female patient treated with ixekizumab who presented meningoradiculitis due to varicella zoster virus (VZV) reactivation.\n\n\nMETHODS\nA 51-year-old woman, treated with ixekizumab for psoriasis, consulted in March 2018 for left hemicrania headache associated with left facial paralysis, but without fever. Brain MRI scans revealed cerebral venous thrombosis of the superior sagittal sinus. Analysis of cerebrospinal fluid (CSF) revealed lymphocytic meningitis and positive VZV-PCR. PCR blood assay for VZV was negative. Blood concentrations of anti-VZV IgG antibody increased while Anti-VZV IgM antibodies remained negative. The final diagnosis was VZV meningoradiculitis complicated by cerebral thrombophlebitis. The absence of skin rash, the rapid increase in anti-VZV IgG antibodies, the absence of anti-VZV IgM antibodies, and the negative blood PCR assay suggested viral reactivation rather than primary infection. The patient received acyclovir and coumadin and her condition improved rapidly. After multidisciplinary discussion, ixekizumab was reintroduced together with valacyclovir prophylaxis.\n\n\nCONCLUSIONS\nThis case raises the question of the risk of viral reactivation during treatment with an IL-17 inhibitor and with biologics in general. Neurological and vascular complications of VZV may occur without skin lesions and their occurrence during ixekizumab therapy must be investigated by PCR testing of CSF for VZV DNA.",
"affiliations": "Dermatology department, Jean-Bernard hospital, Valenciennes, France. Electronic address: manon.dubois.3@gmail.com.;Rheumatology department, Jean-Bernard hospital, Valenciennes, France.;Tropical and infectious diseases department, Jean-Bernard hospital, Valenciennes, France.;Pharmacology department, regional pharmacovigilance center, Lille university hospital, Lille, France.;Pharmacology department, regional pharmacovigilance center, Lille university hospital, Lille, France.;EA3610 virology laboratory, Lille university, Lille university hospital, Lille, France.;Dermatology department, Jean-Bernard hospital, Valenciennes, France.",
"authors": "Dubois|M|M|;Morel|G|G|;Tone|A|A|;Gaboriau|L|L|;Gautier|S|S|;Lazrek|M|M|;Vermersch-Langlin|A|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C549079:ixekizumab; D000212:Acyclovir",
"country": "France",
"delete": false,
"doi": "10.1016/j.annder.2020.04.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "147(10)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": "Anti-IL-17; IL-17 inhibitors; Ixekizumab; Ixékizumab; Meningoradiculitis; Méningoradiculite; Psoriasis; VZV",
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D000212:Acyclovir; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "667-671",
"pmc": null,
"pmid": "32620295",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Meningoradiculitis due to varicella zoster virus reactivation in a patient treated with ixekizumab.",
"title_normalized": "meningoradiculitis due to varicella zoster virus reactivation in a patient treated with ixekizumab"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-264229",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Renal course and clinical outcomes in pregnant women with primary membranous nephropathy are not completely understood. In addition, the use of autoantibodies to M-type phospholipase A2 receptor (PLA2R) as a serologic marker throughout pregnancy and postpartum in the mother and baby is not yet fully elucidated. We followed up a pregnant woman with primary membranous nephropathy during pregnancy and postpartum and describe the clinical course and outcomes of mother and baby and the course of PLA2R antibody titers. We show evidence of transplacental transfer of PLA2R antibody from mother to fetus. In addition, we observe the effect of breastfeeding in a PLA2R antibody-positive pregnancy and describe the transfer of this antibody into breast milk. Although pregnancy in women with underlying PLA2R antibody-positive membranous nephropathy is possible, there is an increase in risk to both mother and fetus, requiring a multidisciplinary team approach and careful monitoring of both neonate and mother during pregnancy and postpartum.",
"affiliations": "Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY. Electronic address: msachdeva@northwell.edu.;Renal Section, Boston University School of Medicine, Boston, MA.;Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY.;Department of Pathology, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY.;Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY.",
"authors": "Sachdeva|Mala|M|;Beck|Laurence H|LH|;Miller|Ilene|I|;Bijol|Vanesa|V|;Fishbane|Steven|S|",
"chemical_list": "D001323:Autoantibodies; C516360:PLA2R1 protein, human; D054507:Receptors, Phospholipase A2",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2019.11.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "76(4)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "M-type phospholipase A(2) receptor (PLA(2)R); Membranous nephropathy (MN); adverse maternal outcome; autoantibody; breastmilk; case report; edema; maternal-fetal transfer; neonate; nephrotic syndrome; peripartum; pregnancy; transplacental passage",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D005260:Female; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008895:Milk, Human; D011247:Pregnancy; D054507:Receptors, Phospholipase A2",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "586-589",
"pmc": null,
"pmid": "32093980",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Phospholipase A2 Receptor Antibody-Positive Pregnancy: A Case Report.",
"title_normalized": "phospholipase a2 receptor antibody positive pregnancy a case report"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP014632",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional... |
{
"abstract": "We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.",
"affiliations": "Department of Neurology, School of Medicine, Sapporo Medical University, Japan.;Department of Neurology, School of Medicine, Sapporo Medical University, Japan.;Department of Neurology, School of Medicine, Sapporo Medical University, Japan.;Department of Neurology, School of Medicine, Sapporo Medical University, Japan.;Department of Neurology, School of Medicine, Sapporo Medical University, Japan.;Department of Neurology, School of Medicine, Sapporo Medical University, Japan.;Department of Orthopedics, Chitose City Hospital, Japan.;Department of Medical Oncology, Department of Hematology, School of Medicine, Sapporo Medical University, Japan.;Department of Neurology, School of Medicine, Sapporo Medical University, Japan.;Department of Medical Oncology, Department of Hematology, School of Medicine, Sapporo Medical University, Japan.;Department of Neurology, School of Medicine, Sapporo Medical University, Japan.",
"authors": "Miyanaga|Rei|R|;Hisahara|Shin|S|;Ohhashi|Ikkei|I|;Yamamoto|Daisuke|D|;Matsumura|Akihiro|A|;Suzuki|Syuuichirou|S|;Tanimoto|Katsumasa|K|;Hirakawa|Masahiro|M|;Kawamata|Jun|J|;Kato|Junji|J|;Shimohama|Shun|S|",
"chemical_list": "D054328:Proton Pump Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.5168-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32669503\n10.2169/internalmedicine.5168-20\nCase Report\nHyperemesis-induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors\nMiyanaga Rei 1 Hisahara Shin 1 Ohhashi Ikkei 1 Yamamoto Daisuke 1 Matsumura Akihiro 1 Suzuki Syuuichirou 1 Tanimoto Katsumasa 23 Hirakawa Masahiro 4 Kawamata Jun 1 Kato Junji 4 Shimohama Shun 1 \n1 Department of Neurology, School of Medicine, Sapporo Medical University, Japan\n\n2 Department of Orthopedics, Chitose City Hospital, Japan\n\n3 Department of Orthopedics, School of Medicine, Sapporo Medical University, Japan\n\n4 Department of Medical Oncology, Department of Hematology, School of Medicine, Sapporo Medical University, Japan\nCorrespondence to Dr. Shin Hisahara, hisahara@sapmed.ac.jp\n\n\n14 7 2020 \n1 11 2020 \n59 21 2783 2787\n26 4 2020 25 5 2020 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/).We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency. \n\nWernicke-Korsakoff syndrome (WKS)hypergastrinemiaproton pump inhibitor (PPI)hyperemesisvitamin B1\n==== Body\nIntroduction\nThe major cause of Wernicke-Korsakoff syndrome (WKS) is alcoholism. However, this neurological syndrome is also known to be a heterogeneous disorder with a wide range of precipitating illnesses including gastrointestinal disease (including surgery) and hyperemesis gravidarum (1). Thiamine storage is depleted due to persistent vomiting, poor food intake, and increased metabolic demand (2). According to a previous report, 17% cases of WKS not related to alcoholism were caused by dietary insufficiency, starvation or recurrent vomiting (1). It is also important to emphasize that the long-term treatment of the suppression of the secretion of gastric acid with proton pump inhibitors (PPIs) may result in hypergastrinemia and persistent vomiting (3).\n\nCase Report\nA-56-year-old woman with a refractory gastric ulcer was admitted to our hospital because of an altered level of consciousness, and an abnormal sensation in her limb. One month before presentation, she showed mild drowsiness during the day. She was admitted to a previous hospital because she was unable to walk due to lower limb weakness ten days before she was admitted to our hospital. Her drowsiness worsened four days before admission to our hospital.\n\nShe had no history of alcohol consumption and an umbalanced diet, and no family history of intractable gastrointestinal diseases. About ten years before admission to our hospital, she presented with progressively worsening dyspepsia. She was diagnosed with Helicobacter pylori infection and a peptic ulcer, and was treated with a PPI, 30 mg/day of lansoprazole, and an antiemesis. Helicobacter pylori eradication therapy was successful, however, her occasional epigastric pain and nausea remained. She did not have repetitive diarrhea. Further investigation revealed a refractory gastric ulcer due to hypergastrinemia. Gastroenterologists performed more than one upper gastrointestinal endoscopy, computed tomography (CT), and positron emission tomography (PET) scan due to a suspicion of gastrinoma, but no tumors other than gastric ulcers were detected. Four years before admission, the gastric mucosa protective agent was changed to esomeprazole 20 mg/day, but dyspepsia and hyperemesis did not improve. At the age of 54, she had a genetic test for a direct sequence analysis of exon2-10 of multiple endocrine neoplasia (MEN) I gene, and no significant abnormalities were found. She also underwent pancreaticoduodenectomy, which also showed no significant pathological findings including microtumors. Frequent vomiting and hypergastrinemia persisted despite treatment with esomeprazole. Six months before admission, esomeprazole was replaced by 20 mg/day of vonoprazan fumarate, resulting in an elevated gastrin level (peak level; 5,360 pg/mL) and worsening of dyspepsia and hyperemesis. One month before admission, she complained of an abnormal sensation and gradually developed disorientation and somnolence (Fig. 1), thereafter she was transferred to our university hospital from previous neighborhood hospital.\n\nFigure 1. The clinical course. Note that hyperemesis tended to occur more often after PPI was changed from lansoprazole and esomeprazole to vonaprazan fumarate at six months before admission. Plasma gastrin promptly decreased to a normal level after discontinuing vonoprazan.\n\nOn admission, the patient's height was 155 cm and weighted 40.4 kg. Her body temperature was 36.6°C, blood pressure was 114/76 mmHg, and heart rate was 61 beats per minute. Her respiratory rate was 11 breaths per minute, and percutaneous oxygen saturation (SpO2) was 97% in supine position on room air. No enlarged lymph nodes in neck, axilla, or groin were detected. No edema or purpura were seen in the limbs. A neurological examination showed mild clouding of consciousness with score 14 (E4V4M6) on Glasgow Coma Scale, suppression of ocular movement in the upward direction, and lateral gaze evoked nystagmus. Manual muscle testing was grade 3 at both the upper limb and lower limb, but it was difficult to evaluate because of her drowsiness. She also complained of dysesthesia in her fingertips. The biceps, triceps, patellar reflexes were diminished bilaterally. A blood gas analysis indicated respiratory compensation for metabolic acidosis. The results of her blood examination are shown in Table. Her electrolytes, blood sugar, and thyroid hormone levels were normal. However, hypergastrinemia and significantly low level of vitamin B1 (8.1 ng/dL) (normal range: 20-50 ng/dL) were observed. The high level of vitamin B12 was presumed to be due to methylcobalamin prescribed by a physician who had been consulted before transfer. A chest X-ray revealed no significant cardiac enlargement (cardiothoracic ratio: 55%). An electrocardiogram showed a normal sinus rhythm at a rate of 64 bpm and nonspecific ST-T changes in V3-V6. An echocardiogram revealed mild segmental asynergy of the left ventricle (EF: 55.2%). No findings indicating beriberi heart such as high out-put heart failure, pericardial effusion, or pulmonary hypertension were observed. A nerve conduction study revealed sensory polyneuropathy. A cerebrospinal fluid analysis showed normal findings including cytology. Brain MRI, fluid-attenuated inversion recovery (FLAIR) images showed abnormal bilaterally symmetrical hyperintense signals in the mammillary bodies, a periaqueduct area of gray matter in the cerebrum, medial thalami, and vermis, indicating Wernicke encephalopathy (Fig. 2). Vitamin B1 at 400 mg/day was administered intravenously for 18 days followed by tapering in a phased manner. Her consciousness status gradually improved, although she experienced some episodes of confabulation. During reinvestigation to determine the cause of hypergastrinemia by gastroenterologists, plasma gastrin promptly decreased to a normal level by discontinuing vonoprazan fumarate. Dyspepsia, hyperemesis, and MRI images also significantly improved (Fig. 2). Two months later, the patient was transferred to a rehabilitation hospital with memory disturbance and walking difficulty but no confabulation. Immediately before the patient was transferred to our hospital, an examination of upper gastrointestinal endoscopy revealed only some linear ulcer scars in the lesser curvature of stomach. Two years after admission, she showed gait instability due to peripheral polyneuropathy without dementia including memory disturbance. We concluded that long-term treatment with PPIs comprising lansoprazole, esomeprazole, and vonoprazan fumarate had caused hypergastrinemia and dyspepsia, with the subsequent development of hyperemesis and vitamin B1 deficiency.\n\nTable. Laboratory Data on Admission.\n\nComplete Blood Count\t\tBiochemistry Test\t\tImmunoserological Test\t\nWBC\t\t6,800\t/µL\t\tTP\t\t5.2\tg/dL\t\tCRP\t\t0.14\tmg/dL\t\nHb\t\t8.8\tg/dL\t\tAlb\t\t2.4\tg/dL\t\tIgG\t\t1,020\tmg/dL\t\nPlt\t\t358,000\t/µL\t\tCK\t\t68\tU/L\t\tIgA\t\t183\tmg/dL\t\nCoagulation\t\tAST\t\t21\tU/L\t\tIgM\t\t130\tmg/dL\t\nPT-INR\t\t1.00\t\t\tALT\t\t14\tU/L\t\tAnti-TG-Ab\t\t<10.0\tIU/mL\t\nAPTT\t\t26.2\tsec\t\tγ-GTP\t\t10\tU/L\t\tAnti-TPO-Ab\t\t3.8\tIU/mL\t\nD-dimer\t\t1.1\tµg/mL\t\tCr\t\t1.43\tmg/dL\t\tIntact-PTH\t\t580.8\tpg/mL\t\nInfectious Disease Test\t\tBUN\t\t26\tmg/dL\t\tPTH-RP\t\t<1.1\tpmol/L\t\nHBsAb\t\tnegative\t\t\tNa\t\t141\tmEq/L\t\tVitamin\t\nHBcAb\t\tnegative\t\t\tK\t\t4.7\tmEq/L\t\tB1\t\t8.1\tng/mL\t\nAnti-HIV-Ab\t\tnegative\t\t\tCl\t\t112\tmEq/L\t\tB12\t\t5,270\tpg/mL\t\n\t\t\t\t\t\t\t\t\t\tFolic acid\t\t5.2\tng/mL\t\nRPR\t\tnegative\t\t\tAmylase\t\t65\tU/L\t\t\t\t\t\t\nTPHA\t\tnegative\t\t\tLipase\t\t19.8\tU/L\t\t\t\t\t\t\n\t\t\t\t\tGastrine\t\t4,950\tpg/mL\t\t\t\t\t\t\nWBC: white blood cell count, Hb: hemoglobin, Plt: platelet, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time, Ab: antibody, TP: total protein, Alb: albumin, CK: creatine kinase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, γ-GTP: γ-glutamyl transpeptidase, Cr: creatinine, CRP: C-reactive protein, Ig: immunoglobulin, TG: thyroglobulin, TPO: thyroid peroxidase, PTH: parathyroid hormone, RPR: rapid plasma regain, TPHA: treponema pallidum hemagglutination\n\nFigure 2. Fluid-attenuated inversion-recovery (FLAIR) images of brain MRI just before admission (A, B) and 35 days after thiamine treatment (C, D). Hyperintense signals were observed in the bilateral gray matter around the third ventricle, aqueduct, and vermis. These abnormalities have partially subsided after thiamine administration.\n\nDiscussion\nThe major cause of WKS is alcoholism. However, this neurological syndrome is also known to be a heterogeneous disorder with a wide range of precipitating illnesses including gastrointestinal disease (including surgery) and hyperemesis gravidarum (1,4). Thiamine storage is depleted due to persistent vomiting, a poor food intake, and an increased metabolic demand (2). According to a previous report, 17% cases of WKS not related to alcoholism were caused by dietary insufficiency, starvation or recurrent vomiting (1). Our patient had at least a 10-year history of hypergastrinemia and a 1-year history of hyperemesis prior to hospitalization for onset of WKS. Except for hyperemesis gravidarum, recurrent vomiting-induced WKS may be caused by gastritis, peptic ulcer, pyloric stenosis, biliary colics, Crohn's disease, intestinal obstruction, migraine attacks, and anorexia nervosa (1). In our case, refractory vomiting and hypergastrinemia promptly remitted after discontinuing PPIs, thus indicating that the recurrent vomiting has been induced by hypergastrinemia rather than a direct adverse effect due to any medication. Actually, although several chemical compounds may reduce the thiamine level, only a few drugs including the hypoglycemic agent tolazamide can cause WKS (5,6).\n\nSeveral gastrointestinal surgical procedures including gasterectomy, gastrojejunostomy, gastric bypass surgery, gastroplasty, and bariatric surgery may predispose patients to develop WKS (2). Although WKS induced by pancreaticoduodenectomy is considered to be rare, the development of WKS could be explained by a deficiency of vitamin B1 absorption after performing this surgical procedure (7). In a literature review, WKS could be observed within days or weeks after pancreaticoduodenectomy with postoperative complications such as infection and hemorrhage, however, some cases were reported even in few years after surgery (8). It is therefore important to consider the relationship between WKS and a past history of gastric surgery if no specific causation can be identified.\n\nThe duration of a precipitating illness prior to presentation of WKS was significantly shorter in the non-alcohol-related WKS (less than 6 months in 83%) than in alcohol-related WKS (more than 1 year in 99%) (1). Many non-alcohol related etiologies were acute illnesses as reflected by a rapid depletion of thiamine storage. However, our patient maintained a thiamine level above the threshold level even after pancreaticoduodenectomy. We suspect that dietary intake and retention of vitamin B1 in nutrients may be relatively preserved during hyperemesis.\n\nHypergastrinemia is a rare adverse effect of PPIs. However, since gastrin secretion is reduced by gastric acidity, prolonged treatment with PPIs tends to cause hypergastrinemia associated with increased gastric mucosal cell proliferation (3,9). Generally, PPIs induce a mild elevation of plasma gastrin (ranging from 200-400 pg/mL) and reach a plateau in the first four months of PPI treatment, however, massive elevations has also been reported in the literature (10). Vonaprazon fumarate is a potassium-competitive acid blocker which is a new type of PPI, and it is effective for peptic ulcer and reflux esophagitis refractory to conventional PPIs. However, vonaprazon fumarate caused a greater increase in the plasma gastrin level in a multicenter prospective cross-sectional study (11). Since long-term stimulation by high levels of gastrin may cause chronic hyperplasia of enterochromaffin-like (ECL)-cells and carcinoid formation, long-term treatment with PPIs should be prescribed with caution. Hypergastrinemia-induced hyperemesis has been reported to be caused by not only peptic ulcer and hemorrhagic gastritis but also by continuous stimulation of the vomiting center in the central nervous system via the abdominal vagal pathway and chemoreceptor trigger zone in the area postrema (12).\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThis study was supported in part by the Grant-in-Aid for Exploratory Research, grants from Smoking Research Foundation and by JSPS KAKENHI Grant Number 16H05279, JSPS KAKENHI Grant Number 17H07099, JSPS KAKENHI Grant Number 17K09783, JSPS KAKENHI Grant Number 15K19288, JSPS KAKENHI Grant Number 16K19776, and JSPS KAKENHI Grant Number 15K09840.\n\n\nRei Miyanaga and Shin Hisahara contribute equally to this work.\n==== Refs\n1. \nScalzo SJ , Bowden SC , Ambrose ML , Whelan G , Cook MJ \nWernicke-Korsakoff syndrome not related to alcohol use: a systematic review\n. J Neurol Neurosurg Psychiatry \n86 : 1362 -1368\n, 2015 .25589780 \n2. \nSechi G , Serra A \nWernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management\n. Lancet Neurol \n6 : 442 -455\n, 2007 .17434099 \n3. \nSchubert ML \nGastric secretion\n. Curr Opin Gastroenterol \n26 : 598 -603\n, 2010 .20838342 \n4. \nThomson AD , Marshall EJ \nThe natural history and pathophysiology of Wernicke's Encephalopathy and Korsakoff's Psychosis\n. Alcohol Alcohol \n41 : 151 -158\n, 2006 .16384871 \n5. \nTanphaichitr V , Shills M , Olsen J , Shike M \nThiamin in Modern Nutrition in Health and Disease\n. In: Williams and Wilkins . Baltimore, MD , 1999 .\n6. \nKwee IL , Nakada T \nWernicke's encephalopathy induced by tolazamide\n. N Engl J Med \n309 : 599 -600\n, 1983 .6410237 \n7. \nKarayiannakis AJ , Souftas VD , Bolanaki H , Prassopoulos P , Simopoulos C \nWernicke encephalopathy after pancreaticoduodenectomy for pancreatic cancer\n. Pancreas \n40 : 1157 -1159\n, 2011 .21926559 \n8. \nKim JS , Rho SY , Hwang HK , Lee WJ , Kang CM \nA case of Wernicke's encephalopathy following complicated laparoscopic pylorus-preserving pancreaticoduodenectomy\n. Ann Hepatobiliary Pancreat Surg \n23 : 295 -299\n, 2019 .31501822 \n9. \nPeghini PL , Annibale B , Azzoni C , et al \nEffect of chronic hypergastrinemia on human enterochromaffin-like cells: insights from patients with sporadic gastrinomas\n. Gastroenterology \n123 : 68 -85\n, 2002 .12105835 \n10. \nKlinkenberg-Knol EC , Festen HP , Jansen JB , et al \nLong-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety\n. Ann Intern Med \n121 : 161 -167\n, 1994 .8017742 \n11. \nKojima Y , Takeuchi T , Sanomura M , et al \nDoes the novel potassium-competitive acid blocker vonoprazan cause more hypergastrinemia than conventional proton pump inhibitors? A multicenter prospective cross-sectional study\n. Digestion \n97 : 70 -75\n, 2018 .29393198 \n12. \nHorn CC \nWhy is the neurobiology of nausea and vomiting so important?\n\nAppetite \n50 : 430 -434\n, 2008 .17996982\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Wernicke-Korsakoff syndrome (WKS); hyperemesis; hypergastrinemia; proton pump inhibitor (PPI); vitamin B1",
"medline_ta": "Intern Med",
"mesh_terms": "D005260:Female; D006801:Humans; D020915:Korsakoff Syndrome; D008875:Middle Aged; D010437:Peptic Ulcer; D054328:Proton Pump Inhibitors; D013832:Thiamine Deficiency; D016896:Treatment Outcome; D014899:Wernicke Encephalopathy",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2783-2787",
"pmc": null,
"pmid": "32669503",
"pubdate": "2020-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12105835;17434099;6410237;8017742;29393198;17996982;25589780;20838342;21926559;16384871;31501822",
"title": "Hyperemesis-induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors.",
"title_normalized": "hyperemesis induced wernicke korsakoff syndrome due to hypergastrinemia during long term treatment with proton pump inhibitors"
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"abstract": "Macrophage activation syndrome (MAS) is a form of secondary hemophagocytic lymphohistiocytosis (HLH) and is a life-threatening complication of adult-onset Still disease. MAS has been usually treated with high-dose glucocorticoid with additional immunosuppressive agents, such as cyclosporine. Etoposide has been used for the treatment of severe refractory MAS based on the successful results of HLH-2004 protocol in patients with mostly primary form of HLH. We herein describe a case of severe refractory MAS secondary to adult-onset Still disease in an elderly woman that inadequately responded to etoposide but remarkably responded to additional tocilizumab. Furthermore, short-term tocilizumab led her into remission and enabled tapering off glucocorticoids after 15 months. Tocilizumab may be effective for the treatment of refractory HLH after the failure of the etoposide-containing induction regimen.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital, Nagoya, Japan.;Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital, Nagoya, Japan.;Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital, Nagoya, Japan.;Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital, Nagoya, Japan.;Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital, Nagoya, Japan.;Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital, Nagoya, Japan.",
"authors": "Ohmura|Shin-Ichiro|SI|;Uehara|Koji|K|;Yamabe|Toru|T|;Tamechika|Shinya|S|;Maeda|Shinji|S|;Naniwa|Taio|T|0000-0002-0489-2611",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D005047:Etoposide; D016572:Cyclosporine; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1080/24725625.2020.1741073",
"fulltext": null,
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"issn_linking": "2472-5625",
"issue": "4(2)",
"journal": "Modern rheumatology case reports",
"keywords": "Biological therapy; drug resistance; hemophagocytic lymphohistiocytosis; interleukin 6; remission induction",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D016572:Cyclosporine; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005047:Etoposide; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D055501:Macrophage Activation Syndrome; D058990:Molecular Targeted Therapy; D012720:Severity of Illness Index; D016706:Still's Disease, Adult-Onset; D016896:Treatment Outcome",
"nlm_unique_id": "101761026",
"other_id": null,
"pages": "202-207",
"pmc": null,
"pmid": "33086994",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful use of short-term add-on tocilizumab for refractory adult-onset still's disease with macrophage activation syndrome despite treatment with high-dose glucocorticoids, cyclosporine, and etoposide.",
"title_normalized": "successful use of short term add on tocilizumab for refractory adult onset still s disease with macrophage activation syndrome despite treatment with high dose glucocorticoids cyclosporine and etoposide"
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"abstract": "We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A- ( G6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the PIGA gene. PIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol ( GPI) anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been selected because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking co-trimoxazole, a drug that precipitates hemolysis in G6PD deficient individuals. Since both G6PD and PIGA are X-linked we hypothesized that the PIGA mutation was on the X-chromosome carrying the G6PDA- allele. Investigations showed that in fact the PIGA mutation was on the X-chromosome carrying the normal G6PD B allele. We speculate that complement activation on G6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of G6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing G6PDA- at the time of the hemolytic episode.",
"affiliations": "Division of Hematology, Department of Pediatrics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, 19104, USA.;Division of Hematology, Department of Pediatrics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, 19104, USA.;Division of Hematology, Department of Pediatrics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, 19104, USA.;Division of Hematology, Department of Pediatrics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, 19104, USA ; Division of Hematology, University of Pennsylvania School of Medicine, Philadelphia, 19104-4318, USA.",
"authors": "Perdigones|Nieves|N|;Morales|Mariela|M|;Mason|Philip|P|;Bessler|Monica|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.12688/f1000research.4980.2",
"fulltext": "\n==== Front\nF1000ResF1000ResF1000ResearchF1000Research2046-1402F1000Research London, UK 10.12688/f1000research.4980.2Case ReportArticlesAnemias & Hypocellular Marrow DisordersBleeding & Coagulation DisordersGenetics of the Immune SystemInnate ImmunityMedical GeneticsCase Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A- v2; ref status: indexed\n\nPerdigones Nieves 1Morales Mariela 1Mason Philip a1Bessler Monica 121 Division of Hematology, Department of Pediatrics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, 19104, USA2 Division of Hematology, University of Pennsylvania School of Medicine, Philadelphia, 19104-4318, USAa masonp@email.chop.eduPJM and MB conceived the study, NP designed the experiments and carried out the research. MM collected and collated clinical data. All authors contributed to preparing a draft of the manuscript and have agreed to the final content.\n\n\nCompeting interests: No competing interests were disclosed\n\n21 10 2014 2014 3 19420 10 2014 Copyright: © 2014 Perdigones N et al.2014This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A- (\nG6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the\nPIGA gene. \nPIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol (\nGPI) anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been selected because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking co-trimoxazole, a drug that precipitates hemolysis in G6PD deficient individuals. Since both\nG6PD and\nPIGA are X-linked we hypothesized that the\nPIGA mutation was on the X-chromosome carrying the\nG6PDA- allele. Investigations showed that in fact the\nPIGA mutation was on the X-chromosome carrying the normal\nG6PD B allele. We speculate that complement activation on\nG6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of\nG6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing\nG6PDA- at the time of the hemolytic episode.\n\nBuck Family Endowed Chair in HematologyNCI NIH grants2R01CA1069952R01 CA105312The work has been supported by the Buck Family Endowed Chair in Hematology, and by NCI NIH grants 2R01CA106995 to PJ Mason, and 2R01 CA105312 to M Bessler.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Revised Amendments from Version 1\nThe major change made in this revised version is that we include a much more detailed case history. When the patient presented to our speciality clinic she had an approximately 6 year history of PNH and for most of the case history we present we rely on the available records. In addition, we changed the following:\nWe include normal ranges for lab tests.\n\nWe have corrected our use of Greek characters in units.\n\nWe have included a possible explanation for the hemolysis suggested by one of the reviewers.\n\nWe have corrected errors concerning the terms PNH Types I, II and III.\n\nWe have corrected the use of the names of co-trimoxazole and eculizimab.\n\nWe have added a sentence to Figure 3 legend to indicate the figure is a representative example of our data.\n\nWe have included the concentration of DCF used for ROS detection.\n==== Body\nIntroduction\nIn paroxysmal nocturnal hemoglobinuria (PNH) one or more clones of blood cells develops from stem cells that have an acquired mutation in the X-linked\nPIGA gene\n1. The\nPIGA gene encodes phosphatidylinositol glycan complementation class A, an enzyme that catalyses an early and essential step in glycosylphosphatidylinositol (GPI) anchor synthesis. Thus cells are deficient in all GPI anchored proteins, including CD55 and CD59 which regulate complement activation. PNH usually develops in patients with aplastic anemia (AA) and it is thought that PNH cells have a growth or survival advantage over the AA cells although the mechanism is not known\n2. PNH cells can be completely deficient in GPI anchored proteins (Type III) or partially deficient due to residual activity of the PIGA protein (Type II), while PNH Type I cells express GPI-linked proteins normally.\n\nClinically, PNH is characterized by bone marrow failure, thrombosis and intravascular hemolysis. Recently the use of a complement inhibitor, eculizumab has greatly improved the quality of life of PNH patients as it causes a dramatic reduction in the hemolysis and thrombotic episodes, improvement in anemia, with a stabilization of the hemoglobin levels and reduced transfusion requirements\n3. eculizumab leads to an increase in the number of circulating red blood cells that otherwise are subject to complement-mediated hemolysis\n4.\n\nGlucose-6-Phosphate Dehydrogenase (G6PD) deficiency is the most common red blood cell enzymopathy and is estimated to affect around 400 million people worldwide\n5. It is caused by mutations in the X-linked\nG6PD gene which usually lead to an unstable enzyme. G6PD is needed to maintain NADPH and consequently reduced glutathione levels in red blood cells. G6PD-deficient people, mainly males, can be asymptomatic but are subject to episodes of hemolysis when the red blood cells are subjected to oxidative stress caused by infections, certain drugs or in the case of favism, after eating fava beans\n6. Several polymorphic variants have been described with specific geographical distributions\n7. In the African population the most common deficient variant is the G6PD A- variant. Compared with normal G6PD, which is called G6PD B, G6PD A- has two amino acid substitutions Val68Met and Asn126Asp\n8. These are caused by mutations c.202 G->A and c.376A->G respectively. G6PD A- has a frequency of about 10% in Africans and African Americans. G6PD A differs from G6PD B only by the Asn126Asp change and is electrophoretically distinct but with no significant difference in activity. Though milder than other variants such as G6PD Mediterranean found in Italy, Greece and India, G6PDA- is associated with drug induced hemolysis and patients are advised against taking any substances from a list of those known to cause hemolysis. G6PD deficiency usually only affects hemizygous males and homozygous females but heterozygous females can be affected when, for example, biased X-inactivation has led to a predominance of red blood cells expressing the mutant protein\n9. Here we present a case of an African American woman who was heterozygous for G6PD deficiency and developed PNH, presenting an opportunity to observe the interaction of these two conditions.\n\nMaterials and methods\nPeripheral blood from patient CHOP277.01 was obtained after obtaining written informed consent according to the declaration of Helsinki. The Internal Review Board of the Hospital of the University of Pennsylvania approved this study. DNA and RNA were extracted by using QIAamp DNA and RNA Blood mini Kits, respectively, according to manufacturers’ instructions. Blood samples for fluorescent cytometry and electrophoretic analyses were obtained from EDTA tubes and experiments were performed within 2 hours of blood withdrawal.\n\nPCR primers to detect mutations confirming the\nG6PD A- genotype were designed with Primer3 v4.0. (primers for c.202 G->A mutation: forward 5’- agaagaagatctaccccaccatct-3’ and reverse 5’- ctggtacagagggcagaaccag-3’; primers for c.376A->G: forward 5’-catctgtctgtgtgtctgtctgtc-3’ and reverse 5’- ctcatagagtggtgggaggac-3’). Sanger sequencing was done by the Nucleic Acids core facility at CHOP.\n\nThe HUMARA assay was performed as previously described\n10. Briefly,\nHhaI digested and non digested DNA was subjected to PCR amplification of the first exon of the HUMARA locus (containing a CAG repeat) using fluorochrome-coupled primers. Amplification products were then migrated on an ABI PRISM 3100 Automatic Genetic Analyzer (Applied Biosystems). Allele calling and the area under the curve (AUC) were determined using GeneMapper v.4.0 software (Applied Biosystems). The AUC was used to calculate the skewing from X chromosome inactivation (XCI). The XCI ratio of the digested fraction was corrected with that of the undigested fraction to allow for preferential amplification of the smallest allele (i.e., the allele containing less CAG repeats). Skewing is present when the percentage of the predominant allele exceeds 74%. A percentage of predominant allele between 90% and 100% is considered extreme skewing.\n\nMeasurements of oxidative stress ROS assay was performed as previously described\n11. Briefly, red blood cells were incubated with 0.4mM 20-70-dichlorofluorescein diacetate (DCF; Sigma) dissolved in methanol. After incubation at 37ºC for 15 minutes in a humidified atmosphere of 5% CO2 in air, the cells were washed, resuspended in PBS and analyzed by flow cytometry (FACSCalibur; Becton-Dickinson, Immunofluorometry Systems, Mountain View, CA, USA). The mean fluorescence channel (MFC) was calculated by FACSDiva software. The identity of the red cell population was verified by staining with an antibody to glycophorin-A. To determine the presence of GPI proteins, cells were labeled with a phycoerythrin-conjugated anti-CD55 antibody. For our experiment, cells from a non PNH- non G6PD individual served as control. The MFC of cells stained with 0.4mM DCF, is proportional to generation of ROS.\n\nThe electrophoretic mobility of the protein was performed in cellogel strips as previously described\n12. Hemolysates treated with and without acidified serum were run in order to assess differences in mobility of the G6PD enzyme.\n\nCase report\nA 25-year-old African American woman was referred to the Bone Marrow Failure Outpatient Clinic at the Hospital of the University of Pennsylvania for the evaluation and treatment of her PNH.\n\nThe past medical history was significant in that at the age of 19 years she presented to the emergency department with cough and dark urine. She was otherwise previously healthy. Family history was only significant for a sister with sickle cell trait. She was diagnosed with Mycoplasma pneumonia and anemia (Hemoglobin 6.9 g/dL (12–16 g/dL), Hematocrit 19.9% (37–47%)). The anemia was determined to be an autoimmune hemolytic anemia (AIHA; LDH 3170 U/L (87–225 U/L), total bilirubin 1.9 mg/dL (0–1.2 g/dL), indirect bilirubin 1.6 mg/dL (0.2–0.7 mg/dL), reticulocyte count 5.2% (0.5–2.1%)) in the setting of positive IgM cold agglutinin antibodies and positive direct Coombs test. The patient was treated with packed red blood cell transfusions and antibiotics and was discharged. As an outpatient, she was started on steroids, and her hemoglobin stabilized between 9 and 10 g/dL; the cold agglutinin and direct Coombs test became negative. The following year, the patient presented on two separate occasions to the emergency department complaining of abdominal pain and dark urine (urine analysis: RBC 1–2, WBC 1–2, hyaline cylinders: none, bacteria, few, squamous epithelia 10–20, dipstick analysis, blood moderate positive). This was interpreted as a urinary tract infections and treated with antibiotics. Her emergency record states that the patient developed hemoglobinuria after being treated with trimethoprim-sulfamethoxazole (co-trimoxazole). Hemogobinuria was associated with lightheadedness and dizziness as well as a mild increase of her liver enzymes (aspartate aminotransferase 77U/L (14–36)). She was therefore screened twice for Glucose-6-Phosphate-Dehydrogenase (G6DP) deficiency, but showed enzyme activity levels within normal limits. At the age of 20-years she became pregnant. She continued to have a picture of hemolytic anemia (hemoglobin range between 9–10 g/dL with a reticulocyte count of 4%, LDH of 555 U/L, total bilirubin range 0.4–0.5 mg/dL, haptoglobin of 2 mg/dL (41–165mg/dL)) but this time, she had negative cold agglutinins and negative direct Coombs test. Her pregnancy was complicated with the worsening of her anemia and development of thrombocytopenia requiring red cell and platelet transfusions. At 34 weeks of gestation she was seen by a hematologist who sent for PNH testing. Flow cytometry revealed a significant population of PNH cells in both red blood and white blood cells (65% of red blood cells and 94% of granulocytes) with a large proportion of red cells with an intermediate expression of CD59 (58%, granulocytes 12%). She was started on anticoagulation with low molecular heparin. She had intermittent episodes of overt hemoglobinuria. At 35 weeks of gestation she was diagnosed with severe hypertension and was admitted for the induction of labor. Her hospital course was complicated with the development of preeclampsia and an acute flair of hemolysis leading to acute renal failure requiring hemodialysis. A healthy baby was delivered by cesarean section. She was vaccinated against meningococcal infection and initiated on eculizumab (Soliris, Alexion Pharmaceuticals) with prophylactic antibiotics for the first 14 days. Her anticoagulation was switched from heparin to warfarin. Her renal functions recovered to normal over the next three months. The patient decided to discontinue eculizumab and warfarin on her own as she thought that this was not beneficial and she continued to have episodes of dark urine.\n\nThree years later, she presented again with left upper abdominal pain, vomiting and blurry vision. She was diagnosed with an acute hemolytic exacerbation of PNH and was admitted. The patient was found to have anemia, leukocytosis and mild transaminitis. A Magnetic Resonace Venogram (MRV) of the abdomen and pelvis was obtained and it showed non-specific perfusional abnormalities throughout the liver. A Computed Tomography (CT) of the abdomen and pelvis revealed several ill-defined low attenuation lesions of the posterior segment of the right hepatic lobe. This was thought to be consistent with liver thrombosis so she was restarted on anticoagulation with warfarin and was referred to us for further evaluation and treatment recommendations and to rule out resistance to C5 inhibitor therapy.\n\nOn review of systems, the patient complained of occasional abdominal pain and headaches. On physical exam, she was found to have mildly icteric sclera. Family history was significant for a sister with sickle cell trait. Further questioning revealed that that one of her nephews was diagnosed with G6PD deficiency. The laboratory workup revealed a white blood cell count 4.6 k/uL (4.5–11.0 k/uL), RBC count of 3.8 k/uL (4.2–5.5 k/uL), hemoglobin of 11.8g/dL, hematocrit 35% (37–47%), MCV 91 fl (82–100 fl), platelets 327 k/uL (150–400 k/uL), reticulocytes 24.5%, PTT 27.8 sec (23–36 sec), INR 1.7, D dimer 2.5 ug/mL (0–0.4), bilirubin 1.3 mg/dL, bilirubin direct 0.2 mg/dL (0–0.4 mg/dL), bilirubin indirect 1.1 mg/dL, ANC 2.7 k/uL (1.75–7.59 k/uL), ALC 1.3 k/uL (1.12–4.95 k/uL), G6PD screen normal, LDH 720 U/L. The flow cytometry at this point revealed that 78% of her red blood cells were PNH, 69% were partially deficient for CD59 and 9.1% lacked CD59 completely; 92% of her granulocytes were PNH, 86% were partially deficient for CD59 and 6% lacked the expression of CD59. Due to her history of hepatic vein thrombosis eculizumab was reinitiated at its regular dosing for patients with PNH (600 mg weekly 4x followed by 900 mg every two weeks). In three years of being on eculizumab she had no further relapse of her hemoglobinuria and no evidence of thrombosis.\n\nResults\nThis patient has a classic presentation of a patient whose blood cells mainly have a partial deficiency of GPI-linked proteins (PNH type II) with a significant delay in diagnosis relative infrequent hemolytic events and thrombotic complications. We were intrigued by the emergency physicians note that associated hemoglobinuria and clinical symptoms associated with hemolysis with the co-trimoxazole medication and family history of G6PD deficiency. We were therefore interested to find out whether she actually might have both, and whether her PNH might have been responsible for her G6PD deficiency and thereby explain the hemolysis precipitated by co-trimoxazole as noted by an obervant emergency physician. Sequencing of DNA from her granulocytes confirmed that she was heterozygous for\nG6PD A- having a\nG6PD B allele on one X-chromosome and a\nG6PD A- allele on the other. This finding raised the question as to whether the somatic\nPIGA mutation causing her PNH took place on the X-chromosome carrying the\nB or the\nA- G6PD gene. The flow cytometry data showed that the patient most likely had 2 PNH clones, a class II clone (partial deficiency) of about 86% and a class III clone (complete deficiency) of about 6%. The HUMARA assay, which measures X-inactivation, showed a single clone of about 90% (\nFigure 1), suggesting that in both clones the mutation had taken place on the same X-chromosome. We hypothesized that the mutations in\nPIGA would have taken place on the chromosome carrying the\nG6PD A- allele since this would help explain the patient’s reaction to co-trimoxazole. To determine which\nG6PD allele was expressed in the PNH clone we sequenced cDNA from the patient’s granulocytes. The sequencing trace showed that the vast majority of expressed\nG6PD cDNA contained the wild type (\nG6PD B) sequence at both nucleotides where it differs from\nG6PD A- (\nFigure 2), leaving us to conclude that the\nPIGA mutations had taken place on the X-chromosome containing the\nG6PD B allele. This was confirmed at the protein level since the red blood cells lysed by acidified serum (the PNH cells) contained most of the G6PD activity while the residual cells did not contain detectable G6PD activity. While developing our hypothesis, which turned out to be incorrect, we also considered whether PNH/G6PDA- cells might have high levels of oxidative stress since both G6PD deficiency and PNH have been shown to be associated with elevated levels of reactive oxygen species\n11,\n13. We found that the patient’s red blood cells contained ROS levels that were significantly higher than those from healthy controls, though surprisingly we did not detect any difference in ROS between PNH (CD55-) and normal (CD55+) cells (\nFigure 3).\n\nFigure 1. Clonal hematopoiesis in patient CHOP 277.01.\nThe panel at the bottom shows the migration of the 2 microsatellite alleles in patient CHOP277.01 revealed by PCR analysis of a region of the Androgen receptor gene on the X-chromosome. The amplified region contains both a polymorphic repeat and a site for the methylation sensitive restriction enzyme HhaI. This site is methylated on the inactive X-chromosome. The top panel shows the same sample digested with HhaI before the PCR so only the fragment on the inactive X-chromosome is amplified. An imbalance in the allelic ratio reflects an imbalance in X inactivation and therefore indicates clonality.\n\nFigure 2. Patient CHOP 277.01. is heterozygous for G6PD B/A- and the B allele is predominantly expressed.\nA1 and A2 shows sequencing of genomic DNA around the 202 G->A and the 376 A->G mutation that lead to Val68Met and Asn126Asp changes in G6PD, respectively. Figures B1 and B2 show the cDNA sequence of the exact same mutations in the peripheral blood of the patient. The WT (B) allele is expressed in the majority of cells.\n\nFigure 3. Flow cytometry analysis of the oxidative status of RBCs in the patient and a healthy donor.\nPeripheral blood mononuclear cells from the patient and a normal control were treated with the oxidation sensitive dye, CM-H2DCFDA, and the conversion to its oxidized fluorescent derivative assessed by flow cytometry. The fluorescence distribution histogram and the mean fluorescence channels (MFC) of each population derived from the normal control (orange) and the patient (blue for CD55 negative and red for CD55 positive cells) are shown. The figure shows a representative example of 4 normal controls that gave similar results.\n\nDiscussion\nPNH is a rare condition, having an incidence of about 1 in a million, so the co-incidental finding of a female with PNH and heterozygous for G6PD deficiency was an opportunity to observe the interaction between these 2 conditions which both involve red blood cell hemolysis mediated by X-linked genes. Notably the first demonstration that PNH was a clonal disease took advantage of a female PNH patient who was heterozygous for the electrophoretic variant\nG6PD A\n14. In this patient both isozymes were present in a lysate of total red blood cells, but only one was present after acidified serum lysis, demonstrating clonality of the PNH cells.\n\nIn the case discussed here a female African American patient with PNH suffered episodes of hemolysis, often following treatment with Trimethoprim-Sulfamethoxazole (co-trimoxazole), one of the drugs that is known to cause hemolysis in G6PD patients\n15. When it emerged that she was heterozygous for\nG6PD A- we hypothesized that her expanded PNH clones may be expressing only the G6PD A- protein, which would have explained the observation of the emergency physician. The hypothesis proved incorrect and the clone expressed the wild type\nG6PD allele. An alternative intriguing explanation for the co-trimoxazole associated hemolysis might be that complement activation on\nG6PD A- red cells exposed to co-trimoxazole might have triggered complement activation inducing the lysis of\nG6PD B PNH Type II red blood cells\n16. naturally we cannot rule out that at the time the co-trimoxazole associated hemolysis was observed a\nG6PD A- PNH clone was more prevalent, since PNH patients, like the one described here, often have several PNH clones\n17. Of course it is also possible that co-trimoxazole medication and hemolysis were coincidental and that hemolysis was primarily due to the urinary tract infection. Nevertheless the observation by an unbiased emergency physician and a rather bland urine sediment make us favor the first explanation. Finally, the association of PNH and G6PD deficiency make us also speculate that the combination of G6PD and PIGA deficiency confers a serious growth disadvantage and PNH clones in this situation are more likely to be G6PD wild type. There is no clear mechanism for this however as\nG6PDA- nucleated cells have similar enzyme activity to WT cells\n18 – the deficiency becoming apparent in red blood cells, which do not synthesize new protein\n19.\n\nPatient consent\nWritten informed consent for publication of their clinical details was obtained from the patient.\n\n10.5256/f1000research.5927.r7539Referee response for version 2 Bautista José M. 1Referee1 Department of Biochemistry and Molecular Biology IV and Research Institute Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain\nCompeting interests: No competing interests were disclosed.\n\n18 2 2015 Version recommendationapproveThis case report describes the rare concurrence of two haematological genetic disorders associated to chromosome X (PNH and G6PD deficiency) and provides a retrospective interpretation of the clinical development throughout the detailed and focused experimental analysis of the patient’s cells and the genetics associated to them. Following an appealing and reasonable hypothesis, the results obtained by Perdigones\n et al. offer an authoritative haematology lesson. Thus, the authors take the case report as a centre to discuss the biology of PNH clones and the potential mechanism of red cell lysis when two independent haemolysis-prone genes are associated in the same patient.\n\nThe originality and presentation of the case warrant the readers interest. The final version with the amendments made following the report from two previous reviewers resulted in a solid article worth reading for haematologists and geneticists.\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.5927.r6632Referee response for version 2 Karadimitris Anastasios 1Referee1 Department of Haematology, Imperial College Healthcare NHS Trust and Imperial College, London, UK\nCompeting interests: No competing interests were disclosed.\n\n4 11 2014 Version recommendationapproveI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.5317.r6022Referee response for version 1 Karadimitris Anastasios 1Referee1 Department of Haematology, Imperial College Healthcare NHS Trust and Imperial College, London, UK\nCompeting interests: No competing interests were disclosed.\n\n4 9 2014 Version recommendationapprove-with-reservationsPerdigones and colleagues describe the rare co-occurence in the same patient of two X-linked disorders, one acquired the other inherited, both causing intravascular haemolysis.\n\nHowever how the interaction of the two disorders led to the clinical episode described in the case report is not clear because the temporal analysis of the clinical events and the associated laboratory tests are not presented in sufficient detail.\n\nCharting clinical events, labs and therapeutic interventions might make association of the heamolytic episodes with co-trimoxazole or intercurrent infection clearer.\n\nIt appears that the majority of the PNH clone (in both granulocytes and red cells) is type II, i.e., only partially deficient of GPI. One assumes that this picture was obtained after the haemolytic attack. If so, it could be that type III, i.e., severely deficient RBC were indeed G6PD-deficient. Was flow-cytometry performed after Eculizumab treatment? Eculizumab would protect type III RBC from lysis and thus would allow re-assessment of G6PD activity.\n\n\nMinor points\nWas anti-CD55 or –CD59 was used for flow analysis? The authors state anti-CD55 in methods but describe anti-CD59 in results.\n\nNormal ranges of lab tests need to be provided\n\n‘Another factor was that treatment with eculizumab, by inhibiting lysis of PNH red cells may have led to a higher level of PNH (and concomitantly G6PD deficient) red cells than would be present in untreated patients.’ This statement is rather irrelevant because eculizumab was started after treatment with co-trimoxazole.\n\nNeed to use Greek characters appropriately, i.e., ul should be ml \n\n\n\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\nMason Philip Leonard and Madlyn Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, USA\nCompeting interests: No competing interests were disclosed.\n\n15 10 2014 \nIt appears that the majority of the PNH clone (in both granulocytes and red cells) is type II, i.e., only partially deficient of GPI. One assumes that this picture was obtained after the haemolytic attack. If so, it could be that type III, i.e., severely deficient RBC were indeed G6PD-deficient. Was flow-cytometry performed after Eculizumab treatment? Eculizumab would protect type III RBC from lysis and thus would allow re-assessment of G6PD activity.\n\n\nWe agree with this comment. Of course it is possible that at the time of the observation of association of\nco-trimoxazole associated hemolysis a different PNH clone was more prevalent than when analyzed for G6PD deficiency. We included this possibility in our discussion. The most recent flow cytometry was performed when the patient was on eculizimab.\n\n\nMinor points\n\nWas anti-CD55 or –CD59 was used for flow analysis? The authors state anti-CD55 in methods but describe anti-CD59 in results. The diagnosis for PNH was performed in a CLIA approved clinical laboratory of the hospital.\n\n\nWe present the results for CD59. CD55 was also tested however the discrimination between the three populations is more difficult.\n\n\n Normal ranges of lab tests need to be provided.\n\n\nWe have included normal ranges for laboratory tests in parentheses after the patient’s values.\n\n\nAnother factor was that treatment with eculizumab, by inhibiting lysis of PNH red cells may have led to a higher level of PNH (and concomitantly G6PD deficient) red cells than would be present in untreated patients.’ This statement is rather irrelevant because eculizumab was started after treatment with co-trimoxazole.\n\n\nWe think this statement is valid because treatment with eculizimab increases the level of PIGA deficient red cells. On our hypothesis that the G6PDA- allele was linked with PIGA- then PIGA-,G6PDA- red cells would increase. Our hypothesis however was not correct.\n\n\nNeed to use Greek characters appropriately, i.e., ul should be ml \n\n\nWe have corrected our incorrect use of Greek characters.\n\n\n\n\n10.5256/f1000research.5317.r5816Referee response for version 1 Notaro Rosario 1Referee1 Laboratory of Genetics and Gene Transfer, Core Research Laboratory, Istituto Toscano Tumori, Florence, Italy\nCompeting interests: No competing interests were disclosed.\n\n28 8 2014 Version recommendationapprove-with-reservationsPerdigones and collaborators report an interesting clinical case about the association of PNH and G6PD deficiency. However, the timing of the clinical history is not clear and the report is scanty of some relevant clinical/laboratory data.\n\n\nMajor scientific points.\nThe Authors should provide the exact timing of entire clinical history: diagnosis; infective episode resulting in the prescription of\ntrimethoprim-sulfamethoxazole -co-trimoxazole- (which dose?); start and stop of\nco-trimoxazole; “dark urine episode” associated with\nco-trimoxazole; start of\neculizumab; time of biological studies.\n\nIt is extremely important that the Authors provide more details about the timing and the features of the hemolytic attack apparently associated with\nco-trimoxazole: how long after the start of\nco-trimoxazole treatment the patient experienced the “dark urine episode”? There are any objective data at the time of this “dark urine episode” or the episode has been just self-reported? At the time of this “dark urine episode” there were any signs/symptoms of an ongoing infective condition?\n\nThe Authors provide clinical/laboratory details only at one time point, that seems be after the start of eculizumab (how long after?). They should provide such clinical/laboratory details at time of diagnosis, at the time of the co-trimoxazole associated “hemolytic attack”, at start of eculizumab treatment, etc.: blood count, absolute reticulocyte count, LDH levels (providing the normal range), flow citometry, etc.\n\nIn PNH patients the presence of red blood cells with partial deficiency of GPI-linked molecules is relatively common. However, the presence of granulocyte/monocyte with partial deficiency of GPI-linked molecules is uncommon: thus, it would be interesting to show the dot plot of the “CD59/lineage marker” analysis of granulocytes and monocytes of this patient.\n\nThe Authors, at variance with their starting hypothesis, have clearly proven that in this patient PNH cells express the wild type G6PD B. They provide 2 possible explanations for the\nco-trimoxazole-associated “hemolytic crisis” observed in this patient. These hypotheses are interesting but their probability is very low. I suggest that the Authors should discuss a much more likely explanation: this “hemolytic crisis” was just due to the infective condition that led to the prescription of\nco-trimoxazole.\n\n\nMinor points\nIn the Introduction the Authors report the classical classification of PNH cells as Type III (completely deficient in GPI anchored proteins), Type II (partially deficient) and Type I (normal display of GPI-linked proteins). However, in the Results they write about “\nclass I clone (partial deficiency) … and class II clone (complete deficiency) “: this is extremely confusing.\n\nIn the Results the 2 sentences (from “\nWe hypothesized that …” to “\n…red cells than would be present in untreated patients.”) seem to suggest that the relative expansion of the “PNH (and concomitantly G6PD deficient) red cells” following\neculizumab treatment could have played a role in the\nco-trimoxazole associated hemolytic attack. The Authors should rephrase these sentences since\neculizumab has been started after the\nco-trimoxazole associated hemolytic attack.\n\n\nTrimethoprim-sulfamethoxazole (co-trimoxazole) is a generic drug name thus it should not be capitalized. In the Results, “\neculizumab” should not be capitalized.\n\nThe brand name\nBactrim should be replaced with the generic drug name.\n\nThe levels of ROS in the patient red cells should be compared with a group of healthy controls: the comparison with only one control does not allow any conclusion.\n\nThe Authors should report the concentration of DCF used for ROS detection.\n\n\n\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\nMason Philip Leonard and Madlyn Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, USA\nCompeting interests: No competing interests were disclosed.\n\n15 10 2014 \nPerdigones and collaborators report an interesting clinical case about the association of PNH and G6PD deficiency. However, the timing of the clinical history is not clear and the report is scanty of some relevant clinical/laboratory data.\n\n\n\nMajor scientific points.\n\nThe Authors should provide the exact timing of entire clinical history: diagnosis; infective episode resulting in the prescription of trimethoprim-sulfamethoxazole -co-trimoxazole- (which dose?); start and stop of co-trimoxazole; “dark urine episode” associated with co-trimoxazole; start of eculizumab; time of biological studies.\n\n\nIn our revised manuscript we include a fuller, more detailed case history. Of note is the fact that the patient presented to the specialty clinic with a probably 6 year history of PNH and that most of the patients past history relies on records and notes. Here we demonstrate that the patient has indeed both conditions PNH and G6PD deficiency. With these results in hand we try to explain the patient’s history and clinical observations. It was not our intention to prove that indeed the hemolysis described by the emergency physician after\nco-trimoxazole was indeed triggered by the drug, but rather to evaluate and discuss the possibility as the patient carries on her chart the diagnosis of\nco-trimoxazole hypersensitity due to this incident. We try to make this clearer in the case description. We hope this will answer the criticism of the reviewer.\n\n\nIt is extremely important that the Authors provide more details about the timing and the features of the hemolytic attack apparently associated with co-trimoxazole: how long after the start of co-trimoxazoletreatment the patient experienced the “dark urine episode”? There are any objective data at the time of this “dark urine episode” or the episode has been just self-reported? At the time of this “dark urine episode” there were any signs/symptoms of an ongoing infective condition?\n\n\nThe discussion above and the revised version provides many more details.\n\n\nThe Authors provide clinical/laboratory details only at one time point, that seems be after the start of eculizumab (how long after?). They should provide such clinical/laboratory details at time of diagnosis, at the time of the co-trimoxazole associated “hemolytic attack”, at start of eculizumab treatment, etc.: blood count, absolute reticulocyte count, LDH levels (providing the normal range), flow citometry, etc.\n\n\nWe have provided all the history we can obtain in the revised version.\n\n\nIn PNH patients the presence of red blood cells with partial deficiency of GPI-linked molecules is relatively common. However, the presence of granulocyte/monocyte with partial deficiency of GPI-linked molecules is uncommon: thus, it would be interesting to show the dot plot of the “CD59/lineage marker” analysis of granulocytes and monocytes of this patient.\n\n\nThe diagnosis of PNH and the subtype analysis of PNH granulocytes was performed in a CLIA approved clinical laboratory, and their test results are reported here. The individual dot blots are not available to us. However the senior author who was involved in the setup and quality assessment of flow-cytometric PNH testing at this institution fully trusts their analysis. We agree with the reviewer that partial GPI-anchor deficiency in granulocytes is less frequently observed and very much depends on the underlying mutation and the antibody chosen for the analysis.\n\nThe Authors, at variance with their starting hypothesis, have clearly proven that in this patient PNH cells express the wild type G6PD B. They provide 2 possible explanations for the \nco-trimoxazole-associated “hemolytic crisis” observed in this patient. These hypotheses are interesting but their probability is very low. I suggest that the Authors should discuss a much more likely explanation: this “hemolytic crisis” was just due to the infective condition that led to the prescription of \nco-trimoxazole.\n\n\nWe agree that this is a possible alternative explanation and have added this in the discussion however considering the rather bland urine sediment we actually favor the other two possible explanations.\n\n\n\nMinor points\n\nIn the Introduction the Authors report the classical classification of PNH cells as Type III (completely deficient in GPI anchored proteins), Type II (partially deficient) and Type I (normal display of GPI-linked proteins). However, in the Results they write about “class I clone (partial deficiency) … and class II clone (complete deficiency) “: this is extremely confusing.\n\n\nThis has been corrected\n\n\nIn the Results the 2 sentences (from “We hypothesized that …” to “…red cells than would be present in untreated patients.”) seem to suggest that the relative expansion of the “PNH (and concomitantly G6PD deficient) red cells” following eculizumab treatment could have played a role in the co-trimoxazole associated hemolytic attack. The Authors should rephrase these sentences since eculizumab has been started after the co-trimoxazole associated hemolytic attack.\n\n\nThe timing of the eculizimab treatment and the hemolysis are given in the detailed case report that we now provide.\n\n\nTrimethoprim-sulfamethoxazole (co-trimoxazole) is a generic drug name thus it should not be capitalized. In the Results, “eculizumab” should not be capitalized.\n\n\nWe have corrected this.\n\n\nThe brand name \nBactrim\n should be replaced with the generic drug name.\n\n\nWe have corrected this.\n\n\nThe levels of ROS in the patient red cells should be compared with a group of healthy controls: the comparison with only one control does not allow any conclusion.\n\n\nThe experiment was carried out with several controls and it confirms the results of Amer\net al., cited as our ref 14 that ROS are elevated in PNH. Our point is a small one, that we might expect a further elevation if we compare PNH and normal cells from this patient, if indeed PIGA- is linked with G6PDA-. We didn’t find this. We include the sentence “The figure shows a representative example of 4 normal controls that gave similar results” to clarify this.\n\n\nThe Authors should report the concentration of DCF used for ROS detection.\n\n\nWe have done this.\n==== Refs\n1 Parker CJ :\nParoxysmal nocturnal hemoglobinuria. 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J Infect. 2010 ;61 (5 ):399 –402 .\n10.1016/j.jinf.2010.08.003 20732351 \n16 Arese P Gallo V Pantaleo A :\nLife and Death of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficient Erythrocytes - Role of Redox Stress and Band 3 Modifications. Transfus Med Hemother. 2012 ;39 (5 ):328 –334 .\n10.1159/000343123 23801924 \n17 Mortazavi Y Merk B McIntosh J :\nThe spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot. Blood. 2003 ;101 (7 ):2833 –41 .\n10.1182/blood-2002-07-2095 12424196 \n18 Marks PA Gross RT :\nErythrocyte glucose-6-phosphate dehydrogenase deficiency: evidence of differences between Negroes and Caucasians with respect to this genetically determined trait. J Clin Invest. 1959 ;38 (12 ):2253 –62 .\n10.1172/JCI104006 14421318 \n19 Mason PJ :\nNew insights into G6PD deficiency. Br J Haematol. 1996 ;94 (4 ):585 –91 .\n8826878\n\n",
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"title": "Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A-.",
"title_normalized": "case report paroxysmal nocturnal hemoglobinuria in a woman heterozygous for g6pd a"
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"abstract": "BACKGROUND\nAcute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct clinicopathologic entity with a poor prognosis. However, double inv(3)(q21q26.2) is extremely rare in AML. We report here 3 cases analyzed by oligonucleotide microarray comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP). Clinicopathologic, cytogenetic and molecular findings were correlated with clinical outcome to better understand the entity.\n\n\nRESULTS\nThe study group included one man and two women at 56-74 years of age. The AML arose from myelodysplastic syndrome in one patient and from chronic myelomonocytic leukemia in another patient. Monosomy 7 was found as additional cytogenetic finding in one patient. One patient had a single inv(3) in the initial clone and acquired double inv(3) as part of clonal evolution. EVI1 (MECOM) rearrangement was confirmed using metaphase/interphase fluorescence in situ hybridization (FISH). Microarray (aCGH + SNP) data analysis revealed that the double inv(3) was a result of acquiring copy neutral loss of heterozygosity of chromosome 3q: arr[hg19] 3q13.21q29(10,344,387-197,802,470)x2 hmz, spanning ~ 94.3 Mb in size. Mutational profiling showed a PTPN11 mutation at a low level (~10 %) in one patient and wild type FLT3 and RAS in all patients. No patients achieved cytogenetic remission and all died with an overall survival (OS) of 23, 12 and 5 months, respectively.\n\n\nCONCLUSIONS\nDouble inv(3) is a result of acquired copy neutral loss of heterozygosity, a somatic repair event occurring as a part of mitotic recombination of the partial chromosome 3q. The double inv(3) in AML patients is highly associated with a rapid disease progression.",
"affiliations": "Cytogenetic Technology Program, School of Health Professions, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0002, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;Cytogenetic Technology Program, School of Health Professions, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0002, Houston, TX 77030 USA ; The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;Department of Leukemia, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0428, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.;The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA.",
"authors": "Gu|Jun|J|;Patel|Keyur P|KP|;Bai|Bing|B|;Liu|Ching-Hua|CH|;Tang|Guilin|G|;Kantarjian|Hagop M|HM|;Tang|Zhenya|Z|;Abraham|Ronald|R|;Luthra|Rajyalakshmi|R|;Medeiros|L Jeffrey|LJ|;Lin|Pei|P|;Lu|Xinyan|X|",
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"fulltext": "\n==== Front\nMol CytogenetMol CytogenetMolecular Cytogenetics1755-8166BioMed Central London 17110.1186/s13039-015-0171-2ResearchDouble inv(3)(q21q26.2) in acute myeloid leukemia is resulted from an acquired copy neutral loss of heterozygosity of chromosome 3q and associated with disease progression Gu Jun jungu@mdanderson.org Patel Keyur P. kppatel@mdanderson.org Bai Bing bbai@mdanderson.org Liu Ching-Hua cliu10@mdanderson.org Tang Guilin gtang@mdanderson.org Kantarjian Hagop M. hkantarjian@mdanderson.org Tang Zhenya ztang@mdanderson.org Abraham Ronald rabraham@mdanderson.org Luthra Rajyalakshmi rluthra@mdanderson.org Medeiros L. Jeffrey ljmedeiros@mdanderson.org Lin Pei peilin@mdanderson.org Lu Xinyan Xlu4@mdanderson.org Cytogenetic Technology Program, School of Health Professions, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0002, Houston, TX 77030 USA The Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0149, Houston, TX 77030 USA Department of Leukemia, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0428, Houston, TX 77030 USA 19 8 2015 19 8 2015 2015 8 686 5 2015 4 8 2015 © Gu et al. 2015\nOpen Access This 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\nAcute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct clinicopathologic entity with a poor prognosis. However, double inv(3)(q21q26.2) is extremely rare in AML. We report here 3 cases analyzed by oligonucleotide microarray comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP). Clinicopathologic, cytogenetic and molecular findings were correlated with clinical outcome to better understand the entity.\n\nResults\nThe study group included one man and two women at 56–74 years of age. The AML arose from myelodysplastic syndrome in one patient and from chronic myelomonocytic leukemia in another patient. Monosomy 7 was found as additional cytogenetic finding in one patient. One patient had a single inv(3) in the initial clone and acquired double inv(3) as part of clonal evolution. EVI1 (MECOM) rearrangement was confirmed using metaphase/interphase fluorescence in situ hybridization (FISH). Microarray (aCGH + SNP) data analysis revealed that the double inv(3) was a result of acquiring copy neutral loss of heterozygosity of chromosome 3q: arr[hg19] 3q13.21q29(10,344,387–197,802,470)x2 hmz, spanning ~ 94.3 Mb in size. Mutational profiling showed a PTPN11 mutation at a low level (~10 %) in one patient and wild type FLT3 and RAS in all patients. No patients achieved cytogenetic remission and all died with an overall survival (OS) of 23, 12 and 5 months, respectively.\n\nConclusions\nDouble inv(3) is a result of acquired copy neutral loss of heterozygosity, a somatic repair event occurring as a part of mitotic recombination of the partial chromosome 3q. The double inv(3) in AML patients is highly associated with a rapid disease progression.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nThe 2008 World Health Organization (WHO) classification recognized acute myeloid leukemia (AML) with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) and GATA1-EVI1(MECOM) rearrangement as a clinicopathologic entity, associated with poor clinical outcomes. This disease accounts for less than 2 % of all cases of AML [1, 2] including de novo and AMLs transformed from myelodysplastic syndrome (MDS) [3]. This cytogenetic abnormality also can occur in blast phase of chronic myelogeneous leukemia (CML) [4]. GATA1-MECOM(EVI1) resulting from inv(3)/t(3;3) is known to play a critical role in the leukomogenesis and highly associated with other chromosomal aberrations such as monosomy 7 or 7q deletion (−7/7q-) or a complex karyotype, although these additional cytogenetic findings do not have independent prognostic value in this entity[5].\n\nA double inv(3)(q21q26.2) occurs when the paracentric inv(3) involves both chromosome 3 homologues. Double inv(3)(q21q26.2) is an extremely rare event with about 10 cases reported in the literatures, primarily in AML patients [6–9] and very rarely in MDS [10] or the blast phase in CML [11, 12]. The underlying mechanism for double inv(3) and its clinical impact remains largely unknown.\n\nAlthough double inv(3) can be detected by the traditional chromosome analysis and/or by fluorescence in situ hybridization (FISH) targeting the MECOM/EVI1 gene locus, both techniques cannot delineate the potential underlying mechanism leading to this abnormality. Earlier studies postulated that the double inversion event could be due to loss of the normal chromosome 3 homolog followed by the duplication of the inverted abnormal chromosome 3 [6, 7]. One recent report using single nucleotide polymorphism (SNP) microarrays revealed evidence of an acquired copy neutral loss of heterozygosity (aCN-LOH) or acquired segmental uniparental disomy (aUPD) of only chromosome 3q, instead of the entire chromosome 3, in a CML patient in blast phase [11].\n\nSingle nucleotide polymorphism microarray based technology has clinical utility in the diagnosis and risk stratification of AML patients can identify clinically relevant copy number aberrations and importantly can detect acquired segmental aUPD or aCN-LOH in the tumor genome especially in those myeloid neoplasms with normal karyotypes [13, 14]. The aCN-LOH, resulting from the apparent duplication of oncogenic mutations coupled with the loss of the normal alleles, has been postulated to be associated with myeloid malignancies [15].\n\nTo better understand the clinical features as well as the potential underlying genomic events associated with the unique subgroup of double inv(3) in AML patients, we performed a retrospective data review and aCGH + SNP analysis. We also correlated the clinicopathologic, molecular and cytogenetic data with clinical outcome.\n\nResults\nThe study group included one man and two women who were 72, 64 and 56 years of age, respectively, at the diagnosis of AML. All demographic data are summarized in Tables 1 and 2.Table 1 Summary of clinical data\n\nCase no.\tPatient 1\tPatient 2\tPatient 3\t\nAge\t72\t64\t56\t\nGender\tMale\tFemale\tFemale\t\nInitial referring diagnosis\tMDS-RAEB-2 for <1 month\tCMML <3 months\tPancytopenia/thrombocytopenia for one week\t\nFinal diagnosis at disease progression\tAML\tAMML\tAML\t\nWBC (× 109/L)\t2.4\t8.9\t1.6\t\nHb (g/dL)\t8.5\t11.8\t8.2\t\nPlatelets (× 109/L)\t110\t242\t41\t\nMCV (fl)\t109\t112\t99\t\nNeutrophil percent (%)\t45\t44\t5.6\t\nLymphocyte percent (%)\t50\t22\t90.8\t\nMonocyte percent (%)\t4\t33\t1.8\t\nBM blasts %\t28\t23\t54\t\nFollow up (months)\t4\t3\t3.5\t\nTreatment\tara-C, imatinib vorinostat\tdecitabine\tidarubicin, cytarabin\t\nComplete Remission (CR)\tno\tno\tmorphological\t\nStem cell transplant\tno\tno\tno\t\nOverall survival (months)\t23\t12\t5\t\nTable 2 Summary of cytogenetic and molecular results\n\nCase no.\tPatient 1\tPatient 2\tPatient 3\t\nCytogenetics\t46,XY,inv(3)(q21q26.2)[13]/46,idem,del(7)(q22)[1]/46,XY,inv(3)(q21q26.2)x2[12]/46,XY[7]\t46,XX,inv(3)(q21q26.2)x2[18]/46,XX[2]\t46,XX,inv(3)(q21q26.2)x2[1]/45,idem,-7 [14]/46,XX[5]\t\nFISH\tND\tND\t\nMECOM/EVI1\n\t\naCGH + SNP\taCN-LOH chr3q\tND\tmonosomy 7 (<10 %)\t\nMolecular study\t\t\t\t\n\nFLT3\n\t-\t-\t-\t\n\nK/N-RAS\n\t-\t-\tND\t\n\nPTPN11\n\tND\tND\t+ missense mutation at a very low allelic frequency (<10 %)\t\n\nCEBPA\n\tND\tND\t+ Germline Variant\t\n\naCN-LOH acquired copy neutral loss of heterozygosity, Chr3q chromosome 3q, ND not done, “-” negative, “+” positive\n\n\n\nPatient 1\nPatient 1 was a 72 year-old Hispanic man diagnosed with a myelodysplastic syndrome (refractory anemia with excess blasts-2) with ~15 % blast at a local hospital one month prior to his first visit to MDACC. The bone marrow was heypercellular and involved by acute myeloid leukemia with 28 % of blasts. Flow-cytometry immunophenotyping showed that the blasts were positive for CD13, CD33, CD34, CD38, CD117 and HLA-DR.\n\nCytogenetic analysis showed a single inv(3) (Fig. 1a) as a part of 46,XY,inv(3)(q21q26.2) [13]/46,idem,del(7)(q22)[1]/46,XY[7]. Molecular studies for FLT3 and K/N-RAS were wild type. The patient was treated with reduced dose cytarabine and imatinib but did not respond and after two months of therapy the bone marrow showed 79 % blast. This coincided with cytogenetic evidence of evolution from single inv(3) to double inv(3) (Fig. 1b) in the following karyotype 46,XY,inv(3)(q21q26.2)[3]/46,XY,inv(3)(q21q26.2)x2[13]/46,XY[4]. The patient was switched to vorinostat (suberanilohydroxamic acid or SAHA) therapy due to refractory disease. Although his disease was stable for a short period of time clinically, he had persistent disease without achieving complete remission (CR). In the ensuing 4 months, the double inv(3) became predominant as the only abnormal clone. He died 23 months after initial diagnosis of AML.Fig. 1 Karyotypes from patient a showing 46,XY,inv(3)(q21q26.2) at the diagnosis and b 46,XY,inv(3)(q21q26.2)x2 at disease progression. ACGH + SNP showed evidence of aCN-LOH of chromosome 3q c whole genome view and d chromosome 3 only with 3q highlighted in light blue\n\n\n\nRetrospective aCGH + SNP was performed on the bone marrow sample with double inv(3) and showed aCN-LOH of chromosome 3q:arr[hg19] 3q13.21q29(10,344,387–197,802,470)x2 hmz, spanning ~ 94.3 Mb in size (Fig. 1c and d). No additional clinically relevant copy number aberrations were observed at the level of the aCGH + SNP analysis applied.\n\nPatient 2\nPatient 2 was a 64-year-old Caucasian woman who presented with monocytosis and suspected chronic myelomonocytic leukemia (CMML) type 2 three months prior to visiting our hospital. At our institution, bone marrow examination showed acute myelomonocytic leukemia with 23 % blasts. Flow-cytometry immunophenotyping showed the blasts were positive for CD13, CD14, CD15, CD33, CD38, CD64 (major subset), MPO and HLA-DR and negative for CD34, CD117.\n\nChromosome analysis and FISH targeting chromosomes 5/5q, 7/7q, 8 and 20q were all reported to be normal at the outside hospital. However, the first bone marrow at our hospital showed double inv(3) as predominant clone in a karyotype of 46,XX,inv(3)(q21q26.2)x2 [18]/46,XX[2]. Molecular studies showed that FLT3 and RAS were wild type. The patient was treated with decitabine and showed no response. She was followed up for 3 months and the double inv(3) clone was a persistent finding . The patient died 12 months after initial diagnosis; aCGH + SNP was not performed due to unavailability of diagnostic materials.\n\nPatient 3\nPatient 3 was a 56-year-old Caucasian woman with a history of pancytopenia and thrombocytopenia for one week prior to her visit at MDACC. Flow-cytometry immunophenotyping studies showed that the blast were positive for CD2 (partial), CD4 (partial), CD13, CD14 (partial), CD15 (partial), CD22 (partial), CD33, CD34, CD38, CD56 (partial), CD64 (partial), CD117 (partial), CD123 (dim)and HLA-DR (partial). The blasts were negative for CD3 (surface and cytoplasmic), CD5, CD7, CD10, CD19, and myeloperoxidase.\n\nChromosome analysis showed double inv(3) as the primary clone with a large subset cells showing monosomy 7 (Fig. 2a) as additional finding in the secondary clone in a karyotype of 46,XX,inv(3)(q21q26.2)x2[3]/45,idem,-7[14]/46,XX[3]. Double EVI1 (MECOM) rearrangement was confirmed by metaphase FISH (Fig. 2b). FLT3 and RAS were wild type. However, a next generation sequencing (NGS) targeting 28 genes on this patient showed a PTPN11 missense mutation with ~ 10 % allelic frequency indicating a low level somatic event.Fig. 2 Karyotype from patient 3 showing a 45,XX,inv(3)(q21q26.2)x2,-7 and b a metaphase FISH study using EVI1(MECOM) showing breakapart of green and red signals on both chromosome 3. ACGH + SNP analysis of patient 3 showed no apparent evidence of CN-LOH on chromosome 3q (c) and a very low level of monosomy 7 with a black line slightly below the zero line (d)\n\n\n\nA retrospective aCGH + SNP was performed on the diagnostic bone marrow. However, microarray data showed no apparent indication of aCN-LOH on chromosome 3q (Fig. 2c) and a very low level (~10 %) of mosaicism of monosomy chromosome 7 (Fig. 2d). Although aCGH + SNP did not demonstrate the expected aCN-LOH, the low level mosaicism and clonality for monosomy 7 were consistent with PTPN11 mutation. The discrepancy observed between cell based cytogenetic/FISH analysis and DNA based molecular and aCGH + SNP analyses, is most likely attributable to a low percentage of tumor DNA content in this patient’s specimen, possibly related to DNA degradation of the tumor cells or a high level of contaminated normal cells.\n\nThe patient received induction idarubicin and cytarabine and achieved a morphological complete remission (CR) on day 28, although cytogenetically the double inv(3) was persistent in 10 of 20 cells (50 %) and she died 5 months after initial diagnosis.\n\nDiscussions\nWe report three new cases of AML with double inv(3). Although a small series, this is the largest report to date and we performed a comprehensive review of the clinicopathologic, molecular and cytogenetic data and correlated the findings with clinical outcome.\n\nDouble paracentric inv(3q) is a very rare event with less than 10 cases reported in myeloid neoplasms [6, 16–19]. All reported cases showed involvement of chromosomal bands (3q21 and 3q26.2). However, very limited clinical data were available on most of these cases and almost no molecular and cytogenomic data are available. To better understand this subset of the patients, we reviewed and summarized our data with those 10 cases from literatures in Table 3. Among 12 total cases, six were women and six were men, with an average age of 62 years (range 36–80) at diagnosis [6]. Most of the double inv(3) cases were classified as AMLs (N = 9, 75 %) with one case of MDS [10] and two cases were CML in blast phase (BP) [12, 11]. Monosomy 7 was the most common additional cytogenetic finding, observed in five cases (41.7 %) and 7q deletions were seen in two cases. In two CML cases with BP, the double inv(3) co-existed with the Ph clone or BCR-ABL1 fusion [11]. Similar to AML patients with single inv(3) [2, 5], most patients with double inv(3) patients showed no or a minimal response to the conventional chemotherapy and rapid disease progression. All our patients were negative for FLT3 or RAS mutations, indicating that the double inv(3) entity is less associated with these somatic mutations that have been frequently reported in AML.Table 3 Summary of 12 cases with double inv(3)(q21q26.2) reported in the literature\n\nAge (year)/gender\tBlast (%)\tDiagnosis\tCytogenetic findings\tOverall survival (mo)\tReference\t\n55/F\tNA\tMDS\t46,XX,inv(3)x2\t24\tWalter [10]\t\nNA/F\tNA\tBP-CML\t46,XX,inv(3)x2,t(9;17;22)\tNA\tLevy [12]\t\n80/M\tNA\tAML-M1\t46,XY,inv(3)x2\t13\tSecker-Walker [8]\t\n39/M\tNA\tAML-M4\t45,XY,inv(3)x2,-7\t3\tSecker-Walker [8]\t\n83/F\t63\tAML\t45,XX,inv(3)x2,-7\tNA\tLee [7]\t\n65/M\t49\tAML-M4\t46,XY,inv(3)x2,\t24\tLahortiga [9]\t\n36/M\tNA\tCML\t46,XY,inv(3)x2,7q-\tNA\tToydemir [11]\t\n62/M\t14\tAML-M1\t45,XY,inv(3)x2,-7\t9\tDe Braekeleer [6]\t\n67/F\t35\tAML\t46,XX,inv(3),5q+/45,idem,-7/45,idem,inv(3),-7\t4\tDe Braekeleer [6]\t\n72/M\t79\tAML-M6A\t46,XY,inv(3)(q21q26.2),del(7)(q22)/46,XY,inv(3)(q21q26.2)x2\t23\tPatient 1\t\n64/F\t23\tAMML\t46,XX,inv(3)x2\t12\tPatient 2\t\n56/F\t54\tAML\t46,XX,inv(3)x2/45,idem,-7\t5\tPatient 3\t\n\nNA not available, MDS myelodysplastic syndrome, AML acute myeloid leukemia, CML chronic myelogeneous leukemia, BP blast phase, AMML acute myelomonocytic leukemia, Mo months\n\n\n\nOverall survival (OS) data were available in 9 of 12 cases with the double inv(3) (Table 3). Compare with a previously reported median overall survival of 8.9 months in single inv(3) or t(3;3) positive AML cases [5], the median OS for the double inv(3) AML cases was 12 months (range, 3–24 months). This comparison might indicate that double inv(3) does not impose an extra risk on the OS, however, we note that patients with concurrent additional monosomy 7 (N = 4) seemed do worse (Table 3) and showed a median OS of 4.5 months (range 3–9 months) compared with patients without monosomy 7 (N = 5), who had a median OS of 23 months (range 12–24 months) (p = 0.004). Although monosomy 7 did not show independent prognostic value in single inv(3) AML patients [5], it apparently has adverse impact on AML patients with the double inv(3).\n\nThere are three possible mechanisms of double inv(3q) formation. The first proposed mechanism is that double inv(3) is the result of loss of the normal chromosome 3 followed by a somatic rescue event resulting in duplication of the inverted chromosome 3 [10]. This mechanism would result in uniparental disomy (UPD) for the entire chromosome 3 which was not consistent with what we have observed in patient I in this study who showed segmental aCN-LOH at the chromosome 3q13.21q29. The second proposed mechanism is that double inv(3) could be due to a somatic repair resulting from nonallelic homologous recombination (NAHR) or nonhomologous end-joining (NHEJ) [20] or in short, a somatic recombination event in cancer genome. This mechanism seems more consistent with our aCGH + SNP findings of chromosome 3q: arr[hg19] 3q13.21q29 (10,344,387–197,802,470)x2 hmz, which was almost identical to what has been reported in a CML patient in blast phase with double inv(3) [11], by a high-resolution SNP microarray analysis. The SNP array data in these two double inv(3) patients (our patient 1 and the CML patient) suggest that the double inv(3) was a result of somatic rescue with loss of the chromosome 3 and coupling with a subsequently partial duplication of 3q [16, 11, 18], or a result of a mitotic recombination of the chromosome 3q. The third mechanism proposed is that the double inv(3q) could occur on both chromosome 3 homologues independently although it is less likely and no studies have ever provided evidence to support this hypothesis.\n\nMicroarray based testing including both SNP microarray or oligonucleotide aCGH + SNP is a powerful molecular cytogenetic tool for detecting aberrations that are cytogenetically undetectable but clinically relevant. These methods have been fully utilized in the clinical diagnosis of constitutional disorders [21] and also are widely implemented in cancer genetics, particularly in myeloid neoplasms [22]. However, it is important to note that microarray based testing relies on the level of mosaicism or clonality in cancer diagnosis. False negative array results such as observed in our patient 3 can occur if the tumor sample tested is compromised by high level normal cell contamination.\n\nThe CN-LOH or UPD can only be detected by molecular methods or SNP based microarray testing. Acquired CN-LOH or UPD (aCN-LOH or aUPD) have been frequently reported in myeloid neoplasms [15, 23]. Some aCN-LOH regions encoding known oncogenic mutations such as JAK2, MPL, c-KIT, FLT3, RUNX1 on chromosomes 9p24.1, 1p34, 4q21, 13q12 and 21q22, respectively, are frequently recurrent in AML and MDS, resulting in a “double hit” or “homozygous mutations”. Recent studies have shown that these homozygous mutations are the results of clonal evolution [24] in AML. As observed in patient 1, cytogenetically the double inv(3) evolved from the single inv(3) during the disease progression confirming that the aCN-LOH is the result of clonal evolution.\n\nConclusions\nWe reported three new AML cases with the double inv(3) with comprehensive analysis of clinicopathologic, cytogenetic and molecular/genomic data and patient clinical outcome. We also compared our data with what has been reported in the literatures. We conclude that double inv(3) results from aCN-LOH, a somatic repair event of mitotic recombination of the partial chromosome 3q. The double inv(3) is frequently associated with monosomy 7 and should be recognized as a unique cytogenetic entity in myeloid neoplasms especially in AML patients. This subset of patients often shows a rapid disease progression with a dismal OS.\n\nMethods\nPatient inclusion\nThis study was approved by the institutional review board at The University of Texas MD Anderson Cancer Center (MDACC). Retrospective cytogenetic data review was performed on all patients diagnosed with myeloid neoplasms tested in the Clinical Cytogenetics laboratory between 2002 and 2014 at MDACC. Only patients with double inv(3) were included to the study.\n\nMorphologic and flow-cytometry immunophenotypic analyses\nHematoxylin-eosin-stained histologic sections of bone marrow biopsy specimens, and Wright-Giemsa stained peripheral blood and bone marrow aspirate smears were reviewed. Complete blood cell and differential counts were performed on peripheral blood smears of all three patients.\n\nFour- or eight- color flow cytometry immunophenotypic analysis was performed as described according to standard procedures. The panel included antibodies directed against: CD3, CD4, CD5, CD7, CD9, CD10, CD13, CD19, CD20, CD22, CD25, CD33, CD34, CD38, CD52, CD79a, CD117, BCL-2, HLA-DR, TdT, myeloperoxidase, IgM (cytoplasmic), kappa and lambda light chains. All antibodies were obtained from Becton-Dickinson Biosciences (San Jose, CA, USA), except for TdT (Supertechs Inc, Bethesda, MD, USA).\n\nCytogenetic and FISH analysis\nTwenty-four and/or forty-eight hour unstimulated bone marrow cultures were setup for chromosome preparation, following standard chromosome harvesting procedure. Twenty metaphases were analyzed using a Leica-microscope imaging system (Leica Microsystems Inc., Chicago, IL) and karyotypes were described according to International System for Human Cytogenetic Nomenclature (ISCN 2009 and 2013).\n\nFISH for EVI1 (MECOM) rearrangement was performed on cultured bone marrow metaphases and interphases, using a breakapart probe from Kreatech (Leica Microsystems Inc. Chicago, IL) according to the manufacturer’s instructions.\n\nOligonucleotide microarray comparative genomic hybridization + single nucleotide polymorphism (aCGH + SNP)\nGenomic DNA was extracted from bone marrow aspirate material using Gentra Puregene (Qiagen, Valencia, CA). The Cancer Cytogenomic Microarray Consortium (CCMC) 4x180K chip was used according to the manufacturer’s protocol (Agilent Technologies, Santa Clara, CA) as described previously [25]. The Agilent GeneChip microarray scanner was used for imaging and data analysis was performed using Cytogenomic workbench software.\n\nMolecular study\nGenomic DNA was PCR amplified and subjected to mutation analysis for codons 12, 13 and 61 of KRAS and NRAS by pyrosequencing using a PSQ HS 96 Pyrosequencer (Biotage, Uppsala, Sweden). CEBPA was assessed by direct Sanger sequencing on an ABI Prism 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA) [26]. A fluorescence-based multiplex PCR was used to detect internal tandem duplication (ITD) and D835 point mutation of the FLT3 gene. The PCR products were then subjected to capillary electrophoresis on an ABI Prism 3100 Genetic analyzer to distinguish wild and mutant genotypes. For the third patient KIT, NPM1, KRAS and NRAS mutation were assessed using a next generation sequencing (NGS)-based assay [27].\n\nConsent\nInformed consent was waived per institution IRB.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nJG and XL conception and design. KPP, BB, CHL, RA, performed cytogenetic and molecular analyses; GT, HMK, ZT, RA, RL, JLM, PL, XL, collected patients and performed clinical analyses; JG, XL analyzed data and wrote the manuscript; all authors read and approved final version.\n==== Refs\nReferences\n1. Vardiman JW Thiele J Arber DA Brunning RD Borowitz MJ Porwit A The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 2009 114 5 937 51 10.1182/blood-2009-03-209262 19357394 \n2. Grimwade D Hills RK Moorman AV Walker H Chatters S Goldstone AH Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials Blood 2010 116 3 354 65 10.1182/blood-2009-11-254441 20385793 \n3. Rubin CM Larson RA Anastasi J Winter JN Thangavelu M Vardiman JW t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia Blood 1990 76 12 2594 8 2265251 \n4. Bernstein R Bagg A Pinto M Lewis D Mendelow B Chromosome 3q21 abnormalities associated with hyperactive thrombopoiesis in acute blastic transformation of chronic myeloid leukemia Blood 1986 68 3 652 7 3461853 \n5. Sun J Konoplev SN Wang X Cui W Chen SS Medeiros LJ De novo acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2): a clinicopathologic and cytogenetic study of an entity recently added to the WHO classification Mod Pathol 2011 24 3 384 9 10.1038/modpathol.2010.210 21113141 \n6. De Braekeleer E Douet-Guilbert N Le Bris MJ Ianotto JC Berthou C Gueganic N Double Inv(3)(q21q26), a rare but recurrent chromosomal abnormality in myeloid hemopathies Anticancer Res 2013 33 2 639 42 23393360 \n7. Lee CL Double inversion (3)(q21q26) and monosomy 7 in a case of acute myeloid leukemia Cancer Genet Cytogenet 1999 111 1 99 101 10.1016/S0165-4608(98)00206-4 10326599 \n8. Secker-Walker LM Mehta A Bain B Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study Br J Haematol 1995 91 2 490 501 10.1111/j.1365-2141.1995.tb05329.x 8547101 \n9. Lahortiga I Vazquez I Agirre X Larrayoz MJ Vizmanos JL Gozzetti A Molecular heterogeneity in AML/MDS patients with 3q21q26 rearrangements Genes Chromosomes Cancer 2004 40 3 179 89 10.1002/gcc.20033 15138998 \n10. Walter TA Morgan R Ondreyco S Sandberg AA Apparent duplication of inv(3)(q21q26) in one of five cases with inv (3) in myelodysplastic syndromes and acute leukemia Am J Hematol 1990 33 3 210 4 10.1002/ajh.2830330310 2405651 \n11. Toydemir R Rowe L Hibbard M Salama M Shetty S Cytogenetic and molecular characterization of double inversion 3 associated with a cryptic BCR-ABL1 rearrangement and additional genetic changes Cancer Genet Cytogenet 2010 201 2 81 7 10.1016/j.cancergencyto.2010.05.014 20682391 \n12. Levy ER Parganas E Morishita K Fichelson S James L Oscier D DNA rearrangements proximal to the EVI1 locus associated with the 3q21q26 syndrome Blood 1994 83 5 1348 54 8118036 \n13. Bullinger L Kronke J Schon C Radtke I Urlbauer K Botzenhardt U Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis Leukemia 2010 24 2 438 49 10.1038/leu.2009.263 20016533 \n14. Tiu RV Gondek LP O’Keefe CL Huh J Sekeres MA Elson P New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia J Clin Oncol 2009 27 31 5219 26 10.1200/JCO.2009.21.9840 19770377 \n15. O’Keefe C McDevitt MA Maciejewski JP Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies Blood 2010 115 14 2731 9 10.1182/blood-2009-10-201848 20107230 \n16. Suzukawa K Parganas E Gajjar A Abe T Takahashi S Tani K Identification of a breakpoint cluster region 3′ of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26) Blood 1994 84 8 2681 8 7919381 \n17. Shearer BM Sukov WR Flynn HC Knudson RA Ketterling RP Development of a dual-color, double fusion FISH assay to detect RPN1/EVI1 gene fusion associated with inv(3), t(3;3), and ins(3;3) in patients with myelodysplasia and acute myeloid leukemia Am J Hematol 2010 85 8 569 74 10.1002/ajh.21746 20556821 \n18. Dunbar AJ Gondek LP O’Keefe CL Makishima H Rataul MS Szpurka H 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies Cancer Res 2008 68 24 10349 57 10.1158/0008-5472.CAN-08-2754 19074904 \n19. Costa AR Vasudevan A Krepischi A Rosenberg C Chauffaille ML Single-nucleotide polymorphism-array improves detection rate of genomic alterations in core-binding factor leukemia Med Oncol 2013 30 2 579 10.1007/s12032-013-0579-7 23636907 \n20. Tuna M Knuutila S Mills GB Uniparental disomy in cancer Trends Mol Med 2009 15 3 120 8 10.1016/j.molmed.2009.01.005 19246245 \n21. Lu X Shaw CA Patel A Li J Cooper ML Wells WR Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases PLoS One 2007 2 3 e327 10.1371/journal.pone.0000327 17389918 \n22. Tiu RV Gondek LP O’Keefe CL Elson P Huh J Mohamedali A Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies Blood 2011 117 17 4552 60 10.1182/blood-2010-07-295857 21285439 \n23. Barresi V Romano A Musso N Capizzi C Consoli C Martelli MP Broad copy neutral-loss of heterozygosity regions and rare recurring copy number abnormalities in normal karyotype-acute myeloid leukemia genomes Genes Chromosomes Cancer 2010 49 11 1014 23 10.1002/gcc.20810 20725993 \n24. Paguirigan AL Smith J Meshinchi S Carroll M Maley C Radich JP Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia Sci Transl Med 2015 7 281 281re2 10.1126/scitranslmed.aaa0763 25834112 \n25. Mehrotra M Luthra R Ravandi F Sargent RL Barkoh BA Abraham R Identification of clinically important chromosomal aberrations in acute myeloid leukemia by array-based comparative genomic hybridization Leuk Lymphoma 2014 55 11 2538 48 10.3109/10428194.2014.883073 24446873 \n26. Kanagal-Shamanna R Bueso-Ramos CE Barkoh B Lu G Wang S Garcia-Manero G Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53 Cancer 2012 118 11 2879 88 10.1002/cncr.26537 22038701 \n27. Luthra R Patel KP Reddy NG Haghshenas V Routbort MJ Harmon MA Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring Haematologica 2014 99 3 465 73 10.3324/haematol.2013.093765 24142997\n\n",
"fulltext_license": "CC BY",
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"journal": "Molecular cytogenetics",
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"references": "3461853;20556821;24142997;20107230;19357394;20725993;17389918;25834112;10326599;7919381;20385793;15138998;8118036;23393360;24446873;2405651;20682391;19770377;19246245;23636907;8547101;19074904;2265251;21113141;22038701;20016533;21285439",
"title": "Double inv(3)(q21q26.2) in acute myeloid leukemia is resulted from an acquired copy neutral loss of heterozygosity of chromosome 3q and associated with disease progression.",
"title_normalized": "double inv 3 q21q26 2 in acute myeloid leukemia is resulted from an acquired copy neutral loss of heterozygosity of chromosome 3q and associated with disease progression"
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"abstract": "BACKGROUND\nAcute fibrinous and organizing pneumonia (AFOP) is a rare diffuse pulmonary disease, but it is not yet known whether it is a distinct form of interstitial pneumonia or simply a reflection of a tissue sampling issue.\n\n\nMETHODS\nCross-sectional evaluation of clinical and radiological findings, treatments, and outcomes for patients with histologically confirmed AFOP at a tertiary university hospital between 2002 and 2015.\n\n\nRESULTS\nThirteen patients (7 women, 53.8%) with a mean ± SD age of 53.5 ± 16.1 years were included. The main symptoms were fever (69.2%), cough (46.2%), and chest pain (30.8%). All patients presented a radiological pattern of consolidation and 5 (38.5%) had simultaneous ground-glass areas. Histology was obtained by computed tomography-guided transthoracic biopsy in 61.5% of cases and by surgical lung biopsy in the remaining cases. Several potential etiologic factors were identified. Eight patients (61.5%) had hematologic disorders and 3 had undergone an autologous hematopoietic cell transplant. Two (15.4%) had microbiologic isolates, 5 (38.4%) had drug-induced lung toxicity, and 2 (15.4%) were classified as having idiopathic AFOP. In addition to antibiotics and diuretics used to treat the underlying disease, the main treatment was corticosteroids, combined in some cases with immunosuppressants. Median survival was 78 months and 6 patients (46.2%) were still alive at the time of analysis.\n\n\nCONCLUSIONS\nOur findings for this series of patients confirm that AFOP is a nonspecific reaction to various agents with a heterogeneous clinical presentation and clinical course that seems to be influenced mainly by the severity of the underlying disorder.",
"affiliations": "Pulmonology Department, Hospital Sousa Martins, ULS-Guarda, Guarda, Portugal Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal Pulmonology Department, Centro Hospitalar de São João, Porto, Portugal Faculty of Medicine, University of Porto, Portugal Radiology Department, Centro Hospitalar de São João, Porto, Portugal Pathology Department, Centro Hospitalar de São João, Porto, Portugal.",
"authors": "Gomes|Rita|R|;Padrão|Eva|E|;Dabó|Hans|H|;Soares Pires|Filipa|F|;Mota|Patrícia|P|;Melo|Natália|N|;Jesus|José Miguel|JM|;Cunha|Rui|R|;Guimarães|Susana|S|;Souto Moura|Conceição|C|;Morais|António|A|",
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"doi": "10.1097/MD.0000000000004073",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2739909410.1097/MD.0000000000004073040736700Research ArticleObservational StudyAcute fibrinous and organizing pneumonia A report of 13 cases in a tertiary university hospitalGomes Rita MDab∗Padrão Eva MDcDabó Hans MDcSoares Pires Filipa MDcMota Patrícia MDcdMelo Natália MDcJesus José Miguel MDdeCunha Rui MDdeGuimarães Susana MDdfSouto Moura Conceição MDdfMorais António MD, PhDcdDalar. Levent a Pulmonology Department, Hospital Sousa Martins, ULS-Guarda, Guarda, Portugalb Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugalc Pulmonology Department, Centro Hospitalar de São João, Porto, Portugald Faculty of Medicine, University of Porto, Portugale Radiology Department, Centro Hospitalar de São João, Porto, Portugalf Pathology Department, Centro Hospitalar de São João, Porto, Portugal.∗ Correspondence: Rita Gomes, Pulmonology Department, Hospital Sousa Martins, ULS-Guarda, Avenida Rainha D. Amélia, 6301-857 Guarda, Portugal (e-mail: gomes.rita.dm@gmail.com).7 2016 08 7 2016 95 27 e40732 1 2016 19 5 2016 5 6 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction\nAcute fibrinous and organizing pneumonia (AFOP) is a rare diffuse pulmonary disease, but it is not yet known whether it is a distinct form of interstitial pneumonia or simply a reflection of a tissue sampling issue.\n\nMethods\nCross-sectional evaluation of clinical and radiological findings, treatments, and outcomes for patients with histologically confirmed AFOP at a tertiary university hospital between 2002 and 2015.\n\nResults\nThirteen patients (7 women, 53.8%) with a mean ± SD age of 53.5 ± 16.1 years were included. The main symptoms were fever (69.2%), cough (46.2%), and chest pain (30.8%). All patients presented a radiological pattern of consolidation and 5 (38.5%) had simultaneous ground-glass areas. Histology was obtained by computed tomography-guided transthoracic biopsy in 61.5% of cases and by surgical lung biopsy in the remaining cases. Several potential etiologic factors were identified. Eight patients (61.5%) had hematologic disorders and 3 had undergone an autologous hematopoietic cell transplant. Two (15.4%) had microbiologic isolates, 5 (38.4%) had drug-induced lung toxicity, and 2 (15.4%) were classified as having idiopathic AFOP. In addition to antibiotics and diuretics used to treat the underlying disease, the main treatment was corticosteroids, combined in some cases with immunosuppressants. Median survival was 78 months and 6 patients (46.2%) were still alive at the time of analysis.\n\nConclusion\nOur findings for this series of patients confirm that AFOP is a nonspecific reaction to various agents with a heterogeneous clinical presentation and clinical course that seems to be influenced mainly by the severity of the underlying disorder.\n\nKeywords\nacute fibrinous and organizing pneumonia (AFOP)etiologytreatmentOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAcute fibrinous and organizing pneumonia (AFOP) is a histological pattern characterized predominantly by the presence of intra-alveolar fibrin in the form of fibrin “balls” within the alveolar spaces, with a patchy distribution, and organizing pneumonia.[1,2] It was first described in 2002 by Beasley et al[1] in a series of 17 patients. Since then, there have been essentially isolated reports describing diverse causes and clinical courses.[3–6] Consequently, whether AFOP is a distinct pattern of interstitial pneumonia or whether it simply reflects a tissue sampling issue remains to be elucidated.[2]\n\nA variety of causes have been linked to AFOP, including infections, drugs, immune status, and occupational exposures, but idiopathic cases have also been described. The condition frequently occurs in the context of an underlying disease (Table 1).[1,4,7–12]\n\nTable 1 Possible etiologic and risk factors in acute fibrinous and organizing pneumonia.\n\nGiven the variability in clinical, radiological, and bronchoalveolar lavage findings, diagnosis requires the detection of characteristic features of AFOP in a lung tissue sample.[1,2,13–15] Numerous treatments have been reported for AFOP, but considering the rarity of the condition, together with the diversity of clinical presentations and underlying conditions, there are no standard treatment recommendations.[1,3,5,16–19] Data on outcomes also vary due to this diversity, but a significant number of cases have been associated with poor prognosis.[1,18] The real influence of AFOP versus its causes or associated conditions remains to be elucidated.\n\nThe aim of the study was to describe the clinical evaluation and course of patients with a histological diagnosis of AFOP in a tertiary hospital, to report on the treatments prescribed, and to explore prognostic factors associated with different outcomes.\n\n2 Methods\n2.1 Study design\nWe performed a cross-sectional study of patients with a histological diagnosis of AFOP evaluated at the Centro Hospitalar São João in Oporto, Portugal, between 2002 and 2015. Our hospital is a tertiary referral center serving patients mostly from the Oporto district and the north of Portugal. The study was approved by the institutional review board at our institution. We analyzed clinical, functional, and radiological features, diagnostic methods, investigations of etiologic factors, and treatments and outcomes.\n\nThe histological criteria used were those defined in 2002 by Beasley et al[1] that is, the presence of intra-alveolar fibrin in the form of fibrin balls within the alveolar spaces in a patchy distribution and organizing pneumonia consisting of intraluminal loose connective tissue within bronchioles and alveolar ducts. Additional features described include hyperplasia of type II pneumocytes, alveolar septal expansion, and acute and/or chronic inflammation (Fig. 1).\n\nFigure 1 Histologic findings of acute fibrinous and organizing pneumonia: (A) hematoxylin and eosin stain, ×100; (B) hematoxylin and eosin stain, ×200. Alveoli containing fibrin “balls” and some granulation tissue, in a patchy distribution.\n\n2.2 Statistical analysis\nWe used the Kolmogorov–Smirnov test (P ≥ 0.05) to determine the normality of continuous variables and Levene's test to assess equality of variances. Differences between means were analyzed using the t test for normally distributed variables. A Kaplan–Meier curve was used for the survival analysis. P values < 0.05 were considered to be statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 19.0.\n\n3 Results\nWe analyzed 13 patients with a histological diagnosis of AFOP treated at our hospital between 2002 and 2015. Seven (53.8%) were women and 6 (46.2%) were men. The mean ± SD age (Kolmogorov–Smirnov test, P = 0.956) was 53.5 ± 16.1 years, and was higher in men (60.8 ± 16.2) than in women (47.1 ± 14.1), although the difference was not statistically significant (P = 0.131). Mean time from onset of symptoms to diagnosis was 43.9 ± 33.0 days. The clinical presentation included fever in 9 patients (69.2%), cough in 6 (46.2%), chest pain in 4 (30.8%), constitutional symptoms in 3 (23.1%), and dyspnea in 2 (15.4%). The presentation was acute in 2 patients (15.4%) and subacute in the remaining 11 (84.6%). One patient (7.7%) was asymptomatic.\n\nAll patients presented a radiological pattern of consolidation, and 5 (38.5%) had a consolidation pattern together with ground-glass areas in the high-resolution computed tomography chest scan; the distribution was mostly diffuse random, but 3 patients (23.1%) showed a diffuse peribronchovascular distribution (Fig. 2). AFOP histology was obtained by computed tomography-guided lung transthoracic biopsy in 8 patients (61.5%) and by surgical lung biopsy in 5 (38.5%).\n\nFigure 2 Radiological findings of acute fibrinous and organizing pneumonia. (A, B) High-resolution computed tomography images showing focal areas of airspace consolidation and ground glass along the bronchovascular bundles, with a diffuse random distribution. (C, D) Computed tomography images showing diffuse areas of airspace consolidation and ground glass along the bronchovascular bundles.\n\nThe majority of patients (n = 8, 61.5%) had hematologic disorders: 4 (30.4%) had lymphomas (Hodgkin in 3 cases and non-Hodgkin in 1), 2 (15.4%) had acute leukemia (acute lymphoblastic leukemia and acute myeloid leukemia), 1 (7.7%) had myelodysplastic syndrome, and 1 (7.7%) had multiple myeloma. Three patients (23.1%) with lymphoma had undergone an autologous hematopoietic cell transplant. Two of the patients (15.4%) also had microbiologic isolates, specifically Acinetobacter baumannii and A fumigatus. All 8 patients were receiving medication for their hematologic disorders. However, of all the drugs evaluated, only azacytidine and bleomycin have been linked to AFOP to date.[17,20]\n\nThe patient with multiple myeloma was being treated with everolimus and prolonged corticosteroid therapy for a kidney transplant performed 7 years earlier.\n\nAnother patient (7.7%) had undergone a kidney transplant 6 years earlier and was being treated with sirolimus. Although this drug has never been associated with AFOP, sirolimus can induce a range of adverse respiratory events, and other immunosuppressive macrolides, such as everolimus, have been linked to AFOP.[21,22] In this case, thus, sirolimus was identified as the probable cause of AFOP. One patient (7.7%) had breast cancer and had undergone surgery followed by adjuvant chemotherapy (docetaxel) and radiotherapy. Although neither of these therapies has been linked to AFOP, the co-occurrence of AFOP means that this association must be considered. Two patients (15.4%) were considered to have idiopathic AFOP after an extensive search for possible causes. One patient (7.7%) had AFOP only on the periphery of a lung abscess, and it was considered to be simply a histological feature of this lesion.\n\nTreatment included antibiotics in 11 patients (84.6%), corticosteroids in 10 (76.9%), mycophenolate mofetil in 2 (15.4%), and cyclophosphamide in 2 (15.4%). Drugs suspected to be associated with AFOP were withdrawn. Three patients (23.1%) required invasive mechanical ventilation (IMV) in an intensive care unit.\n\nThe median survival according to the Kaplan–Meier curve was ∼78 months, and 6 patients (46.2%) were still alive at the time of our analysis. The mean duration of follow-up for these 6 patients was 76.7 ± 54.6 months; 5 (83.3%) had acute disease, and 1 (16.7%) developed chronic disease. Seven patients (53.8%) died. AFOP was the cause of death in 3 cases (42.9%); the other 4 patients (57.1%) died of other causes: lymphoma/leukemia progression in 2 cases and septic/hemorrhagic shock in the other 2. The mean time from the onset of symptoms to death due to AFOP progression was 89.3 ± 104.5 days.\n\nTable 2 summarizes the clinical characteristics and treatments administered for the 13 patients.\n\nTable 2 Clinical characteristics and treatment of AFOP patients.\n\n4 Discussion\nOur identification of just 13 cases of histologically confirmed AFOP in a tertiary referral hospital over a period of 14 years confirms the rarity of this entity. The age of the patients was diverse and there was no clear gender difference. A significant number of patients (n = 8) had an underlying hematologic disorder, but the majority of patients had several potential causes of AFOP, including drugs and infectious agents. Due to the diversity of conditions and, consequently, treatments, we were unable to identify any specific potentially effective drugs. Clinical outcomes were also diverse, and ranged from resolution to death (53.8% of cases). We were unable to identify prognostic factors due to the small sample size and the significant number of comorbidities and complications during the clinical course of the patients who died.\n\nAFOP is a rare histological pattern of acute lung injury. It is a relatively new entity that requires better clinical and radiologic characterization and the identification of poor outcome markers. Numerous causes have been associated with AFOP to date.[1,4,7–12] In our sample, 8 patients (61.5%) had a hematologic disorder. AFOP has been linked to hematologic disorders in isolated reports and also in the only 2 cases series published to date, although to a considerably lower extend than in our series.[1,6,7,23,24] Our institution is a university hospital with 1100 beds and covers all medical and surgical specialities, with no particular predominance. One possible explanation for the preponderance of hematologic disorders is that these patients may need aggressive chemotherapy, leading to immunosuppression and consequently the risk of opportunistic infections, which are all possible causes of AFOP. We identified several potential etiologic factors, mostly related to infections (A baumannii and A fumigatus) or drug-induced toxicity (azacytidine, bleomycin, everolimus, and sirolimus), in a significant number of cases. To our knowledge, this is the first series of AFOP to report sirolimus as a potential cause of AFOP, and its implication is based on previous reports of an association between AFOP and drugs with similar pharmacologic proprieties.[21,22] We also believe that combined chemoradiotherapy may have been responsible for AFOP in 1 patient because of the co-occurrence in time and the absence of other probable causes. Although there have been reports of idiopathic AFOP,[5,19,25] an exhaustive investigation is critical as etiology seems to be an important determinant of prognosis and consequently of treatment.\n\nThe presenting symptoms of AFOP were nonspecific. In our sample, the mean time from onset of symptoms to diagnosis was 43.9 days, which is significantly longer than the 19 days described by Beasley et al.[1] Two patients had symptoms for >60 days. This considerable diagnostic delay may be due to the nonspecific nature of the presenting symptoms, which in many cases overlapped with those of several of the comorbidities observed. AFOP has no pathognomonic or specific radiologic features, although bilateral basal opacities are frequently seen, as are occasional diffuse areas of consolidation, sometimes with bronchovascular bundles.[1,14]\n\nAFOP has no specific treatment and therapeutic strategies vary considerably according to the underlying disease and clinical presentation.[1,3,5,16–19] Coinciding with reports in the literature, the treatments used in our series were diverse. In addition to specific treatments for the underlying disease, such as antibiotics or diuretics, AFOP treatments included mostly steroids, combined in some cases with immunosuppressants, such as cyclophosphamide or mycophenolate mofetil. However, none of the treatments was identified as being particularly beneficial.\n\nIn the series described by Beasley et al,[1] 30% of patients required IMV and they all died. In our sample, IMV was used in 23.1% of patients, who all died due to progression of AFOP. This observation would appear to confirm Beasley et al's[1] suggestion that there are 2 main forms of disease: a fulminant form leading to rapid deterioration and death and another, subacute form, which in some cases may resolve after treatment with corticosteroids. Median survival in our sample was ∼78 months. The mortality rate described in the literature is >50%,[1] which coincides with our findings, as 7 (54%) of the patients in our series died. Three of the deaths were due to AFOP progression. Because of the small number of patients, we were unable to isolate any prognostic factors. However, the fact that the 2 patients considered to have idiopathic AFOP had longer survival times deserves some attention, as it could be speculated that it is largely the underlying condition and not AFOP itself that is associated with poor prognosis.\n\nIn conclusion, this cohort analysis confirmed that AFOP is a nonspecific reaction to various agents that follows a heterogeneous clinical course, with variable presentations, that seems to be largely influenced by the severity of the underlying disorder.\n\nAbbreviations: AFOP = acute fibrinous and organizing pneumonia, IMV = invasive mechanical ventilation.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n1 Beasley MB Franks TJ Galvin JR \nAcute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage . Arch Pathol Lab Med \n2002 ; 126 :1064 –1070 .12204055 \n2 Travis WD Costabel U Hansell DM \nAn official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias . Am J Respir Crit Care Med \n2013 ; 188 :733 –748 .24032382 \n3 Piciucchi S Dubini A Tomassetti S \nA case of amiodarone-induced acute fibrinous and organizing pneumonia mimicking mesothelioma . Am J Respir Crit Care Med \n2015 ; 191 :104 –106 .25551348 \n4 Guimarães C Sanches I Ferreira C \nAcute fibrinous and organising pneumonia . BMJ Case Rep \n2012 ; Published online .\n5 Damas C Morais A Moura CS \nAcute fibrinous and organizing pneumonia . Revista Portuguesa Pneumologia \n2006 ; 12 :615 –620 .\n6 Lee SM Park JJ Sung SH \nAcute fibrinous and organizing pneumonia following hematopoietic stem cell transplantation . Kor J Int Med \n2009 ; 24 :156 –159 .\n7 Dai JH Li H Shen W \nClinical and radiological profile of acute fibrinous and organizing pneumonia: a retrospective study . Chin Med J \n2015 ; 128 :2701 –2706 .26481733 \n8 Valim V Rocha RH Couto RB \nAcute fibrinous and organizing pneumonia and undifferentiated connective tissue disease: a case report . Case Rep Rheumatol \n2012 ; Published online .\n9 Heo JY Song JY Noh JY \nAcute fibrinous and organizing pneumonia in a patient with HIV infection and Pneumocystis jiroveci pneumonia . Respirology \n2010 ; 15 :1259 –1261 .20920123 \n10 Jamous F Ayaz SZ Choate J \nAcute fibrinous organising pneumonia: a manifestation of trimethoprim-sulfamethoxazole pulmonary toxicity . BMJ Case Rep \n2014 ; Published online .\n11 Paraskeva M McLean C Ellis S \nAcute fibrinoid organizing pneumonia after lung transplantation . Am J Resp Crit Care Med \n2013 ; 187 :1360 –1368 .23614642 \n12 Ribera A Llatjos R Casanova A \nChlamydia pneumoniae infection associated to acute fibrinous and organizing pneumonia . Enfermedades Infecciosas y Microbiologia Clinica \n2011 ; 29 :632 –634 .\n13 Santos C Fradinho F Catarino A \nAcute fibrinous and organizing pneumonia . Revista Portuguesa Pneumologia \n2010 ; 16 :607 –616 .\n14 Johkoh T Fukuoka J Tanaka T \nRare idiopathic intestinal pneumonias (IIPs) and histologic patterns in new ATS/ERS multidisciplinary classification of the IIPs . Eur J Radiol \n2015 ; 84 :542 –546 .25591580 \n15 Kobayashi H Sugimoto C Kanoh S \nAcute fibrinous and organizing pneumonia: initial presentation as a solitary nodule . J Thorac Imaging \n2005 ; 20 :291 –293 .16282908 \n16 Yokogawa N Alcid DV \nAcute fibrinous and organizing pneumonia as a rare presentation of abacavir hypersensitivity reaction . AIDS \n2007 ; 21 :2116 –2117 .17885309 \n17 Vasu TS Cavallazzi R Hirani A \nA 64-year-old male with fever and persistent lung infiltrate . Resp Care \n2009 ; 54 :1263 –1265 .\n18 Rapaka V Hussain MA Niazi M \nSevere acute fibrinous and organizing pneumonia causing acute respiratory distress syndrome and shock . J Bronchol Interv Pulmonol \n2011 ; 18 :269 –273 .\n19 Bhatti S Hakeem A Torrealba J \nSevere acute fibrinous and organizing pneumonia (AFOP) causing ventilatory failure: successful treatment with mycophenolate mofetil and corticosteroids . Resp Med \n2009 ; 103 :1764 –1767 .\n20 Hankollari E Saleem S Jones J \nAcute fibrinous and organizing pneumonia: a rare histopathologic variant of bleomycin-induced lung injury . Chest J \n2013 ; 144 :456A –1456A .\n21 Nazer L Alnajjar T Salah S \nFatal case of cryptogenic organizing pneumonia associated with everolimus . Ann Saudi Med \n2014 ; 34 :437 –439 .25827702 \n22 Foucher P Camus P \nPneumotox online: the drug-induced respiratory disease . See: www.pneumotox.com \nAccessed August 19, 2015.\n23 Merrill AL Smith H \nMyelodysplastic syndrome and autoimmunity: a case report of an unusual presentation of myelodysplastic syndrome . Case Rep Hematol \n2011 ; 2011 :560106 .22937307 \n24 Kim C \nAcute lymphoblastic leukemia presenting with an acute fibrinous and organizing pneumonia . J Resp Dis \n2007 ; 28 :33 –133 .\n25 Al-Khouzaie TH Dawamneh MF Hazmi AM \nAcute fibrinous and organizing pneumonia . Ann Saudi Med \n2013 ; 33 :301 –303 .23793436\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "95(27)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000208:Acute Disease; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D011014:Pneumonia; D011174:Portugal; D011658:Pulmonary Fibrosis; D012307:Risk Factors",
"nlm_unique_id": "2985248R",
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"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
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"title": "Acute fibrinous and organizing pneumonia: A report of 13 cases in a tertiary university hospital.",
"title_normalized": "acute fibrinous and organizing pneumonia a report of 13 cases in a tertiary university hospital"
} | [
{
"companynumb": "PT-PFIZER INC-2016414041",
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... |
{
"abstract": "METHODS\nA 41 year old patient started treatment with 300 mg/d allopurinol for asymptomatic hyperuricaemia (9,2 mg/dl).\n\n\nRESULTS\n4 weeks later he developed exfoliative skin lesions with haemorrhage, fever, eosinophilia and acute liver and renal failure, typical for an allopurinol hypersensitivity syndrome (AHS).An orthotopic liver-transplantation was performed.\n\n\nCONCLUSIONS\nThe AHS is a serious iatrogenic disease. 2 % of the treated patients develop a skin rash. 0,4 % of these patients experience suddenly and unforeseen a severe hypersensitivity with a mortality of 14-30 %. An early diagnosis is often very difficult. In the pathogenesis different causes are discussed. A hereditary component is involved. Of essential importance is the amount of the starting dose, the kidney function and concomitant drugs. In an asymptomatic hyperuricaemia the application of allopurinol is not indicated. If strong indications are present, the allopurinol therapy has to start with the lowest dose (100 mg/d). If required this dose should be increased under consequent supervision only.",
"affiliations": "Glockenstr. 9A, Berlin.;Rechtsanwalt, Berlin.",
"authors": "Miederer|S E|SE|;Miederer|K O|KO|",
"chemical_list": "D000493:Allopurinol; D000658:Amoxicillin",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0034-1387408",
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"issn_linking": "0012-0472",
"issue": "139(49)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000328:Adult; D000493:Allopurinol; D000658:Amoxicillin; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006801:Humans; D033461:Hyperuricemia; D007676:Kidney Failure, Chronic; D016031:Liver Transplantation; D008297:Male; D012307:Risk Factors; D012541:Scarlet Fever; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "2537-40",
"pmc": null,
"pmid": "25423467",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Allopurinol hypersensitivity syndrome: Liver transplantation after treatment of asymptomatic hyperuricaemia.",
"title_normalized": "allopurinol hypersensitivity syndrome liver transplantation after treatment of asymptomatic hyperuricaemia"
} | [
{
"companynumb": "DE-MYLANLABS-2015M1004650",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
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... |
{
"abstract": "The authors describe a family of three related individuals with a previously unreported mutation in the PRPH2 gene (C213W), which is associated with pattern dystrophy simulating fundus flavimaculatus. Four eyes later developed exudative maculopathy with choroidal neovascularization, which required injections of intravitreal anti-vascular endothelial growth factor (VEGF). This study reports the effectiveness of anti-VEGF therapy and long-term follow-up data in a family with a C213W mutation in the PRPH2 gene. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:354-362.].",
"affiliations": null,
"authors": "Lee|Chang Sup|CS|;Leys|Monique|M|",
"chemical_list": "C578997:PRPH2 protein, human; D064531:Peripherins; D004247:DNA",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20200603-06",
"fulltext": null,
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"issn_linking": "2325-8160",
"issue": "51(6)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D000328:Adult; D000368:Aged; D020256:Choroidal Neovascularization; D004247:DNA; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D008268:Macular Degeneration; D009154:Mutation; D010375:Pedigree; D064531:Peripherins; D013997:Time Factors; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "354-362",
"pmc": null,
"pmid": "32579694",
"pubdate": "2020-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Family Affected by Novel C213W Mutation in PRPH2: Long-Term Follow-Up of CNV Secondary to Pattern Dystrophy.",
"title_normalized": "a family affected by novel c213w mutation in prph2 long term follow up of cnv secondary to pattern dystrophy"
} | [
{
"companynumb": "US-BAYER-2020-182801",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "HYDROCHLOROTHIAZIDE"
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... |
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"abstract": "We report a 43-year-old woman, who underwent therapy with interferon-α for hairy cell leukemia. During interferon-α therapy she developed multiple subcutaneous swellings, accompanied by fever and fatigue. A skin biopsy revealed lobular, T-cell lymphocytic panniculitis. In conjunction with the clinical and immunological findings, the diagnosis of lupus panniculitis was made and interferon-α therapy stopped. Initially, she responded well to oral prednisone and hydroxychloroquine, but after several months she became resistant to it. Her condition worsened, she developed skin ulcers in the inflamed regions. Only with the leukemia-targeted therapy using cladribine and rituximab her skin condition could be controlled, suggesting hairy cell leukemia as an additional trigger of the lupus panniculitis. Our report is the first one to show induction of lupus panniculitis under interferon therapy of hairy cell leukemia and its presumable sustentation by the latter.",
"affiliations": "Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.",
"authors": "Urosevic-Maiwald|Mirjana|M|;Nobbe|Stephan|S|;Kerl|Katrin|K|;Benz|Rudolf|R|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016898:Interferon-alpha; D017338:Cladribine; D000069283:Rituximab; D006886:Hydroxychloroquine",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.12389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "41(4)",
"journal": "The Journal of dermatology",
"keywords": "cladribine; hairy cell leukemia; interferon-α; lupus panniculitis; rituximab",
"medline_ta": "J Dermatol",
"mesh_terms": "D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D017338:Cladribine; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D016898:Interferon-alpha; D007943:Leukemia, Hairy Cell; D015435:Panniculitis, Lupus Erythematosus; D000069283:Rituximab",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "329-33",
"pmc": null,
"pmid": "24612373",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated ulcerating lupus panniculitis emerging under interferon therapy of hairy cell leukemia: treatment- or disease-related?",
"title_normalized": "disseminated ulcerating lupus panniculitis emerging under interferon therapy of hairy cell leukemia treatment or disease related"
} | [
{
"companynumb": "CH-CONCORDIA PHARMACEUTICALS INC.-GSH201710-005620",
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"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
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"drug... |
{
"abstract": "Patients with germ cell tumours (GCT) receiving cisplatin-based chemotherapy are at high risk of thromboembolic events (TEE). Previously, we identified serum lactate dehydrogenase (LDH) and body surface area (BSA) as independent predictive factors for TEE. The aim of this study was to validate these predictive factors and to assess the impact of thromboembolism prophylaxis in patients at risk of deep venous thrombosis (DVT).\n\n\n\nBetween 2001 and 2014, 295 patients received first-line cisplatin-based chemotherapy for GCT. Preventive anticoagulation with low-molecular-weight heparin (LMWH) was progressively implemented in patients with predictive factors. Sixteen patients with evidence of TEE before starting chemotherapy were excluded from the analysis.\n\n\n\nAmong 279 eligible patients, a TEE occurred in 38 (14%) consisting of DVT (n = 26), arterial thrombosis (n = 2), and superficial thrombophlebitis (n = 10). DVT occurred in 26 (12.7%) of 204 patients with risk factors versus two (2.6%) of 75 patients with no risk factors (p = 0.01). After a prevention protocol was progressively implemented from 2005, primary thromboprophylaxis was administered to 104 patients (68%) with risk factors. Among patients at risk (n = 151), the incidence of DVT decreased by roughly half when they received a LMWH: 9/97 (9.2%) and 9/54 (16.6%), respectively (p = 0.23).\n\n\n\nPatients with GCT who receive cisplatin-based chemotherapy are at risk of developing a TEE which can be predicted by elevated serum LDH. To our knowledge this is the first study exploring LMWH as thromboprophylaxis in GCT patients. A prospective trial testing prophylactic anticoagulation is warranted.",
"affiliations": "Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Radiation Oncology, Institut Gustave Roussy, University of Paris Sud, 94800 Villejuif, France.;Department of Radiation Oncology, Institut Gustave Roussy, University of Paris Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France.;Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France. Electronic address: Karim.Fizazi@gustaveroussy.fr.",
"authors": "Gizzi|Marco|M|;Oberic|Lucie|L|;Massard|Christophe|C|;Poterie|Audrey|A|;Le Teuff|Gwenael|G|;Loriot|Yohann|Y|;Albiges|Laurence|L|;Baciarello|Giulia|G|;Michels|Judith|J|;Bossi|Alberto|A|;Blanchard|Pierre|P|;Escudier|Bernard|B|;Fizazi|Karim|K|",
"chemical_list": "D000925:Anticoagulants; D000970:Antineoplastic Agents; D006495:Heparin, Low-Molecular-Weight; D007770:L-Lactate Dehydrogenase; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2016.10.003",
"fulltext": null,
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"issn_linking": "0959-8049",
"issue": "69()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Chemotherapy; Cisplatin; Germ cell tumours; Thrombosis",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000925:Anticoagulants; D000970:Antineoplastic Agents; D001830:Body Surface Area; D018890:Chemoprevention; D002945:Cisplatin; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D015994:Incidence; D007770:L-Lactate Dehydrogenase; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D018239:Seminoma; D013736:Testicular Neoplasms; D013924:Thrombophlebitis; D013927:Thrombosis; D020246:Venous Thrombosis; D055815:Young Adult",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "151-157",
"pmc": null,
"pmid": "27821318",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Predicting and preventing thromboembolic events in patients receiving cisplatin-based chemotherapy for germ cell tumours.",
"title_normalized": "predicting and preventing thromboembolic events in patients receiving cisplatin based chemotherapy for germ cell tumours"
} | [
{
"companynumb": "FR-ACCORD-047365",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nThis report describes a Successful treatment of anti-NMDA receptor encephalitis with early teratoma removal and plasmapheresis.\nWe present a 31-year-old Caucasian nulliparous patient who was admitted as an emergency with general illness status accompanied by holocranial cephalalgia and fever.\nThe previous symptoms were followed by disorientation, persecutory delusion, incoherent language, and tonic-clonic seizure.\n\n\nMETHODS\nThe patient was admitted in the intensive care unit (ICU) with Glasgow score 7.\n\n\nRESULTS\nMost of complementary exams (brain CT, brain MRI, blood analysis, PCR for virus on CSF) were normal except CSF leucocytosis and hyperproteinorrhachia. An abdominopelvic ultrasound revealed a 5-cm solid-cystic tumor in the left adnexal region, suggestive of teratoma. At that stage, the possibility of autoimmune encephalitis was considered, and confirmed later.\n\n\nCONCLUSIONS\nThis disease can only be successfully treated with fast surgical intervention and an early implementation of immunosuppressive therapies. The optimal timing of initiation and duration of therapeutic plasma exchange necessary to achieve good outcomes in patients with NMDAR remains unknown. This case report intends to increase awareness about the importance of early surgical treatment and early implementation of this potentially life-saving therapy and of continuing the treatment until complete remission of symptoms.",
"affiliations": "Department of Obstetrics and Gynecology, University Clinic Hospital of Salamanca, Salamanca Biomedical Research Institute of Salamanca (IBSAL)-University Hospital of Salamanca, Spain.",
"authors": "Gomes Ferreira|Monica|M|;Lapresa Alcalde|Victoria|V|;García Sánchez|María Helena|MH|;Hernández Hernández|Lourdes|L|;Doyague Sánchez|María José|MJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000011325",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30075499MD-D-18-0168710.1097/MD.0000000000011325113255600Research ArticleClinical Case ReportSuccessful treatment of anti-NMDA receptor encephalitis with early teratoma removal and plasmapheresis A case reportGomes Ferreira Monica MDab∗Lapresa Alcalde Victoria MDabGarcía Sánchez María Helena MD, PhDaHernández Hernández Lourdes MD, PhDabDoyague Sánchez María José MD, PhDabNA. a Department of Obstetrics and Gynecology, University Clinic Hospital of Salamanca, Salamancab Biomedical Research Institute of Salamanca (IBSAL)—University Hospital of Salamanca, Spain.∗ Correspondence: Monica Gomes Ferreira, Department of Obstetrics and Gynecology, University Clinic Hospital of Salamanca, and Biomedical Research Institute of Salamanca (IBSAL)—University Hospital of Salamanca, (e-mail: gomesferreiramonica@usal.es).8 2018 03 8 2018 97 31 e1132520 3 2018 4 6 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale\nThis report describes a Successful treatment of anti-NMDA receptor encephalitis with early teratoma removal and plasmapheresis.\n\nPatient Concerns\nWe present a 31-year-old Caucasian nulliparous patient who was admitted as an emergency with general illness status accompanied by holocranial cephalalgia and fever.\n\nDiagnoses\nThe previous symptoms were followed by disorientation, persecutory delusion, incoherent language, and tonic-clonic seizure.\n\nInterventions\nThe patient was admitted in the intensive care unit (ICU) with Glasgow score 7.\n\nOutcomes\nMost of complementary exams (brain CT, brain MRI, blood analysis, PCR for virus on CSF) were normal except CSF leucocytosis and hyperproteinorrhachia. An abdominopelvic ultrasound revealed a 5-cm solid-cystic tumor in the left adnexal region, suggestive of teratoma. At that stage, the possibility of autoimmune encephalitis was considered, and confirmed later.\n\nLessons\nThis disease can only be successfully treated with fast surgical intervention and an early implementation of immunosuppressive therapies. The optimal timing of initiation and duration of therapeutic plasma exchange necessary to achieve good outcomes in patients with NMDAR remains unknown. This case report intends to increase awareness about the importance of early surgical treatment and early implementation of this potentially life-saving therapy and of continuing the treatment until complete remission of symptoms.\n\nKeywords\nanti-NMDA receptor encephalitisovarian teratoma removalplasmapheresissurvivalyoung womanOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAnti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is an autoimmune disorder with a wide spectrum of neuropsychiatric symptoms with a progressive clinical course and the possibility of effective management, which was first described in 2005 by Vitaliani et al.[1]\n\nA positive serum or CSF sample screening for antibodies to the NMDAR subunit remains the gold standard in the diagnosis and must be performed in all patients with an acute onset of psychiatric symptoms with atypical features or unusual movements.\n\nThe triggers of the disorder include viral infections, tumors, and other unknown factors. Herpes simplex encephalitis (HSE) plays a vital role in triggering the synthesis of anti-NMDAR antibodies.[2] In young adult women, encephalitis is frequently accompanied with ovarian teratomas,[3,4] while in men and children the presence of a tumor is uncommon.[5]\n\nElimination of the ovarian tumor and early immunotherapy frequently improves the outcome with complete recovery or only a residual neurological deficit.[6–8]\n\nThere is still an important lack of data regarding the optimal treatment of the disease, predominantly since the type of immunotherapy that is most effective in controlling the symptoms of the disease remains a matter of debate. Numerous patients, particularly those with a severe form of the disease, do not respond to first-line immunotherapy [steroids or intravenous immunoglobulins (IVIg)] and may require therapeutic plasma exchange (TPE).\n\nWe report a case of an ovarian mature cystic teratoma in a young woman which was associated with clinical anti-NMDAR encephalitis and the successful therapeutic management applied by a multidisciplinary team.\n\n2 Case report\nThe patient is a 31-year-old Caucasian nulliparous woman who was admitted as an emergency on March 23, 2017 with general malaise accompanied by holocranial cephalalgia and bilateral otalgia of 3 days of evolution. The only relevant element in her history is the presence of migraines without aura. The general emergencies unit diagnosed her with temporomandibular joint dysfunction and she returned on the same day with disorientation, persecutory delusion, and incoherent language. After an assessment by the Service of Psychiatry, she was diagnosed with anxiety syndrome secondary to a stressful family situation. On the next day, she was transferred by the emergency services with convulsive tonic-clonic seizure which was controlled with intranasal midazolam, and she was assessed by the Service of Neurology. She showed intermittently incoherent language and altered behavior. During anamnesis, she claims that “there are cameras recording us” or “they want to hurt us.” During the observation period in the emergency department, she presented an episode of fever with a temperature of 38.3°C. The blood results were normal, and the CSF showed 75 leukocytes/mm3 (mononuclear) and hyperproteinorrhachia at 88 mg/dL, with clear fluid. The computed tomography (CT) scan did not reveal significant alterations. The patient was initially diagnosed with lymphocytic encephalitis and prescribed an antibiotic treatment against Gram−, Gram+, herpesvirus, and tuberculosis (ceftriaxone, ampicillin, vancomycin, rifater and aciclovir), and antiseizure treatment with levetiracetam.\n\nOn March 25, the patient was admitted in the intensive care unit (ICU) with Glasgow score 7 and signs of unrest, language without response to pain and apraxia of lid opening. She presented with neck and upper limb dystonia, oculomasticatory myorhythmia, and involuntary movements of the lower limbs. During admission, the condition of the patient worsened, with no language, and she presented with progressive rigidity of the back of the neck which spread to the entire body, including the mandible, with sialorrhea. Sedation was applied, followed by orotracheal intubation and mechanical ventilation. A more exhaustive study was performed with a complete analysis (complete blood count, biochemical analysis, coagulation, renal function, hepatic function, electrolyte levels, polymerase chain reaction [PCR], glucose, urine analysis, and urine sediment) which revealed normal values except for PCR, which was 12.2 on March 27 (levels were normal on admission). Brain CT and magnetic resonance imaging (MRI) were performed, without pathological findings (Fig. 1), and several lumbar punctures that showed CSF with leukocytes 187/mm3 on March 27 and proteins 111.5 mg/dL. On March 28 results for antibodies against neuronal nuclear antigens (anti-Hu, -Yo, -Ri, -CV2, -PMA2, -amphiphysin, -recoverin, -SOX1, -titin, -Zic4, -GAD65, and -Tr) were negative. PCR was performed for enterovirus, herpesvirus, and Mycobacterium tuberculosis, which were negative in CSF. At that stage, the possibility of autoimmune encephalitis was considered, and a CSF sample was submitted to an external laboratory for the study of anti-NMDA glutamate receptor antibodies.\n\nFigure 1 MRI—nonpathological findings. MRI = magnetic resonance imaging.\n\nAfter showing immunoglobulin A levels within normal values, the patient was treated with immunoglobulins, 0.4 g/kg/day for 2 days, followed by 1 g/day methylprednisolone for 5 days. Given the lack of improvement after the second dose of immunoglobulins, rituximab was administered at 375 mg/m2/week.\n\nOn March 31, 2017, an abdominopelvic ultrasound revealed a moderate amount of free fluid in the pelvis, and a 5-cm solid-cystic tumor in the left adnexal region, suggestive of teratoma (Fig. 2). Given the suspicion of autoimmune encephalitis secondary to teratoma, an emergency surgical excision was decided by the Service of Gynecology. A laparoscopic left salpingo-oophorectomy was performed and it showed an image compatible with teratoma (Fig. 3)—which was confirmed in the postoperative analysis by pathological anatomy: “Mature cystic teratoma.” Multiple lavages of the abdominal cavity were performed to prevent—according to the literature—a chemical peritonitis caused by a potential spillage of the fluid of the sebaceous cyst.\n\nFigure 2 US—image compatible with 5 cm left ovarian teratoma. US = Ultrasound.\n\nFigure 3 Laparoscopic surgery—image compatible with ovarian teratoma.\n\nSimilarly, on April 4 our suspicions were confirmed with positive results in CSF for oligoclonal bands and anti-NMDA glutamate receptor antibodies, with titre 1:64 (negative in blood). Anti-AMPA 1 and 2 glutamate receptor, anti-LGI1, anti-GABAB1/B2 receptor and anti-VGKC antibodies were negative.\n\nIn the immediate postoperative period, the patient showed a slight improvement of her general symptoms. Afterward, she presented with fever of infectious origin, a maintained colonization of enterococci in blood and of multi-resistant Pseudomonas aeruginosa in bronchial aspirate. Consequently, the treatment with monoclonal antibodies was interrupted and plasmapheresis cycles were initiated (3 cycles with 5 sessions per cycle in total), with alternate-day high doses of steroids. A slight improvement in the myoclonus was observed after each session. The jejunal biopsy was negative for Whipple's disease on April 10. Repeated electroencephalograms (EEG) were performed, and they revealed generalized slowing with unspecific characteristics and without evidence of paroxysmal activity. Since May 11, a slight improvement was observed, with a decrease in myoclonic activity, which made it possible to reduce the sedation doses.\n\nOn June 27, after several days without fever and without any evidence of infection, treatment with rituximab was initiated again. In total, 4 doses were administered without relapse of infection.\n\nOn July 12, during one of the periods in which sedation was withdrawn and with almost no antiseizure treatment, the EEG (Fig. 4) showed clear epileptic activity and the antiseizure treatment was increased.\n\nFigure 4 Epileptic activity in EEG. EEG = electroencephalograms.\n\nGiven the profuse sialorrhea of the patient, which even interfered with her fluid balance, botulinum toxin was applied on July 22. Sialorrhea disappeared without signs of mouth dryness until discharge. On September 7, the tracheotomy cannula was removed.\n\nThe CSF and blood parameters during this period are presented in Table 1.\n\nTable 1 Follow-up of cerebrospinal fluid (CSF) and blood parameters.\n\nAfter 5 months in the ICU and several weeks in the Service of Neurology, the patient was discharged on September 29, 2017 with Glasgow score 15 and modified Rankin Scale (mRS) 3. She was capable of maintaining a conversation with some fluency and presented with slight dysarthria and ambulation with assistance. The anti-NMDA antibodies started to decrease 5 months after surgery. The patient is currently under antiepileptic and rehabilitation treatment, and she is monitored by the Service of Neurology.\n\nDue to there is no concern that a patient's anonymity cannot be maintained in written text or with use of photographs we consider that the ethical approval was waived or not necessary. However, the patient has provided informed consent for publication of the case.\n\nA timeline of the events is present in Figure 5.\n\nFigure 5 Timeline of events.\n\n3 Discussion\nEncephalitis is an acute or chronic inflammatory disease of the central nervous system (CNS) where the presence of the neuronal surface antibodies can be demonstrated.[6] The present clinical case described a progression of anti-NMDAR encephalitis. This relatively unusual disorder has a typical chronological presentation: sudden onset with prodromal, fever-like symptoms, followed by a psychiatric disorder, decreased level of consciousness with focal and clonic seizures, dyskinesias, and autonomic instability.[7] In our clinical case, all of the cited symptoms were observed, so the clinical course of the anti-NMDAR encephalitis was typical. Furthermore, the patient was a young woman, which is also a common feature of this type of autoimmunological encephalitis. The female patient population represents around 80% of reported cases.[8] Additionally, the coexistence of an ovarian tumor, a teratoma in this case, is also typical for anti-NMDAR encephalitis.\n\nWhen anti-NMDAR is suspected the diagnostic tests contain detection of NMDAR autoantibodies in CSF and/or in the serum as the fundamental part of diagnosis, predominantly because other laboratory tests and imaging studies are not relevant.[9] According to some authors, CSF antibody testing is highly sensitive and specific for anti-NMDAR encephalitis and false positive and negative results may occur when testing only serum.[10]\n\nThere is currently some discussion as to whether serum or CSF must be tested for in the presence of anti-NMDAR antibodies. In the present case, high levels of anti-NMDAR antibodies were detected in the CSF, but not in the plasma. The association between the prodromal flu-like symptoms and the antibodies against NMDAR is also a material of debate. Some authors emphasize the connection between a viral infection and injury of the blood–brain barrier, which facilitates transmission of NMDAR autoantibodies to the CNS.[11]\n\nAn EEG may be important in distinguishing between primary psychiatric disorder and encephalitis, since a vast majority of patients with anti-NMDAR encephalitis exhibit nonspecific slowing at a certain stage during the illness.\n\nTreatment for anti-NMDAR encephalitis remains challenging, due to the fact that no complete guidelines have been published to date.\n\nThe wide majority of authors agree that treatment must target both the cause and the clinical consequences of the encephalitis. Anti-NMDAR encephalitis treatment is more effective in patients who have a primary tumor removed and there are cases in which ovarian teratomas were discovered years after the initial onset of symptoms, mainly in patients with a slow recovery.[12] Some authors believe in early oophorectomy even in cases when the presence of an ovarian tumor cannot be established in imaging studies. In a case described by Peery et al[12] postoperative biopsy discovered an occult teratoma, and the tumorectomy resulted in an improvement of the symptoms. In most cases, immunotherapy is the first-line treatment and includes corticosteroids, IVIg and TPE, unaccompanied or in combination.[13] The second-line treatment includes rituximab and cyclophosphamide, and is used in patients who show a late diagnosis or did not have a primary malignancy.[14]\n\nIn the present case, the patient was firstly treated with corticosteroids (methylprednisolone), IVIg and rituximab. Nevertheless, she started with repeated infections, so rituximab had to be stopped. This first-line immunosuppressive treatment failed to produce any improvement of the patient's clinical condition. She only improved following the TPE, although clinical improvement of anti-NMDAR encephalitis is not always achieved with TPE.[15,16] According to the guidelines published by the American Society for Apheresis, the use of TPE must be considered as a third-line treatment in paraneoplastic neurological syndromes (grade 2C).[17] Regarding the role of plasmapheresis, we still have several debates and conflicting data in the literature. According to Dalmau et al[5] the use of plasmapheresis should not be routinely. On the other hand, there are recent data supporting the use of plasmapheresis to improve the patient clinical status.[18,19] DeSena et al[20] compare the use of plasmapheresis alone versus before intravenous corticoids in the treatment of anti-NMDAR receptor encephalitis, with better results in the last case.\n\nThis case report has some strengths and some limitations. Regarding the limitations, it is not based on systematic studies so, it may not be generalizable. However, this case report may help the medical identification of this rare disease and therefore is an important educational article.\n\n4 Conclusion\nNMDAR encephalitis mainly affects young women with ovarian teratomas and is a potentially lethal but reversible disorder with a good clinical outcome if diagnosed and treated promptly. The gold standard for diagnosing anti-NMDAR encephalitis is the detection of IgG antibodies against the GluN1 subunit of NMDA receptors in either the CSF or plasma; however, other diagnostic measures, including EEG or MRI may also assist clinicians in obtaining the diagnosis. The early detection of tumor, its surgical removal, and early immunotherapy make it possible to shorten the progression of disease, improve the survival rates, and limit the negative long-term consequences for the patients. So far TPE must similarly be considered in the clinician's armamentarium, mainly in cases where initial treatment has failed. In the current case, a long-term follow-up examination revealed a good clinical outcome, without any major neurological or psychiatric complications following the anti-NMDAR encephalitis. A multidisciplinary team, including gynecologist, psychiatrists, neurologists and intensivists, must be involved in the process of recognition and management of the disease. Available data remain unclear and therefore there is an urgent need for good quality clinical trials.\n\nAuthor contributions\nConceptualization: Monica Gomes Ferreira\n\nFormal analysis: Monica Gomes Ferreira.\n\nProject administration: Monica Gomes Ferreira.\n\nWriting – original draft: Monica Gomes Ferreira, Victoria Lapresa Alcalde.\n\nWriting – review & editing: Monica Gomes Ferreira, Maria Helena García Sánchez, Lourdes Hernández Hernández, María José Doyague Sánchez.\n\nAbbreviations: Anti-NMDAR = anti-N-methyl-D-aspartate receptor, CSF= cerebrospinal fluid, HSE = herpes simplex encephalitis, IVIg = intravenous immunoglobulins, TPE = therapeutic plasma exchange, PCR = polymerase chain reaction, CT = computed tomography, MRI = magnetic resonance imaging, EEG = electroencephalograms, mRS = modified Rankin scale, CNS = central nervous system.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Vitaliani R Mason W Ances B \nParaneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma . Ann Neurol \n2005 ;58 :594–604 .16178029 \n[2] Seki M Suzuki S Iizuka T \nNeurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis . J Neurol Neurosurg Psychiatry \n2008 ;79 :324–6 .18032452 \n[3] Dalmau J Gleichman AJ Hughes EG \nAnti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies . Lancet Neurol \n2008 ;7 :1091–8 .18851928 \n[4] Uchino A Iizuka T Urano Y \nPseudopiano playing motions and nocturnal hypoventilation in anti-NMDA receptor encephalitis: response to prompt tumor removal and immunotherapy . Intern Med \n2011 ;50 :627–30 .21422691 \n[5] Dalmau J Lancaster E Martinez-Hernandez E \nClinical experience and laboratory investigations in patients with anti-NMDAR encephalitis . Lancet Neurol \n2011 ;10 :63–74 .21163445 \n[6] Zuliani L Graus F Giometto B \nCentral nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition . J Neurol Neurosurg Psychiatry \n2012 ;83 :638–45 .22448032 \n[7] Granerod J Ambrose HE Davies NW \nUK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group: causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study . Lancet Infect Dis \n2010 ;10 :835–44 .20952256 \n[8] Titulaer MJ McCracken L Gabilondo I \nTreatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study . Lancet Neurol \n2013 ;12 :157–65 .23290630 \n[9] Motta E Gołba A Kazibutowska Z \nAnti-NMDA receptor encephalitis-case report . Neurol Neurochir Pol \n2012 ;46 :288–93 .22773517 \n[10] Gresa-Arribas N Titulaer MJ Torrents A \nAntibody titers at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study . Lancet Neurol \n2014 ;13 :167–77 . Epub 2013 Dec 18 .24360484 \n[11] Hammer C Stepniak B Schneider A \nNeuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity . Mol Psychiatry \n2014 ;19 :1143–9 .23999527 \n[12] Peery HE Day GS Doja A \nAnti-NMDA receptor encephalitis in children: the disorder, its diagnosis, and treatment . Handb Clin Neurol \n2013 ;112 :1229–33 .23622333 \n[13] Mann AP Grebenciucova E Lukas RV \nAnti-N-methyl-D-aspartate-receptor encephalitis: diagnosis, optimal management, and challenges . Ther Clin Risk Manag \n2014 ;10 :517–25 .25061311 \n[14] Florance NR Davis RL Lam C \nAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents . Ann Neurol \n2009 ;66 :11–8 .19670433 \n[15] Mirza MK Pogoriler J Paral K \nAdjunct therapeutic plasma exchange for anti-N-methyl-D-aspartate receptor antibody encephalitis: a case report and review of literature . J Clin Apher \n2011 ;26 :362–5 .22038876 \n[16] Ikeguchi R Shibuya K Akiyama S \nRituximab used successfully in the treatment of anti-NMDA receptor encephalitis . Intern Med \n2012 ;51 :1585–9 .22728495 \n[17] Schwartz J Winters JL Padmanabhan A \nGuidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue . J Clin Apher \n2013 ;28 :145–284 .23868759 \n[18] Zhang Y Gao D Ye H \nSafety of plasma exchange therapy in patients with anti-NMDA receptor encephalitis . Zhonghua Yi Xue Za Zhi \n2015 ;95 :1505–8 .26178503 \n[19] Shahani L \nSteroid unresponsive anti-NMDA receptor encephalitis during pregnancy successfully treated with plasmapheresis . BMJ Case Rep \n2015 ;2015 :bcr2014208823.\n[20] DeSena AD Noland DK Matevosyan K \nIntravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptor antibody encephalitis: a retrospective review . J Clin Apher \n2015 ;30 :212–6 .25664728\n\n",
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"mesh_terms": "D000328:Adult; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D010956:Plasmapheresis; D013724:Teratoma",
"nlm_unique_id": "2985248R",
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"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of anti-NMDA receptor encephalitis with early teratoma removal and plasmapheresis: A case report.",
"title_normalized": "successful treatment of anti nmda receptor encephalitis with early teratoma removal and plasmapheresis a case report"
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"abstract": "Little is known about severe anaphylaxis in the pediatric population. In this retrospective cohort study, we aimed to describe the characteristics of children who required admission from an outpatient setting to one of two Pediatric Intensive Care Units in Atlantic Canada with a primary diagnosis of anaphylaxis. During the 10-year study period, there were 12 admissions (58% females) for a population incidence of 2.4 per 100,000 children. Both patients who died were adolescents with a witnessed anaphylaxis event, immediately recognized as such after exposure to a known allergen, with immediate access to epinephrine that was not administered until after cardiorespiratory arrest occurred. This study highlights the high mortality associated with severe anaphylaxis and the ongoing need for education surrounding the early administration of intramuscular epinephrine.",
"affiliations": "Department of Paediatric Critical Care, IWK Health Centre, Halifax, Canada.;Department of Clinical Immunology and Allergy, Hospital for Sick Children, Toronto, Canada.;Department of Paediatric Critical Care, IWK Health Centre, Halifax, Canada.;Department of Paediatric Critical Care, IWK Health Centre, Halifax, Canada.",
"authors": "Krmpotic|Kristina|K|;Weisser|Caroline|C|;O'Hanley|Alexandra|A|;Soder|Christian|C|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0039-1683869",
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"issue": "8(2)",
"journal": "Journal of pediatric intensive care",
"keywords": "anaphylaxis; child; critical care; management; pediatric",
"medline_ta": "J Pediatr Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101592756",
"other_id": null,
"pages": "113-116",
"pmc": null,
"pmid": "31093466",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "17931562;20560905;22607557;25468198;25495512;29787624",
"title": "Incidence and Outcomes of Severe Anaphylaxis in Paediatric Patients in Atlantic Canada.",
"title_normalized": "incidence and outcomes of severe anaphylaxis in paediatric patients in atlantic canada"
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"abstract": "We report the first case of a ruptured intracranial aneurysm-related Staphylococcus epidermidis bacteremia in a patient supported by a continuous flow left ventricular assist device (LVAD). Mycotic aneurysms (MAs) are aneurysmal degeneration of the arterial wall as a result of infection. Current recommendations for management of intracranial mycotic aneurysms are based on a few retrospective case studies. There are only a few cases of intracranial MA reported in patients with LVAD infections caused by Pseudomonas aeruginosa and Klebsiella rhinos. Here, we describe the first case of a ruptured intracranial aneurysm caused by a less virulent organism (Staphylococcus epidermidis) and conclude that screening for asymptomatic MA should be strongly considered in patients with persistent LVAD- and implantable cardiac defibrillator pacemaker-associated infections.",
"affiliations": "Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA. Electronic address: dinesh-voruganti@uiowa.edu.;Division of Infectious Diseases, University of Iowa Hospitals and Clinics, Iowa City, IA.;Department of Surgery, Division of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA.;Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Cincinnati Hospitals, Cincinnati, OH.",
"authors": "Voruganti|D|D|;Gajurel|K|K|;Bhama|J K|JK|;Cotarlan|V|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.08.027",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "50(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000785:Aneurysm, Infected; D017147:Defibrillators, Implantable; D004697:Endocarditis, Bacterial; D005260:Female; D006353:Heart-Assist Devices; D006801:Humans; D002532:Intracranial Aneurysm; D008875:Middle Aged; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D013212:Staphylococcus epidermidis",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "4064-4066",
"pmc": null,
"pmid": "30577316",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ruptured Intracranial Mycotic Aneurysm in Infective Endocarditis With Left Ventricular Assist Device and Implantable Cardiac Defibrillator Device: A Clinical Course.",
"title_normalized": "ruptured intracranial mycotic aneurysm in infective endocarditis with left ventricular assist device and implantable cardiac defibrillator device a clinical course"
} | [
{
"companynumb": "US-009507513-1901USA002546",
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"abstract": "BACKGROUND\nHidradenitis suppurativa (HS) is a chronic and debilitating disorder. Despite its significant prevalence, few reports of therapeutic studies are available. Recent case studies have reported the efficacy of antitumor necrosis factor monoclonal antibodies in treating the condition. In the study presented here, we assessed the safety and efficacy of infliximab in a series of patients with severe HS.\n\n\nMETHODS\nWe reviewed all consecutive patients with severe HS and treated with infliximab between October 2004 and December 2005. They were evaluated using the Sartorius severity score, a physician and patient overall assessment, and the Skindex-29 quality-of-life index. A substantive response was defined as marked or moderate overall improvement assessed by both physician and patient.\n\n\nRESULTS\nSeven patients were reviewed. All received at least 3 infusions of infliximab (5 mg/kg) in weeks 0, 2, and 6, and 5 patients received a fourth infusion at week 10. At week 6, a substantive improvement was seen in 5 patients. With the other 2 patients, any improvement was minimal or nonexistent. At week 10, there was a substantive response in 2 of the 5 patients. Adverse events occurred in 3 patients: abdominal pain caused by colon cancer, a multifocal motor neuropathy with conduction block, and a severe allergic reaction.\n\n\nCONCLUSIONS\nWe have reported on only 7 patients. All had severe and chronic disease.\n\n\nCONCLUSIONS\nThe efficacy of infliximab in patients with severe HS seems transient and is associated with significant toxicity. Prospective randomized studies are required to better assess the benefit-risk ratio of antitumor necrosis factor agents for this indication.",
"affiliations": "Department of Dermatology, Hospital Saint-Antoine, Paris, France. laurence.fardet@sat.aphp.fr",
"authors": "Fardet|Laurence|L|;Dupuy|Alain|A|;Kerob|Delphine|D|;Levy|Annabelle|A|;Allez|Matthieu|M|;Begon|Edouard|E|;Bachelez|Hervé|H|;Morel|Patrice|P|;Lebbé|Celeste|C|",
"chemical_list": "D000911:Antibodies, Monoclonal; D003879:Dermatologic Agents; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2006.07.027",
"fulltext": null,
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"issn_linking": "0190-9622",
"issue": "56(4)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": null,
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D015331:Cohort Studies; D003879:Dermatologic Agents; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D017497:Hidradenitis Suppurativa; D006801:Humans; D000069285:Infliximab; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017060:Patient Satisfaction; D011379:Prognosis; D011788:Quality of Life; D018570:Risk Assessment; D012494:Sampling Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "7907132",
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"pmc": null,
"pmid": "17240478",
"pubdate": "2007-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Infliximab for severe hidradenitis suppurativa: transient clinical efficacy in 7 consecutive patients.",
"title_normalized": "infliximab for severe hidradenitis suppurativa transient clinical efficacy in 7 consecutive patients"
} | [
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"companynumb": "FR-JNJFOC-20200619486",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
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"... |
{
"abstract": "BACKGROUND\nAnaplastic large cell lymphoma is rarely diagnosed during pregnancy, and patients may be erroneously diagnosed with a dermatosis.\n\n\nMETHODS\nA 34-year-old female was diagnosed with pruritic urticarial papules and plaques of pregnancy in the third trimester. She underwent elective repeat cesarean section with a postoperative course complicated by skin and gingival ulcers and persistent fever. Imaging revealed lung and brain nodules. Video-assisted thoracic surgery lung biopsy demonstrated anaplastic large cell lymphoma.\n\n\nCONCLUSIONS\nIt is important to consider the diagnosis of anaplastic large cell lymphoma in a pregnant patient who presents with cutaneous symptoms.",
"affiliations": null,
"authors": "Kanj|Rula V|RV|;Gerber|Deanna|D|;Frey|Melissa K|MK|;Rahmanou|Farzin|F|;Hardy|Curtis|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"issn_linking": "0024-7758",
"issue": "60(5-6)",
"journal": "The Journal of reproductive medicine",
"keywords": null,
"medline_ta": "J Reprod Med",
"mesh_terms": "D000328:Adult; D001932:Brain Neoplasms; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D017728:Lymphoma, Large-Cell, Anaplastic; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011537:Pruritus; D017444:Skin Diseases, Papulosquamous; D014581:Urticaria",
"nlm_unique_id": "0173343",
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"title": "Anaplastic Large Cell Lymphoma in Pregnancy. A Case Report.",
"title_normalized": "anaplastic large cell lymphoma in pregnancy a case report"
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"abstract": "We report a case of acute vascular rejection occurring during antituberculosis therapy in a patient who had received a kidney transplant. A 29 year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.5 mg/dL 1 year after primary kidney transplantation. Histological examination yielded no evidence of rejection but a routine chest CT scan revealed typical lung tuberculosis and his serum was positive for QFT. We commenced antituberculosis therapy, including rifampicin, on June 29 2012. We paid close attention to the weekly trough tacrolimus (TAC) level but the S-Cr concentration increased to 3.7 mg/dL on October 16 2012, and he was admitted for biopsy. Histological examination revealed, first, a diffuse aggressive infiltration of tubulointerstitial inflammatory cells accompanied by severe tubulitis and mild intimal arteritis and, second, peritubular capillary infiltration by inflammatory cells (including neutrophils). Laboratory data revealed that our patient did not express donor-specific antibody and the peritubular capillaries did not exhibit C4d immunoreactivity. Upon consideration of both histological and laboratory findings, we diagnosed acute vascular rejection of Banff 2007 class ACR IIA. We commenced 3-day sessions of intravenous steroid pulse therapy twice weekly and adjusted the trough TAC level to 5-8 ng/mL by varying the TAC dose. We next performed an allograft biopsy and found no evidence of rejection (the S-Cr level was 2.7 mg/dL on April 1 2013). The present case report demonstrates the difficulties associated with management of TAC-based regimens in kidney transplant patients undergoing antituberculosis therapy. We also review the relevant literature.",
"affiliations": "Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Nakada|Yasuyuki|Y|;Yamamoto|Izumi|I|;Kobayashi|Akimitsu|A|;Mafune|Aki|A|;Yamakawa|Takafumi|T|;Matsuo|Nanae|N|;Tanno|Yudo|Y|;Ohkido|Ichiro|I|;Yamamoto|Hiroyasu|H|;Yokoyama|Keitaro|K|;Yokoo|Takashi|T|",
"chemical_list": "D000995:Antitubercular Agents; D013256:Steroids",
"country": "Australia",
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"doi": "10.1111/nep.12244",
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"issn_linking": "1320-5358",
"issue": "19 Suppl 3()",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": "acute vascular rejection; antituberculosis therapy; rifampicin",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000995:Antitubercular Agents; D006084:Graft Rejection; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D011183:Postoperative Complications; D013256:Steroids; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9615568",
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"pages": "27-30",
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"pmid": "24842818",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute vascular rejection during antituberculosis therapy in a kidney transplant patient.",
"title_normalized": "acute vascular rejection during antituberculosis therapy in a kidney transplant patient"
} | [
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"abstract": "Overactive bladder (OAB) is urgency, with or without urgency incontinence. For OAB, an injection of onabotulinumtoxin A (BOTOX®) can be a low-risk outpatient procedure. We present a patient on a novel anticoagulant that experienced excessive bleeding after this procedure. This 80-year-old G2P2002 Caucasian female had a history of urge urinary incontinence. She presented for intravesicular onabotulinumtoxin A injection (150 units) after recent initiation of rivaroxaban (Xarelto®) for her atrial fibrillation. Several hours after an uncomplicated procedure, she presented with anuria and pain after gross hematuria earlier in the day. Her pain was immediately alleviated with bladder irrigation. She was discharged home and remained asymptomatic. With the popularity of the novel anticoagulants, new guidance on management of these medications during procedures is limited. When managing a patient on a novel anticoagulant before any procedure, even a low risk procedure, several factors should be considered to determine if the medication should be held, bridged, or continued. In sum, each patient on anticoagulation undergoing any procedure should be assessed individually for thrombotic risk, bleeding risk, and the procedural risk to best avoid postprocedural hemorrhage.",
"affiliations": "Department of Urogynecology in Obstetrics & Gynecology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Department of Urogynecology in Obstetrics & Gynecology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Department of Urogynecology in Obstetrics & Gynecology, Walter Reed National Military Medical Center, Bethesda, MD, USA.",
"authors": "Eubanks|Allison|A|0000-0002-2980-3857;Dengler|Katherine|K|;Gruber|Daniel|D|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2019/5947153",
"fulltext": "\n==== Front\nCase Rep Obstet GynecolCase Rep Obstet GynecolCRIOGCase Reports in Obstetrics and Gynecology2090-66842090-6692Hindawi 10.1155/2019/5947153Case ReportIntravesicular Onabotulinumtoxin A Hemorrhage on Rivaroxaban http://orcid.org/0000-0002-2980-3857Eubanks Allison aac.eubanks@gmail.comDengler Katherine Gruber Daniel Department of Urogynecology in Obstetrics & Gynecology, Walter Reed National Military Medical Center, Bethesda, MD, USAAcademic Editor: Erich Cosmi\n\n2019 2 1 2019 2019 594715323 7 2018 27 11 2018 Copyright © 2019 Allison Eubanks 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.Overactive bladder (OAB) is urgency, with or without urgency incontinence. For OAB, an injection of onabotulinumtoxin A (BOTOX®) can be a low-risk outpatient procedure. We present a patient on a novel anticoagulant that experienced excessive bleeding after this procedure. This 80-year-old G2P2002 Caucasian female had a history of urge urinary incontinence. She presented for intravesicular onabotulinumtoxin A injection (150 units) after recent initiation of rivaroxaban (Xarelto®) for her atrial fibrillation. Several hours after an uncomplicated procedure, she presented with anuria and pain after gross hematuria earlier in the day. Her pain was immediately alleviated with bladder irrigation. She was discharged home and remained asymptomatic. With the popularity of the novel anticoagulants, new guidance on management of these medications during procedures is limited. When managing a patient on a novel anticoagulant before any procedure, even a low risk procedure, several factors should be considered to determine if the medication should be held, bridged, or continued. In sum, each patient on anticoagulation undergoing any procedure should be assessed individually for thrombotic risk, bleeding risk, and the procedural risk to best avoid postprocedural hemorrhage.\n==== Body\n1. Introduction\nThe International Continence Society defines overactive bladder (OAB) as “urgency, with or without urgency incontinence usually with increased daytime frequency and nocturia” [1]. OAB often has a significant impact on quality of life.\n\nBehavioral modifications are first-line treatment for OAB. The patient should focus on lifestyle changes, such as weight loss, caffeine and alcohol reduction, bladder control strategies, and fluid management. In addition, pelvic floor physical therapy can help with bladder retraining and pelvic floor muscle training. If these conservative measures fail then medication, nerve stimulation, and injection of bladder onabotulinumtoxin A (BOTOX®) can help relax detrusor muscles.\n\nIntravesicular onabotulinumtoxin A injection is a quick, outpatient procedure that has been shown to be more effective than mirabegron in a large meta-analysis and, furthermore, without the invasiveness of sacral neuromodulation as shown in a randomized control trial [1, 2]. The risks of this procedure include urinary tract infections, elevated postvoid residual volumes requiring intermittent catheterization, and hematuria that can occur in 3.6-5.2% of patients [2, 3].\n\nAs the likelihood of overactive bladder increases with patient age along with other medical comorbidities, it is not uncommon for patients with OAB to be on blood thinners. Furthermore, patients are on newer, novel anticoagulants that do not have reversal agents. Given the small size of the needle and minimal bleeding expected, there is currently no guidance on stopping or bridging any anticoagulation medications for this same day procedure typically performed in the office setting.\n\n2. Case\nThis is the case of an 80-year-old G2P2002 Caucasian female with a long history of urge urinary incontinence. She presented to clinic for intravesicular onabotulinumtoxin A injection (150 units). She had undergone this procedure seven times with six- to twelve-month intervals, depending on the return of symptoms, ranging from 50 to 150 units of onabotulinumtoxin A since March of 2011. These treatments have significantly improved her symptoms of urgency incontinence after previously trying several anticholinergic medications and sacral neuromodulation.\n\nHer other past medical history is significant for hypertension, peripheral vascular disease, scoliosis, hypothyroidism, diverticulosis, and open-angle glaucoma. She was diagnosed with paroxysmal atrial fibrillation in the beginning of 2016 and developed renal emboli prior to initiation of warfarin. She was transitioned to rivaroxaban (Xarelto®) in mid-2016 after struggling with frequent clinic visits and limited diet while on warfarin. She tolerated this medication transition well.\n\nThe patient had not undergone intravesicular onabotulinumtoxin A injections while on warfarin but however did have a single treatment just one month after initiating rivaroxaban without issues. She returned for the repeat procedure one year later. Using sterile technique, the bladder was filled with 20 mL of 1% lidocaine and 2% viscous lidocaine was administered to the urethra 15 minutes before the procedure. The onabotulinumtoxin A dose was reconstituted in 20 milliliters' saline solution. A 30-degree operative cystoscope was inserted into the bladder. A total of 150 units of onabotulinumtoxin A were injected into the bladder wall in 20 sites with one milliliter in each injection covering the posterior surface of the bladder wall and sparing the trigone. The depth of the injection was set at 3 mm under the urothelium layer with the Laborie injeTAK® (Williston, VT) needle; see Figures 1–6. The patient tolerated the procedure well. There was minor bleeding from a few needle injection sites, but not an atypical amount. She voided immediately after the procedure without difficulty and was sent home from the office feeling well.\n\nSeven hours later, the patient called the clinic and reported two hours of frank blood in her urine with passage of several clots. She reported drinking large volumes of water and frequent voiding without improvement. She was encouraged to keep her bladder full to allow distension to tamponade the bleeding, rather than empty frequently. She was given strict return precautions to present to the emergency department if her bleeding persisted or for any retention symptoms. The following morning, the patient presented to the emergency department in pain with no urine output for the last several hours. She was given intravenous morphine, which alleviated her immediate pain.\n\nA 14-French Foley catheter was placed and slowly drained dark red urine with clots. Only about 200 milliliters returned in the catheter. Several flushes were attempted to alleviate the blockage without success. Continuous bladder irrigation (CBI) was initiated which cleared the obstruction. The patient continued to put out frank blood with the CBI. Her complete blood cell count was normal and did not show a significant drop [15.2/45.8 to 14.0/43.5]. Her pain was completely alleviated with the CBI until new clots developed that caused a repeat obstruction two more times overnight requiring Foley adjustment.\n\nCardiology was consulted to aid with management of her anticoagulation in the setting of bleeding and her rivaroxaban was held for three days. Following 36 hours of CBI, her urine was lighter, indicating bleeding cessation. The CBI was stopped and the patient was taught to flush the catheter with normal saline.\n\nThe patient returned for a scheduled clinic appointment four days later and reported that she only had a few episodes of hematuria that resolved with minimal flushing. The bladder was back-filled with 400 milliliters and the Foley catheter removed. She voided 350 milliliters of clear yellow urine without difficulty. The patient continued on prophylactic nitrofurantoin for ten days. She followed up three weeks later without return of the hematuria. She reported some continued overactive bladder symptoms such as frequent voiding, some urgency incontinence upon standing, and nighttime voids up to four to five times per night; however the frequency of these symptoms was all decreased from prior to her procedure. She continues to find the best solution to manage her symptoms.\n\n3. Discussion\nDespite the resulting hemorrhage from this intravesicular onabotulinumtoxin A injection, bleeding with this procedure is rare. This case is significant in that bleeding is so rare and the injection sites are so small. The patient had additionally not bled during the procedure while previously on rivaroxaban, approximately one year priorly. She reported no tobacco or alcohol use, and her medications at the time of this procedure had not changed.\n\nAntifactor Xa was not collected during or around the time of either procedure. Her weight and renal function remained unchanged and liver function was previously normal. However, it is important to consider any changes to these values in patients on novel anticoagulants as they can cause patients to be supratherapeutic and increase risk of bleeding with even minor procedures. There is only one case report that reviews the management of a patient using warfarin before intravesicular onabotulinumtoxin A injection [4]. The purpose of that publication was to simply demonstrate the proper discontinuation, bridging management, and reinitiation of warfarin to safely complete the procedure for a patient [4].\n\nAllergan, the onabotulinumtoxin A manufacturer, does not list anticoagulation as a contraindication and suggests only managing patients on anticoagulant therapy appropriately to decrease the risk of bleeding [5]. It is at the clinician's discretion to determine the procedural bleeding risk and weigh the patient's thrombotic risk.\n\nSpyropoulos et al. and the American College of Cardiology (ACC) both compiled a list of procedures and delineated their bleed risk level [6, 7]. According to the list from Spyropoulos et al., a bladder biopsy is considered a low procedural risk, with a 2-day risk of major bleed at 0% to 2%. According to the list from the ACC, as contributed by Dr. Bruce Jacobs and the American Urological Association, uncomplicated ureteral stenting and exchange is considered a low bleed risk. Intravesicular onabotulinumtoxin A injections are much less invasive than bladder biopsies and less invasive than ureteral stenting. ACCP gives 2C recommendations regarding continuing vitamin K antagonists (VKAs) in minor dermatologic procedures and cataract surgery. It is also recommended to discontinue VKAs for two to three days before the procedure or coadministration of an oral prohemostatic, a suggestion that may be applied to this situation [8].\n\nThe patient was taking rivaroxaban for paroxysmal atrial fibrillation, diagnosed in the wake of a renal infarct attributed to a cardioembolic source. Given the prior documented history of cardioembolic phenomenon to the kidneys, the patient's cardiologist determined that she requires lifelong anticoagulation. Her CHA2DS2-Vasc score of at least five points estimated her stroke risk at 7.2% per year. It was not unreasonable to continue anticoagulation during this minimal procedure for such a high-risk patient.\n\nIn future intravesicular onabotulinumtoxin A injections performed for this patient, and similar patients, it would be reasonable to consider discontinuing her anticoagulant for two to three days before procedure and bridging with low-molecular weight heparin or heparin. The physician could also consider coadministering an oral prohemostatic agent such as tranexamic acid. Working with the prescribing physician managing these medications and comorbidities may prove beneficial. However, for other intravesicular onabotulinumtoxin A procedures performed for OAB, we would continue to treat this as a low-risk procedure. Each patient on anticoagulation undergoing any procedure should be assessed individually for thrombotic risk, bleeding risk, and the procedural risk to best avoid postprocedural hemorrhage.\n\nEthical Approval\nIRB approval was not required for this case report. It has been submitted for local institutional publication approval.\n\nConsent\nThe involved patient has signed consent for publication.\n\nDisclosure\nThe opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Departments of the Army, Navy, Air Force, or the Department of Defense.\n\nConflicts of Interest\nThe authors report no conflicts of interest or disclosures.\n\nFigure 1 Laborie injeTAK® (Williston, VT) needle.\n\nFigure 2 Injection of needle through uroepithelium.\n\nFigure 3 Needle retracting from uroepithelium, appropriate amount of bleeding noted.\n\nFigure 4 Needle replaced into uroepithelium.\n\nFigure 5 Needle removed completely with no bleeding noted from injection site.\n\nFigure 6 Needle replaced into uroepithelium, appropriate amount of bleeding noted.\n==== Refs\n1 Freemantle N. Ginsberg D. A. McCool R. Comparative assessment of onabotulinumtoxinA and mirabegron for overactive bladder: An indirect treatment comparison BMJ Open 2016 6 2 2-s2.0-84960398542 10.1136/bmjopen-2015-009122 e009122 26908514 \n2 Chapple C. Sievert K.-D. Macdiarmid S. OnabotulinumtoxinA 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: A randomised, double-blind, placebo-controlled trial European Urology 2013 64 2 249 256 2-s2.0-84879972906 10.1016/j.eururo.2013.04.001 23608668 \n3 Ginsberg D. Gousse A. Keppenne V. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity The Journal of Urology 2012 187 6 2131 2139 2-s2.0-84861095162 10.1016/j.juro.2012.01.125 22503020 \n4 Peters G. L. Vouri S. M. Use of onabotulinumtoxinA for overactive bladder with concomitant warfarin The Consultant Pharmacist: The Journal of the American Society of Consultant Pharmacists 2014 29 7 480 486 10.4140/TCP.n.2014.480 25203108 \n5 Botox (onabotulinumtoxinA) [package insert] 2017 Irvine, CA, USA Allergan \n6 Spyropoulos A. C. Douketis J. D. How I treat anticoagulated patients undergoing an elective procedure or surgery Blood 2012 120 15 2954 2962 2-s2.0-84867881603 10.1182/blood-2012-06-415943 22932800 \n7 Common Procedures And Associated Procedural Bleed Risk 2017 American College of Cardiology http://jaccjacc.acc.org/Clinical_Document/PMAC_Online_Appendix.pdf \n8 Douketis J. D. Spyropoulos A. C. Spencer F. A. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines Chest 2012 141 2 e326S e350S 22315266\n\n",
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"issue": "2019()",
"journal": "Case reports in obstetrics and gynecology",
"keywords": null,
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"title": "Intravesicular Onabotulinumtoxin A Hemorrhage on Rivaroxaban.",
"title_normalized": "intravesicular onabotulinumtoxin a hemorrhage on rivaroxaban"
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"abstract": "The primary objective of this study was to determine the activity and safety of 3-weekly oxaliplatin combined with gemcitabine and oral capecitabine in the first-line treatment of advanced biliary tract cancer. Treatment consisted of intravenous oxaliplatin 100 mg/m every 3 weeks combined with intravenous gemcitabine 1000 mg/m on days 1 and 8 and oral capecitabine 1500 mg/m 14 days on 21 in two divided doses. Treatment was administered until progressive disease, unacceptable toxicity, or patient refusal. Thirty-seven patients were enrolled: eight patients had Eastern Cooperative Oncology Group 2 performance status at presentation. The overall response rate was 35.1% [95% confidence interval (CI): 20.2-52.5%] and the disease control rate was 72.9%. The median progression-free survival was 9.4 months (95% CI: 4.1-12.2 months) and the median overall survival was 13.8 months (95% CI: 7.7-17.1 months). There were no grade 4 toxicities. Grade 3 neutropenia occurred in 13.5% of patients and grade 3 thrombocytopenia in 10.8%. The present study suggests that 3-weekly oxaliplatin combined with gemcitabine and oral capecitabine is an active and well-tolerated chemotherapy regimen in the first-line treatment of metastatic biliary tract cancer.",
"affiliations": "aMedical Oncology Unit bPharmacology Unit, Department of Medicine, Surgery and Neuroscience cUnit of General and Minimally Invasive Surgery dUnit of Surgical Oncology, Department of Surgery and Neurosciences, University of Siena, Siena eMedical Oncology Unit, Policlinico Umberto I Hospital, University of Rome, Rome, Italy.",
"authors": "Petrioli|Roberto|R|;Roviello|Giandomenico|G|;Fiaschi|Anna I|AI|;Laera|Letizia|L|;Roviello|Franco|F|;Marrelli|Daniele|D|;Francini|Edoardo|E|",
"chemical_list": "D003841:Deoxycytidine; D000069287:Capecitabine; C056507:gemcitabine; D005472:Fluorouracil",
"country": "England",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D017734:Bile Ducts, Extrahepatic; D001653:Bile Ducts, Intrahepatic; D001661:Biliary Tract Neoplasms; D000069287:Capecitabine; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D005706:Gallbladder Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis",
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"title": "Three-weekly oxaliplatin combined with gemcitabine and capecitabine in the first-line treatment of patients with advanced biliary tract cancer.",
"title_normalized": "three weekly oxaliplatin combined with gemcitabine and capecitabine in the first line treatment of patients with advanced biliary tract cancer"
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"abstract": "Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9-24 years) with ALL who developed Grade 3-4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy. Five of these patients were treated with levocarnitine with subsequent improvement of hyperbilirubinemia, while one patient was given levocarnitine prophylactically during induction and developed Grade 3 hyperbilirubinemia, but did not require therapy adjustments or delays. Increased awareness in the pediatric oncology community regarding asparaginase-associated hepatic toxicity and the potential role of levocarnitine in management is warranted.",
"affiliations": "a Department of Pediatrics, Division of Pediatric Hematology/Oncology , Monroe Carell Jr. Children's Hospital, Vanderbilt University Medical Center , Nashville , TN , USA.;b Division of Pediatric Hematology/Oncology , Children's Hospital and Research Center , Oakland , CA , USA.;c Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation , New York Medical College , Valhalla , NY , USA.;c Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation , New York Medical College , Valhalla , NY , USA.;d Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplantation , Medical College of Wisconsin , Milwaukee , WI , USA.;e Department of Pediatrics, Section of Pediatric Hematology/Oncology/Stem Cell Transplant , University of Chicago Medical Center , Chicago , IL , USA.;f Department of Medicine, Division of Hematology and Medical Oncology, and Department of Pediatrics, Division of Pediatric Hematology/Oncology, OHSU Doernbecher Children's Hospital , Oregon Health and Science University , Portland , OR , USA.;g Department of Radiation Medicine , Oregon Health and Science University , Portland , OR , USA.",
"authors": "Schulte|Rachael R|RR|0000-0002-7869-9099;Madiwale|Manasi V|MV|;Flower|Allyson|A|;Hochberg|Jessica|J|;Burke|Michael J|MJ|;McNeer|Jennifer L|JL|;DuVall|Adam|A|;Bleyer|Archie|A|0000-0001-7738-5146",
"chemical_list": "D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase; D002331:Carnitine",
"country": "United States",
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"issue": "59(10)",
"journal": "Leukemia & lymphoma",
"keywords": "ALL; Asparaginase; hepatic injury; hyperbilirubinemia; leukemia; levocarnitine",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002331:Carnitine; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia; D008099:Liver; D008111:Liver Function Tests; D008297:Male; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D016896:Treatment Outcome; D014463:Ultrasonography; D055815:Young Adult",
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"references": null,
"title": "Levocarnitine for asparaginase-induced hepatic injury: a multi-institutional case series and review of the literature.",
"title_normalized": "levocarnitine for asparaginase induced hepatic injury a multi institutional case series and review of the literature"
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... |
{
"abstract": "BACKGROUND\nTo identify demographic and clinical characteristics associated with cases of hepatosplenic T-cell lymphoma (HSTCL) in patients with Crohn's disease, and to assess strength of evidence for a causal relationship between medications and HSTCL in Crohn's disease.\n\n\nMETHODS\nWe identified cases of HSTCL in Crohn's disease in studies included in a comparative effectiveness review of Crohn's disease medications, through a separate search of PubMed and Embase for published case reports, and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We used three causality assessment tools to evaluate the relationship between medication exposure and HSTCL.\n\n\nRESULTS\nWe found 37 unique cases of HSTCL in patients with Crohn's disease. Six cases were unique to the published literature and nine were unique to AERS. Cases were typically young (<40 years of age) and male (86%). The most commonly reported medications were anti-metabolites (97%) and anti-tumor necrosis factor alpha (anti-TNFa) medications (76%). Dose and duration of therapy were not consistently reported. Use of aminosalicylates and corticosteroids were rarely reported, despite the high prevalence of these medications in routine treatment. Using the causality assessment tools, it could only be determined that anti-metabolite and anti-TNFa therapies were possible causes of HSTCL in Crohn's disease based on the data contained in the case reports.\n\n\nCONCLUSIONS\nSystematic reviews that incorporate case reports of rare lethal events should search both published literature and AERS, but consideration should be given to the limitations of case reports. In this study, establishing a causative effect other than 'possible' between anti-metabolite or anti-TNFa therapies and HSTCL was not feasible because case reports lacked data required by the causality assessments, and because of the limited applicability of causality assessment tools for rare irreversible events. We recommend minimum reporting requirements for case reports to improve causality assessment and routine reporting of rare life-threatening events, including their absence, in clinical trials to help clinicians determine whether rare adverse events are causally related to a medication.",
"affiliations": "Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205-2196, USA. sselvar1@jhmi.edu",
"authors": "Selvaraj|Saranya A|SA|;Chairez|Elizabeth|E|;Wilson|Lisa M|LM|;Lazarev|Mark|M|;Bass|Eric B|EB|;Hutfless|Susan|S|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000963:Antimetabolites; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1186/2046-4053-2-53",
"fulltext": "\n==== Front\nSyst RevSyst RevSystematic Reviews2046-4053BioMed Central 2046-4053-2-532382692810.1186/2046-4053-2-53MethodologyUse of case reports and the Adverse Event Reporting System in systematic reviews: overcoming barriers to assess the link between Crohn’s disease medications and hepatosplenic T-cell lymphoma Selvaraj Saranya A 14sselvar1@jhmi.eduChairez Elizabeth 2elizabeth_chairez@valleymed.orgWilson Lisa M 1lisawilson@jhmi.eduLazarev Mark 1mlazare@jhmi.eduBass Eric B 13ebass@jhmi.eduHutfless Susan 1shutfle1@jhmi.edu1 Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205-2196, USA2 Valley Medical Center, 400 South 43rd Street, Renton, WA 98055-5010, USA3 Johns Hopkins University Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA4 University of Maryland Medical Center, 22 South Greene Street, Room N3E09, Baltimore, MD 21201-1595, USA2013 5 7 2013 2 53 53 16 3 2013 24 6 2013 Copyright © 2013 Selvaraj et al.; licensee BioMed Central Ltd.2013Selvaraj 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/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nTo identify demographic and clinical characteristics associated with cases of hepatosplenic T-cell lymphoma (HSTCL) in patients with Crohn’s disease, and to assess strength of evidence for a causal relationship between medications and HSTCL in Crohn’s disease.\n\nMethods\nWe identified cases of HSTCL in Crohn’s disease in studies included in a comparative effectiveness review of Crohn’s disease medications, through a separate search of PubMed and Embase for published case reports, and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We used three causality assessment tools to evaluate the relationship between medication exposure and HSTCL.\n\nResults\nWe found 37 unique cases of HSTCL in patients with Crohn’s disease. Six cases were unique to the published literature and nine were unique to AERS. Cases were typically young (<40 years of age) and male (86%). The most commonly reported medications were anti-metabolites (97%) and anti-tumor necrosis factor alpha (anti-TNFa) medications (76%). Dose and duration of therapy were not consistently reported. Use of aminosalicylates and corticosteroids were rarely reported, despite the high prevalence of these medications in routine treatment. Using the causality assessment tools, it could only be determined that anti-metabolite and anti-TNFa therapies were possible causes of HSTCL in Crohn’s disease based on the data contained in the case reports.\n\nConclusion\nSystematic reviews that incorporate case reports of rare lethal events should search both published literature and AERS, but consideration should be given to the limitations of case reports. In this study, establishing a causative effect other than ‘possible’ between anti-metabolite or anti-TNFa therapies and HSTCL was not feasible because case reports lacked data required by the causality assessments, and because of the limited applicability of causality assessment tools for rare irreversible events. We recommend minimum reporting requirements for case reports to improve causality assessment and routine reporting of rare life-threatening events, including their absence, in clinical trials to help clinicians determine whether rare adverse events are causally related to a medication.\n\nCrohn’s diseaseHepatosplenic T-cell lymphomaCausality assessmentAdverse event reportingCase reportsSystematic reviews\n==== Body\nBackground\nCrohn’s disease is an idiopathic, chronic, inflammatory bowel disease that affects the gastrointestinal tract. An estimated 565,000 to 720,000 people in the United States have Crohn’s disease [1]. In the 1950s, corticosteroids and sulfasalazine were adopted as the first immunosuppressive treatments for Crohn’s disease, followed by the anti-metabolites, 6-mercaptopurine and azathioprine, in the 1960s [2]. The twenty-first century has brought with it the first biologic agent for Crohn’s disease, infliximab, a monoclonal antibody against tumor necrosis factor alpha (anti-TNFa). Adalimumab and certolizumab pegol are the other approved anti-TNFa agents.\n\nHepatosplenic T-cell lymphoma (HSTCL) is a rare and often fatal outcome associated with Crohn’s disease. A boxed warning was issued in 2006 for an association between infliximab and HSTCL. As of October 2011, the label for infliximab reads:\n\n‘Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers including infliximab. All infliximab cases were reported in patients with Crohn’s disease or ulcerative colitis, the majority of whom were adolescent or young adult males. All had received azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to diagnosis (brand name changed to generic in italics)’ [3].\n\nDespite increasing concerns about the use of anti-TNFa medications, there is no definitively established causal mechanism for HSTCL. Risk factors for HSTCL are thought to include young age, male gender, Crohn’s disease, and renal transplantation [4]. However, HSTCL has occurred in the absence of immunosuppressive treatment and immunodeficiency [5]. Symptoms of HSTCL include fever, cytopenias, and an enlarged spleen and liver [4]. Because of the rarity of HSTCL, cases are unlikely to be identified in trials. Case reports leading to better understanding of Crohn’s disease patients who experience HSTCL may help to identify those patients at increased risk. Causality assessment tools developed for case reports can then be used to determine the likelihood that a medication is causally associated with HSTCL.\n\nWe aimed to identify demographic and clinical characteristics and medication histories associated with HSTCL in Crohn’s disease cases published in the peer-reviewed literature or reported to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database. We used three different causality assessment tools to assess the strength of evidence supporting a causal relationship between medication exposures and HSTCL in Crohn’s disease. This project was performed as part of a comparative effectiveness review of treatments for Crohn’s disease [6]. We will also discuss the implications of our findings for the use of case reports in systematic reviews.\n\nMethods\nLiterature search and identification of cases from the published literature\nPubMed and Embase were queried on 25 January 2011 using predetermined search strings that included the terms ‘Crohn’s disease,’ ‘inflammatory bowel disease,’ and ‘hepatosplenic T cell lymphoma’ (see full search strings in Additional file 1: Table S1). We included all study types with human patients. Studies were excluded if they were not written in English or if they did not include patients with Crohn’s disease who had developed HSTCL. Additionally, all studies that met the inclusion criteria for the original systematic review were included if they specifically mentioned HSTCL. We also performed a hand-search of references in relevant articles. To avoid double counting of cases that had been reported multiple times in the literature, we checked the footnotes and references, as well as the demographic and clinical characteristics.\n\nSearch of the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database and identification of AERS cases\nThe FDA AERS database was searched for all reported cases of HSTCL from January 2004, the first year data is available online, through December 2010. Only cases that had Crohn’s disease listed as an indication for therapy were included. To avoid double counting of cases reported by multiple sources (such as by a treating physician and a pharmaceutical company), the case entries were matched by case number. If the case number did not match but the report had identical information for three of five criteria (age at diagnosis, date of death, diagnosis date, reporting country, sex), then this entry was reported as a unique case, similar to previous efforts to avoid duplicates using AERS [7].\n\nMatching cases from the published literature with AERS cases\nWe sought to distinguish cases reported in both the published literature and AERS from those cases reported in only one source, using the following information: age at HSTCL diagnosis; date of HSTCL diagnosis or date of publication or AERS report when HSTCL date not reported; sex; medication history; reporting country (AERS) or country of origin (published literature); and date of death (AERS) or survival status or months of survival (published literature) (see Additional file 2: Table S2). If a case report from AERS and the literature matched on three of the five criteria, then the case was reported as a single unique case reported in both sources. We then identified cases reported in the published literature or AERS with sufficient information to consider them a unique case reported in only one source. Finally, some entries did not have sufficient details to determine if they were a unique case. We recorded the demographics of entries with insufficient reporting, but excluded the entries with insufficient reporting from the causality assessment.\n\nCausality assessment\nTo evaluate the evidence supporting the association of medication exposures with HSTCL, we used causality assessment tools developed by the World Health Organization (WHO), Naranjo et al., and Kramer et al. [8-10]. Two evaluators (EC and SS) independently calculated the causality assessment score for each medication used in each case and then met to discuss and resolve by consensus differences between the scores.\n\nTable 1 compares the characteristics and content of the three causality assessments. The Naranjo and Kramer assessments produced numerical scores that corresponded with causal categories of definite, probable, possible, and unlikely/doubtful. The WHO assessment assigns cases to the same categories as well as two additional categories of conditional/unclassified and unassessable/unclassifiable.\n\nTable 1 Characteristics of published instruments assessing causal relationship between medication exposure and adverse events\n\n \tNaranjo\tKramer\tWHO\t\nNumerical range\t−4 to +13\t−7 to +7\tn/a\t\nFormat\tTen questions answered ‘yes,’ ‘no,’ or ‘don’t know,’ each with a numerical value; numbers summed for final score. Higher scores indicate greater likelihood of causality.\tAn algorithm with six separate axes/flowcharts. Each axis contributes points to the final score. Higher scores indicate greater likelihood of causality.\tContains six categories; the user selects the one for which most criteria are met.\t\nDistinguishes irreversible adverse events from other adverse events?\tNo\tYes\tNo\t\nAddresses methods used to confirm adverse event?\tYes\tNo\tNo\t\nAsks about serum medication levels?\tYes\tYes\tNo\t\nConsiders prior experience with medication?\tYes\tYes\tYes\t\nConsiders alternate etiologies?\tYes\tYes\tYes\t\nQuestions about rechallenge?\tYes\tYes\tYes\t\nQuestions about dechallenge?\tYes\tYes\tYes\t\nn/a, not applicable; WHO, World Health Organization.\n\nResults\nSearch results and identification of unique cases\nOf the 123 citations identified by the PubMed and Embase searches, 19 case reports or case series [5,11-28] and three conference-presentation abstracts [29-31] met the inclusion criteria of reporting at least one Crohn’s disease-related HSTCL case (Figure 1). Three additional conference-presentation abstracts were identified through a hand-search of the references of the included articles [32-34]. No comparative studies that met the inclusion criteria for the systematic review reported a case of HSTCL. One prospective study reported specifically that no cases of HSTCL were observed [35]. Thirty-four cases were identified from the published literature with 28 having sufficient information to be considered unique cases.\n\nFigure 1 Identification of unique cases by PubMed and Embase searches. AERS, Adverse Event Reporting System; HSTCL, hepatosplenic T-cell lymphoma.\n\nA search of the publicly available AERS data files yielded 139 patient identification numbers representing 50 unique case numbers, which after matching yielded 34 cases with 31 having sufficient information to be considered unique.\n\nAfter matching unique cases from the published literature with the unique cases from AERS, 37 total cases were considered unique (22 from both sources, six from the published literature only, and nine from AERS only; Additional file 1: Table S1). Thirty-six HSTCL cases were considered unique based on age, sex, and medication exposures. An additional case was considered unique based on the case’s use of cyclosporine even though age at HSTCL diagnosis and sex were not reported [32]. Nine cases had insufficient reporting (Additional file 2: Table S2).\n\nDemographics, presenting symptoms and survival\nThe 37 unique patients were young (84% of patients were younger than age 40 years) and male (86%; Table 2). Patients had Crohn’s disease for a mean of 10 years prior to their diagnosis of HSTCL (range: 4 to 35 years). All patients reporting any symptoms presented with hepatosplenomegaly or splenomegaly (100%), and approximately one-half presented with fever (47%) or cytopenia (58%). The median length of survival among the 26 cases with information was 7 months (range: 5 days to 9.7 years). HSTCL resulted in death for 65% of patients. Survival was not reported for 30% of cases and two patients were alive at the time of the case report: one patient at 3 months after receiving chemotherapy and a bone marrow transplant, and another patient at 20 months after HSTCL diagnosis.\n\nTable 2 Demographic and clinical characteristics of reported Crohn’s disease patients with hepatosplenic T-cell lymphoma (HSTCL)\n\n \tUnique cases (n = 37)\tCases with insufficient reportinga (n = 9)\t\nAge at HSTCL diagnosis, years\tn = 36\tn = 0\t\nMean\t30\t-\t\nMedian\t26\t-\t\nRange\t12 to 79\t-\t\nDisease duration, years\tn = 16\tn = 0\t\nMean\t10\t-\t\nMedian\t6\t-\t\nRange\t4 to 35\t-\t\nSex, n (%)\tn = 36\tn = 6\t\nFemale\t5 (14%)\t1 (17%)\t\nSurvival, n (%)\tn = 26\tn = 4\t\nDied\t24 (92%)\t4 (100%)\t\nSurvived\t2 (8%)\t0 (0%)\t\nPhysical examination and laboratory abnormalities at time of HSTCL diagnosis, n (%)\tn = 19\tn = 1\t\nHepatosplenomegaly or splenomegaly\t19 (100%)\t1 (100%)\t\nFever\t9 (47%)\t-\t\nCytopenia of any type\t11 (58%)\t-\t\nAltered liver enzymes and/or LDH\t5 (26%)\t-\t\naInsufficient reporting on demographic information prevented us from identifying if the cases were unique. With each patient characteristic heading, the adjacent ‘n = x’ cells indicate the number of cases that reported on that particular demographic. The percentages calculated for sex, survival, and physical examination/laboratory abnormalities use this ‘n’ as the denominator. HSTCL, hepatosplenic T-cell lymphoma, LDH, lactate dehydrogenase.\n\nInformation about the patient’s race, Crohn’s disease location, behavior, and severity was infrequently reported in published case reports and case series. This information is not requested in the AERS case report form. Race was reported for two patients, both of whom were white [15,25]. Five patients had information on disease location: one patient had ileal disease [25], two patients had ileocolonic disease [12,17], one patient had ileal and perianal disease [15], and one patient had perianal disease [32]. Disease behavior was reported for one patient who had inflammatory disease [14].\n\nMedication history\nThe timeline in Figure 2 displays the report of new HSTCL cases in patients with Crohn’s disease from 1998 through 2010, including the 37 unique cases and the nine cases with insufficient information. Case exposure patterns for biologic medications were similar to the timeline of FDA approval for Crohn’s disease: 96% of biologic exposures among the 37 unique cases involved infliximab (approved in 1998), 29% adalimumab (approved in 2007), 4% natalizumab (approved in 2008), 4% ustekinumab (not approved as of December 2012), and thus far no affected patients had certolizumab pegol exposure (approved in 2008). All cases that used a biologic had also used infliximab, with the exception of one case who used adalimumab only. The use of concurrent medications or medications at the time of HSTCL diagnosis cannot be summarized because this information was not uniformly reported.\n\nFigure 2 Timeline of medication approval by the Food and Drug Administration (FDA) and occurrence of hepatosplenic T-cell lymphoma (HSTCL). Includes 37 unique cases and nine cases with insufficient reporting, for a total of 46 cases. Each box includes a unique case by year the case was reported. The horizontal axis indicates the year the case was diagnosed. The numbers in each square are ordered oldest to youngest age at HSTCL diagnosis. They match up to the numbers with detailed case information in Additional file 2: Table S2. Vertical arrows indicate years that the particular medications were approved by the FDA. Ustekinumab is not approved by the FDA for Crohn’s disease. The numbers within each box refer to case numbers in Additional file 2: Table S2. Patients were reported through 25 January 2011 (published) and December 2010 (AERS). *Date of case reported as 2007 to 2008. **Date of case reported as 2000 to 2009. AERS, Adverse Event Reporting System; FDA, Food and Drug Administration; HSTCL, hepatosplenic T-cell lymphoma.\n\nThe most frequently reported medications used were anti-metabolites and anti-TNFa agents (Table 3). Thirty-six unique cases (97%) used an anti-metabolite and 28 cases (76%) used an anti-TNFa. Eight cases had used an anti-metabolite without an anti-TNFa agent. One case had used cyclosporine and an anti-metabolite. Of the patients who used anti-TNFa therapy, 27 cases (96%) had also used an anti-metabolite, but not necessarily at the same time. One patient who used anti-TNFa therapy without anti-metabolites was reported in the AERS database. This patient had infliximab and adalimumab exposure (Additional file 2: Table S2).\n\nTable 3 Medications used to treat Crohn’s disease prior to the diagnosis of hepatosplenic T-cell lymphoma (HSTCL) among unique cases\n\nMedication\tNumber of cases with exposure reported, n (%) (n = 37)\tMean cumulative dose, mg (minimum - maximum)a\tMean duration of use, years (minimum - maximum)a\tMean number of infusions or injections (minimum - maximum)a\t\nBiologics\t28 (76%)\t \t \t \t\nAdalimumab\t8 (22%)\t920 (800 to 1040)\t1.5 (120 days to 2.6 years)\t11.5 (10 to 13)\t\nn = 2\tn = 2\tn = 2\t\nInfliximaba\t27 (73%)\t41 (10 to 120) mg/kg\t1.8 (1 day to 6 years)\t9 (1 to 24)\t\nn = 7\tn = 12\tn = 17\t\nNatalizumab\t1 (3%)\tNR\tNR\t3\t\nUstekinumab\t1 (3%)\tNR\tNR\tNR\t\nCertolizumab pegol\t0\t \t \t \t\nAnti-metabolites\t365 (97%)\t \t \t \t\n6-mercaptopurine\t20 (54%)\t94,508 (3,900 to 212,160)\t4.8 (39 days to 8 years)\t \t\nn = 4\tn = 10\t\nAzathioprine\t23 (62%)\t192,108 (1,450 to 301,125)\t5.8 (39 days to 13.5 years)\t \t\nn = 3\tn = 17\t\nAminosalicylates\t15 (41%)\t \t \t \t\nBalsalazide\t1 (3%)\tNR\tNR\t \t\nMesalamine\t13 (35%)\tNR\t5 (n = 1)\t \t\nSulfasalazine\t2 (5%)\tNR\t10 (n = 1)\t \t\nCorticosteroids\t22 (59%)\t \t \t \t\nBudesonide\t2 (5%)\tNR\tNR\t \t\nHydrocortisone\t1 (3%)\tNR\tNR\t \t\nPrednisone\t14 (38%)\tNR\tNR\t \t\nPrednisolone\t5 (14%)\tNR\t13 (n = 1)\t \t\nCorticosteroid\t4 (11%)\tNR\t10 (n = 1)\t \t\nOther medicationsb\t15 (41%)\t \t \t \t\nAntibioticsc\t8 (22%)\tNR\tNR\t \t\nCyclosporine\t1 (3%)\tNR\tNR\t \t\naAmong those that reported this data. Cumulative dose excludes cases that only provided mg/kg dosing but did not provide patient weight in kilograms and those cases which reported a daily dose but did not report duration of treatment. bExcluding vitamin/mineral supplements. cThe antibiotics used included ciprofloxacin, doxycycline, metronidazole, nitrofurantoin, and piperacillin/tazobactam. HSTCL, hepatosplenic T-cell lymphoma; NR, not reported.\n\nDaily dose, duration, or cumulative dose of therapy were not consistently reported (Table 3). The majority of ‘mean doses’ were based on one to two patients. Infliximab was the only medication where measures of dose and duration were consistently provided. For the anti-metabolites, information on duration of treatment was also frequently provided, but information on daily or cumulative dose less so. Aminosalicylate and corticosteroid exposures were less commonly reported, despite the frequent use of aminosalicylates to treat colonic inflammatory disease and the use of corticosteroids to treat disease flares.\n\nMedication causality assessment\nTable 4 summarizes causality assessments based on the 37 unique cases. Using three causality assessment tools, the majority of medications received a score consistent with ‘possible’ cause. All three tools had criteria for rechallenge and dechallenge tests that could not be performed for an irreversible outcome like lymphoma, thus lowering the score. The tool of Kramer et al. included criteria for the incidence of HSTCL, which has not been estimated for Crohn’s disease, thus lowering the score.\n\nTable 4 Results of the published instruments assessing causal relationship between medication exposure and adverse events when applied to patients in this case series\n\nMedication(s)\tNaranjo score\tKramer score\tWHO score\t\nBiologics\t\nAdalimumab\tPossible\tPossible\tPossible\t\nCertolizumab pegol\tNo use reported in any case report\t\nInfliximab\tPossible\tPossible\tPossible\t\nNatalizumab\tPossible\tPossible\tPossible\t\nUstekinumab\tPossible\tPossible\tPossible\t\nAnti-metabolites\t\n6-mercaptopurine\tPossible\tPossible\tPossible\t\nAzathioprine\tPossible\tPossible\tPossible\t\nAminosalicylates\t\nBalsalazide\tPossible\tUnlikely\tPossible\t\nMesalamine\tPossible\tUnlikely\tPossible\t\nSulfasalazine\tPossible\tUnlikely\tPossible\t\nCorticosteroids\t\nBudesonide\tPossible\tUnlikely\tPossible\t\nHydrocortisone\tPossible\tUnlikely\tPossible\t\nPrednisone\tPossible\tUnlikely\tPossible\t\nPrednisolone\tPossible\tUnlikely\tPossible\t\nCorticosteroid unspecified\tPossible\tUnlikely\tPossible\t\nOther medications\t\nCyclosporine\tPossible\tPossible\tPossible\t\nMetronidazole\tPossible\tUnlikely\tPossible\t\nNitrofurantoin\tPossible\tUnlikely\tPossible\t\nPiperacillin/tazobactam\tPossible\tUnlikely\tPossible\t\nDoxycycline\tPossible\tUnlikely\tPossible\t\nCiprofloxacin\tPossible\tUnlikely\tPossible\t\nPossible, all cases reporting that medication received a score of ‘possible’ using that particular causality assessment; unlikely, all cases reporting that medication received a score of ‘unlikely’ using that particular causality assessment. WHO, World Health Organization.\n\nScores calculated using the Naranjo method ranged from 1 to 2 points, corresponding with ‘possible’ causation (1 to 4 points) for each patient who used each medication. The items that contributed to the score for most patients included a point for administration prior to the development of HSTCL, and documentation of histopathology to confirm HSTCL diagnosis. All patients and medications lost one point because HSTCL has been reported in the absence of medications [5].\n\nScores calculated using the Kramer method did vary between medication classes. Anti-metabolites, biologics, and cyclosporine were determined to be a ‘possible’ cause of HSTCL (0 to 3 points). All other medications scored −1 point, determined to be an ‘unlikely’ cause (< 0 points). The variation in scores was due to previous reports of adverse reactions with the medication and availability of the medication. Anti-metabolites and cyclosporine were scored 0 points because they have been linked to other lymphomas. Natalizumab and ustekinumab were scored 0 points because they have been available for less than 20 years, so all adverse reactions have not yet been described. Anti-TNFa medications were scored 1 point because they have been associated with other lymphomas and have been available for less than 20 years. Antibiotics and corticosteroids received scores of −1 point because the medications have been available for long enough for most adverse reactions to have been previously reported and they have not been associated with lymphoma.\n\nAssessments of causality using the WHO method provided determination of ‘possible’ causation. Because the time required for development of HSTCL is unknown, any medication administered before HSTCL diagnosis was considered to be within a ‘reasonable’ time period leading up to HSTCL development. Because HSTCL could have been explained by another medication or Crohn’s disease itself, each medication used for each patient met the criterion for an alternative etiology.\n\nDiscussion\nAll medications were possibly related to HSTCL according to at least one causality assessment tool. Anti-metabolites, biologics, and cyclosporine were possibly related to HSTCL according to all three causality assessment tools. Despite the possible causal relationship found across three different tools for these medications, only the anti-TNFas carry a boxed warning for HSTCL. The label for azathioprine includes a boxed warning for malignancy with mention of HSTCL, and mercaptopurine’s label mentions HSTCL in the non-boxed warnings. The label for cyclosporine mentions the risk of lymphoma in the boxed warnings, but not HSTCL specifically. The labels for natalizumab and ustekinumab do not mention lymphoma. The most common demographic risk factors were male sex and younger age, similar to previous studies [22,26,27]. No comparative study from the main systematic review included a case of HSTCL, and only one study specifically mentioned that no HSTCL cases were observed.\n\nThe methods guides for systematic reviews of the Evidence-based Practice Center (EPC) Program and the Cochrane Collaboration recommend using case series in some instances [36-38]. Based on the importance of HSTCL to patients, HSTCL’s high mortality and the rarity of HSTCL, we performed a separate search of the published literature for HSTCL case reports and case series, and searched AERS as part of a systematic review for treatments of Crohn’s disease. Our rationale for including cases is consistent with the recommendations of the methods guides. Other systematic reviews have included case reports and case series identified from the literature or cases from AERS based on similar rationale [39-43]. In contrast to many previous systematic reviews, we searched both case sources. Searching AERS yielded nine cases not identified in the published literature. However, because the majority of cases were identified in both AERS and the published literature, we had to create a process to identify the overlapping cases.\n\nInsufficient reporting prevented us from determining the uniqueness of all identified cases. A few case reports failed to include patient age or sex. Many cases identified as unique did not include information on medication dose, frequency, or dates of use, even though reporting systems such the FDA AERS request this demographic and medication data on their submission forms [44]. Incomplete reporting is also prevalent in case reports on other types of adverse medication events, and calls have been made for a standardized list of case report guidelines similar to the checklists created by organizations for other types of observational studies [45]. Other agencies beside the FDA also request specific demographic, clinical, laboratory, and medication information in adverse event reports [46]. Nevertheless, no standard checklist exists for case reporting, and journal requirements for case report content are variable [47].\n\nThe usefulness of case reports to identify potential adverse medication events will be enhanced by a standardized checklist for case reporting. Such a checklist should incorporate information commonly requested for adverse event reports and causality assessment, including: basic demographics, documentation of the use and timing of use of the individual and concomitant medications used to treat the condition (including absence of use), all other medications used by the patient, rechallenge and dechallenge information (including absence), laboratory results (including serum medication levels), and diagnostic tests used to confirm the adverse event. Reporting the complete list of medications used by the cases, rather than focusing on medications previously associated with the adverse events, as was common in the case reports we identified, will also aid in the understanding of drug interactions and the adverse event. Modifying the AERS database to require these elements for submission and standardizing the information in case reports submitted to journals will help to match AERS cases to the published cases, identify trends by items like race that are not consistently reported, and improve causality assessments. The suggested modifications are consistent with the Institute for Safe Medication Practices’s (ISMP) recommendation to update AERS to improve the quality of reporting so that the FDA can make more targeted safety warnings [48,49].\n\nUsing the causality assessment tools for an irreversible and almost uniformly fatal condition such as HSTCL was challenging. Based on available data, we could not make any causal assessments other than ‘possible’ for all medications. Some elements, such as rechallenge with medication, are not possible for events that rapidly progress to mortality. Improvement of symptoms for cancer with dechallenge is also rare, although regression of lymphoma with withdrawal of azathioprine has been documented [50]. Other items in the causality tools required more complete reporting, such as serum medication levels or details of the case confirmation, were not available for all cases. Better case reporting and understanding how to modify causality tools for use with irreversible adverse events will assist in making causality assessments for rare events from case reports. For events such as HSTCL that likely have a complex, multifactorial etiology that may develop over months to years, reporters should be prompted to include more detailed information on patient medical history (few of the reports had details on Crohn’s disease severity and behavior), family history, and the absence of use or past use of certain medications commonly used to treat the underlying disease. This data could be requested as part of the FDA’s existing enhanced safety surveillance of TNFa-blockers and pediatric and young adult malignancy, or even in routine submission of MedWatch forms for adverse events such as malignancy [51]. Journals can also request that authors provide this history when submitting case reports on malignancies that are possibly associated with medications. Routine reporting of this additional information may accelerate identification of other medications and risk factors associated with the adverse event. Causal assessments can then be modified to incorporate relevant biology and epidemiology and used to prioritize which safety events should be studied further to estimate a rate by medication use.\n\nWhen possible causality has been established from case reports, trials and observational studies can contribute information to estimate a rate of disease by medication use. Trials and prospective studies may begin collecting information on safety events like HSTCL. If trials and observational studies report the occurrence of these rare events and details of the active or passive collection process, the rate of HSTCL can be estimated. For trials and comparative medication studies, a rate by medication use can be calculated by pooling the studies. Understanding the rate of disease, which is not possible from case reports, can help patients and their caretakers make better treatment decisions. Trials and observational studies should also attempt to collect specific details about the events. For example, the TREAT Registry, a Phase IV study for infliximab, reported a case of fatal peripheral T-cell lymphoma with infliximab and immunomodulator use within 6 months of death [52]. Readers cannot determine whether the T-cell lymphoma was HSTCL because details were not provided in the main text of the publication or the supplemental table. By providing more detailed information about the cause of death, particularly when a death may be due to a black box warning-related event, Phase IV studies could help to improve understanding of the rate of life-threatening events such as HSTCL in these important safety studies.\n\nConclusions\nConsistent with FDA safety warnings, we confirmed that anti-metabolites, anti-TNFas, and cyclosporine have a possible causal association with HSTCL. We were unable to assign any score other than ‘possible’ using existing causality assessments because of limitations in data reported in case reports and difficulty in obtaining rechallenge and dechallenge data for a fatal event such as HSTCL. Minimum reporting requirements for peer-reviewed literature and AERS will help facilitate the use of case reports to identify adverse events and assess causality. Reporting the absence of HSTCL in trials and cohort studies will provide information to estimate a rate of HSTCL occurrence by medication use. Intentional assessment will be particularly useful in studies that include children and young adults who appear to be at a greater risk of HSTCL. Our findings provide support for the development and adoption of case report guidelines, a topic that will be discussed at the next International Congress on Peer Review and Biomedical Publication [53]. Standards for collecting additional patient history in case reports and modifying causality assessment tools for irreversible events such as a fatal lymphoma will assist in making causal assessments using case reports.\n\nAbbreviations\nAERS: Adverse event reporting system; AHRQ: Agency for Healthcare Research and Quality; anti-TNFa: anti-tumor necrosis factor alpha; EPC: Evidence-based Practice Center; FDA: Food and Drug Administration; HSTCL: Hepatosplenic T-cell lymphoma; ISMP: Institute for Safe Medication Practices; NCRR: National Center for Research Resources; NIH: National Institutes of Health; WHO: World Health Organization.\n\nCompeting interests\nThe authors do not have any competing interests to declare.\n\nAuthors’ contributions\nSS and EC reviewed search results, performed data extraction and analysis, and applied the causality assessment tools. SS, EC, LW, and SH drafted the manuscript. EB was responsible for overseeing all work done on this project by the Evidence-based Practice Center (EPC) as part of its contract with the Agency for Healthcare Research and Quality (AHRQ). All authors contributed to the conception and design of the study, and read, revised, and approved the final manuscript.\n\nSupplementary Material\nAdditional file 1: Supplemental Table 1\nSearch strings used to identify cases in PubMed and Embase.\n\nClick here for file\n\n Additional file 2: Supplemental Table 2\nCase series: characteristics of individual cases identified in the literature and Adverse Event Reporting System.\n\nClick here for file\n\n Acknowledgments\nThis project was funded under contract number HHSA 290-2007-10061-I from the AHRQ, US Department of Health and Human Services. The authors of this article are responsible for its content, including any clinical treatment recommendations. No statement in this article should be construed as an official position of the AHRQ or of the US Department of Health and Human Services. SS was supported by the Johns Hopkins Predoctoral Clinical Research Training Program grant number 1TL1RR-025007 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). This article’s contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Publication of this article was funded in part by the Open Access Promotion Fund of the Johns Hopkins University Libraries.\n==== Refs\nTalley NJ Abreu MT Achkar JP Bernstein CN Dubinsky MC Hanauer SB Kane SV Sandborn WJ Ullman TA Moayyedi P An evidence-based systematic review on medical therapies for inflammatory bowel disease Am J Gastroenterol 2011 106 Suppl 1 2 25 quiz S26 \nKorelitz BI Present DH A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at the Mount Sinai Hospital Mt Sinai J Med 1996 63 191 201 8692165 \nJanssen Biotech, Inc Highlights of prescribing information: Remicade (infliximab) 2011 Horsham, PA: Janssen Biotech, Inc http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103772s5295lbl.pdf \nArmitage JO The aggressive peripheral T-cell lymphomas: 2012 update on diagnosis, risk stratification, and management Am J Hematol 2012 87 511 519 10.1002/ajh.23144 22508369 \nFalchook GS Vega F Dang NH Samaniego F Rodriguez MA Champlin RE Hosing C Verstovsek S Pro B Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment Ann Oncol 2009 20 1080 1085 10.1093/annonc/mdn751 19237479 \nEffective Health Care Program Comparative effectiveness of pharmacologic therapies for the management of Crohn's disease 2010 Rockville, MD: Agency for Healthcare Research and Quality http://effectivehealthcare.ahrq.gov/ehc/products/192/515/Crohns%20Protocol%2081%2026%2010.pdf \nPoluzzi E Raschi E Moretti U De Ponti F Drug-induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS) Pharmacoepidemiol Drug Saf 2009 18 512 518 10.1002/pds.1746 19358226 \nUppsala Monitoring Centre The use of the WHO-UMC system for standardised case causality assessment Uppsala: Uppsala Monitoring Centre http://who-umc.org/Graphics/24734.pdf \nNaranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \nKramer MS Leventhal JM Hutchinson TA Feinstein AR An algorithm for the operational assessment of adverse drug reactions. I. Background, description, and instructions for use JAMA 1979 242 623 632 10.1001/jama.1979.03300070019017 449002 \nNavarro JT Ribera JM Mate JL Granada I Junca J Batlle M Milla F Feliu E Hepatosplenic T-gammadelta lymphoma in a patient with Crohn's disease treated with azathioprine Leuk Lymphoma 2003 44 531 533 10.1080/1042819021000035662 12688327 \nThayu M Markowitz JE Mamula P Russo PA Muinos WI Baldassano RN Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease J Pediatr Gastroenterol Nutr 2005 40 220 222 10.1097/00005176-200502000-00026 15699701 \nKotlyar DS Blonski W Diamond RH Wasik M Lichtenstein GR Hepatosplenic T-cell lymphoma in inflammatory bowel disease: a possible thiopurine-induced chromosomal abnormality Am J Gastroenterol 2010 105 2299 2301 10.1038/ajg.2010.213 20927075 \nBeigel F Jurgens M Tillack C Subklewe M Mayr D Goke B Brand S Ochsenkuhn T Hepatosplenic T-cell lymphoma in a patient with Crohn's disease Nat Rev Gastroenterol Hepatol 2009 6 433 436 10.1038/nrgastro.2009.87 19575026 \nDrini M Prichard PJ Brown GJ Macrae FA Hepatosplenic T-cell lymphoma following infliximab therapy for Crohn's disease Med J Aust 2008 189 464 465 18928444 \nHe S Roberts A Ritchie D Grigg A Graft-versus-lymphoma effect in progressive hepatosplenic gamma/delta T-cell lymphoma Leuk Lymphoma 2007 48 1448 1450 10.1080/10428190701400071 17613781 \nHumphreys MR Cino M Quirt I Barth D Kukreti V Long-term survival in two patients with hepatosplenic T cell lymphoma treated with interferon-alpha Leuk Lymphoma 2008 49 1420 1423 10.1080/10428190802087488 18452073 \nMackey AC Green L Leptak C Avigan M Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease: update J Pediatr Gastroenterol Nutr 2009 48 386 388 10.1097/MPG.0b013e3181957a11 19274799 \nMackey AC Green L Liang LC Dinndorf P Avigan M Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease J Pediatr Gastroenterol Nutr 2007 44 265 267 10.1097/MPG.0b013e31802f6424 17255842 \nMittal S Milner BJ Johnston PW Culligan DJ A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab Eur J Haematol 2006 76 531 534 10.1111/j.1600-0609.2006.00646.x 16548918 \nMoran G Dillon J Green J Crohn's disease, hepatosplenic T-cell lymphoma and no biological therapy: are we barking up the wrong tree? Inflamm Bowel Dis 2009 15 1281 1282 10.1002/ibd.20802 19067412 \nOchenrider MG Patterson DJ Aboulafia DM Hepatosplenic T-cell lymphoma in a young man with Crohn's disease: case report and literature review Clin Lymphoma Myeloma Leuk 2010 10 144 148 10.3816/CLML.2010.n.021 20371449 \nRosh JR Gross T Mamula P Griffiths A Hyams J Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale? Inflamm Bowel Dis 2007 13 1024 1030 10.1002/ibd.20169 17480018 \nShale M Kanfer E Panaccione R Ghosh S Hepatosplenic T cell lymphoma in inflammatory bowel disease Gut 2008 57 1639 1641 10.1136/gut.2008.163279 18667489 \nZeidan A Sham R Shapiro J Baratta A Kouides P Hepatosplenic T-cell lymphoma in a patient with Crohn's disease who received infliximab therapy Leuk Lymphoma 2007 48 1410 1413 10.1080/10428190701345433 17613771 \nKotlyar DS Osterman MT Diamond RH Porter D Blonski WC Wasik M Sampat S Mendizabal M Lin MV Lichtenstein GR A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease Clin Gastroenterol Hepatol 2011 9 36 41 e31 10.1016/j.cgh.2010.09.016 20888436 \nThai A Prindiville T Hepatosplenic T-cell lymphoma and inflammatory bowel disease J Crohns Colitis 2010 4 511 522 10.1016/j.crohns.2010.05.006 21122554 \nPozadzides JV Pro B Hepatosplenic T-cell lymphoma and TNF-alpha inhibitors Expert Rev Hematol 2009 2 611 614 10.1586/ehm.09.62 21082951 \nGrimpen F Yeung D Joseph J Fay K Buckland M Talaulikar D Elijah J Clarke AC Pavli P Moore J Hepatosplenic T cell lymphoma, immunosuppressive agents and biologicals: What are the risks? J Gastroenterol Hepatol 2009 24 A314 \nKotlyar D Blonski W Mendizabal M Lin MV Lichtenstein GR Case report of trisomy 13 in bone marrow in a case of hepatosplenic T-cell lymphoma (HSTCL) and inflammatory bowel disease (IBD) Gastroenterology 2009 136 A146 \nKotlyar D Blonski W Porter DL Mendizabal M Lin MV Lichtenstein GR Hepatosplenic T-cell lymphoma (HSTCL) and inflammatory bowel disease (IBD): A rare complication after long-term thiopurine exposure: Case report and systematic review of the literature Gastroenterology 2009 136 A196 A197 10.1053/j.gastro.2008.09.019 \nLémann M Gérard de La Valussière F Carbonnel F Bouhnik Y Bonnet J Allez M Matuchansky C Cosnes J Jian R Rambaud JC Gendre JP Modigliani R Intravenous cyclosporine for perianal Crohn's disease (CD) Gastroenterology 1998 114 A1020 \nFalchook GS Champlin R Hagemeister FB Hosing C Kwak LW O'Brien S Rodriguez MA Verstovsek S Pro B Hepatosplenic T-cell lymphoma: clinical characteristics and treatment outcome ASH Annual, Meeting Abstracts 2006 108 2460 \nFowler S Beyak M Depew WT Justinich C Ropeleski MJ W1212 hepatosplenic T-cell lymphoma in Crohn's disease. Where does the risk lie? Gastroenterology 2010 138 675 \nBeaugerie L Brousse N Bouvier AM Colombel JF Lémann M Cosnes J Hébuterne X Cortot A Bouhnik Y Gendre JP Simon T Maynadié M Hermine O Faivre J Carrat F CESAME Study Group Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study Lancet 2009 374 1617 1625 10.1016/S0140-6736(09)61302-7 19837455 \nChou R Aronson N Atkins D Ismaila AS Santaguida P Smith DH Whitlock E Wilt TJ Moher D AHRQ series paper 4: assessing harms when comparing medical interventions: AHRQ and the effective health-care program J Clin Epidemiol 2010 63 502 512 10.1016/j.jclinepi.2008.06.007 18823754 \nAgency for Healthcare Research and Quality Methods guide for medical test reviews 2010 Rockville, MD: Agency for Healthcare Research and Quality http://effectivehealthcare.ahrq.gov \nHiggins JPT, Green S Cochrane handbook for systematic reviews of interventions. Version 5.1.0 (updated March 2011) 2011 Oxford: The Cochrane Collaboration http://www.cochrane-handbook.org \nJefferson T Jones M Doshi P Del Mar C Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis BMJ 2009 339 5106 10.1136/bmj.b5106 \nBybee KA Kara T Prasad A Lerman A Barsness GW Wright RS Rihal CS Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction Ann Intern Med 2004 141 858 865 10.7326/0003-4819-141-11-200412070-00010 15583228 \nEffective Health Care Program Evidence-based practice center systematic review protocol pressure ulcer treatment strategies: A comparative effectiveness review 2011 Rockville, MD: Agency for Healthcare Research and Quality http://effectivehealthcare.ahrq.gov/ehc/products/308/838/Pressure-Ulcer-Treatment_%20Protocol_20111108.pdf \nReeves BC Vardulaki KA Tsang VTC Bennett-Lloyd BD O’Riordan PA A systematic review of case series of paediatric cardiac surgery [abstract] 2000 Cape Town: 8th Annual Cochrane Colloquium http://cmr.cochrane.org/?CRGReportID=2998 \nGartlehner G Hansen RA Jonas BL Thieda P Lohr KN The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis J Rheumatol 2006 33 2398 2408 17225293 \nUS Food and Drug Administration The FDA Safety Information and Adverse Event Reporting Program. MedWatch 3500 form 2013 Silver Spring, MD: US Food and Drug Administration http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf \nAronson JK Anecdotes as evidence BMJ 2003 326 1346 10.1136/bmj.326.7403.1346 12816800 \nNational Institute of Diabetes and Digestive and Kidney Diseases Important elements to include in reporting cases of drug-induced liver injury 2013 Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases http://livertox.niddk.nih.gov/ImportantElements.aspx \nSorinola O Olufowobi O Coomarasamy A Khan KS Instructions to authors for case reporting are limited: a review of a core journal list BMC Med Educ 2004 4 4 10.1186/1472-6920-4-4 15043755 \nInstitute for Safe Medication Practices QuarterWatch: Monitoring FDA MedWatch reports: Signals for dabigatran and metoclopramide 2012 Horsham, PA: Institute for Safe Medication Practices http://www.ismp.org/quarterwatch/pdfs/2011Q1.pdf \nMoore TJ Singh S Furberg CD The FDA and new safety warnings Arch Intern Med 2012 172 78 80 10.1001/archinternmed.2011.618 22232155 \nLarvol L Soule JC Le Tourneau A Reversible lymphoma in the setting of azathioprine therapy for Crohn's disease N Engl J Med 1994 331 883 884 8078549 \nUS Food and Drug Administration FDA drug safety communication: Update on tumor necrosis factor (TNF) blockers and risk for pediatric malignancy 2013 Silver Spring, MD: US Food and Drug Administration http://www.fda.gov/Drugs/DrugSafety/ucm278267.htm \nLichtenstein GR Feagan BG Cohen RD Salzberg BA Diamond RH Chen DM Pritchard ML Sandborn WJ Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry Clin Gastro and Hepatol 2006 4 621 630 10.1016/j.cgh.2006.03.002 \nInternational Congress on Peer Review and Biomedical Publication The Seventh International Congress on Peer Review and Biomedical Publication, September 8–10, 2013 2013 Chicago, IL: JAMA and London: BMJ http://www.peerreviewcongress.org/preliminary-program.html\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2046-4053",
"issue": "2()",
"journal": "Systematic reviews",
"keywords": null,
"medline_ta": "Syst Rev",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000963:Antimetabolites; D002648:Child; D003424:Crohn Disease; D003625:Data Collection; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D008113:Liver Neoplasms; D016399:Lymphoma, T-Cell; D008297:Male; D008875:Middle Aged; D013160:Splenic Neoplasms; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "101580575",
"other_id": null,
"pages": "53",
"pmc": null,
"pmid": "23826928",
"pubdate": "2013-07-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "19358226;12816800;16548918;17255842;8692165;18452073;19575026;20927075;20888436;18667489;19067412;17480018;21082951;19995812;18928444;16678077;17613781;7249508;22508369;19837455;21122554;19274799;19237479;18823754;15043755;21472012;20371449;15699701;15583228;24621284;22232155;8078549;17613771;449002;17225293;12688327",
"title": "Use of case reports and the Adverse Event Reporting System in systematic reviews: overcoming barriers to assess the link between Crohn's disease medications and hepatosplenic T-cell lymphoma.",
"title_normalized": "use of case reports and the adverse event reporting system in systematic reviews overcoming barriers to assess the link between crohn s disease medications and hepatosplenic t cell lymphoma"
} | [
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-123709",
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"activesubstancename": "NATALIZUMAB"
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"abstract": "OBJECTIVE\nComplete signal transducer and activator of transcription 1 (STAT1) deficiency is a rare autosomal recessive condition characterized by impairment of intracellular signaling from both type I and type II interferons (IFN). Affected patients are prone to early severe mycobacterial and viral infections, which usually result in death before 18 months of age. We previously reported a patient affected by complete STAT1 deficiency who underwent hematopoietic stem cell transplantation (HSCT). Here, we describe the transplantation procedures and long-term outcomes.\n\n\nMETHODS\nThe patient, who had suffered multiple life-threatening mycobacterial and viral infections in the first years of life, underwent HSCT at 4 years of age from a partially matched (HLA compatibility 8/10) unrelated donor after a myeloablative conditioning regimen consisting of busulfan, cyclophosphamide, and anti-thymocyte globulin.\n\n\nRESULTS\nHematological reconstitution was detected at d+15, with full donor engraftment demonstrated by molecular analysis of leukocytes. Several complications occurred in the post-transplantation phase, including acute graft versus host disease, posterior reversible encephalopathy, thrombotic thrombocytopenic purpura, bilateral keratoconjunctivitis with complete loss of vision, and chronic lower limb lymphedema. Analysis of STAT1 in CD3+ cells at 90 and 120 days after HSCT by flow cytometry showed normal STAT1 phosphorylation levels in response to IFN-α.\n\n\nCONCLUSIONS\nNotably, no severe infections occurred after discharge (day + 90) during a 9-year follow-up, suggesting that normal response to IFNs in hematopoietic cells is sufficient to provide protection in humans.",
"affiliations": "Department of Medicine, Surgery, and Health Sciences, University of Trieste, Trieste, Italy.;U.O. Oncoematologia pediatrica e Trapianto di Midollo osseo, Asst Spedali Civili, Brescia, Italy.;Istituto di Medicina Molecolare \"Angelo Nocivelli\", Brescia, Italy.;U.O. Laboratorio di Analisi chimico cliniche, Sezione di Ematologia Lab, Cellule staminali, Asst Spedali Civili, Brescia, Italy.;Istituto di Medicina Molecolare \"Angelo Nocivelli\", Brescia, Italy. raffaele.badolato@unibs.it.;U.O. Oncoematologia pediatrica e Trapianto di Midollo osseo, Asst Spedali Civili, Brescia, Italy.",
"authors": "Naviglio|Samuele|S|;Soncini|Elena|E|;Vairo|Donatella|D|;Lanfranchi|Arnalda|A|;Badolato|Raffaele|R|;Porta|Fulvio|F|",
"chemical_list": "D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-017-0430-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "37(7)",
"journal": "Journal of clinical immunology",
"keywords": "Hematopoietic stem cell transplantation; Primary immunodeficiency; STAT1 deficiency; Signaling",
"medline_ta": "J Clin Immunol",
"mesh_terms": "D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D008297:Male; D050794:STAT1 Transcription Factor; D016896:Treatment Outcome",
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "701-706",
"pmc": null,
"pmid": "28815344",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23452095;21892158;22520845;24278020;26214525;19436109;12590259;22573496;16585605;22651901;27803128;24227816;20841510;21772053",
"title": "Long-Term Survival After Hematopoietic Stem Cell Transplantation for Complete STAT1 Deficiency.",
"title_normalized": "long term survival after hematopoietic stem cell transplantation for complete stat1 deficiency"
} | [
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"companynumb": "IT-SA-2017SA166527",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"actiondrug": "3",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Although historically known as a genetic disorder, epidermodysplasia verruciformis (EV) might be acquired in patients with a noninherited defective cell-mediated immunity. This article reports a case of EV in a patient with systemic lupus erythematosus and a history of 3 years immunosuppressive methylprednisolone treatment. The microscopic features of the skin biopsy showed morphologic changes of the keratinocytes characteristic of human papilloma virus (HPV) infections and immunoreactivity to p16. HPV genotyping demonstrated the presence of HPV 6 which belongs to a low-risk mucosal HPV group and has not been reported in EV previously. The clinical recognition of EV in immunocompromised patients and subsequent HPV typing is important because some patients will develop squamous cell carcinoma.",
"affiliations": "Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.;Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and.;Department of Dermatology and Venereology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.;Department of Dermatology and Venereology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.;Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.",
"authors": "Ferronika|Paranita|P|;Sijmons|Rolf H|RH|;Febiyanto|Novian|N|;Radiono|Sunardi|S|;Widodo|Irianiwati|I|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001738",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "42(11)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D004819:Epidermodysplasia Verruciformis; D005260:Female; D052163:Human papillomavirus 6; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D030361:Papillomavirus Infections",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "e156-e158",
"pmc": null,
"pmid": "32675468",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired Human Papilloma Virus Type 6-Associated Epidermodysplasia Verruciformis in a Patient With Systemic Lupus Erythematosus.",
"title_normalized": "acquired human papilloma virus type 6 associated epidermodysplasia verruciformis in a patient with systemic lupus erythematosus"
} | [
{
"companynumb": "ID-LUPIN PHARMACEUTICALS INC.-2022-00167",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "OBJECTIVE\nOur study aimed to review adverse drug reactions (ADRs) associated with ibuprofen treatment of patent ductus arteriosus (PDA) in premature neonates.\n\n\nMETHODS\nWe retrospectively evaluated electronic patient records from neonates treated with ibuprofen for PDA during 5 years in a French neonatal intensive care unit. Full chart review and targeted triggers were used to detect ADRs. The causality between suspected ADRs and medication was evaluated using the WHO causality assessment method by pharmacovigilance experts. Categorical variables were compared using chi-square tests or Fisher's test. Quantitative variables were compared using the Student t test. We explored the risk factors associated with ADR using univariate model analysis.\n\n\nRESULTS\nOf 227 infants with a mean gestational age (GA) of 27 weeks (24-33), 12 (5%) developed intestinal perforation and seven, necrotizing enterocolitis (3%). The perforation occurred less frequently in infants older than 27 weeks GA (OR=0.14; 95% CI=0.03-0.66, P=0.01). Other observed ADRs were acute renal failure (25 infants, 11%) and thrombocytopenia (five infants, 2%).\n\n\nCONCLUSIONS\nGastrointestinal complications observed in infants treated with ibuprofen for PDA including gastrointestinal perforations occur in less mature infants. Active chart review of the patient's medical file with a trigger tool should be evaluated for routine ADR monitoring.",
"affiliations": "Hospices civils de Lyon, Neonatal Intensive Care Unit and Neonatology, hôpital Femme-Mère-Enfant, Lyon, France.;Hospices civils de Lyon, Neonatal Intensive Care Unit and Neonatology, hôpital Femme-Mère-Enfant, Lyon, France.;Hospices civils de Lyon, Clinical and Epidemiological Research Unit, Public Health Department, Lyon, France.;Hospices civils de Lyon, Neonatal Intensive Care Unit and Neonatology, hôpital Femme-Mère-Enfant, Lyon, France.;Hospices civils de Lyon, Neonatal Intensive Care Unit and Neonatology, hôpital Femme-Mère-Enfant, Lyon, France.;Hospices civils de Lyon, Neonatal Intensive Care Unit and Neonatology, hôpital Femme-Mère-Enfant, Lyon, France; Hospices civils de Lyon, Pharmacotoxicology, Lyon, France; Univ Lyon 1, UMR 5558, CRNS, LBBE, EMET, Lyon, France. Electronic address: kim-an.nguyen@chu-lyon.fr.",
"authors": "Ndour|D|D|;Bouamari|H|H|;Berthiller|J|J|;Claris|O|O|;Plaisant|F|F|;Nguyen|K A|KA|",
"chemical_list": "D016861:Cyclooxygenase Inhibitors; D007052:Ibuprofen",
"country": "France",
"delete": false,
"doi": "10.1016/j.arcped.2020.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-693X",
"issue": "27(8)",
"journal": "Archives de pediatrie : organe officiel de la Societe francaise de pediatrie",
"keywords": "Adverse drug reactions; Ibuprofen; Patent ductus arteriosus; Premature newborns",
"medline_ta": "Arch Pediatr",
"mesh_terms": "D016861:Cyclooxygenase Inhibitors; D004374:Ductus Arteriosus, Patent; D005260:Female; D005865:Gestational Age; D006801:Humans; D007052:Ibuprofen; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D007416:Intestinal Perforation; D008297:Male; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9421356",
"other_id": null,
"pages": "452-455",
"pmc": null,
"pmid": "33011033",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adverse events related to ibuprofen treatment for patent ductus arteriosus in premature neonates.",
"title_normalized": "adverse events related to ibuprofen treatment for patent ductus arteriosus in premature neonates"
} | [
{
"companynumb": "FR-STRIDES ARCOLAB LIMITED-2021SP002003",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nTo determine the epidemiology of acute childhood poisoning in Shiraz, southern Iran.\n\n\nMETHODS\nThis was a prospective cross-sectional descriptive study, being performed in Nemazee and Dastgheib Hospitals affiliated with Shiraz University of Medical Sciences. The study included pediatric patients (<18 years) referred to our centers due to acute poisoning. Demographic and etiological factors were prospectively recorded and analyzed.\n\n\nRESULTS\nA total of 773 patients with mean age of 3.86 ± 1.5 years were recruited in the study. The most common group which included 352 (45.5%) patients, aged between 8 months and 5 years followed by 330 (42.6%) cases aged from 12-18 years. In majority of cases, poisoning was due to opium in 222 (23.5%) followed by analgesics in 181 (19.1%), which mostly included acetaminophen in 75(7.9%), anti-depressants in 170 (17.9%), anti-hypertensive drugs in 65 (6.8%) and hydrocarbons in 60 (6.3%). There were 260 (33.7%) boys and 513 (66.3%) girls. The poisoning occurred inadvertently in 387 (50.1%) cases while 298 (38.5%) patients committed suicide. Most cases (255 patients; 32.9%) were asymptomatic at presentation.\n\n\nCONCLUSIONS\nOur study substantiated the following findings: A) Alarmingly, opium is the most common cause of acute childhood poisoning in our area. B) Easy access to toxic material is the most common risk factor for acute childhood poisoning. C) Female predominance of acute childhood poisoning accompanied by high rate of suicidal attempts shows that psychiatric problems, especially depression is most common among young girls.",
"affiliations": "Department of Pediatrics Gastroenterology, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran.",
"authors": "Haghighat|Mahmood|M|;Moravej|Hossein|H|;Moatamedi|Maryam|M|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2322-2522",
"issue": "1(1)",
"journal": "Bulletin of emergency and trauma",
"keywords": "Acute poisoning; Epidemiology; Pediatrics; Risk factors",
"medline_ta": "Bull Emerg Trauma",
"mesh_terms": null,
"nlm_unique_id": "101614018",
"other_id": null,
"pages": "28-33",
"pmc": null,
"pmid": "27162818",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": "15214744;20978013;11991021;15850278;10771987;11227336;3975099;18608278;20692080;18581069;1452977;12955997;17264581;6655419;20438635;20028214;9808971;1358147;7305768;10501099;7908812",
"title": "Epidemiology of Pediatric Acute Poisoning in Southern Iran: A Hospital-Based Study.",
"title_normalized": "epidemiology of pediatric acute poisoning in southern iran a hospital based study"
} | [
{
"companynumb": "IR-JNJFOC-20160516869",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "We report the first clinical investigation conducted in Japan to confirm the safety, tolerability, and pharmacokinetics of ixazomib alone and combined with lenalidomide-dexamethasone (Rd) in Japanese patients with relapsed/refractory multiple myeloma. Adult patients with measurable disease and ≥2 prior lines of therapy received oral ixazomib 4.0 mg on days 1, 8, 15 alone or combined with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, 22 in 28-day cycles. Fourteen patients who had received a median of seven prior therapies were enrolled (seven per cohort). One of six evaluable patients in each cohort experienced dose-limiting toxicities [diarrhea, nausea, hypokalemia, hypertension, thrombocytopenia, hyponatremia (ixazomib cohort); thrombocytopenia, and neutropenia (ixazomib + Rd cohort)]. The most common drug-related adverse events were neutropenia, thrombocytopenia, leukopenia, and lymphopenia. Drug-related grade ≥3 adverse events occurring in ≥3 patients per cohort were (ixazomib/ixazomib + Rd cohort, n): neutropenia (4/2), thrombocytopenia (3/2), and lymphopenia (5/2). Ixazomib was rapidly absorbed with a median T max of approximately 1-2-h post-dose, and had a geometric mean terminal half-life of 5-6 days. Of 13 response-evaluable patients, one achieved a partial response (duration ∼38 weeks; ixazomib cohort) and seven had stable disease.",
"affiliations": "Department of Hematology, Japanese Red Cross Medical Center, 4-1-22 Hiroo Shibuya-ku, Tokyo, 150-8935, Japan. ken-suzuki@mtb.biglobe.ne.jp.;Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan.;Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.;Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Pharmacology Department, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.;Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, Osaka, Japan.",
"authors": "Suzuki|Kenshi|K|;Handa|Hiroshi|H|;Chou|Takaaki|T|;Ishizawa|Kenichi|K|;Takubo|Takatoshi|T|;Kase|Yoichi|Y|",
"chemical_list": "D001896:Boron Compounds; D061988:Proteasome Inhibitors; D013792:Thalidomide; C548400:ixazomib; D003907:Dexamethasone; D000077269:Lenalidomide; D005998:Glycine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-016-2149-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "105(4)",
"journal": "International journal of hematology",
"keywords": "Ixazomib; Japan; Multiple myeloma; Pharmacokinetics; Safety",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D001896:Boron Compounds; D003907:Dexamethasone; D004334:Drug Administration Schedule; D005260:Female; D005998:Glycine; D006801:Humans; D000077269:Lenalidomide; D007970:Leukopenia; D008297:Male; D009101:Multiple Myeloma; D061988:Proteasome Inhibitors; D012008:Recurrence; D016879:Salvage Therapy; D013792:Thalidomide; D013921:Thrombocytopenia",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "445-452",
"pmc": null,
"pmid": "28000099",
"pubdate": "2017-04",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "10706191;22585692;24429336;26872892;25377318;16855634;25669658;26337806;25482145;25456369;17766651;21509679;24920586;18615002;24904120;27121262;27119237",
"title": "Phase 1 study of ixazomib alone or combined with lenalidomide-dexamethasone in Japanese patients with relapsed/refractory multiple myeloma.",
"title_normalized": "phase 1 study of ixazomib alone or combined with lenalidomide dexamethasone in japanese patients with relapsed refractory multiple myeloma"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1034341",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IXAZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "Fluvoxamine has a similar spectrum of adverse effects as compared to other selective serotonin reuptake inhibitors. However, fluvoxamine induced oculogyric dystonia is a rare instance in clinical practice. In this report, we present a case of obsessive compulsive disorder that developed oculogyric dystonia during the course of fluvoxamine mono-therapy and subsequently had a manic switch.",
"affiliations": "Department of Psychiatry, Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand, India.",
"authors": "Tikka|Sai Krishna|SK|;Garg|Shobit|S|;Das|Basudeb|B|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016666:Fluvoxamine",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.117760",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-45-53210.4103/0253-7613.117760Drug WatchFluvoxamine induced oculogyric dystonia and manic switch in a patient with obsessive compulsive disorder Tikka Sai Krishna Garg Shobit Das Basudeb Department of Psychiatry, Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand, IndiaCorrespondence to: Dr. Sai Krishna Tikka, E-mail: cricsai@gmail.comSep-Oct 2013 45 5 532 533 05 2 2013 23 4 2013 04 7 2013 Copyright: © Indian Journal of Pharmacology2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Fluvoxamine has a similar spectrum of adverse effects as compared to other selective serotonin reuptake inhibitors. However, fluvoxamine induced oculogyric dystonia is a rare instance in clinical practice. In this report, we present a case of obsessive compulsive disorder that developed oculogyric dystonia during the course of fluvoxamine mono-therapy and subsequently had a manic switch.\n\nKEY WORDS:\nInduced manic switchoculogyric dystoniaselective serotonin reuptake inhibitor\n==== Body\nIntroduction\nFluvoxamine, a commonly used drug for obsessive compulsive disorder (OCD), has a similar spectrum of adverse events compared to other selective serotonin reuptake inhibitors (SSRIs). Although less frequent, fluvoxamine, like other SSRIs is known to cause various types of movement disorders like akathisia, parkinsonism and tardive dyskinesia.[1] Also, fluvoxamine has comparable degree of propensity to precipitate a manic switch to that of other SSRIs like fluoxetine, paroxetine and sertraline.[2] Here, we present a case of OCD that developed oculogyric dystonia during the course of fluvoxamine mono-therapy and subsequently had a manic switch.\n\nCase Report\nA 21-year-old, Muslim male belonging to middle socio-economic status and educated up to intermediate degree had a family history of bipolar affective disorder in his paternal grandfather. He was well adjusted premorbidly and presented with 4 years of illness with no obvious precipitating factor, characterized by repeated, intrusive doubts about symmetry and repeatedly arranging household articles like clothes, shoes, furniture, books etc. He also had doubts on the linearity of the sentences he writes on pages and would write several times before he moved to the next page. He clearly was distressed with these symptoms and for the past 4 months was also complaining of predominant low mood, decreased interest in activities, ideas of decreased self-worth and pessimistic future. He was admitted as an inpatient with a diagnosis of OCD and comorbid moderated depressive episode according to ICD-10. His routine blood investigations including thyroid profile, computed tomography scan brain and electroencephalography were normal. He scored a total of 24 on Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and 15 on Hamilton Depression (HAM-D-17) Rating Scale. He was started on morning dose of fluvoxamine, with an initial dose of 50 mg to be hiked by 50 mg every 4th day. By the 2nd week, he started reporting of improvement especially in depressive symptoms (HAM-D-17 scores reduced to 10 whereas on Y-BOCS, he scored 22). On the 11th day of admission, he complained of oculogyric dystonia characterized by involuntary sustained upward gaze in both his eyes during morning hours. There were no signs and symptoms suggestive of pseudo-parkinsonism or any other movement disorders. He was administered injection promethazine 50 mg stat intramuscularly and the symptom subsided within an hour. Dose of fluvoxamine was decreased to 150 mg and further hiking was planned every 8th day. This symptom did not recur subsequently. By 25th day the fluvoxamine dose was increased to 250 mg and he showed significant improvement in both obsessive (Y-BOCS total score –14) and depressive symptoms (HAM-D-17 total score – 4). However, 2 days later, mental status examination revealed over familiar manner of relating, over productive speech, euphoric affect and inflated self-esteem. He scored 16 on Young Mania Rating Scale (YMRS). Fluvoxamine dose was reduced to 150 mg and 900 mg lithium was added, which was later increased to 1050 mg to obtain optimal serum level, i.e., 0.72 meq/L. He showed an improvement in manic symptoms within 10 days (YMRS total score –3) and maintained the improvement shown in obsessive symptoms.\n\nThere is a clear temporal relationship between the occurrence of dystonia and relatively faster titration in the dose of fluvoxamine to 200 mg. And reduction in the dose and subsequent slow titration was helpful. Also, temporal relationship between the occurrence of manic switch and dose of fluvoxamine was established. This particular class of drugs is known to cause the spectrum of side-effects as in our case. However, specific case of fluvoxamine causing oculogyric dystonia has not been reported in the literature. While considering the manic switch, a positive family history of bipolar illness in this case might have predisposed the patient to a manic switch; but neurobiological mechanisms of fluvoxamine might be sufficient to trigger a manic switch. The Naranjo adverse drug reaction probability score for oculogyric dystonia was –6 and for the induced manic switch was –5; both suggesting a “probable” association with administration of fluvoxamine.\n\nDiscussion\nAlthough, dystonia is found to be a most common type of extrapyramidal symptom induced by SSRIs,[1] apart from a few case reports[3] oculogyric dystonia precipitated by an SSRI is a rare instance in clinical practice. No study has reported of an association between extrapyramidal symptoms induced by SSRI and their potential to precipitate a manic switch. Interestingly, the index case presents a possible association between movement disorders induced by an SSRI (in this case oculogyric dystonia and manic switch with fluvoxamine). Fluvoxamine with a half-life of less than 24 h (i.e., 15.6 h) has a possibility of inter-dose withdrawal. Also, rise and fall of its blood levels in rapid cycles cause rapidly fluctuating biochemical imbalances in the brain.[4] Inhibitory modulation of dopaminergic neurons resulting from the increase in 5-hydroxytryptamine (5-HT) and disturbance in the reciprocal balance between dopaminergic, serotonergic and noradrenergic, or cholinergic activity[1] have been proposed as mechanisms underlying SSRI induced dystonia. On the other hand, fluvoxamine induced manic switch might be related to the inter-dose withdrawal and also to rapid fluctuations in the blood levels of serotonin leading to reciprocal changes in dopamine[4] - implying imbalances in the 5HT2 to D2 receptor occupancy. Reciprocal enhancement in the blood levels of norepinephrine also has been suggested as a mechanism underlying a manic switch.[5]\n\nThis case suggests that rapid hiking in dose (every 4th day increase in fluvoxamine by 50 mg) caused a sudden shift in the 5HT2:D2 balance toward D2 causing oculogyric dystonia; and at higher doses (fluvoxamine 250 mg and above) there might have been a disturbance in the reciprocal balance of serotonin, dopamine and norepinephrine neurotransmission, due to rise and fall in blood levels of fluvoxamine in rapid cycles, resulting in a manic switch. Inter-dose withdrawal might also have played some role also. Moreover, fluvoxamine induced dystonia in a case of OCD could also imply the role of glutaminergic system. Abnormal glutaminergic neurotransmission in cortical-striatal-thalamic circuits underlie both movement disorders (via motor projections) and OCD (via limbic associative projections).[6] SSRIs have been shown to normalize this excessive glutaminergic drive pathology; specifically fluvoxamine reduces N-Methyl-D-aspartate (NMDA) activity via sigma 1 receptors.[7] This report of ours therefore implicate the role of this “sigma enigma” in both fluvoxamine induced oculogyric dystonia and manic switch in a case of OCD.\n\nInterestingly, existing molecular genetic studies reveal a mixed support for the association between SSRI induced extrapyramidal symptoms and manic switch. There are reports that extrapyramidal symptoms induced by SSRIs are associated with the presence of the A1 allele of DRD2 Taq1A polymorphism,[8] which is also implicated in the etiology of bipolar disorder.[9] However, polymorphisms in serotonin transporter genes, which are implicated in antidepressant induced manic switch,[10] have not been found to be significantly associated with SSRI induced extrapyramidal symptoms.[8] Occurrence of oculogyric dystonia and manic switch in a patient of OCD during the course of fluvoxamine therapy suggests further investigation in the association between SSRI induced movement disorders and manic switch.\n\nSource of Support: Nil\n\nConflict of Interest: No\n==== Refs\n1 Madhusoodanan S Alexeenko L Sanders R Brenner R Extrapyramidal symptoms associated with antidepressants — A review of the literature and an analysis of spontaneous reports Ann Clin Psychiatry 2010 22 148 56 20680187 \n2 Peet M Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants Br J Psychiatry 1994 164 549 50 8038948 \n3 Patel OP Simon MR Oculogyric dystonic reaction to escitalopram with features of anaphylaxis including response to epinephrine Int Arch Allergy Immunol 2006 140 27 9 16514246 \n4 Breggin PR Fluvoxamine as a cause of stimulation, mania and aggression with a critical analysis of the FDA-approved label Int J Risk Saf Med 2001 14 71 86 \n5 Bhanji NH Margolese HC Saint-Laurent M Chouinard G Dysphoric mania induced by high-dose mirtazapine: A case for ‘norepinephrine syndrome’? Int Clin Psychopharmacol 2002 17 319 22 12409687 \n6 MacMaster FP Rosenberg DR Janicak PG Glutamate and the treatment of obsessive compulsive disorder Psychopharm Review 2010 45 33 40 \n7 Hindmarch I Hashimoto K Cognition and depression: The effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered Hum Psychopharmacol 2010 25 193 200 20373470 \n8 Hedenmalm K Güzey C Dahl ML Yue QY Spigset O Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme, and serotonin and dopamine transporter and receptor polymorphisms J Clin Psychopharmacol 2006 26 192 7 16633151 \n9 Huang CC Chang YH Lee SY Chen SL Chen SH Chu CH The interaction between BDNF and DRD2 in bipolar II disorder but not in bipolar I disorder Am J Med Genet B Neuropsychiatr Genet 2012 159B 501 7 22514151 \n10 Biernacka JM McElroy SL Crow S Sharp A Benitez J Veldic M Pharmacogenomics of antidepressant induced mania: A review and meta-analysis of the serotonin transporter gene (5HTTLPR) association J Affect Disord 2012 136 e21 9 21680025\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "45(5)",
"journal": "Indian journal of pharmacology",
"keywords": "Induced manic switch; oculogyric dystonia; selective serotonin reuptake inhibitor",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D004421:Dystonia; D005133:Eye Movements; D016666:Fluvoxamine; D006801:Humans; D008297:Male; D009771:Obsessive-Compulsive Disorder",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "532-3",
"pmc": null,
"pmid": "24130396",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8038948;20680187;12409687;21680025;20373470;22514151;16514246;24634707;16633151",
"title": "Fluvoxamine induced oculogyric dystonia and manic switch in a patient with obsessive compulsive disorder.",
"title_normalized": "fluvoxamine induced oculogyric dystonia and manic switch in a patient with obsessive compulsive disorder"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-120101",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "FLUVOXAMINE"
},
"dru... |
{
"abstract": "BACKGROUND\nCertolizumab, a pegylated tumour necrosis factor-α inhibitor, reduced disease activity in randomized trials of patients with psoriasis and psoriatic arthritis. Real-life data are missing.\n\n\nOBJECTIVE\nTo confirm the effectiveness and safety of certolizumab in patients with psoriasis and psoriatic arthritis in routine clinical practice.\n\n\nMETHODS\nIn this retrospective study involving 11 Italian sites, patients with psoriasis and psoriatic arthritis received subcutaneous certolizumab (400 mg loading dose at 0, 2 and 4 weeks, followed by 200 mg every 2 weeks) for up to 52 weeks. Primary outcomes included mean change from baseline in Psoriasis Area and Severity Index (PASI) and modified Nail Psoriasis Severity Index (mNAPSI) scores, and the proportion of patients achieving a 75%, 90% or 100% reduction in PASI score. Other endpoints included Disease Activity Score computed on 44 joints correlated with the erythrocyte sedimentation rate during the first hour (DAS44-ESR), Tender Joint Count (TJC), Swollen Joint Count (SJC), pain [visual analogue scale (VAS) score], inflammatory markers and quality of life (QOL).\n\n\nRESULTS\nIn the study were enrolled 153 patients (mean age: 55 years). Certolizumab reduced the mean PASI score from baseline by 4.45, 6.30 and 7.58 at weeks 12, 24 and 52, respectively (P < 0.001 for all). At weeks 24 and 52, 69.6% and 83.3% of patients had a PASI score ≤3. DAS44-ESR, TJC, SJC and mNAPSI scores, and pain VAS were also all significantly improved from baseline at each time point. C-reactive protein levels decreased during treatment, being significant at week 24. On multivariate analysis, psoriasis duration, baseline PASI, mNAPSI and pain VAS scores were found to be predictive of the improvement in PASI score at week 12.\n\n\nCONCLUSIONS\nCertolizumab displayed also in the real-life encouraging results in both psoriasis and psoriatic arthritis patients.",
"affiliations": "Department of Dermatology, University of Rome, \"Tor Vergata\", Rome, Italy.;Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy.;Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy.;Institute of Dermatology, Catholic University, Rome, Italy.;Institute of Dermatology, Catholic University, Rome, Italy.;Dermatology Unit, Department of Medicine, University of Padua, Padua, Italy.;Dermatology Unit, Department of Medicine, University of Padua, Padua, Italy.;Department Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.;Department Dermatology, San Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.;Section of Dermatology, DISSAL, San Martino-IST Polyclinic Hospital, University of Genoa, Genoa, Italy.;Section of Dermatology, DISSAL, San Martino-IST Polyclinic Hospital, University of Genoa, Genoa, Italy.;Dermatology Unit, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy.;Dermatology Unit, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy.;Department of Medical-Surgical Sciences and Bio-Technologies, Sapienza University of Rome, Polo Pontino, Terracina, Italy.;Dermatology Unit, Surgical, Medical and Dental Department of Morphological Sciences related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Institute of Dermatology, Catholic University, Rome, Italy.;Department of Dermatology, University of Rome, \"Tor Vergata\", Rome, Italy.;Department of Dermatology, University of Rome, \"Tor Vergata\", Rome, Italy.",
"authors": "Dattola|A|A|https://orcid.org/0000-0001-9504-5882;Balato|A|A|https://orcid.org/0000-0001-5485-0172;Megna|M|M|https://orcid.org/0000-0003-1803-2046;Gisondi|P|P|https://orcid.org/0000-0002-1777-9001;Girolomoni|G|G|https://orcid.org/0000-0001-8548-0493;De Simone|C|C|;Caldarola|G|G|https://orcid.org/0000-0002-8837-9232;Cama|E|E|;Piaserico|S|S|;Fargnoli|M C|MC|https://orcid.org/0000-0002-7249-2556;Fidanza|R|R|;Parodi|A|A|;Burlando|M|M|https://orcid.org/0000-0002-4381-6718;Offidani|A|A|;Diotallevi|F|F|;Potenza|C|C|;Conti|A|A|;Chiricozzi|A|A|;Campione|E|E|;Bianchi|L|L|",
"chemical_list": null,
"country": "England",
"delete": false,
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"abstract": "Ischemic and hemorrhagic stroke are recognized complications of Varicella zoster virus (VZV) infections, although uncommon and poorly documented. The authors report the case of a 31-year-old woman admitted with acute ischemic stroke of the right posterior cerebral artery and a history of a thoracic rash 1 month before. Aspirin and simvastatin were prescribed, but the patient suffered a stepwise deterioration the following days, with new areas of infarction on brain imaging. Despite no evidence of cardiac or large vessel embolic sources, anticoagulation was started empirically 6 days after stroke onset. One week later, symptomatic hemorrhagic transformation occurred. The diagnosis of VZV vasculopathy was then considered, and treatment with acyclovir and prednisolone was started with no further vascular events. Cerebrospinal fluid analysis and digital subtraction angiography findings corroborated the diagnosis. The patient was discharged to the rehabilitation center with a modified Rankin scale (mRS) score of 4. On the 6-month follow-up, she presented only a slight disability (mRS score 2). In conclusion, VZV vasculopathy needs to be considered in young adults with stroke. A high index of suspicion and early treatment seem to be important to minimize morbidity and mortality. Anticoagulation should probably be avoided in stroke associated with VZV vasculopathy.",
"affiliations": "Neurology Department, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Neurology Department, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Neurology Department, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal; CEDOC, Nova Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.;Neurology Department, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal; CEDOC, Nova Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.",
"authors": "Borbinha|Cláudia|C|;Marto|João Pedro|JP|;Calado|Sofia|S|;Viana-Baptista|Miguel|M|",
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"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000447296crn-0008-0145Case ReportA Young Woman with Ischemic Stroke: Should We Pay More Attention to Varicella Zoster Infection? Borbinha Cláudia a*Marto João Pedro aCalado Sofia abViana-Baptista Miguel abaNeurology Department, Hospital Egas Moniz – Centro Hospitalar de Lisboa Ocidental, Lisbon, PortugalbCEDOC, Nova Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal*Cláudia Borbinha, Neurology Department, Hospital Egas Moniz, Rua Da Junqueira 126, PT–1349-019 Lisbon (Portugal), claudiaborbinha3@gmail.comMay-Aug 2016 7 7 2016 7 7 2016 8 2 145 150 11 4 2016 30 5 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Ischemic and hemorrhagic stroke are recognized complications of Varicella zoster virus (VZV) infections, although uncommon and poorly documented. The authors report the case of a 31-year-old woman admitted with acute ischemic stroke of the right posterior cerebral artery and a history of a thoracic rash 1 month before. Aspirin and simvastatin were prescribed, but the patient suffered a stepwise deterioration the following days, with new areas of infarction on brain imaging. Despite no evidence of cardiac or large vessel embolic sources, anticoagulation was started empirically 6 days after stroke onset. One week later, symptomatic hemorrhagic transformation occurred. The diagnosis of VZV vasculopathy was then considered, and treatment with acyclovir and prednisolone was started with no further vascular events. Cerebrospinal fluid analysis and digital subtraction angiography findings corroborated the diagnosis. The patient was discharged to the rehabilitation center with a modified Rankin scale (mRS) score of 4. On the 6-month follow-up, she presented only a slight disability (mRS score 2). In conclusion, VZV vasculopathy needs to be considered in young adults with stroke. A high index of suspicion and early treatment seem to be important to minimize morbidity and mortality. Anticoagulation should probably be avoided in stroke associated with VZV vasculopathy.\n\nKeywords\nVaricella zoster virusVasculopathyIschemic strokeHemorrhagic strokeYoung adultsAnticoagulation\n==== Body\nIntroduction\nVaricella zoster virus (VZV) is a neurotropic DNA alpha herpesvirus that infects more than 95% of the world population. Usually, varicella results from primary infection. The virus then becomes latent in ganglion neurons along the entire neuroaxis, and after reactivation, VZV moves transaxonally to the skin resulting in zoster [1]. Less often, VZV reactivation leads to neurologic complications more common in immunocompromised patients, such as VZV vasculopathy [2]. The typical presentation in adults is ophthalmic zoster followed by acute contralateral hemiplegia [3]. Vasculitis has, however, been reported in patients with dermatomal herpes zoster infection without trigeminal nerve involvement. The average time from rash to neurologic symptoms and signs is 4.1 months, but sporadically the patient can present with rash and stroke simultaneously. Nonetheless, approximately one third of patients have no history of rash [2]. In recent years, the number of recognized VZV vasculopathies has grown [1], but the diagnosis is not easy because, frequently, clinical presentation and imaging features are not specific of this entity. Antiviral and antithrombotic treatment should probably be considered in stroke associated with VZV vasculopathy, but data on which to base therapeutic decisions are lacking.\n\nCase Report\nA 31-year-old right-handed female was admitted to the emergency department because of headache associated with visual disturbance. She had no previous history of headache and no known vascular risk factors but she used an oral contraceptive pill. On admission, she reported a 9-hour progressive pulsatile headache, with nausea and photophobia, followed by a sudden left visual field defect. Neurological examination documented left homonymous hemianopia. A head computed tomography (CT) scan was judged to be normal (fig. 1a). She was treated with paracetamol and metoclopramide with subjective improvement followed by hospital discharge. The next day, the patient was observed at an outpatient consultation and subsequently admitted in the neurology ward because the headache had worsened and she felt weakness and numbness of the left limbs. She also recalled a history of thoracic rash 1 month before and she reported having had varicella at the age of 7 years. Neurological examination at that time revealed slight drowsiness, mild left hemiparesis, left hemihypesthesia and homolateral homonymous hemianopia. A new CT scan showed an ischemic infarct on the territory of the right posterior cerebral artery (fig. 1b) and contrast administration excluded dural sinus venous thrombosis. Cervical and transcranial ultrasound did not disclose significant abnormalities, namely vasospasm. She was started on acetylsalicylic acid 150 mg and simvastatin 20 mg i.d.\n\nTwo days after admission, the neurological picture worsened with acute onset of left central facial palsy, visual and tactile inattention and worsening of the left motor deficit. A new CT scan showed enlargement of the ischemic lesion with involvement of the right thalamus (fig. 1c) and new areas of infarction involving different arterial territories, further depicted on MRI (fig. 2a, b). MR angiography showed an occlusion of the right posterior cerebral artery 5 mm after its origin (fig. 2c). Transthoracic and transesophageal echocardiography and Holter ECG were within the norms, as were the of laboratory blood tests (including HIV antibodies). Clinical deterioration continued with further motor compromise, and although no cardiac or large vessel embolic source had been documented, facing neurological worsening, acetylsalicylic acid was substituted by low molecular weight heparin (60 mg subcutaneously twice a day) 6 days after admission. The patient remained stable for a week, but then a new episode occurred, with headache and slight drowsiness associated with hemorrhagic transformation involving the thalamus but sparing the cortical territory of the posterior cerebral artery (fig. 3a). Anticoagulation was stopped immediately.\n\nBecause of the medical history of recent VZV reactivation, it was then hypothesized that the stroke could be secondary to VZV vasculopathy. However, at that time, evidence of increased intracranial pressure contraindicated the lumbar puncture. Acyclovir and prednisolone were started empirically (acyclovir 750 mg three times daily, and prednisolone 60 mg once a day for 21 days), with slow but steady improvement. Digital subtraction angiography (DSA) showed narrowing at the origin of the right posterior cerebral artery and demonstrated an irregular lumen of the posterior segment of the pericallosal artery with beading-like pattern appearance (fig. 3b). She underwent a lumbar puncture 11 days after initiation of therapy (27 days after admission). Cerebrospinal fluid (CSF) protein content was slightly increased (48 mg/dl), glucose 59 mg/dl, and a discrete mononuclear pleocytosis was detected (6 cells). VZV-DNA was not detected by polymerase chain reaction, but there was an increased CSF/serum ratio of VZV IgG (3.3), confirming intrathecal production of anti-VZV antibodies.\n\nMotor function improved, but the patient was discharged with persistent left homonymous hemianopia and spatial inattention, unable to walk without assistance [modified Rankin scale (mRS) score 4]. After antiviral therapy, she restarted acetylsalicylic acid 150 mg once a day. On the 6-month follow-up, only a mild to moderate paresis of the left limbs was present. Hemianopia also, improved but an incomplete deficit of the left visual field persisted. The patient was able to walk unassisted and look after her own affairs (mRS score 2).\n\nDiscussion\nThis case study raised several important clinical issues. One of them was the difficulty of diagnosis with prompt treatment. Recognition of VZV vasculopathy was not straightforward because this is an uncommon entity and strokes of other etiologies may present with a similar neurologic picture and imaging abnormalities. On the other hand, the classic clinical presentation of VZV vasculopathy is acute contralateral hemiplegia after ophthalmic zoster. Finally, VZV-induced central nervous system (CNS) disease seems to be rare in immunocompetent patients [4].\n\nDespite no previous history of headache and sudden presentation of the visual deficit, migrainous infarction could be considered in our patient on account of presentation with pulsatile progressive headache in a young female and the known predilection of this complication for the posterior circulation [5]. Cryptogenic stroke, which may be responsible for as much as 50% of strokes in young adults [6, 7], was also considered in the absence of findings that supported cardiac embolism, atherosclerosis, arterial dissection, inflammatory or drug-induced etiologies.\n\nAlthough there was no evidence to support the decision, anticoagulation was considered because of the stepwise deterioration of the neurological status under aspirin, with new ischemic areas in different territories, and a MR angiography not indicative of vasculitis. Looking backwards, anticoagulation may not have been the most suitable therapeutic choice and should probably be avoided with in-patients with stroke and recent VZV infection, as hemorrhagic transformation occurred probably in the context of vessel wall damage but may also have been triggered by anticoagulation [1].\n\nA stroke syndrome can develop after primary or secondary VZV infection. The biological mechanisms are probably multifactorial: inflammation associated with systemic infection may lead to endothelial dysfunction [3]; in addition, the VZV virus spreads along nerve fibers and directly involves the vessels [1]. Vasculitis has been described in patients with dermatomal herpes zoster infection without trigeminal nerve involvement, as in our case [8]. The vasculopathy typically involves the anterior circulation, but VZV vasculitis involvement of the vertebrobasilar system has also been reported. These studies suggest that VZV may enter the CNS not only from trigeminal ganglia but also from other pathways [9].\n\nAs suggested in previous reports, this case highlights the usefulness of DSA and CSF/serum ratio of VZV IgG for the diagnosis of VZV vasculopathy [2]. VZV DNA was not present in CSF, but several studies with serial analysis revealed its presence only during the first 2 weeks of disease, while anti-VZV IgG antibodies become detectable during the second week after infection [2]. The diagnostic value of detecting anti-VZV IgG antibody in CSF is greater than that of detecting VZV DNA [1]. The multifocal nature of VZV vasculopathy makes biopsy a test with low sensitivity and high morbidity [4]. Considering the difficulties in diagnosis, González-Suárez et al. [4] proposed diagnostic criteria for CNS VZV vasculopathy. In our case, when the diagnosis of VZV vasculopathy was considered, a lumbar puncture was contraindicated due to increased intracranial pressure; nevertheless, we began treatment with intravenous acyclovir and steroids. Although there are no controlled trials to access the optimal treatment schemes, we continued treatment during 21 days. Duration of antiviral treatment as well as acyclovir dosage and benefit of steroids are issues that deserve further research [10].\n\nIn conclusion, our case underlines that vasculopathy and stroke related to VZV infection should be borne in mind when dealing with stroke in young adults. In fact, available data suggest that this complication of a frequent infection may be more common than usually reported, not only after herpes zoster or varicella but also in cases of a stroke of unknown origin [1, 2]. DSA seems to be important to the diagnosis of VZV vasculopathy, which is confirmed by intrathecal synthesis of anti-VZV IgG antibody. Prompt treatment with empiric intravenous acyclovir and oral prednisone should be started. Anticoagulation should probably be avoided in stroke associated with VZV vasculopathy.\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare.\n\nDisclosure Statement\nThe authors declare that there are no conflicts of interest and that no funding was received for this report.\n\nFig. 1 Head CT scan performed in the emergency department (a), on the third day after the event (b), with a large hypodensity (arrow) on the territory of the right posterior cerebral artery, and 6 days after admission (c), showing enlargement of the ischemic lesion with involvement of the right thalamus (arrow).\n\nFig. 2 Brain MRI performed on the seventh day after admission. T2 FLAIR images showed hyperintensity in the right periventricular white matter and posterior corpus callosum (a), and medial juxtacortical parietal region (b), indicative of ischemic lesions. MR angiography (TOF) showed occlusion of the right posterior cerebral artery 5 mm after its origin (c).\n\nFig. 3 a Head CT scan made 13 days after the ictal event showing hemorrhagic transformation involving the thalamus (arrow). b DSA of the left carotid artery showing an irregular lumen of the pericallosal artery with beading-like pattern appearance (arrow).\n==== Refs\nReferences\n1 Nagel MA Gilden D The relationship between herpes zoster and stroke Curr Neurol Neurosci Rep 2015 15 16 25712420 \n2 Nagel MA Cohrs RJ Mahalingam R Wellish MC Forghani B Schiller A Safdieh JE Kamenkovich E Ostrow LW Levy M Greenberg B Russman AN Katzan I Gardner CJ Häusler M Nau R Saraya T Wada H Goto H de Martino M Ueno M Brown WD Terborg C Gilden DH The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features Neurology 2008 70 853 18332343 \n3 Kleinschmidt-Demasters BK Gilden DH Varicella-zoster virus infections of the nervous system: clinical and pathologic correlates Arch Pathol Lab Med 2001 125 770 780 11371229 \n4 González-Suárez I Fuentes-Gimeno B Ruiz-Ares G Martínez-Sánchez P Diez-Tejedor E Varicella-zoster virus vasculopathy A review description of a new case with multifocal brain hemorrhage. J Neurol Sci 2014 338 34 38 24461566 \n5 Wolf ME Szabo K Griebe M Förster A Gass A Hennerici MG Kern R Clinical and MRI characteristics of acute migrainous infarction Neurology 2011 76 1911 1917 21624990 \n6 Kittner SJ Stern BJ Wozniak M Buchholzet DW Earley CJ Feeser BR Johnson CJ Macko RF McCarter RJ Price TR Sherwin R Sloan MA Wityk RJ Cerebral infarction in young adults Neurology 1998 50 890 894 9566368 \n7 Amarenco P Cryptogenic stroke, aortic arch atheroma, patent foramen ovale, and the risk of stroke Cerebrovasc Dis 2005 20 (suppl 2) 68 74 16327255 \n8 Gilden DH Lipton HL Wolf JS Akenbrandt W Smith JE Mahalingam R Forghani B Two patients with unusual forms of varicella-zoster virus vasculopathy N Engl J Med 2002 347 1500 1503 12421892 \n9 Matsuo K Uozumi Y Miyamoto H Tatsumi S Kohmura E Varicella-zoster vasculitis presenting with cerebellar hemorrhage J Stroke Cerebrovasc Dis 2015 24 e153 e155 25840954 \n10 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella Zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment Lancet Neurol 2009 8 731 19608099\n\n",
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... |
{
"abstract": "A 67-year-old man presented to the hospital with complaints of fever and cough. He had a past medical history of renal cell carcinoma and had just started treatment with temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor. A 1-week course of antibiotics did not have any effect on his symptoms. A chest computed tomography (CT) scan showed the reversed halo sign (RHS). Organizing pneumonia induced by mTOR inhibitor treatment was initially considered. However, transbronchial biopsy revealed clusters of fungal organisms, suggesting infection with Aspergillus spp. Within just 2 weeks, a CT scan showed drastic enlargement of the cavitary lesion, with multiple newly formed consolidations. The patient was diagnosed with invasive pulmonary aspergillosis. Concomitant treatment with voriconazole and micafungin was started. Two weeks after the initiation of treatment, he became afebrile with gradual regression of the cavitary lesion and consolidations.",
"affiliations": "Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi 400-8506, Japan.;Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi 400-8506, Japan.;Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi 400-8506, Japan.;Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi 400-8506, Japan.;Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi 400-8506, Japan.;Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi 400-8506, Japan.;Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi 400-8506, Japan.",
"authors": "Iijima|Yuki|Y|;Fujioka|Namiko|N|;Uchida|Yoshinori|Y|;Kobayashi|Yoichi|Y|;Tsutsui|Toshiharu|T|;Kakizaki|Yumiko|Y|;Miyashita|Yoshihiro|Y|",
"chemical_list": "D054714:Echinocandins; D055666:Lipopeptides; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D065819:Voriconazole; D000077551:Micafungin; D020123:Sirolimus",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2018.01.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "69()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Immunocompromise; Invasive pulmonary aspergillosis; Organizing pneumonia; Reversed halo sign; mTOR inhibitor",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000368:Aged; D001230:Aspergillus; D002292:Carcinoma, Renal Cell; D054714:Echinocandins; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D055666:Lipopeptides; D008297:Male; D000077551:Micafungin; D011014:Pneumonia; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D065819:Voriconazole",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "75-77",
"pmc": null,
"pmid": "29408183",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Invasive pulmonary aspergillosis mimicking organizing pneumonia after mTOR inhibitor therapy: A case report.",
"title_normalized": "invasive pulmonary aspergillosis mimicking organizing pneumonia after mtor inhibitor therapy a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2018142311",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMSIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe porphyrias are a group of disorders of the heme biosynthesis pathway that may present with acute life-threatening attacks, commonly exacerbated by a wide variety of medications. Many newer immunosuppressive medications, which are in use following kidney transplantation, have not been fully explored in acute porphyrias.\n\n\nMETHODS\nA 53-year-old woman received a kidney from a deceased donor, after being on hemodialysis for 4 years. Hereditary coproporphyria was diagnosed at age 19 years. We administered tacrolimus, mycophenolate mofetil and steroid immunosuppression. In the immediate post-transplant periods she displayed abdominal pain and transient uroporphyrin elevation in parallel with slightly elevated (15 ng/mL) tacrolimus concentrations. As the target tacrolimus level was achieved, these findings disappeared.\n\n\nCONCLUSIONS\nTacrolimus, mycophenolate- mofetil, and steroid therapy for hereditery coproporphyri was safe, in the long term.",
"affiliations": "Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary. Electronic address: telkes.gabor@med.semmelweis-univ.hu.",
"authors": "Telkes|G|G|;Pusztai|A|A|;Földes|K|K|;Langer|R M|RM|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "45(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D015746:Abdominal Pain; D046349:Coproporphyria, Hereditary; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008875:Middle Aged; D009173:Mycophenolic Acid; D012307:Risk Factors; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3703-4",
"pmc": null,
"pmid": "24315002",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Kidney transplantation in hereditary coproporphyria using tacrolimus and mycophenolate mofetil: a case report.",
"title_normalized": "kidney transplantation in hereditary coproporphyria using tacrolimus and mycophenolate mofetil a case report"
} | [
{
"companynumb": "HU-WATSON-2014-18927",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "We investigated protracted low-dose oral Clofarabine for the treatment of myelodysplastic syndromes (MDS). Adults with an International Prognostic Scoring System (IPSS) score of INT-1 or higher who had failed first line therapy were eligible. INT-1 patients had to be transfusion-dependent. We started with oral Clofarabine at 5mg (fixed dose) daily for 10 consecutive days on a 28-day cycle. Toxicity prompted a modification to 1mg PO daily for 10 days and then 1mg PO daily for 7 days. Patients received treatment indefinitely until loss of response or unacceptable toxicity. Nine patients (5 women) were enrolled and evaluable (median age 65 years; range 55-81). A 10-day regimen of oral Clofarabine at 5mg/day induced Grade IV pancytopenia. A dose of 1 mg/day for 7/28 days was very well tolerated without significant toxicity. Three patients had responses (2 with responses lasting up to 21 and 51 cycles) defined as stable disease in spite of no significant change on bone marrow evaluation. Low-dose oral Clofarabine (1mg daily for 7/28 days) proved both effective and safe for patients with MDS who had failed prior therapy. This patient population is particularly sensitive to more protracted Clofarabine treatment schedules.",
"affiliations": "Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United States.;Hematology/Oncology, St. Joseph Mercy Hospital, Ann Arbor, MI, United States.;Division of Epidemiology, University of Utah-Huntsman Cancer Institute, Salt Lake City, UT, United States.;Hematology/Oncology, St. Alphonsus Cancer Care Center, Nampa, ID, United States.;Hematology/Oncology, Snake River Oncology of Eastern Idaho, Idaho Falls, ID, United States.;Division of Hematology and Hematologic Malignancies, University of Utah-Huntsman Cancer Institute, Salt Lake City,, UT, United States.;Division of Hematology and Hematologic Malignancies, University of Utah-Huntsman Cancer Institute, Salt Lake City,, UT, United States. Electronic address: paul.shami@utah.edu.",
"authors": "Rudrapatna|Venkatesh K|VK|;Morley|Kimberly|K|;Boucher|Kenneth M|KM|;Pierson|Andrew S|AS|;Shull|Christian T|CT|;Kushner|James P|JP|;Shami|Paul J|PJ|",
"chemical_list": "D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000077866:Clofarabine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "39(8)",
"journal": "Leukemia research",
"keywords": "Clofarabine; Myelodysplasia; Myelodysplastic syndrome",
"medline_ta": "Leuk Res",
"mesh_terms": "D000227:Adenine Nucleotides; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000077866:Clofarabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D020360:Neoadjuvant Therapy; D017211:Treatment Failure",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "835-9",
"pmc": null,
"pmid": "26038120",
"pubdate": "2015-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I trial of low-dose oral Clofarabine in myelodysplastic syndromes patients who have failed frontline therapy.",
"title_normalized": "phase i trial of low dose oral clofarabine in myelodysplastic syndromes patients who have failed frontline therapy"
} | [
{
"companynumb": "US-SA-2014SA030051",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOFARABINE"
},
"drugadditional": null,
"d... |
{
"abstract": "We compared the outcomes of salvage chemotherapy in 146 patients with relapsed (57.5%) or refractory (42.5%) AML who received CLAG-M (51%), MEC (39%) or CLAG (10%). Minimal residual disease (MRD) was assessed by flow cytometry. Bivariate, Kaplan-Meier, and Cox regression analyses were conducted. Complete remission (CR) rate of 46% (CLAG-M 54% versus MEC/CLAG 40%, p = .045) was observed with MRD-negative CR of 33% (CLAG-M 39% versus MEC/CLAG 22%, p = .042). Median overall survival (OS) was 9.7 months; the longest OS occurred with CLAG-M (13.3, 95%CI 2.4-24.3) versus MEC (6.9, 95%CI 2.9-10.9) or CLAG (6.2, 95%CI 2.4-12.6) (p = .025). When adjusted for age, gender, relapsed/refractory AML, poor risk AML, MRD, chemotherapy and transplant, CLAG-M (HR 0.63, 95% CI 0.40-0.98, p = .042), MRD-negativity (HR 0.15, 95% CI 0.07-0.30, p < .001) and transplant (HR 0.22, 95% CI 0.13-0.39, p < .001) were associated with higher OS. Our findings confirm that CLAG-M is a reasonable salvage regimen for RR-AML followed by transplant.",
"affiliations": "Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;University of Wisconsin Carbone Cancer Center, Madison, WI, USA.;Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.",
"authors": "Mushtaq|Muhammad Umair|MU|0000-0001-8122-0563;Harrington|Alexandra M|AM|;Chaudhary|Sibgha Gull|SG|;Michaelis|Laura C|LC|;Carlson|Karen-Sue B|KB|;Abedin|Sameem|S|;Runass|Lyndsey|L|;Callander|Natalie S|NS|;Fallon|Michael J|MJ|;Juckett|Mark|M|;Hall|Aric C|AC|;Hematti|Peiman|P|;Mattison|Ryan J|RJ|;Atallah|Ehab L|EL|;Guru Murthy|Guru Subramanian|GS|",
"chemical_list": "D003561:Cytarabine; D017338:Cladribine",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2020.1821009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "62(1)",
"journal": "Leukemia & lymphoma",
"keywords": "Acute myeloid leukemia; hematopoietic stem cell transplant; minimal residual disease; relapsed/refractory leukemia; salvage chemotherapy",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D017338:Cladribine; D003561:Cytarabine; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D018365:Neoplasm, Residual; D011379:Prognosis; D012074:Remission Induction; D016879:Salvage Therapy",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "158-166",
"pmc": null,
"pmid": "32951486",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Comparison of salvage chemotherapy regimens and prognostic significance of minimal residual disease in relapsed/refractory acute myeloid leukemia.",
"title_normalized": "comparison of salvage chemotherapy regimens and prognostic significance of minimal residual disease in relapsed refractory acute myeloid leukemia"
} | [
{
"companynumb": "US-AMGEN-USASP2021021301",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nProgressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system caused by John Cunningham virus, mostly associated with immunodeficiency conditions, such as the human immunodeficiency virus infection. Progressive multifocal leukoencephalopathy can have multiple clinical features and usually presents a typical lesion pattern on brain magnetic resonance imaging. Its course may be rapidly progressive, although immunological responsiveness can be associated with an improved prognosis.\n\n\nMETHODS\nWe performed a retrospective analysis of the clinical and radiological data from patients admitted in our institution between January 2005 and April 2014 with the diagnosis of definitive progressive multifocal leukoencephalopathy (ICD10:A81.2) in the setting of human immunodeficiency virus infection.\n\n\nRESULTS\nTwenty-one patients were included in our study, mostly men (n = 20, 95.2%). Mean age at diagnosis was 39 years. Motor deficits were the most common clinical finding. John Cunningham virus-DNA was detected in the cerebral spinal fluid in 20 patients (95.2%). Brain imaging studies most commonly disclosed bilateral supratentorial, asymmetric lesions. Four (19%) patients developed immune reconstitution inflammatory syndrome in the follow-up. Therapeutic approach included initiation and continuation/optimization of antiretroviral therapy, with adjunctive therapy with corticosteroids in four patients. Seventeen (81%) patients died during the study period; median survival time following progressive multifocal leukoencephalopathy diagnosis was 3 months (range 1 - 13).\n\n\nCONCLUSIONS\nThe results of our study are in accordance with the data previously published on progressive multifocal leukoencephalopathy in human immunodeficiency virus patients. Progressive multifocal leukoencephalopathy is predominantly associated with severe immunosuppression, particularly in patients who are not under anti-retroviral therapy, and usually presents with motor and cognitive symptoms and signs. A typical bilateral asymmetric pattern in conventional magnetic resonance imaging is present in the majority of the patients. There is no specific therapy for progressive multifocal leukoencephalopathy and it is usually fatal, although outcomes can improve with highly active anti-retroviral therapy. Immune reconstitution inflammatory syndrome is also an important complication related with progressive multifocal leukoencephalopathy, usually associated with anti-retroviral therapy. Progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome presents with different imaging characteristics from progressive multifocal leukoencephalopathy and treatment with steroids can improve survival.\n\n\nCONCLUSIONS\nThe mortality rate and long-term neurological morbidity associated with progressive multifocal leukoencephalopathy are quite high. These data should increase clinician awareness to the occurrence of progressive multifocal leukoencephalopathy among human immunodeficiency virus patients and highlight the important role of magnetic resonance imaging, as early diagnosis may beassociated with better outcome.",
"affiliations": "Neuroradiology Department. Centro Hospitalar São João. Porto. Portugal.;Infectious Diseases Department. Centro Hospitalar São João. Porto. Portugal.;Neuroradiology Department. Centro Hospitalar São João. Porto. Portugal.;Infectious Diseases Department. Centro Hospitalar São João. Porto. Portugal.;Infectious Diseases Department. Centro Hospitalar São João. Porto. Portugal. Infectious Diseases Department. Faculty of Medicine. University of Porto. Porto. Portugal.",
"authors": "Augusto|Luís|L|;Neves|Nélia|N|;Reis|Carina|C|;Abreu|Cândida|C|;Sarmento|António|A|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.5950",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": "28(3)",
"journal": "Acta medica portuguesa",
"keywords": null,
"medline_ta": "Acta Med Port",
"mesh_terms": "D000328:Adult; D005260:Female; D015658:HIV Infections; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "7906803",
"other_id": null,
"pages": "286-96",
"pmc": null,
"pmid": "26421780",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clinical and Radiological Characterization of Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients: A Retrospective Analysis and Review of the Literature.",
"title_normalized": "clinical and radiological characterization of progressive multifocal leukoencephalopathy in hiv infected patients a retrospective analysis and review of the literature"
} | [
{
"companynumb": "PT-BIOGENIDEC-2012BI030380",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We describe a 69-year-old white man with a recent history of a left forearm sarcoma resection treated with a split-thickness skin graft and radiotherapy who presented with cellulitis of the left forearm, for which a 2-week course of trimethoprim-sulfamethoxazole was prescribed. Ten days into treatment, he presented with flu-like symptoms and a rash. He was eventually diagnosed with Stevens-Johnson syndrome accentuated on the donor split-thickness skin graft on the left thigh region mimicking a recall reaction. There are no other reported cases of Stevens-Johnson syndrome localized within donor graft sites; therefore, this case may represent a novel form of recall reaction.",
"affiliations": "Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas.;Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock, Texas.;Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock, Texas.;Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock, Texas.",
"authors": "Najmi|Maleka|M|;Sharp|Leigha|L|;Tarbox|Michelle|M|;Stetson|Cloyce|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2020.1814484",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "34(1)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": "Donor graft; Stevens-Johnson syndrome; recall-like reaction; toxic epidermal necrolysis",
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "85-86",
"pmc": null,
"pmid": "33456153",
"pubdate": "2020-09-17",
"publication_types": "D002363:Case Reports",
"references": "25160108;23866878;29651444;7697529;31150704",
"title": "Stevens-Johnson syndrome with a recall-like reaction within a donor graft site.",
"title_normalized": "stevens johnson syndrome with a recall like reaction within a donor graft site"
} | [
{
"companynumb": "US-EMCURE PHARMACEUTICALS LTD-2021-EPL-000230",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "BACKGROUND\nDaily cannabis assumption is currently associated with several physical and mental health problems, however in the past it was prescribed for a multitude of symptoms, including vomiting, abdominal pain and diarrhea. Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders.\n\n\nMETHODS\nWe retrospectively analysed the efficacy and safety of a CB1-receptor agonist administered in six patients with refractory chronic diarrhea, between April 2008 and July 2016. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. Most of the benefits persisted through the three-month follow-up. Only one patient interrupted the treatment after one month, due to severe fatigue and mental confusion; the symptoms disappeared in the follow-up period.\n\n\nCONCLUSIONS\nThese findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.",
"affiliations": "Medical Toxicology and Headache Center, University of Modena and Reggio Emilia, via del Pozzo 71, 41124, Modena, Italy. lanfranco.pellesi@gmail.com.;Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Medical Toxicology and Headache Center, University of Modena and Reggio Emilia, via del Pozzo 71, 41124, Modena, Italy.;Medical Toxicology and Headache Center, University of Modena and Reggio Emilia, via del Pozzo 71, 41124, Modena, Italy.",
"authors": "Pellesi|Lanfranco|L|http://orcid.org/0000-0003-4137-5039;Verga|Maria Chiara|MC|;De Maria|Nicola|N|;Villa|Erica|E|;Pini|Luigi Alberto|LA|;Guerzoni|Simona|S|",
"chemical_list": "D005765:Gastrointestinal Agents; D043884:Receptor, Cannabinoid, CB1; C011941:nabilone; D013759:Dronabinol",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-019-1024-y",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 102410.1186/s12876-019-1024-yCase ReportNabilone administration in refractory chronic diarrhea: a case series http://orcid.org/0000-0003-4137-5039Pellesi Lanfranco 0039-0594222099lanfranco.pellesi@gmail.com 1Verga Maria Chiara vergamariachiara@gmail.com 2De Maria Nicola demaria.nicola@policlinico.mo.it 2Villa Erica erica.villa@unimore.it 2Pini Luigi Alberto pinila@unimore.it 13Guerzoni Simona simona.guerzoni@gmail.com 11 0000000121697570grid.7548.eMedical Toxicology and Headache Center, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy 2 0000000121697570grid.7548.eGastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy 3 0000000121697570grid.7548.eCentre for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy 25 6 2019 25 6 2019 2019 19 1056 12 2018 17 6 2019 © The Author(s). 2019Open Access This 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\nDaily cannabis assumption is currently associated with several physical and mental health problems, however in the past it was prescribed for a multitude of symptoms, including vomiting, abdominal pain and diarrhea. Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders.\n\nCase presentation\nWe retrospectively analysed the efficacy and safety of a CB1-receptor agonist administered in six patients with refractory chronic diarrhea, between April 2008 and July 2016. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. Most of the benefits persisted through the three-month follow-up. Only one patient interrupted the treatment after one month, due to severe fatigue and mental confusion; the symptoms disappeared in the follow-up period.\n\nConclusions\nThese findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.\n\nKeywords\nCB1 receptorCannabinoidsNabiloneChronic diarrheaGastrointestinal disordersRefractoryCase seriesissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCannabis is the most abused illicit drug in the world [1]. In the past, it played a strong and prominent role in medicine. Until 1941, when cannabis preparations were taken off the United States Pharmacopeia and National Formulary, it was prescribed for a multitude of symptoms, including nausea, vomiting, abdominal pain and diarrhea [2, 3]. Even though the consumption of cannabis is currently associated with major health issues, such as an increase in respiratory diseases, psychosis and suicidal ideations [4], the medical use of its derivatives continues to increase worldwide. At the time of this writing, several European nations and more than 30 United States territories allow marijuana for medical purposes, although their approaches are significantly different. Moderate evidence now supports the use of cannabis for the treatment of chronic pain and spasticity, and improvements have been observed in nausea and vomiting due to chemotherapy, anorexia in HIV infection, sleep disorders and Tourette syndrome [5].\n\nAmong the active ingredients of cannabis, cannabinoids are the most studied in the medical literature. Δ [9]-tetrahydrocannabinol (Δ [9]-THC) is the most familiar of them, and the responsible for the psychotropic activity. Once absorbed by the human body, several cannabinoids interact with the endocannabinoid system (ECS), a physiologic system involved in establishing and maintaining homeostasis of different organs and body systems. ECS is composed by endogenous ligands, known as endocannabinoids, by G protein-coupled cannabinoid receptors 1 and 2 (CB1 and CB2) and the enzymes involved in endocannabinoids turnover [6–8]. It interacts within its own pathways, as well as with all major inflammatory and painful pathways, including endorphins, enkephalins, transient receptor potential cation channels (TRPV) and peroxisome proliferator-activated receptors (PPARs) [9]. ECS components are in the human brain and in the peripheral nervous system, but they are also detectable outside the brain, e.g. on immune cells, in the gastrointestinal (GI) tract and other organs [10].\n\nIn recent years, the knowledge of the ECS and its role in the gut has grown rapidly. The actions of the ECS appear to be largely homeostatic, contributing to the gut protection from inflammation and regulating GI motility [11–13]. CB1 receptors are expressed in the normal human colon and in the enteric nervous system (ENS), regulating neurotransmitters release, intestinal smooth muscle tone and peristalsis [14], whereas CB2 receptors were found in the lamina propria and in the ENS [15]. Rimonabant, an inverse agonist of CB1 receptors, was able to increase colonic motility in mice [14], while the agonist activity of dronabinol inhibited gastric emptying and colonic motility in healthy humans [16]. Furthermore, the endocannabinoid signalling is intensified during intestinal inflammation; CB2 receptors are up regulated in colonic mucosal samples from inflammatory bowel disease (IBD) patients [17] and JWH-133, a CB2 receptor agonist, inhibits the increase in GI transit elicited by an intraperitoneal injection of lipopolysaccharides [18]. These results are consistent in over than 10% of patients with IBD, who confirmed that they had used cannabis as self-medication at least once in their life [19], and most of them found that marijuana was very helpful to relieve abdominal pain and diarrhea [20, 21]. Accordingly, cannabinoids acting on CB1 and CB2 receptors might have beneficial effects for patients with symptoms of abdominal pain, inflammation and hypermotility [22–24]. The latter often coexist in chronic diarrhea. Chronic diarrhea is defined as a symptom with at least three bowel movements per day, with a faecal weight of more than 200 g/day, lasting for at least four weeks [25]. It is due to many non-specific causes; as a result, patients take nonspecific antidiarrheal therapy (such as opiates, intraluminal pro-absorptive agents or glucocorticoids) for several months, and do not solve their problem.\n\nCase presentation\nWe present the course of six patients with refractory chronic diarrhea, treated with a synthetic CB1-receptor agonist. The baseline characteristics of patients are presented in Table 1. The reasons for chronic diarrhea are manifold and are explained in the subsequent description of the cases. All patients were previously treated with etiologic and symptomatic drugs, without benefits. The pharmacological properties of the drug, nabilone, are summarized in Fig. 1. They are deduced from the work of Lemberger et al. [26]. The drug was administered orally in the hospital setting, as a compassionate drug, for three months. For the duration of the treatment and the following three months, all patients were periodically monitored by medical toxicologists due to the possible occurrence of adverse events and/or addictive behaviours.Table 1 Baseline characteristics of patients with refractory chronic diarrhea\n\nPatient\tSex\tAge (years)\tWeight (Kg)\tPrimary disease\tDuration of chronic diarrhea\tDaily bowel movements\t\n1\tF\t45\t50\tCrohn’s disease\t5 months\t6\t\n2\tF\t54\t42\tCrohn’s disease\t12 years\t10\t\n3\tF\t75\t38\tPancreatic cancer treated with spleno-pancreatectomy\t25 months\t3\t\n4\tM\t40\t46\tSequelae of an extended mesenteric thrombosis\t2 months\t8\t\n5\tF\t71\t45\tSystemic sclerosis\t7 months\t10\t\n6\tF\t47\t38\tShort bowel syndrome\t11 months\t8\t\nFig. 1 Pharmacological properties of nabilone reported by Lemberger et al. [26]. Chemical structure of nabilone is reproduced by permission of The Royal Society of Chemistry [27]\n\n\n\nPatient 1\nShe was a 45-year-old, white female, with a history of intestinal obstruction and ileocecal resection occurred in January 2006, followed by a histologic diagnosis of Crohn’s disease. In May 2007, she was admitted to the hospital for a reactivation of the inflammatory disease, the colonoscopy revealed an anastomotic recurrence, which was treated with steroids (prednisone, 25 mg daily). A daily diarrhea appeared in November 2007; at the same time, the patient suffered from chronic headache with non-steroidal anti-inflammatory drugs (NSAIDs) abuse, and chronic gastritis. A new admission was performed in April 2008 for a worsening of chronic diarrhea and headache (weight = 50 Kg, haemoglobin or Hb = 7.9 g/dl, haematocrit or Ht = 25.3%, C-reactive protein or CRP = 1.33 mg/dl, Erythrocyte Sedimentation Rate or ESR = 43 mm/h, Crohn’s Disease Activity Index or CDAI = 157). On admittance, the patient complained of abdominal pain and six bowel movements per day, with watery stools. Colonoscopy showed a narrow stenosis of the anastomosis, with large mucosal erosion, that did not allow the instrument progression (lack of visualization of the ileal mucosa). The patient was treated with steroids (prednisone, 50 mg daily) and azathioprine (100 mg daily). Due to the failure of previous therapies (including rifaximin), the patient started taking nabilone (1 mg/day) to control both diarrhea and chronic headache. Concurrent medications included mesalazine (1500 mg/day), lansoprazole (30 mg/day), sodium valproate (600 mg/day), prednisone (50 mg/day), citalopram (40 mg/day), azathioprine (100 mg/day), tramadol (15 drops as needed) and clonazepam (15 drops/day). After three months of treatment, nabilone was discontinued, the patient had one bowel movement per day, without blood or mucus in the stools (weight = 52 Kg, Hb = 9 g/dl, CRP = 1.69 mg/dl, ESR = 19 mm/h, CDAI = 82); no colonoscopy was performed. Three months after the end of therapy, the patient had 2 bowel movements per day, no abdominal pain, diarrhea and/or blood in the stools (weight = 52 Kg, Hb 11.7 g/dl, Ht = 34,3%, CRP = 0.23 mg/dl, ESR = 10 mm/h). The patient had no further diarrhea episodes, but she is still suffering from chronic headache, despite numerous therapeutic changes.\n\nPatient 2\nShe was a white female, 54-year-old, with a history of Crohn’s disease since the age of 22, when an acute appendicitis surgery happened. She had undergone other abdominal surgeries, in 1986 (removal of 45 + 5 cm of bowel and ileocecal resection, latero-lateral anastomosis), in 1990 (resection of 36 cm of residual bowel, right colon and transverse colon, end-to-end anastomosis), and in 2004 (ileo-colonic resection of 20 cm and surgical removal of an abscess). The first symptoms of diarrhea occurred after the last surgical operation, the patient started to use loperamide tablets (2 mg), up to four daily. In 2010, an entero-cutaneous fistula appeared; it was successfully treated with adalimumab (discontinued due to mild hypertransaminasemia) and hyperbaric therapy. In July 2015, a new surgical scraping was performed because of the re-emergence of the fistula, along with an ileo-colonic anastomosis resection and ileostomy. The patient received a histologic diagnosis of rectal adenocarcinoma, treated with chemotherapy and radiotherapy. In January 2016, she returned to the hospital, due to a sepsis from methicillin-sensitive Staphylococcus aureus, an acute kidney injury and worsening of diarrhea (up to 10 bowel movements per day). On admittance, there was no abdominal pain. Weight = 42 Kg, Hb = 9.4 g/dl, CRP = 4.6 mg/dl, CDAI = 183. She was treated with parenteral feeding, antibiotic therapy (rifampicin and levofloxacin) and nabilone (1 mg per day), considering her severe malnutrition. She had watery stool and about 10 bowel movements per day. Concurrent medications included kaolin, loperamide (12 mg, daily) and nutritional supplement. After 3 months, nabilone was discontinued; she had only one bowel movement per day, without blood or mucus in the stools (weight = 45.5 kg). The symptoms did not reappear in the following three months. She had 4 bowel movements per day, with semi-solid stools, no evidence of blood or mucus. Weight = 45 kg. No adverse events were reported during and after nabilone treatment.\n\nPatient 3\nShe is a 75-year-old, white female, with a history of melanoma resected from her right leg in 1989 and reactivated to inguinal lymph nodes in 2012. In November 2013, the patient underwent a spleno-pancreatic resection, due to pancreatic cancer; the post-operative course was complexed due to an entero-pancreatic fistula and intestinal obstruction. From March 2014, the patient began to complain of post-prandial diarrhea, not present when the patient was fasting. Colonoscopy did not show mucosal alterations, loperamide (2 mg, as needed) and pancreatic enzymes were not effective. In March 2015, a computerized tomography (CT) scan was performed, with no evidence of abdominal recurrence of melanoma. With the medical prescription of mesalazine and budesonide, in April 2015, the patient had a general improvement, the diarrheal symptoms decreased, and the results of stool cultures were negative. In October 2015, a metastatic pulmonary nodule was removed; the patient began chemotherapy the following month (dabrafenib, 300 mg daily), together with painkillers. Diarrhea reappeared, the patient had poor appetite (weight = 38 kg), therefore she started to take nabilone (1 mg/day) in April 2016. Concurrent medications included pregabalin (150 mg daily), dabrafenib (300 mg daily), trametinib (2 mg daily), tramadol (150 mg daily), budesonide (6 mg daily), rabeprazol (10 mg daily), mesalazine and pancreatic enzymes. Nabilone treatment lasted three months, the patient improved, and the diarrheal symptoms. Weight post-nabilone = 38 kg. No side effects were reported during and after treatment. Three months after the end of the therapy, the benefits remained.\n\nPatient 4\nPatient 4 is a 40-year-old, white male, afflicted by the consequences of an extended mesenteric thrombosis. On admittance, he also complained of pre-hepatic portal hypertension, cavernous transformation of the portal vein and esophageal varices (grade F1). In the history, the patient suffered from chronic hepatitis C virus infection. Diarrhea began in March 2013, the patient was suffering simultaneously from malabsorption (hypoproteinaemia with low albumin levels, hyposideraemia and decreased levels of pseudocholinesterase). Screening for celiac disease was negative, colonoscopy revealed no pathologies in act. There were no intestinal infections and no histologic or endoscopic features of IBD. Despite the introduction of mesalazine and steroids, the patient suffered from 8 bowel movements per day. For severe diarrhea and malabsorption, we started administering nabilone (1 mg/day) in June 2013 (Hb = 9.2 g/dl, platelets = 548,000/mmc, white blood cells or WBC = 4890/mmc, CRP < 0.2 mg/dl). Weight = 46 Kg. Concomitant medications included lansoprazole (60 mg, daily), levosulpiride (50 mg, daily), pregabalin (150 mg, daily), mesalazine (3200 mg daily), low molecular weight heparin (8000 U daily) and oxycodone (5 mg as needed). The therapy was discontinued in July 2013, the patient interrupted autonomously the intake of nabilone because of severe fatigue and mental confusion. At the end of the therapy, the patient reported 2–3 bowel movement per day, without blood or mucus (CRP < 0,2 mg/dl, no leucocytosis or piastrinosis). Weight = 49 kg. Side effects disappeared in the next three months, the patient reported 1 bowel movement per day (weight = 48.5 kg). Concomitant medications were unaltered. A second nabilone administration was denied to the patient due to the risk of adverse events.\n\nPatient 5\nShe is a 71-year-old, white female, affected by systemic sclerosis. The diagnosis was done in June 2010, the first symptoms reported were polyarthritis and the Raynaud’s phenomenon (antinuclear antibody and rheumatoid factor tests positive). In that episode, the patient also reported GI bleeding due to a gastric antral vascular ectasia, treated with argon plasma coagulation and other medicines (levonorgestrel/etinilestradiol and octreotide), with a partial response. In August 2012, colonoscopy revealed the presence of inflammation and substenosis in the sigmoid colon. Diarrhea started in January 2015, she complained of 4 liquid feces evacuations per day, without the presence of blood, despite the simultaneous assumption of rifaximin, kaolin and lactic ferments. In August 2015, she was admitted to hospital because of severe diarrhea (10 liquid feces evacuations per day) and malabsorption with hypoalbuminemia, decreased levels of pseudocholinesterase (PCHE = 3071 UI/l), hypokalemia, hypocalcemia (blood calcium = 7.5 mg/dl), leucocytosis and mild anemia (WBC = 14,290/mmc, Hb = 12.1 g/dl). Weight = 45 Kg. Blood magnesium = 1.1 mg/dl, serum iron = 28 mcg/dl, serum ferritin = 24 ng/ml, CRP < 0.2 mg/dl. This episode was treated with rifaximin, mesalazine and budesonide, with a general improvement, but without controlling the diarrheal symptoms. The introduction of nabilone (1 mg daily, for five days, then 1 mg on alternate days) immediately improved the symptoms. Upon discharge the patient reported 3 evacuations per day, with semi-solid stools. Concomitant medications included levotiroxin (200 mcg daily), budesonide (9 mg daily, decreasing gradually over the following three months), rifaximin (800 mg daily for seven days a month), lansoprazole (60 mg daily), furosemide (25 mg daily) and tramadol (15 drops as needed). In September 2015, the patient reported a worsening of diarrhea; the clinical situation improved with increasing the dosage of nabilone (1 mg daily). Weight = 49 Kg. Daily bowel movements = 4. Nabilone therapy finished in November 2015. After three months the patient was stable, she had no abdominal pain, and reported 3 evacuations per day, without blood or mucus (weight = 50 Kg). No side effects were reported.\n\nPatient 6\nShe is a 47-year-old, white female, affected by short bowel syndrome and chronic diarrhea, which had occurred after ileal and colonic resection. Diarrhea began in April 2008, after a surgical intervention, due to an intestinal obstruction. Histological investigations identified a tubular adenoma (dysplasia: low grade). In her history, the patient had undergone hysterectomy and bilateral annessiectomy because of uterine cancer, followed by radiotherapy. In 2006, she underwent a left unilateral nephrectomy, due to an adhesiolysis. On admittance, in March 2009, she had 8 bowel movements per day, no sign of inflammation (WBC = 7560/mmc, platelets = 184,000/mmc, CRP = 1.94 mg/dl) and nutritional values unaltered (serum proteins = 7.0 g/dl, serum iron = 48 mcg/dl, serum vitamin B12 = 222 pg/dl, serum folic acid = 11.60 mg/dl, serum pre-albumin = 20.0 mg/dl). Weight = 38 Kg. Having excluded gastro-intestinal infections and celiac disease, a high-calorie diet was started. Colonoscopy revealed no sign of inflammation and regular anastomosis. Initially, diarrhea was treated with loperamide (2 mg, as needed) and kaolin, with no benefit. Later, also octreotide therapy (0.1 mg, subcutaneously) failed to relieve diarrheal symptoms. Nabilone treatment (1 mg daily) lasted three months and proved to have partial control of symptoms (5 bowel movements per day). Concomitant medications included fosinopril (20 mg daily), paroxetine (20 mg daily), alprazolam (1 mg daily), lormetazepam (2 mg daily), alendronate (70 mg weekly), kaolin (two daily doses) and loperamide (8 mg daily). In June 2009, she had no abdominal pain but reported 5 bowel movements per day. Weight = 39 Kg. After three months, the patient continued to report 5 bowel movements/daily, she also reduced the loperamide dosage (2 mg daily). Weight = 37.5 Kg. No side effect and/or signs of addiction were reported during and after nabilone treatment.\n\nDiscussion and conclusions\nWe report the progression of six cases of chronic diarrhea treated with an oral CB1-receptor agonist, previously managed with etiologic and symptomatic drugs, without benefits. Most of them used antibiotics and steroids without benefit; others did not improve with the nonspecific antidiarrheal therapy (loperamide and kaolin). The sample of patients was heterogeneous, considering the etiology; they were suffering from different GI disorders, chronic diarrhea was their common symptom. All patients complained of a poor quality of life and other symptoms, such as pain, fatigue, appetite loss and dehydration. Accordingly, it was decided to prescribe nabilone for the evidence linking the endocannabinoid system and pain, regulation of appetite and intestinal motility [28], when no other treatment was available. It was administered daily as a compassionate drug, for three months. The main outcome was focused on the safety and efficacy of oral nabilone, the number of bowel movements and the change in body weight were the parameters considered before and after therapy.\n\nAfter three months, nabilone improved the health of almost every patient (data are reported in Table 2). The daily bowel movements dropped by over 50% and the patients gained weight; the number of antidiarrheal medicines decreased for many of them. Three months after the end of the therapy, the improvements were essentially maintained. In one case, a patient kept the number of daily bowel movements, whereas the body weight was stable, but he reported to feel better. Current results speculate about cannabis and cannabinoids as an attractive approach for chronic GI disorders presenting abdominal pain, inflammation and/or hypermotility, when conventional treatments are not effective. An interesting aspect of this study consisted of the use of a synthetic cannabinoid, a selective agonist for CB1 receptors. The daily administration of nabilone has made possible to highlight only the CB1-mediated effects, emphasizing their importance in inhibiting GI motility and transit [29], and stimulating appetite [30, 31] both short- and long-term. To date, only another study has studied the impact of a CB1 receptor agonist on colonic transit, in irritable bowel syndrome patients [32]. The results were not entirely satisfactory, probably the duration of the treatment was too short.Table 2 Retrospective results of nabilone in the treatment of refractory chronic diarrhea\n\n\tPre-nabilone\tPost-nabilone\tFollow-up (3 months)\t\nDaily bowel movements (mean ± SD)\t7,5 ± 2,66\t2,25 ± 1,94\t2,5 ± 1,97\t\nWeight (mean ± SD)\t43,2 ± 4,75\t45,4 ± 5,75\t45,2 ± 6,19\t\nSD standard deviation\n\n\n\nAs far as the safety and tolerability are concerned, oral nabilone was well tolerated by almost all patients. In addition, it is important to note that five out of six patients were taking at the same time opiates, anticonvulsants and/or benzodiazepines. A single patient interrupted nabilone after one month, due to severe fatigue and mental confusion; the symptoms disappeared over the next three months. Together, he assumed pregabalin (150 mg/daily) and oxycodone (5 mg as needed). For some years, the patient had previously suffered from a generalized anxiety disorder. In some cases, the use of cannabinoids may unmask psychiatric symptoms, especially in individuals receiving psychoactive drugs, as well as in patients with concomitant manic-depressive illnesses, schizophrenia, anxiety and depression. Accordingly, the benefit/risk ratio of nabilone use should be carefully evaluated case by case. In this patient, the adverse event was transient, and a second administration was denied.\n\nTo the best of our knowledge, this is the first study that provide preliminary evidence that a CB1-receptor agonist may be safe and play a beneficial role when the outcomes are focused on chronic GI disorders, especially on the diarrheal symptom. Moreover, even though the duration of the therapy did not exceed three months, improvements were maintained over time. Despite all, we are still a long way from the answers about the role of cannabis in GI disorders, because of the limited generalizability of this study and the mixed retrospective results in the medical literature, often due to the wide variety of doses and formulations of cannabis used, as well as the lack of randomized clinical trials [33–35].\n\nOur approach benefits from evaluating CB1-receptor mediated outcomes in clinical practice, in a small population with multifaceted problems, thereby reflecting real adherence to treatment/intervention. However, it also has some limitations; only six patients were evaluated, a contemporaneous placebo treatment group was missing, and the duration of treatment was only three months. These outcomes encourage the study of cannabinoids acting on CB1 receptors in chronic GI disorder, offering a chance for a significant improvement in the quality of life of selected patients when traditional approaches are not beneficial.\n\nAbbreviations\nCB1G protein-coupled cannabinoid receptors 1\n\nCB2G protein-coupled cannabinoid receptors 2\n\nCDAICrohn’s Disease Activity Index\n\nCRPC-reactive protein\n\nCTComputerized tomography\n\nECSEndocannabinoid system\n\nENSEnteric nervous system\n\nESRErythrocyte Sedimentation Rate\n\nGIGastrointestinal\n\nHbHaemoglobin\n\nHtHaematocrit\n\nIBDInflammatory bowel disease\n\nNSAIDsNon-steroidal anti-inflammatory drugs\n\nPCHEPseudocholinesterase\n\nPPARsPeroxisome proliferator-activated receptors\n\nTRPVTransient receptor potential cation channels\n\nWBCWhite blood cells\n\nΔ9-THCΔ9-tetrahydrocannabinol\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNot applicable.\n\nAuthors’ contributions\nLP, MCV and SG analysed the data and wrote the paper. All the authors (LP, MCV, NDM, EV, LAP and SG) conducted medical visits and collected the data during treatment and the follow-up period. All authors read and approved the final manuscript.\n\nFunding\nThe authors declare that they have no sources of funding for the research.\n\nAvailability of data and materials\nThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from every patient for publication of their medical history in this manuscript. A copy of each 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==== Refs\nReferences\n1. World Drug Report 2016. https://www.unodc.org/doc/wdr2016/WORLD_DRUG_REPORT_2016_web.pdf. Accessed 30 Sept 2018.\n2. 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Lal S Prasad N Ryan M Tangri S Silverberg MS Gordon A Cannabis use amongst patients with inflammatory bowel disease Eur J Gastroenterol Hepatol 2011 23 891 896 10.1097/MEG.0b013e328349bb4c 21795981 \n20. Ravikoff Allegretti J Courtwright A Lucci M Korzenik JR Levine J Marijuana use patterns among patients with inflammatory bowel disease Inflamm Bowel Dis 2013 19 2809 2814 10.1097/01.MIB.0000435851.94391.37 24185313 \n21. Storr M Devlin S Kaplan GG Panaccione R Andrews CN Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Chron’s disease Inflamm Bowel Dis 2014 20 472 480 10.1097/01.MIB.0000440982.79036.d6 24407485 \n22. Wasilewski A Misicka A Sacharczuk M Fichna J Modulation of the endocannabinoid system by the fatty acid amide hydrolase, monoacylglycerol and diacylglycerol lipase inhibitors as an attractive target for secretory diarrhoea therapy J Physiol Pharmacol 2017 68 591 596 29151076 \n23. Abalo R. Uranga J. A. Pérez-García I. de Andrés R. Girón R. Vera G. López-Pérez A. E. Martín-Fontelles M. I. May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat Neurogastroenterology & Motility 2016 29 3 e12952 10.1111/nmo.12952 \n24. Fabisiak A. Fichna J. Cannabinoids as gastrointestinal anti-inflammatory drugs Neurogastroenterology & Motility 2017 29 3 e13038 10.1111/nmo.13038 \n25. Cooper BT Diarrhoea as a symptom Clin Gastroenterol 1985 14 599 613 4064356 \n26. Lemberger R Rubin A Wolen R De Sante K Rowe H Forney R Pharmacokinetics, metabolism and drug-abuse potential of nabilone Cancer Treat Rev 1982 9 Suppl B 17 23 10.1016/S0305-7372(82)80031-5 6299550 \n27. The Royal Society of Chemistry. http://www.chemspider.com/Chemical-Structure.4447641.html. Accessed 20 Mar 2019.\n28. Aviello G Romano B Izzo AA Cannabinoids and gastrointestinal motility: animal and human studies Eur Rev Med Pharmacol Sci 2008 12 Suppl 1 81 93 18924447 \n29. Coutts AA Irving AJ Mackie K Pertwee RG Anavi-Goffer S Localisation of cannabinoid CB(1) receptor immunoreactivity in the Guinea pig and rat myenteric plexus J Comp Neurol 2002 448 410 422 10.1002/cne.10270 12115703 \n30. Foltin RW Fischman MW Byrne MF Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory Appetite. 1988 11 1 14 10.1016/S0195-6663(88)80017-5 \n31. Haney M Rabkin J Gunderson E Foltin RW Dronabinol and marijuana in HIV(+) marijuana smokers: acute effects on caloric intake and mood Psychopharmacology 2005 181 170 178 10.1007/s00213-005-2242-2 15778874 \n32. Wong BS Camilleri M Eckert D Carlson P Ryks M Burton D Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colonic transit in irritable bowel syndrome-diarrhea Neurogastroenterol Motil 2012 24 358 e169 10.1111/j.1365-2982.2011.01874.x 22288893 \n33. Kafil TS, Nguyen TM, MacDonald JK, Chande N. Cannabis for the treatment of Crohn's disease. Cochrane Database Syst Rev. 2018;(11):CD012853.\n34. Ambrose T, Simmons A. Cannabis, cannabinoids and the endocannabinoid system - is there therapeutic potential for inflammatory bowel disease? J Crohns Colitis. 2018 Nov 12.\n35. Hasenoehrl C Storr M Schicho R Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go? Expert Rev Gastroenterol Hepatol 2017 11 329 337 10.1080/17474124.2017.1292851 28276820\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-230X",
"issue": "19(1)",
"journal": "BMC gastroenterology",
"keywords": "CB1 receptor; Cannabinoids; Case series; Chronic diarrhea; Gastrointestinal disorders; Nabilone; Refractory",
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D002908:Chronic Disease; D003967:Diarrhea; D013759:Dronabinol; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D043884:Receptor, Cannabinoid, CB1",
"nlm_unique_id": "100968547",
"other_id": null,
"pages": "105",
"pmc": null,
"pmid": "31238887",
"pubdate": "2019-06-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12105851;12115703;1470919;15249429;15778874;16751708;16918762;1718258;17906675;18924447;21457226;21795981;22288893;24185313;24275607;24407485;25796370;26103030;26935536;27561826;27686064;27792038;28239924;28276820;29151076;30031300;30076849;30407616;30418525;3228283;4064356;6299550;7556170",
"title": "Nabilone administration in refractory chronic diarrhea: a case series.",
"title_normalized": "nabilone administration in refractory chronic diarrhea a case series"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1119600",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nCollecting duct carcinoma is a rare pathologic entity with a paucity of clinical data in the literature. We aim to evaluate our institutional experience with the management of this disease.\n\n\nMETHODS\nAll renal tumors in the Mayo Clinic Nephrectomy Registry were re-reviewed retrospectively by an expert urologic pathologist. Cases of collecting duct carcinoma were identified. Descriptive statistics were used to characterize these cases. Overall survival and metastases-free survival were estimated using Kaplan-Meier methodology.\n\n\nRESULTS\nBetween 1970 and 2018, a total of 21 cases were identified with an incidence of 0.2%. Cases were seen predominantly in men (N = 17, 81%) with a median age at diagnosis of 57 years old. At the time of nephrectomy, high grade disease (grade 3 or 4) was noted in the majority of patients (90%). The median times to local recurrence and distant metastases were 5.6 and 5.1 months, respectively. Median overall survival occurred at 1.5 years. Median distant metastases-free survival among M0 patients occurred at 0.5 years. Four patients with localized disease and small tumor size who underwent nephrectomy lived longer than 10 years. No systemic therapies achieved a durable response in the metastatic setting.\n\n\nCONCLUSIONS\nThe Mayo Clinic nephrectomy registry contains 21 patients with collecting duct carcinoma over nearly 50 years. Early local recurrence and distant metastases were seen after nephrectomy. However, M0 patients with a small tumor may have long-term benefits from nephrectomy. Neither chemotherapy nor targeted therapy resulted in a durable response in the metastatic setting.",
"affiliations": "Department of Oncology, Mayo Clinic, Rochester, MN.;Department of Oncology, Mayo Clinic, Rochester, MN.;Department of Urology, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Department of Oncology, Mayo Clinic, Rochester, MN.;Department of Urology, Mayo Clinic, Rochester, MN.;Department of Urology, Mayo Clinic, Rochester, MN.;Department of Urology, Mayo Clinic, Rochester, MN.;Department of Urology, Mayo Clinic, Rochester, MN.;Department of Oncology, Mayo Clinic, Rochester, MN. Electronic address: Costello.Brian@mayo.edu.",
"authors": "Xie|Zhuoer|Z|;Yadav|Siddhartha|S|;Lohse|Christine M|CM|;Cheville|John C|JC|;Pagliaro|Lance C|LC|;Shah|Paras H|PH|;Boorjian|Stephen A|SA|;Thompson|Houston|H|;Leibovich|Bradley C|BC|;Costello|Brian A|BA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.urolonc.2021.09.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1439",
"issue": "40(1)",
"journal": "Urologic oncology",
"keywords": "Collecting duct carcinoma; Non-clear cell renal cell carcinoma",
"medline_ta": "Urol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9805460",
"other_id": null,
"pages": "13.e9-13.e18",
"pmc": null,
"pmid": "34750052",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Collecting duct carcinoma: A single-institution retrospective study.",
"title_normalized": "collecting duct carcinoma a single institution retrospective study"
} | [
{
"companynumb": "US-009507513-2203USA007685",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INTERFERON ALFA-2B"
},
"drugadditional": "4"... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT.\n\n\nMETHODS\nWe identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low-intermediate risk group; 13.6% had B symptoms; 29.8% had bulky tumors (≥ 7 cm); and 75.3% underwent ≥ 6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy).\n\n\nRESULTS\nAfter a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed ≥ 6 cycles of R-CHOP (PFS, P=.004; OS, P=.004) and ILRT (PFS, P=.021; OS, P=.014) were favorable prognosticators of PFS and OS. A bulky tumor (P=.027) and response to R-CHOP (P=.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, P=.014; OS, P=.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, P=.004; OS, P=.012).\n\n\nCONCLUSIONS\nOur results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level.",
"affiliations": "Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea. Electronic address: ihkim@snu.ac.kr.;Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.",
"authors": "Kwon|Jeanny|J|;Kim|Il Han|IH|;Kim|Byoung Hyuck|BH|;Kim|Tae Min|TM|;Heo|Dae Seog|DS|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D007770:L-Lactate Dehydrogenase; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "92(1)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D000704:Analysis of Variance; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007770:L-Lactate Dehydrogenase; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D047368:Tumor Burden; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "91-8",
"pmc": null,
"pmid": "25721091",
"pubdate": "2015-05-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Additional survival benefit of involved-lesion radiation therapy after R-CHOP chemotherapy in limited stage diffuse large B-cell lymphoma.",
"title_normalized": "additional survival benefit of involved lesion radiation therapy after r chop chemotherapy in limited stage diffuse large b cell lymphoma"
} | [
{
"companynumb": "KR-ROCHE-1572358",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nInvolvement of intracranial arteries in giant cell arteritis (GCA) is rare. We describe the neurologic complications of intracranial GCA (IC GCA) and available treatment options.\n\n\nMETHODS\nWe describe 5 IC GCA cases from 3 Canadian vasculitis centers and review the literature. We searched English-language publications reporting similar patients meeting American College of Rheumatology (ACR) criteria for GCA and having intracranial artery involvement diagnosed by autopsy, magnetic resonance angiography, computed tomography angiography, or conventional angiography.\n\n\nRESULTS\nAll 5 cases of IC GCA met ACR criteria for GCA; 4 cases had a temporal artery biopsy that was consistent with GCA. All cases experienced cerebrovascular accident(s). Arteritis involved the following vessels: intracranial internal carotid (n = 1), vertebrobasilar arteries (n = 1), or both (n = 3). All cases received aspirin and oral prednisone (preceded by intravenous methylprednisone in 3 cases), combined with an immunosuppressant in 4 cases. All patients survived; 2 had complete neurological recovery, 3 had residual neurologic sequelae. The literature review included 42 cases from 28 publications. The clinical features of the reported cases were similar to those of our 5 cases. However, mortality was 100% in untreated cases (n = 2), 58% in those treated with corticosteroid alone (n = 31), and 40% in those treated with corticosteroid and an immunosuppressant (n = 10).\n\n\nCONCLUSIONS\nIC GCA appears to be associated with neurologic complications and mortality. In some cases corticosteroid alone was not sufficient to prevent neurologic complications. The role of additional immunosuppressive agents needs further investigation.",
"affiliations": "From the Division of Rheumatology, Western University, London; Division of Rheumatology, McMaster University, Hamilton; Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto; Department of Clinical Neurological Sciences and Division of Radiology, Western University, London, Ontario, Canada; and Department of Medicine, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia.R.S. Alsolaimani, MD, Division of Rheumatology, Western University, Department of Medicine, King Abdul-Aziz University Hospital; S.V. Bhavsar, MD; N.A. Khalidi, MD, FRCPC, FACP, FACR, Division of Rheumatology, McMaster University; C. Pagnoux, MBI, MPH, PhD, Division of Rheumatology, Mount Sinai Hospital, University of Toronto; J.L. Mandzia, MD, PhD, FRCPC, Department of Clinical Neurological Sciences, Western University; K.Y. Tay, MBBS, BSc(Med), FRCR, Division of Radiology, Western University; L.J. Barra, MD, MPH, FRCPC, Division of Rheumatology, Western University.;From the Division of Rheumatology, Western University, London; Division of Rheumatology, McMaster University, Hamilton; Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto; Department of Clinical Neurological Sciences and Division of Radiology, Western University, London, Ontario, Canada; and Department of Medicine, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia.R.S. Alsolaimani, MD, Division of Rheumatology, Western University, Department of Medicine, King Abdul-Aziz University Hospital; S.V. Bhavsar, MD; N.A. Khalidi, MD, FRCPC, FACP, FACR, Division of Rheumatology, McMaster University; C. Pagnoux, MBI, MPH, PhD, Division of Rheumatology, Mount Sinai Hospital, University of Toronto; J.L. Mandzia, MD, PhD, FRCPC, Department of Clinical Neurological Sciences, Western University; K.Y. Tay, MBBS, BSc(Med), FRCR, Division of Radiology, Western University; L.J. Barra, MD, MPH, FRCPC, Division of Rheumatology, Western University.;From the Division of Rheumatology, Western University, London; Division of Rheumatology, McMaster University, Hamilton; Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto; Department of Clinical Neurological Sciences and Division of Radiology, Western University, London, Ontario, Canada; and Department of Medicine, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia.R.S. Alsolaimani, MD, Division of Rheumatology, Western University, Department of Medicine, King Abdul-Aziz University Hospital; S.V. Bhavsar, MD; N.A. Khalidi, MD, FRCPC, FACP, FACR, Division of Rheumatology, McMaster University; C. Pagnoux, MBI, MPH, PhD, Division of Rheumatology, Mount Sinai Hospital, University of Toronto; J.L. Mandzia, MD, PhD, FRCPC, Department of Clinical Neurological Sciences, Western University; K.Y. Tay, MBBS, BSc(Med), FRCR, Division of Radiology, Western University; L.J. Barra, MD, MPH, FRCPC, Division of Rheumatology, Western University.;From the Division of Rheumatology, Western University, London; Division of Rheumatology, McMaster University, Hamilton; Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto; Department of Clinical Neurological Sciences and Division of Radiology, Western University, London, Ontario, Canada; and Department of Medicine, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia.R.S. Alsolaimani, MD, Division of Rheumatology, Western University, Department of Medicine, King Abdul-Aziz University Hospital; S.V. Bhavsar, MD; N.A. Khalidi, MD, FRCPC, FACP, FACR, Division of Rheumatology, McMaster University; C. Pagnoux, MBI, MPH, PhD, Division of Rheumatology, Mount Sinai Hospital, University of Toronto; J.L. Mandzia, MD, PhD, FRCPC, Department of Clinical Neurological Sciences, Western University; K.Y. Tay, MBBS, BSc(Med), FRCR, Division of Radiology, Western University; L.J. Barra, MD, MPH, FRCPC, Division of Rheumatology, Western University.;From the Division of Rheumatology, Western University, London; Division of Rheumatology, McMaster University, Hamilton; Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto; Department of Clinical Neurological Sciences and Division of Radiology, Western University, London, Ontario, Canada; and Department of Medicine, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia.R.S. Alsolaimani, MD, Division of Rheumatology, Western University, Department of Medicine, King Abdul-Aziz University Hospital; S.V. Bhavsar, MD; N.A. Khalidi, MD, FRCPC, FACP, FACR, Division of Rheumatology, McMaster University; C. Pagnoux, MBI, MPH, PhD, Division of Rheumatology, Mount Sinai Hospital, University of Toronto; J.L. Mandzia, MD, PhD, FRCPC, Department of Clinical Neurological Sciences, Western University; K.Y. Tay, MBBS, BSc(Med), FRCR, Division of Radiology, Western University; L.J. Barra, MD, MPH, FRCPC, Division of Rheumatology, Western University.;From the Division of Rheumatology, Western University, London; Division of Rheumatology, McMaster University, Hamilton; Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto; Department of Clinical Neurological Sciences and Division of Radiology, Western University, London, Ontario, Canada; and Department of Medicine, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia.R.S. Alsolaimani, MD, Division of Rheumatology, Western University, Department of Medicine, King Abdul-Aziz University Hospital; S.V. Bhavsar, MD; N.A. Khalidi, MD, FRCPC, FACP, FACR, Division of Rheumatology, McMaster University; C. Pagnoux, MBI, MPH, PhD, Division of Rheumatology, Mount Sinai Hospital, University of Toronto; J.L. Mandzia, MD, PhD, FRCPC, Department of Clinical Neurological Sciences, Western University; K.Y. Tay, MBBS, BSc(Med), FRCR, Division of Radiology, Western University; L.J. Barra, MD, MPH, FRCPC, Division of Rheumatology, Western University.;From the Division of Rheumatology, Western University, London; Division of Rheumatology, McMaster University, Hamilton; Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto; Department of Clinical Neurological Sciences and Division of Radiology, Western University, London, Ontario, Canada; and Department of Medicine, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia.R.S. Alsolaimani, MD, Division of Rheumatology, Western University, Department of Medicine, King Abdul-Aziz University Hospital; S.V. Bhavsar, MD; N.A. Khalidi, MD, FRCPC, FACP, FACR, Division of Rheumatology, McMaster University; C. Pagnoux, MBI, MPH, PhD, Division of Rheumatology, Mount Sinai Hospital, University of Toronto; J.L. Mandzia, MD, PhD, FRCPC, Department of Clinical Neurological Sciences, Western University; K.Y. Tay, MBBS, BSc(Med), FRCR, Division of Radiology, Western University; L.J. Barra, MD, MPH, FRCPC, Division of Rheumatology, Western University. lbarra2@uwo.ca.",
"authors": "Alsolaimani|Roaa S|RS|;Bhavsar|Sankalp V|SV|;Khalidi|Nader A|NA|;Pagnoux|Christian|C|;Mandzia|Jennifer L|JL|;Tay|KengYeow|K|;Barra|Lillian J|LJ|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.150143",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "43(3)",
"journal": "The Journal of rheumatology",
"keywords": "CRANIAL ARTERY; GIANT CELL ARTERITIS; STROKE",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain; D002533:Cerebral Angiography; D005260:Female; D013700:Giant Cell Arteritis; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D020521:Stroke",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "648-56",
"pmc": null,
"pmid": "26773119",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Severe Intracranial Involvement in Giant Cell Arteritis: 5 Cases and Literature Review.",
"title_normalized": "severe intracranial involvement in giant cell arteritis 5 cases and literature review"
} | [
{
"companynumb": "CA-BAYER-2016-066599",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "A case of severe lithium intoxication treated successfully with hemodialysis is presented. In addition to the common neurological manifestations of toxicity the patient demonstrated three rarely reported cardiotoxic manifestations: reversible first degree A-V block, intraventricular conduction delay, and prolonged Q-T interval. These findings demonstrate the need to include lithium intoxication in the differential diagnosis of drug overdose with prominent ECG changes. The pharmacology, presenting signs and symptoms, and current treatment modalities of lithium intoxication are reviewed.",
"affiliations": null,
"authors": "Mateer|J R|JR|;Clark|M R|MR|",
"chemical_list": "D008094:Lithium",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(82)80500-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "11(4)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000328:Adult; D001145:Arrhythmias, Cardiac; D004562:Electrocardiography; D005260:Female; D006327:Heart Block; D006801:Humans; D008094:Lithium; D006435:Renal Dialysis; D019966:Substance-Related Disorders",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "208-11",
"pmc": null,
"pmid": "7073038",
"pubdate": "1982-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lithium toxicity with rarely reported ECG manifestations.",
"title_normalized": "lithium toxicity with rarely reported ecg manifestations"
} | [
{
"companynumb": "US-APOTEX-2017AP013537",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
"drugadditional": "3",
... |
{
"abstract": "The ascomycetous yeast Cyberlindera fabianii is not only present in the environment, but is also occasionally pathogenic. Especially, neonates seem to be prone to infection. Here, we describe a case of peritoneal infection of a neonate after congenital heart surgery. The correct identification of this peculiar species is made by MALDI-TOF and especially by molecular biology methods, whereas the standard biochemical identification methods fail.The neonate with a hypoplastic left heart syndrome had a Norwood palliation followed by transient ECMO therapy for 3 days. The patient developed a renal insufficiency, so that peritoneal dialysis was initiated. After a few days, a peritoneal infection due to C. fabianii emerged. The proper source of this rare and particular yeast remains obscure. In spite of a reasonable antimycotic therapy, the patient developed a capillary leak syndrome and died finally in septic shock with multiorgan failure. One reason is probably that the yeast population, which was highly susceptible to all common antimycotic drugs at the beginning of therapy with fluconazole (and for a short period with caspofungin and liposomal amphotericin B), became rapidly resistant.",
"affiliations": "MVZ Labor Limbach, Im Breitspiel 16, 69126, Heidelberg, Germany. herbert.hof@labor-limbach.de.;Paediatric Cardiac Intensive Care Unit, German Paediatric Heart Center, Asklepios Klinik St. Augustin GmbH, Arnold-Janssen Str. 29, 53757, Sankt Augustin, Germany.;MVZ Labor Limbach, Im Breitspiel 16, 69126, Heidelberg, Germany.;Paediatric Cardiac Intensive Care Unit, German Paediatric Heart Center, Asklepios Klinik St. Augustin GmbH, Arnold-Janssen Str. 29, 53757, Sankt Augustin, Germany.",
"authors": "Hof|H|H|;Amann|V|V|;Tauber|C|C|;Paulun|A|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-017-1062-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "45(6)",
"journal": "Infection",
"keywords": "Cyberlindnera; MALDI-TOF; Neonate; Peritoneal infection",
"medline_ta": "Infection",
"mesh_terms": "D002175:Candida; D002177:Candidiasis; D006348:Cardiac Surgical Procedures; D026141:Drug Resistance, Multiple, Fungal; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D009102:Multiple Organ Failure; D010538:Peritonitis; D011183:Postoperative Complications; D004718:Saccharomycetales",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "921-924",
"pmc": null,
"pmid": "28825212",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23637950;27357226;23510524;26354806;24478407;20118752;25103752;26763103;16784449;28385833;23163108;23551835;16519022;28397475;26618013",
"title": "Peritonitis in a neonate due to Cyberlindnera fabianii, an ascomycetic yeast.",
"title_normalized": "peritonitis in a neonate due to cyberlindnera fabianii an ascomycetic yeast"
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"abstract": "BACKGROUND\nThe widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells.\n\n\nRESULTS\nIn conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC50=110±3 μmol/L) and Na+ current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for INa in cardiomyocytes. Mild block occurred for K+ currents representing IKr (CHO cells expressing hERG; IC50=219±21 μmol/L) and IKs (CHO cells expressing KCNQ1+KCNE1; IC50=184±12 μmol/L), whereas azithromycin suppressed L-type Ca++ currents (rabbit ventricular myocytes, IC50=66.5±4 μmol/L) and IK1 (HEK cells expressing Kir2.1, IC50=44±3 μmol/L).\n\n\nCONCLUSIONS\nChronic exposure to azithromycin increases cardiac Na+ current to promote intracellular Na+ loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.",
"affiliations": "From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.;From the Department of Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN. kathy.murray@vanderbilt.edu.",
"authors": "Yang|Zhenjiang|Z|;Prinsen|Joseph K|JK|;Bersell|Kevin R|KR|;Shen|Wangzhen|W|;Yermalitskaya|Liudmila|L|;Sidorova|Tatiana|T|;Luis|Paula B|PB|;Hall|Lynn|L|;Zhang|Wei|W|;Du|Liping|L|;Milne|Ginger|G|;Tucker|Patrick|P|;George|Alfred L|AL|;Campbell|Courtney M|CM|;Pickett|Robert A|RA|;Shaffer|Christian M|CM|;Chopra|Nagesh|N|;Yang|Tao|T|;Knollmann|Bjorn C|BC|;Roden|Dan M|DM|;Murray|Katherine T|KT|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; C489622:KCNE1 protein, human; C489457:KCNJ2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D026941:Sodium Channel Blockers; D017963:Azithromycin",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCEP.115.003560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-3084",
"issue": "10(4)",
"journal": "Circulation. Arrhythmia and electrophysiology",
"keywords": "calcium channel; mice; pharmacology; potassium channels; sodium channels",
"medline_ta": "Circ Arrhythm Electrophysiol",
"mesh_terms": "D000200:Action Potentials; D000818:Animals; D000900:Anti-Bacterial Agents; D001145:Arrhythmias, Cardiac; D017963:Azithromycin; D016466:CHO Cells; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015716:Electrocardiography, Ambulatory; D005260:Female; D057809:HEK293 Cells; D006339:Heart Rate; D006801:Humans; D051657:KCNQ1 Potassium Channel; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D026941:Sodium Channel Blockers; D013686:Telemetry; D013997:Time Factors; D014162:Transfection; D055815:Young Adult",
"nlm_unique_id": "101474365",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28408648",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7787031;19027025;11459586;25210054;23608603;18184962;9501201;19358226;17890431;17109296;12021266;10707089;21463272;15090000;25772295;18845675;9449325;14615808;17497254;11707055;21824921;19615375;21454796;16506357;23557754;18070319;18288182;9530184;16973141;22591294;15698834;24895457;16856707;20881602;24472431;20391905;2830841;24561134;22539774;16359290;16755206;9705313;10947683;1655433;25772289;19185812;18552874;21937582;17546486",
"title": "Azithromycin Causes a Novel Proarrhythmic Syndrome.",
"title_normalized": "azithromycin causes a novel proarrhythmic syndrome"
} | [
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"companynumb": "US-PFIZER INC-2017085262",
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"actiondrug": "6",
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"activesubstancename": "AZITHROMYCIN DIHYDRATE"
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{
"abstract": "The aim of this paper is to describe the incidence of decayed, missing, and filled teeth (DMFT) and periodontal disease in 32 osteoporotic patients affected by bisphosphonate-related osteonecrosis of the jaw (BRONJ). Moreover, an investigation between the obtained data and 20 patients treated with bisphosphonate drugs and with no evidence of ONJ has been performed. Osteonecrosis of the jaws is a rare complication in a subset of patients receiving bisphosphonate drugs. Based on a growing number of case reports and institutional reviews, this kind of therapy can cause exposed and necrotic bone specifically in the jawbones. From April 2009 to June 2012, 32 osteoporotic patients treated with oral or intravenous (I.V.) bisphosphonates have been recorded. The patients' oral health has been compared with 20 bisphosphonates patients with no ONJ. The incidence of decayed, missing, and filled teeth (DMFT) and periodontal disease was recorded in all patients and student's t-test was applied for comparing the two investigated groups data. Data demonstrated how the poor dental hygiene and periodontal disease of the BRONJ patients' are connected with the occurrence of jawbone necrosis.",
"affiliations": "Department of Biomedical Sciences and Specialist Medical-Surgical Dentistry, University of Messina, Via Consolare Valeria, 98100 Messina, Italy.;Department of Biomedical Sciences and Specialist Medical-Surgical Dentistry, University of Messina, Via Consolare Valeria, 98100 Messina, Italy.;Department of Biomedical Sciences and Specialist Medical-Surgical Dentistry, University of Messina, Via Consolare Valeria, 98100 Messina, Italy.;Human Pathology Department, Dental School, University of Messina, Via Consolare Valeria, 98100 Messina, Italy.",
"authors": "Oteri|Giacomo|G|;Bramanti|Ennio|E|;Nigrone|Valentina|V|;Cicciù|Marco|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2013/231289",
"fulltext": "\n==== Front\nJ OsteoporosJ OsteoporosJOSTEOJournal of Osteoporosis2090-80592042-0064Hindawi Publishing Corporation 10.1155/2013/231289Research ArticleDecayed, Missing, and Filled Teeth Index and Periodontal Health in Osteoporotic Patients Affected by BRONJ: An Observational Study Oteri Giacomo \n1\nhttp://orcid.org/0000-0002-6136-3425Bramanti Ennio \n1\nNigrone Valentina \n1\nhttp://orcid.org/0000-0003-2311-9728Cicciù Marco \n2\n*1Department of Biomedical Sciences and Specialist Medical-Surgical Dentistry, University of Messina, Via Consolare Valeria, 98100 Messina, Italy2Human Pathology Department, Dental School, University of Messina, Via Consolare Valeria, 98100 Messina, Italy*Marco Cicciù: acromarco@yahoo.itAcademic Editor: Manuel Diaz Curiel\n\n2013 12 12 2013 2013 23128922 9 2013 6 11 2013 7 11 2013 Copyright © 2013 Giacomo Oteri et al.2013This 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 aim of this paper is to describe the incidence of decayed, missing, and filled teeth (DMFT) and periodontal disease in 32 osteoporotic patients affected by bisphosphonate-related osteonecrosis of the jaw (BRONJ). Moreover, an investigation between the obtained data and 20 patients treated with bisphosphonate drugs and with no evidence of ONJ has been performed. Osteonecrosis of the jaws is a rare complication in a subset of patients receiving bisphosphonate drugs. Based on a growing number of case reports and institutional reviews, this kind of therapy can cause exposed and necrotic bone specifically in the jawbones. From April 2009 to June 2012, 32 osteoporotic patients treated with oral or intravenous (I.V.) bisphosphonates have been recorded. The patients' oral health has been compared with 20 bisphosphonates patients with no ONJ. The incidence of decayed, missing, and filled teeth (DMFT) and periodontal disease was recorded in all patients and student's t-test was applied for comparing the two investigated groups data. Data demonstrated how the poor dental hygiene and periodontal disease of the BRONJ patients' are connected with the occurrence of jawbone necrosis.\n==== Body\n1. Introduction \nOsteoporosis is a systemic skeletal disorder characterized by skeletal fragility, microarchitectural variation, and low bone mineral density estimated with a T-score for bone mineral density below −2.5 (National Institutes of Health Consensus Conference) [1]. Osteoporosis is one of the most common chronic diseases referred in 1/3 postmenopausal women and 1/5, men over the age of 50 years (European Parliament Osteoporosis Interest Group and EU Osteoporosis Consultation Panel 2004) [2]. Although it is widely recognized that low bone mass is not the only determinant of bone fragility, the strength of the skeleton is influenced by other bone tissue properties, collectively named “bone quality” [3, 4]. Change of bone remodelling pattern in osteoporosis patients resulted in perforation of trabecular plates and loss of cancellous trabecular elements with consequent bone mineral density reduction.\n\nBisphosphonates are a new class of drugs indicated for use in patients with osteoporosis, Paget's disease of bone, hypercalcemia in a malignant disease, osteolytic bone metastases, and osteolytic lesions of multiple myeloma. Despite the benefits of bisphosphonate therapy like increasing bone density and preventing bone pathological fractures, osteonecrosis of the jaw is a rare complication in a subset of patients receiving these drugs. This complication often occurs after simple dentoalveolar surgery. The pathogenesis for this complication is still debated. It seems to be related to the profound inhibition of osteoclast function and bone remodelling even if it has been documented also in patients not receiving bisphosphonates [2, 4, 5].\n\nThe rationale for the use of bisphosphonates in the postmenopausal patient for osteoporosis management is provided by a sequence of modified biological events [2–5]. The introduction of bisphosphonates therapy for the treatment of bone remodelling diseases has been correlated with the increasing of bisphosphonate-related osteonecrosis (BRONJ). During the past two decades, BP therapy has become an elective clinical intervention for osteoporosis. Oral BP therapy was prescribed in 73% of 6.3 million visits for osteoporosis in 2003 and it is estimated that over 190 million prescriptions for oral BP have been dispensed in the world [6, 7]. The enzyme target for BPs is farnesyl pyrophosphate synthase by this enzyme inhibition in the osteoclast; BP interferes with geranylgeranylation (attachment of the lipid to regulatory proteins), thus inducing osteoclast inactivation and also apoptosis [8]. Osteoclast inhibition leads to a reduction in bone turnover and the prevention of bone resorption [9]. The potency of osteoclast inhibition is related to the chemical structure of the BP, with nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) being up to 10,000 times more potent than non-nitrogen-containing BPs [10].\n\nThis study tested the hypothesis that osteoporotic patients affected by BRONJ have a poorer dental and periodontal history than non-BRONJ patients, analysing them retrospectively, comparing medical and oral history and standardized radiographs.\n\n2. Material and Methods\nFrom April 2007 to June 2012, the oral condition of periodontal health and caries prevalence of 32 osteoporotic patients affected by BRONJ (Figure 1) have been recorded (mean age 60.25 years, range 44–80 years); the same condition was reported for 20 osteoporotic patients (mean age 61.95 years, range 44–80 years) without ONJ. The patients were referred to the “A.O.U Gaetano Martino” dental clinic, the Department of Biomedical Sciences, University of Messina, and Specialist Medical-Surgical Dentistry, from the Geriatric Department of the IRCSS Neurolesi Bonino Pulejo Messina. One of the investigators clinically inspected the oral cavity by performing a periodontal evaluation by using the periodontal screening index (PSI) at four proximal sites per tooth. According to the PSI scores, the findings were diagnosed as follows: scores 0–2 “no periodontitis” and scores 3 and 4 “periodontitis” (Figure 2) [11, 12].\n\nEdentulous patients were not included in the study. Clinical investigation was completed by a mouth mirror for evaluating the presence of dental caries and the number of missed and filled teeth.\n\nPatients were classified as affected by BRONJ according to the American Association of Oral and Maxillofacial Surgeons (AAOMS) guidelines. All the patients included in the study were taking BP for osteoporotic therapy. The questionnaire included age, gender, modality of administration, duration and type of BP, associated pathology, and possible corticosteroid usage. Patients were asked if they had undergone any oral surgical procedure since they started bisphosphonate therapy. The same examiner visited all the patients. The data was collected in a database and the oral check-up recorded dental caries, missing teeth, and filled teeth. The data were classified accordingly with the DMFT index, namely, D (decayed), M (missing), and F (filled) teeth for both groups. Digital panoramic radiographs were taken of each patient (Orhophos Plus Ds, Sidexis, with image processor Sidexis Next Generation 1.31; Long Island City, NY). The DMFT index was epidemiologically assessed both from the patient's radiograph and through clinical examination [11]. The PSI was taken with the WHO probe which was inserted into the periodontal pocket in the apical direction parallel to the tooth axis [11, 12]. Every tooth was probed at four sites (mesiovestibular, distovestibular, mesiooral, and distooral) and the PSI score (0 to 4) was recorded. The highest score was determined for each sextant. A periodontal pocket deeper than 4 mm was considered a pathologic periodontal condition according to the Community Periodontal Index of Treatment Needs' assessment sequence. The following classifications were made for each participant in this study: PSI scores 0, 1, and 2: “no periodontitis”; PSR/PSI score 3 and 4: “periodontitis.”\n\nStudent's t-test, in statistics, is defined as a method of testing hypotheses about the mean of a small sample drawn from a normally distributed population when the population standard deviation is unknown [13]. For this reason the Student's t-test was used to statistically analyse the DMFT index and the PSI score in the groups of the investigated patients.\n\n3. Results and Discussion\nA total of 52 patients have been examined. The study involved two groups of patients: A Control Group, 20 osteoporotic patients (16 females, 4 males) without BRONJ (Table 1); B Group, 32 osteoporotic patients (26 females, 6 males) affected by BRONJ (Table 2).\n\nThe mean age of BRONJ patients was comparable and similar to the Control Group.\n\nThis was also true for bisphosphonates administration duration that is comparable between the two groups (Control: 4.3 years ± 2.5 years; BRONJ: 4.5 years ± 2.6 years) and the t value did not show any statistical difference in A and B Groups (P = 0.7503) (Figure 3).\n\n\nD: Number of Decayed Teeth\nThe number of untreated caries per patient ranged from 0 to 6 in the Control Group with an average of 3.3 ± 1.5 decayed teeth per person (Table 1 and Figure 4).\n\nThe number of untreated caries per patient ranged from 2 to 10 in the BRONJ Group with an average of 5 ± 1.9 decayed teeth per person (Table 2 and Figure 4).\n\n\n\n\n\nM: Number of Missed Teeth. According to the International Consensus, a complete denture is composed of 28 teeth in the upper and lower jaws, avoiding the presence of the wisdom teeth [14].The number of missed teeth per patient ranged from 2 to 18 in the Control Group with an average of 7.3 ± 3.9 missed teeth per person (Table 1 and Figure 4).\n\nThe number of missed teeth per patient ranged from 4 to 18 in the BRONJ Group with an average of 10.0 ± 3.8 missed teeth per person (Table 2 and Figure 4).\n\n\n\n\n\nF: Number of Filled Teeth\nThe number of filled teeth per patient ranged from 1 to 9 in the Control Group with an average value of 5.1 ± 2.2 teeth (Table 1 and Figure 4).\n\nThe number of filled teeth per patient ranged from 1 to 16 in the BRONJ Group with an average value of 7.9 ± 3.3 teeth (Table 2 and Figure 4).\n\n\n\n\n\nT: Number of Healthy Teeth\nThe number of healthy teeth remaining per patient ranged from 10 to 24 in the Control Group with an average value of 16.1 ± 3.8 teeth (Table 1 and Figure 4).\n\nThe number of healthy teeth per patient ranged from 3 to 14 in the BRONJ Group with an average value of 9 ± 3.4 teeth (Table 2 and Figure 4).\n\n\n\n\n\nProbing Pocket Depth\nThe periodontal pockets per patient ranged from 1 to 9 mm of depth in the Control Group with an average of 4.7 ± 2.3 mm (Table 1 and Figure 5).\n\nThe periodontal pockets per patient ranged from 4 to 10 mm of depth in the BRONJ Group with an average of 7.0 ± 1.8 mm (deep pocket and severe periodontal disease) (Table 2 and Figure 5).\n\n\n\n\nAll of the 32 BRONJ patients of the B Group present a larger and meaningful number of decayed (P = .001342731), missed (P = .018622821), and filled (P = .000901775) teeth (Table 3).\n\nThis study shows that the oral health of a consecutive group of BRONJ patients for an oral health check and treatment, generally, had a poorer standard of oral health than bisphosphonate patients with no evidence of ONJ. We tested the hypothesis that the poor periodontal conditions of osteoporotic patients might increase susceptibility to BRONJ.\n\nThe American Academy of Oral and Maxillofacial Surgeons defined BRONJ as the presence of necrotic bone in the oral cavity for at least 8 weeks in a patient who is taking (or has taken) BP and who has not received radiation to the head and neck. Four different grades (from 0 to III) of pathology based on clinical severity of symptoms have been identified [15]. Patients affected by BRONJ may have swelling of oral and perioral tissues, pain, bleeding, persistent purulent discharge and draining fistulas, severe halitosis, lower lip paraesthesia, and mobility and loosening of teeth. Patients receiving bisphosphonates who are undergoing dentoalveolar surgery (extractions, dental implant placement, periapical surgery, and periodontal surgery involving osseous injury) are seven times more likely to develop BRONJ than patients who are not having dental surgical procedures [16]. Osteonecrosis of the jaw with oral BP formulations has an estimated incidence of less than one case per 100,000 person-years of exposure. Patients under treatment with oral bisphosphonate therapy have a considerably lower risk of BRONJ than patients treated with IV bisphosphonates. Based on data from the manufacturer of alendronate (Merck), the incidence of BRONJ was calculated to be 0.7/100,000 person/years of exposure. Correspondence with Alastair Goss, DDSc (September 2006), reported that the estimated incidence of BRONJ for patients treated weekly with alendronate is 0.01–0.04%, based on prescription data in Australia. Following extractions, this rate increased to 0.09–0.34%. Other studies pointed out how the incidence of BRONJ in osteoporosis patients taking oral BPs could be significantly higher than previously reported [17]. It has been suggested that BRONJ can be predicted with a combination of environmental and genetic risk factors. Genetic risk factors include polymorphisms of the CYP2C8 gene [18], vascular endothelial growth factor polymorphisms, and mutations in the prothrombin gene [19, 20]. A published case series including at least 10 patients identified in a single city or a limited geographical region showed that 55% of reports come from Mediterranean countries such as Italy (25, 24, and 13 cases; total = 62) [18–21].\n\nWhile other broader studies on dental and periodontal conditions of patients on bisphosphonates with and without BRONJ including clinical data on the activity and progression of oral diseases might disclose differences that did not reach a statistically significant difference [21], our experimental study found a highly statistically significant difference both of DMFT index and of periodontal probing depth (Table 3).\n\nThe incidence of periodontal disease was statistically significant (P = .000452719) (Table 3). Furthermore all the BRONJ patients have a pathological periodontal pocket of 4 mm at least (Table 2). The limits of the confidence interval are 6.3 mm and 7.7 mm on average of the probing depth within which there is the a probability of 95% to find the “true” periodontal probing average of BRONJ patients.\n\nPrevention by the combination of improving oral health and improved management of their bone disease is the best management of these cases [22–26].\n\n4. Conclusions\nThis study also shows the fairly simple treatment measures we required for making the patients' oral cavities healthy. Commonly, this involved extraction of hopeless teeth, endodontics and referral back to their general dentist for simple scaling, and cleaning and oral hygiene instruction.\n\nWhen extractions were performed the patients had a full informed consent discussion. Extractions should be performed in accordance with the recommendations in the Therapeutic Guidelines, namely, preextraction antibiotic cover, minimal trauma, and suturing of the socket avoiding postoperative complications like bleeding or pain. All the patients were checked after one week and one month. Although some patients had a delayed healing, none developed ONJ [24, 26]. Given that the risk of ONJ for patients on oral bisphosphonates has been calculated in the range of 1 in 225 to 1 in 1100, then the probability of such a study being completed at a single centre is low.\n\nData results clearly showed how the frequencies of decayed, missed, and filled teeth and periodontal disease were significantly higher in the BRONJ patients group than in the Control Group (Table 3 and Figures 4 and 5).\n\nFor this reason, clinicians should recommend patients with osteoporosis paying special attention to the maintenance of their oral hygiene. Regular dental visits are fundamental, with frequent scaling and root planning and conservative, periodontal, and endodontic therapy as needed. Dental extractions should be performed only in the case of hopeless teeth.\n\nThe severity of oral health increases with excessive duration of administration of the drug. Black et al. showed that prolonged use of bisphosphonates over five years does not have a therapeutic value because the risk of vertebral fracture remains similar and mineral bone density does not tend to improve [27]. New clinical therapeutic options like growth factor application may be applied for reducing patient pain and for improving the clinical healing after jawbone necrosis [28].\n\nPatients with BRONJ appear to have a higher incidence of periodontal disease and for this reason they should undergo supervised dental care in order to maintain sufficient periodontal attachment without further disease progression. This study highlights how patients with existing untreated periodontal disease and a higher DMFT Index undergoing BP therapy may be at a higher risk for BRONJ and need close supervision and care of their dental condition (Table 3).\n\nAcknowledgment\nThe authors want to thank Dr. Rahul Tandon DMD for his English grammar correction on the paper text. The clinical study has been approved as an observational study by Bonino Pulejo IRCCS Neurolesi Center with number CE/E/04/2013.\n\nFigure 1 Sample of patients affected by BRONJ.\n\nFigure 2 Sample of periodontal probe on osteoporotic patients without BRONJ.\n\nFigure 3 Years of BP administration—A and B Groups.\n\nFigure 4 Average number of decayed, missed, and filled teeth recorded for patients in each group.\n\nFigure 5 Periodontal probing average depth recorded for patients in each group.\n\nTable 1 Anamnestic and clinical details of A Group—20 osteoporotic non-BRONJ patients.\n\nAge\tOS type\tBP therapy\tBP (years)\tAssociated pathology\tCorticosteroid assumption\tD\tM\tF\tPeriodontal probing (mm)\t\n52\t1\tAle* + Clo**\t2\tNo\tNo\t4\t6\t6\t3\t\n67\t1\tClo** + Ris***\t3\tDiabetes mellitus II\tNo\t6\t8\t5\t2\t\n59\t2\tClo**\t5\tNo\tYes\t3\t4\t7\t5\t\n73\t1\tAle*\t6\tNo\tNo\t3\t11\t2\t4\t\n77\t1\tAle*\t8\tRheumatoid arthritis\tNo\t5\t9\t5\t7\t\n44\t1\tIba****\t2\tNo\tNo\t2\t3\t4\t3\t\n61\t1\tAle*\t3\tRheumatoid arthritis\tNo\t4\t5\t8\t4\t\n70\t1\tClo** + Ris*** + Ner*****\t9\tHypertension\tNo\t4\t10\t6\t6\t\n49\t1\tAle* + Clo**\t4\tNo\tNo\t3\t5\t3\t2\t\n55\t1\tNer*****\t3\tNo\tNo\t4\t6\t8\t7\t\n78\t2\tAle*\t6\tRheumatoid arthritis\tYes\t6\t12\t4\t9\t\n65\t1\tAle* + Clo**\t3\tNo\tNo\t5\t7\t1\t3\t\n52\t1\tRis***\t2\tNo\tNo\t3\t4\t7\t6\t\n80\t1\tAle*\t10\tCardiovascular diseases\tNo\t2\t18\t2\t9\t\n66\t2\tAle* + Clo**\t4\tDiabetes mellitus II\tYes\t1\t6\t9\t2\t\n54\t1\tClo** + Ris*** + Ner*****\t4\tNo\tNo\t3\t5\t8\t4\t\n47\t1\tAle* + Clo**\t2\tNo\tNo\t0\t2\t6\t1\t\n71\t1\tIba****\t6\tDiabetes mellitus II\tNo\t2\t14\t3\t6\t\n59\t2\tAle*\t1\tNo\tYes\t4\t6\t5\t5\t\n60\t1\tAle* + Clo**\t3\tHypertension\tNo\t3\t6\t4\t6\t\n(i) Ale: alendronate: oral assumption, **Clo: clodronate: oral assumption, ***Ris: risedronate: oral assumption, ****Iba: ibandronate: oral assumption, and *****Ner: neridronate: IV assumption.\n\n(ii) OS type: postmenopausal ostep “1”; corticosteroid related osteop “2.”\n\nTable 2 Anamnestic and clinical details of B Group—32 osteoporotic BRONJ patients.\n\nAge\tOS type\tTrigger event\tPlace of infection\tBRONJ stage\tBF therapy\tBF (years)\tAssociated pathology\tCortc ST \tD\tM\tF\tPeriod probing (mm)\t\n66\t1\tTeeth extract\tMAN\t2\tAle*\t6\tDiabetes mellitus II\tNo\t4\t12\t10\t7\t\n60\t1\tTeeth extract\tMAN\t1\tAle*\t5\tDiabetes mellitus II\tNo\t6\t8\t7\t6\t\n56\t1\tCyst enucl\tMAN\t1\tClo**\t4\tNo\tNo\t10\t5\t6\t5\t\n72\t1\tTeeth extract\tMAS\t1\tAle* + Clo**\t8\tNo\tNo\t4\t18\t6\t7\t\n80\t1\tTeeth extract\tMAS\t1\tAle*\t11\tNo\tNo\t5\t17\t1\t9\t\n61\t2\tTeeth extract\tMAS\t3\tAle* + Clo**\t1\tRheumatoid arthritis\tYes\t3\t11\t12\t8\t\n63\t1\tTeeth extract\tMAN\t2\tAle*\t5\tHypertension\tNo\t4\t14\t7\t9\t\n47\t1\tTeeth extract\tMAS\t1\tAle*\t3\tNo\tNo\t10\t6\t3\t10\t\n51\t1\tPeriodontal infection\tMAN\t1\tAle* + Clo**\t4\tNo\tNo\t8\t4\t9\t6\t\n56\t1\tTeeth extract\tMAN\t0\tAle*\t5\tRheumatoid arthritis\tNo\t3\t10\t9\t9\t\n49\t1\tTeeth extract\tMAN\t3\tRis***\t2\tNo\tNo\t4\t17\t4\t6\t\n47\t1\tImplant insertion\tMAS\t1\tNer*****\t3\tNo\tNo\t8\t4\t6\t4\t\n61\t1\tTeeth extract\tMAS\t1\tAle*\t6\tNo\tNo\t6\t11\t3\t8\t\n51\t1\tTeeth extract\tMAN\t1\tAle*\t3\tNo\tNo\t5\t8\t10\t5\t\n63\t1\tImplant removal\tMAN\t1\tAle* + Clo**\t4\tNo\tNo\t4\t9\t10\t7\t\n62\t1\tTeeth extract\tMAN\t2\tAle* + Clo**\t5\tNo\tNo\t5\t10\t9\t9\t\n69\t1\tPeriodontal infection\tMAN\t2\tAle* + Clo**\t6\tCardiovascular diseases\tNo\t5\t14\t9\t5\t\n75\t1\tNot identified\tMAS\t1\tAle*\t9\tDiabetes mellitus II\tNo\t6\t11\t10\t9\t\n77\t1\tTeeth extract\tMAN\t1\tAle*\t11\tRheumatoid arthritis\tNo\t5\t17\t6\t8\t\n74\t1\tTeeth extract\tMAS\t1\tClo**\t8\tHypertension\tNo\t4\t9\t5\t10\t\n65\t2\tTeeth extract\tMAN\t1\tClo** + Ris\t4\tRheumatoid arthritis\tYes\t3\t10\t16\t9\t\n67\t2\tTeeth extract\tMAN\t2\tAle*\t2\tRheumatoid arthritis\tYes\t4\t6\t14\t7\t\n54\t2\tImplant insertion\tMAS\t1\tClo** + Ris*** + Ner*****\t3\tNo\tYes\t4\t8\t11\t5\t\n64\t1\tTeeth extract\tMAN\t0\tAle*\t4\tHypertension\tNo\t7\t6\t8\t9\t\n59\t1\tPeriodontal infection\tMAN\t0\tAle*\t2\tNo\tNo\t6\t12\t4\t4\t\n56\t1\tTeeth extract\tMAN\t0\tIba****\t4\tNo\tNo\t3\t10\t7\t6\t\n63\t1\tTeeth extract\tMAS\t0\tIba****\t3\tCardiovascular diseases\tNo\t4\t9\t6\t7\t\n47\t2\tTeeth extract\tMAS\t1\tAle*\t2\tNo\tYes\t6\t6\t9\t6\t\n48\t1\tTeeth extract\tMAN\t1\tAle*\t1\tNo\tNo\t2\t9\t8\t5\t\n44\t1\tImplant insertion\tMAN\t1\tAle* + Clo**\t2\tNo\tNo\t5\t8\t5\t4\t\n56\t1\tTeeth extract\tMAS\t1\tAle* + Clo**\t3\tNo\tNo\t4\t15\t10\t9\t\n65\t2\tTeeth extract\tMAN\t2\tAle*\t6\tRheumatoid arthritis\tYes\t3\t9\t13\t8\t\n(i) Ale: alendronate: oral assumption, **Clo: clodronate: oral assumption, ***Ris: risedronate: oral assumption, ****Iba: ibandronate: oral assumption, and *****Ner: neridronate: IV assumption.\n\n(ii) OS type: postMenopausal ostep “1”; Corticosteroid related osteop “2.”\n\nTable 3 A Group versus B Group—evaluation of clinical and statistical significance.\n\n \tAdministrations (years)\tD \tM\tF\tPeriodontal probing (mm)\t\nA Group (osteoporotic patients)\t4.3 (2.49)\t3.35 (1.53)\t7.35 (3.96)\t5.15 (2.28)\t4.7 (±2.29)\t\nB Group (BRONJ patients)\t4.53 (2.6)\t5 (1.93)\t10.09 (3.85)\t7.91 (3.34)\t7.06 (±1.85)\t\n\nP value\t0.75\t0.001342731*\t0.018622821*\t0.000901775*\t0.000452719*\t\nAverage values ± SD; DMFT index; *statistically significant difference.\n==== Refs\n1 NIH Consensus Statement Osteoporosis Prevention, Diagnosis and Therapy 2000 17 Washington, DC, USA NIH Consensus Statement \n2 Compston J Action Plan for the prevention of osteoporotic fractures in the European Community Osteoporosis International 2004 15 4 259 262 2-s2.0-2142753140 14985947 \n3 Stafford RS Drieling RL Hersh AL National trends in osteoporosis visits and osteoporosis treatment, 1988–2003 Archives of Internal Medicine 2004 164 14 1525 1530 2-s2.0-3242808066 15277283 \n4 Felsenberg D Boonen S The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management Clinical Therapeutics 2005 27 1 1 11 2-s2.0-14844323000 15763602 \n5 Ruggiero SL Mehrotra B Rosenberg TJ Engroff SL Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases Journal of Oral and Maxillofacial Surgery 2004 62 5 527 534 2-s2.0-2142817155 15122554 \n6 Russell RG Bisphosphonates: the first 40 years Bone 2011 49 1 2 19 2-s2.0-79958695940 21555003 \n7 Rodan GA Reszka AA Bisphosphonate mechanism of action Current Molecular Medicine 2002 2 6 571 577 2-s2.0-0036727151 12243249 \n8 Russell RG Bisphosphonates: mode of action and pharmacology Pediatrics 2007 119 supplement 2 S150 S162 2-s2.0-33947109369 17332236 \n9 Ruggiero SL Dodson TB Assael LA Landesberg R Marx RE Mehrotra B American association of oral and Maxillofacial surgeons position paper on bisphosphonate-related osteonecrosis of the jaws-2009 update Journal of Oral and Maxillofacial Surgery 2009 67 5 2 12 2-s2.0-64649105333 \n10 Otto S Abu-Id MH Fedele S Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: not just a sporadic coincidence-a multi-centre study Journal of Cranio-Maxillofacial Surgery 2011 39 4 272 277 2-s2.0-79956014458 20580566 \n11 Becker T Levin L Shochat T Einy S How much does the DMFT index underestimate the need for restorative care? Journal of Dental Education 2007 71 5 677 681 2-s2.0-34347206706 17493976 \n12 Eickholz P Clinical periodontal diagnosis: probing pocket depth, vertical attachment level and bleeding on probing Perio 2004 1 1 75 80 \n13 Neely JG Hartman JM Forsen JW Jr. Wallace MS Tutorials in clinical research: VII. Understanding comparative statistics (contrast)-part B: application of t-test, Mann-Whitney U, and chi-square Laryngoscope 2003 113 10 1719 1725 2-s2.0-0141864405 14520096 \n14 Brunello DL Mandikos MN Construction faults, age, gender, and relative medical health: factors associated with complaints in complete denture patients Journal of Prosthetic Dentistry 1998 79 5 545 554 2-s2.0-0032065620 9597608 \n15 Sarasquete ME García-Sanz R Marín L Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytoehrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis Blood 2008 112 7 2709 2712 2-s2.0-53449093633 18594024 \n16 Coskun Benlidayi I Guzel R Oral bisphosphonate related osteonecrosis of the jaw: a challenging adverse effect ISRN Rheumatology 2013 2013 6 pages 215034 \n17 Sambrook P Olver I Goss AN Bisphosphonates and osteonecrosis of the jaw. Position statement on behalf of the Australian and New Zealand Bone Mineral Society, Osteoporosis Australia, Medical Oncology Group of Australia and the Australian Dental Society Australian Family Physician 2006 35 801 803 17019456 \n18 Vairaktaris E Vassiliou S Avgoustidis D Stathopoulos P Toyoshima T Yapijakis C Bisphosphonate-induced avascular osteonecrosis of the Mandible associated with a common thrombophilic mutation in the prothrombin gene Journal of Oral and Maxillofacial Surgery 2009 67 9 2009 2012 2-s2.0-68549085211 19686941 \n19 Manfredi M Merigo E Guidotti R Meleti M Vescovi P Bisphosphonate-related osteonecrosis of the jaws: a case series of 25 patients affected by osteoporosis International Journal of Oral and Maxillofacial Surgery 2011 40 3 277 284 2-s2.0-79952317178 21163625 \n20 Favia G Pilolli GP Maiorano E Osteonecrosis of the jaw correlated to bisphosphonate therapy in non-oncologic patients: clinicopathological features of 24 patients Journal of Rheumatology 2009 36 12 2780 2787 2-s2.0-72449200764 19884275 \n21 Gasparini G Saponaro G Di Nardo F Clinical experience with spiramycin in bisphosphonate-associated osteonecrosis of the jaw International Journal of Immunopathology and Pharmacology 2010 23 2 619 626 2-s2.0-77955371421 20646357 \n22 Carmagnola D Celestino S Abati S Dental and periodontal history of oncologic patients on parenteral bisphosphonates with or without osteonecrosis of the jaws: a pilot study Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology 2008 106 6 e10 e15 2-s2.0-55549121545 \n23 Woo S-B Hellstein JW Kalmar JR Systematic review: bisphosphonates and osteonecrosis of the jaws Annals of Internal Medicine 2006 144 10 753 761 2-s2.0-33646836925 16702591 \n24 Arduino PG Menegatti E Scoletta M Vascular endothelial growth factor genetic polymorphisms and haplotypes in female patients with bisphosphonate-related osteonecrosis of the jaws Journal of Oral Pathology and Medicine 2011 40 6 510 515 2-s2.0-79959975670 21251073 \n25 Pichardo SE van Merkesteyn JP Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin? Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology 2013 116 3 287 292 \n26 Dentino A Lee S Mailhot J Hefti AF Principles of periodontology Periodontol 2000 2013 61 1 16 53 23240942 \n27 Black D Bauer D Schwartz A Cummings S Rosen C Continuing bisphosphonate treatment for osteoporosis—for whom and for how long? The New England Journal of Medicine 2012 366 22 2051 2053 22571169 \n28 Cicciù M Herford AS Juodžbalys G Stoffella E Recombinant human bone morphogenetic protein type 2 application for a possible treatment of bisphosphonates-related osteonecrosis of the jaw Journal of Craniofacial Surgery 2012 23 3 784 788 2-s2.0-84860508688 22565901\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2042-0064",
"issue": "2013()",
"journal": "Journal of osteoporosis",
"keywords": null,
"medline_ta": "J Osteoporos",
"mesh_terms": null,
"nlm_unique_id": "101538878",
"other_id": null,
"pages": "231289",
"pmc": null,
"pmid": "24455411",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "23762600;21251073;21163625;19686941;17332236;19884275;22571169;21555003;20646357;19371809;15277283;23240942;12243249;15122554;15763602;22565901;9597608;17493976;14520096;14985947;20580566;23953415;18594024;18801674;17019456;16702591",
"title": "Decayed, Missing, and Filled Teeth Index and Periodontal Health in Osteoporotic Patients Affected by BRONJ: An Observational Study.",
"title_normalized": "decayed missing and filled teeth index and periodontal health in osteoporotic patients affected by bronj an observational study"
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"abstract": "BACKGROUND\nMultiple myeloma (MM) is an incurable hematologic malignancy, and outcomes remain poor for patients with triple-class relapsed/refractory MM (RRMM). Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes of the KCd on triple-class RRMM patients at our institution.\n\n\nMETHODS\nTwenty-three patients with triple-class RRMM treated with KCd between June 2017 and October 2020 were included in our analysis. The regimen KCd consisted of 28 days cycles of carfilzomib 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, and 16, cyclophosphamide 300 mg/m2 IV weekly, and dexamethasone (20-40) mg orally weekly.\n\n\nRESULTS\nPatients received a median of 6 (3-10) prior regimens. The median number of cycles administered was 4 (1-11) cycles. Overall response rate was 52%, 6 patients (26%) achieved very good partial response (VGPR), 6 patients (26%) achieved partial response (PR), and 5 patients (22%) achieved stable disease (SD). Progression-free survival (PFS) and Overall-survival (OS) were 4 and 11.9 months, respectively. There was no reported treatment-related mortality. The most common grade ≥3 adverse events were neutropenia (26%), thrombocytopenia (56.5%), and anemia (56.5%).\n\n\nCONCLUSIONS\nKCd showed clinically meaningful efficacy and manageable safety profile in patients with triple-class RRMM in real-world.",
"affiliations": "University of Kansas Medical Center, Westwood, Kansas, USA.;University of Kansas Medical Center, Westwood, Kansas, USA.;University of Kansas Medical Center, Westwood, Kansas, USA.;Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Westwood, Kansas, USA.;US Myeloma Research Consortium (USMRC), Westwood, Kansas, USA.;US Myeloma Research Consortium (USMRC), Westwood, Kansas, USA.;US Myeloma Research Consortium (USMRC), Westwood, Kansas, USA.;US Myeloma Research Consortium (USMRC), Westwood, Kansas, USA.;University of Kansas Medical Center, Westwood, Kansas, USA.;Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Westwood, Kansas, USA.;US Myeloma Research Consortium (USMRC), Westwood, Kansas, USA.;US Myeloma Research Consortium (USMRC), Westwood, Kansas, USA.",
"authors": "Pennipede|Dante|D|;Mohyuddin|Ghulam Rehman|GR|;Hawkins|Ryan|R|;Ganguly|Siddhartha|S|;Shune|Leyla|L|;Ahmed|Nausheen|N|;Mohan|Meera|M|https://orcid.org/0000-0002-6913-6526;Cui|Wei|W|;Mahmoudjafari|Zahra|Z|;McGuirk|Joseph|J|;Atrash|Shebli|S|;Abdallah|Al-Ola|AO|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13697",
"fulltext": null,
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"issn_linking": "0902-4441",
"issue": "107(6)",
"journal": "European journal of haematology",
"keywords": "carfilzomib; cyclophosphamide; multiple myeloma; triple-class refractory myeloma",
"medline_ta": "Eur J Haematol",
"mesh_terms": null,
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "602-608",
"pmc": null,
"pmid": "34378251",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Carfilzomib, cyclophosphamide, and dexamethasone (KCd) for the treatment of triple-class relapsed/refractory multiple myeloma (RRMM).",
"title_normalized": "carfilzomib cyclophosphamide and dexamethasone kcd for the treatment of triple class relapsed refractory multiple myeloma rrmm"
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332355",
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "A wide variety of cytotoxic medications cause interstitial lung disease (ILD). For the first time, we describe ILD in an 82-year-old woman with muscle invasive bladder cancer 10 days after receiving cetuximab as part of a novel trial. She had no significant medical history or drug allergies, had good exercise tolerance and a 5 pack-year smoking history. She received neoadjuvant chemotherapy (gemcitabine, cisplatin) with a good response on MRI. She was eligible for a phase 2 trial of cetuximab with chemotherapy and radiotherapy for muscle invasive bladder cancer (TUXEDO), in which the trial arm used cetuximab plus standard chemoradiotherapy to the bladder (64 grey in 32 fractions plus mitomycinandfluorouracil). Ten days after her third infusion of cetuximab, she was presented with type 1 respiratory failure. Thoracic CT scan demonstrated new widespread ground glass change in the lungs. She received high-dose steroids (prednisolone 1 mg/kg), broad spectrum antibacterial cover and non-invasive ventilation. She survived to be discharged with residual respiratory failure.",
"affiliations": "The Cancer Centre, Queen Elizabeth Hospital Birmingham, Birmingham, UK.;The Cancer Centre, Queen Elizabeth Hospital Birmingham, Birmingham, UK.;The Cancer Centre, Queen Elizabeth Hospital Birmingham, Birmingham, UK.",
"authors": "Price|Louise|L|http://orcid.org/0000-0002-1046-412X;Glynn|Patricia|P|;Zarkar|Anjali|A|",
"chemical_list": "D013256:Steroids; D003841:Deoxycytidine; D011239:Prednisolone; C056507:gemcitabine; D000068818:Cetuximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220181",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "chemotherapy; radiotherapy; urological cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068818:Cetuximab; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D020360:Neoadjuvant Therapy; D063087:Noninvasive Ventilation; D011239:Prednisolone; D012131:Respiratory Insufficiency; D013256:Steroids; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29269357",
"pubdate": "2017-12-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22843749;17965079;25210144;18940975;12531582;26775618;24114566;22076388;19339720;698608;19739274;23950208;19682368;17522249;22512481;22896776",
"title": "Interstitial lung disease secondary to Cetuximab in bladder cancer: an Oncologist's perspective.",
"title_normalized": "interstitial lung disease secondary to cetuximab in bladder cancer an oncologist s perspective"
} | [
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"companynumb": "GB-MYLANLABS-2019M1020435",
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... |
{
"abstract": "DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a rare type of delayed drug hypersensitivity reaction characterised by fever, skin rash, lymphadenopathy, and visceral involvement, which can be life threatening and is a childhood event. An eight-year-old boy was admitted with complaints of extensive rash and fever three weeks after the onset of treatment with carbamazepine for a diagnosis of epilepsy. Fever, as well as patches and plaques with indeterminate limits that tended to merge and were non-blanchable on a widespread erythematous layer, were revealed in physical examination. Extensive cervical, submandibular, and inguinal lymphadenopathy was observed. We present ours as the second case of myocarditis secondary to DRESS syndrome after carbamazepine use in the literature.",
"affiliations": "Yüzüncü Yil University, Turkey.;Yüzüncü Yil University, Turkey.;Yüzüncü Yil University, Turkey.;Yüzüncü Yil University, Turkey.;Yüzüncü Yil University, Turkey.;Yüzüncü Yil University, Turkey.;Yüzüncü Yil University, Turkey.",
"authors": "Çetin|Mecnun|M|;Mis|Mevsim Demir|MD|;Karaman|Kamuran|K|;Yavuz|Íbrahim H|ÍH|;Geylan|Hadi|H|;Tunçdemir|Perihan|P|;Demir|Feyza|F|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/ceji.2019.83700",
"fulltext": "\n==== Front\nCent Eur J ImmunolCent Eur J ImmunolCEJICentral-European Journal of Immunology1426-39121644-4124Polish Society of Experimental and Clinical Immunology 8370010.5114/ceji.2019.83700Case ReportCarbamazepine-induced DRESS syndrome leading to reversible myocarditis in a child Çetin Mecnun Mis Mevsim Demir Karaman Kamuran Yavuz Íbrahim H. Geylan Hadi Tunçdemir Perihan Demir Feyza Yüzüncü Yil University, TurkeyCorrespondence: Mecnun Çetin, Yüzüncü Yil University, Turkey. e-mail: drmecnun@hotmail.com15 4 2019 2019 44 1 102 105 04 9 2017 28 9 2017 Copyright: © 2019 Polish Society of Experimental and Clinical Immunology2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a rare type of delayed drug hypersensitivity reaction characterised by fever, skin rash, lymphadenopathy, and visceral involvement, which can be life threatening and is a childhood event. An eight-year-old boy was admitted with complaints of extensive rash and fever three weeks after the onset of treatment with carbamazepine for a diagnosis of epilepsy. Fever, as well as patches and plaques with indeterminate limits that tended to merge and were non-blanchable on a widespread erythematous layer, were revealed in physical examination. Extensive cervical, submandibular, and inguinal lymphadenopathy was observed. We present ours as the second case of myocarditis secondary to DRESS syndrome after carbamazepine use in the literature.\n\ncarbamazepineDRESS syndromelymphadenopathymyocarditis\n==== Body\nIntroduction\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but life-threatening reaction to drugs such as phenytoin, phenobarbital, carbamazepine, valproate, and allopurinol. The disease is characterized by skin rashes, fever, haematological abnormalities, lymphadenopathy, and organ failure such as hepatic dysfunction [1]. Carbamazepine is widely used as an anti-epileptic agent in paediatric neurology patients. In the literature there have been many reports showing adverse reactions due to the carbamazepine usage. However, there is only one case reported in the literature that shows myocarditis secondary to DRESS syndrome after carbamazepine use [2]. Herein we present ours as the second case of myocarditis secondary to DRESS syndrome after carbamazepine use in the literature.\n\nCase presentation\nThe patient was admitted to Yuzuncu Yil University medical faculty paediatric outpatient clinic with complaints of a sudden rash initially on his hands and then spreading all over his body, with a fever of 39°C and pruritus about a week earlier. The patient was admitted to our hospital in Van, Turkey in January 2017. Our hospital is a university referral hospital that serves about one million people. The hospital has 670 beds with six paediatric clinical sections. The patient was an eight-year-old boy. On his medical history, carbamazepine was started due to a diagnosis of epilepsy about four weeks earlier. In the patient’s physical examination a temperature of 39.2°C, heart rate of 123 beats/minute, respiratory rate of 23 breaths/minute, blood pressure of 105/60 mmHg, and O2 saturation of 95% were measured. There were common millimetric lymph nodes in bilateral cervical and inguinal regions. There were patches and plaques with indeterminate limits that tended to merge and were non-blanchable on a widespread erythematous layer in the physical examination (Fig. 1).\n\nFig. 1 Common rash on entire body\n\nIn the laboratory review of the patient the following were reported: no hepatosplenomegaly was observed, haemoglobin 12.9 gr/dl, leucocytes 14 400/mm3, thrombocytes 433 000/mm3, 30% neutrophil in peripheral spread, 12% stab neutrophil, 44% lymphocytes, 4% monocytes, 16% eosinophil, total eosinophil count 2300/mm3, AST 72 IU/l, troponin I 1.7 ng/ml (normal value: < 0.04 ng/ml), CK-MB 72 5 ng/ml, and CRP 21 mg/dl. Serological studies of Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, hepatitis A, B, and C, and mycoplasma were normal. Chest radiography was normal. Electrocardiography revealed sinus tachycardia. Table 1 shows the clinical characteristics and variables of our case. An echocardiogram revealed global hypokinesis, mild mitral regurgitation, and decreased contractility (LV ejection fraction 47%, fractional shortening 23%) consistent with the diagnosis of myocarditis (Fig. 2). A skin biopsy was performed, which demonstrated an inflammatory infiltrate that was predominantly perivascular and lymphocytic in nature (Fig. 3).\n\nTable 1 The clinical characteristics and variables of our case\n\nCarbamazepine use\t\nAcute rash on whole body\t\nPruritus\t\nFever above 38°C\t\nEnlarged lymph nodes in bilateral cervical and inguinal regions\t\nBlood count parameters\t\n Leucocytosis\t\n Eosinophilia\t\nElevated serum aspartate aminotransferase (AST), troponin I, CK-MB, and C-reactive protein (CRP) levels\t\nEchocardiographic abnormalities (global hypokinesis, mild mitral regurgitation, and decreased contractility)\t\nFig. 2 M-mode echocardiography showing systolic dysfunction\n\nFig. 3 Showed various degrees of basal vacuolization, dyskeratosis, infiltration of the epidermis by lymphocytes, dermal edema, superficial perivascular inflammation\n\nThe patient was diagnosed with DRESS syndrome and secondary myocarditis, according to both the biopsy results and the RegiSCAR study group scoring system criteria in Table 2. He was treated with methylprednisolone 2 mg/kg/day and diphenhydramine 1 mg/kg i.v. q6h. After carbamazepine was discontinued and the second day of the initiation of the treatment, the clinical symptoms and the general condition improved. Eruptions were completely resolved within seven days. The patient received a total of 45 days of steroid treatment. After two months, echocardiogram showed normal cardiac contractility.\n\nTable 2 Diagnostic criteria for DRESS syndrome [3]\n\nBorquet et al.\tRegiSCAR study group\tJapanese consensus group\t\nDRESS is confirmed by presence of 1 and 2 and 3Cutaneous drug eruption\n\nAdenopathies > 2 cm in diameter of hepatitis (liver transaminases > 2 times upper limit of normal) (or) interstitial nephritis (or) interstitial pneumonitis (or) carditis\n\nHaematological abnormalities; eosinophilia > 1.5 × 109/l (or) atypical lymphocytes\n\n\tMore than 3 of the criteria are required for the diagnosis of DRESSHospitalisation\n\nReaction suspected to be drug related\n\nAcute rash\n\nFever above 38°C\n\nEnlarged lymph nodes involving at least two sites\n\nInvolvement of at least one internal organ\n\nBlood count abnormalities Lymphocytes above or below laboratory limits Eosinophils above laboratory limits (in percentage or absolute count) Platelets below laboratory limits\n\n\tTypical DRESS (presence of all 7 criteria): atypical DIHS (all criteria present except lymphadenopathy and HHV-6 reactivation)HHV-6 reactivation\n\nProlonged clinical symptoms 2 weeks after discontinuation of causative drug\n\nMaculopapular rash developing > 3 weeks after starting drug\n\nFever above 38°C\n\nLymphadenopathy\n\nALT > 100 U/l or other organ involvement\n\nLeukocyte abnormalities (at least one) Leucocytosis (> 11 × 109/l) Atypical lymphocytosis (> 5%)Eosinophilia (1.5 × 109/l)\n\n\t\nDRESS – drug rash with eosinophilia and systemic symptoms, RegiSCAR – European registry of severe cutaneous adverse reactions, DIHS – drug-induced hypersensitivity syndrome, HHV-6 – human herpesvirus 6, ALT – alanine aminotransferase\n\nDiscussion\nDRESS syndrome, which is a drug eruption syndrome accompanied by eosinophilia and systemic symptoms, is a febrile dermatosis with cutaneous and visceral organ involvement that can develop in both paediatric and adult patients, which is a rare condition among drug eruptions, and it can be fatal [1]. For the first time, in 1950 Chaiken et al. reported a case of fever, morbilliform rash, and hepatitis developing in a patient using phenytoin, and they named the illness phenytoin hypersensitivity. Then in 1996, Bocquet et al. defined it as DRESS, an abbreviation based on clinical and laboratory findings [3].\n\nAlthough the aetiology of DRESS syndrome is not fully understood, many drugs are blamed, but it is thought to be a drug reaction that is most often caused by aromatic anticonvulsants [4-6]. Yang et al. reported that carbamazepine and phenytoin, which are anticonvulsant medications, were responsible for 43.6% of all DRESS syndrome cases [7]. Patients with a genetic predisposition develop a severe hypersensitivity reaction within two months of using these drugs (average of 2-6 weeks), and this reaction continues for a long time.\n\nEnzyme defects related to drug metabolism, lymphocyte activation, eosinophilia, and viral agents (especially human herpes virus-6 and -7, EBV, and HIV) are reported to be responsible for the aetiopathogenesis. DRESS syndrome associated with aromatic anticonvulsant drugs is thought to arise from a pharmacogenetic defect in the epoxide hydroxylase enzyme system, which is involved in drug detoxification. Also, increased reactive metabolites after detoxification failure are thought to cause an immunological reaction. Because aromatic anticonvulsant drugs (phenytoin, phenobarbital, carbamazepine) are metabolised in the same way, the potential cross-reaction risk between these drugs is reported to be between 40% and 80% [8].\n\nIn this syndrome, fever, rash, lymphadenopathy, haematological abnormalities (eosinophilia, lymphocytosis), hepatosplenomegaly, and hepatitis can be seen. DRESS syndrome is a type 4 hypersensitivity reaction, and type 2 T-helper cells play a role in the occurrence of this disease. Skin lesions can be seen, from a broad spectrum of diffuse maculopapular rashes to erythroderma, and rarely Stevens-Johnson syndrome and toxic epidermal necrosis [9].\n\nAlthough systemic involvement of the liver, kidney, and lymph nodes is frequently observed in this syndrome, pulmonary and cardiac involvements are rarely reported. Liver and kidney involvement may result in ALT, AST elevation, hypoalbuminaemia, proteinuria, and haematuria. Eosinophilia can be seen frequently in the blood count [9, 10].\n\nIn our case, a common rash over the whole body, fever, and diffuse lymphadenopathy, which is an important criterion of DRESS syndrome, were present three weeks after carbamazepine usage. Liver function tests, such as ALT, AST, and cardiac involvement markers including CK-MB and troponin I value, were found to be high. There was leukocytosis in the blood count and marked eosinophilia in peripheral spread. Although renal function tests and chest X-ray were normal, myocardial systolic dysfunction and mild mitral failure, which pointed to myocarditis, were observed on echocardiography examination. A literature search revealed that Lo et al. reported the first case of a 14-year-old girl in the paediatric population, who developed myocarditis after carbamazepine use [2]. Ours is the second case in the literature to present myocarditis that developed after carbamazepine use in a paediatric patient.\n\nDiagnostic criteria defined by the RegiSCAR study group and the Japanese consensus group are used for the diagnosis of DRESS syndrome. In addition, diagnostic criteria are also defined by Bocquet et al. To meet the DRESS definition, patients must have three of the four main RegiSCAR criteria in Table 2. The Japanese consensus group developed a second diagnostic criterion group. According to these criteria, seven of the criteria in Table 2 or all of the first five criteria must be present for the diagnosis [3, 6]. We could not study HHV-6, the first criterion of the Japanese consensus group as seen in Table 2, but our case met the remaining criteria. In addition, our case met all of the RegiSCAR study group scoring system criteria. According to these criteria, the case was diagnosed as DRESS syndrome and secondary myocarditis.\n\nTreatment of DRESS syndrome includes discontinuation of the underlying agent and application of corticosteroids, and supportive care. Intravenous immunoglobulin is not routinely recommended; nevertheless, for patients with myocarditis, intravenous immunoglobulin should be considered [11]. Myocarditis is a potentially fatal complication of a drug reaction with eosinophilia and systemic symptoms. Early recognition and treatment with corticosteroids may improve clinical outcomes. We used corticosteroid and supportive treatment for the presence of cardiac involvement, and we had a rapid clinical response. We did not need IVIG treatment because the myocarditis findings were not severe and there were no life-threatening clinical findings.\n\nIn conclusion, DRESS syndrome is an uncommon drug reaction in childhood, which could be fatal if not treated. It should be considered in the differential diagnosis of patients with common rash with medication use in anamnesis. Although DRESS syndrome is rare, it is a clinical condition that should be considered as a fatal disease in cases of reuse of the same group of drugs, and it should be promptly recognised and dealt with because of frequent use of the anticonvulsants in many diseases. We think that reporting this case is important because DRESS syndrome is seen very rarely, and ours is the second case with cardiac involvement in the literature.\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Ferrero NA Pearson KC Zedek DC Morrell DS Case report of drug rash with eosinophilia and systemic symptoms demonstrating human herpesvirus-6 reactivation Pediatr Dermatol 2013 30 608 613 24016284 \n2 Lo MH Huang CF Chang LS Drug reaction with eosinophilia and systemic symptoms syndrome associated myocarditis: a survival experience after extracorporeal membrane oxygenation support J Clin Pharm Ther 2013 38 172 174 23173909 \n3 Husain Z Reddy BY Schwartz RA DRESS syndrome: Part I. Clinical perspectives J Am Acad Dermatol 2013 68 693 23602182 \n4 Cacoub P Musette P Descamps V The DRESS syndrome: A literature review Am J Med 2011 124 588 597 21592453 \n5 Knowles SR Dewhurst N Shear NH Anticonvulsant hypersensitivity syndrome: An update Expert Opin Drug Saf 2012 11 767 778 22794330 \n6 Kardaun SH Sekula P Valeyrie-Allanore L RegiSCAR study group. Drug reaction with eosinophilia and systemic symptoms (DRESS): An original multisystem adverse drug reaction. Results from the prospective RegiSCAR study Br J Dermatol 2013 169 1071 1080 23855313 \n7 Yang CY Dao RL Lee TJ Lu CW Yang CH Hung SI Chung WH Severe cutaneous adverse reactions to antiepileptic drugs in Asians Neurology 2011 77 2025 2033 22116946 \n8 Criado PR Avancini J Santi CG Drug reaction with eosinophilia and systemic symptoms (DRESS): A complex interaction of drugs, viruses and the immune system Isr Med Assoc J 2012 14 577 582 23101424 \n9 Peyrière H Dereure O Breton H Network of the French Pharmacovigilance Centers. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2006 155 422 428 16882184 \n10 Darban M Bagheri B Drug reaction with eosinophilia and systemic symptoms induced by valproic acid: a case report Iran Red Crescent Med J 2016 18 e36825 28144463 \n11 Ho CH Uzunyan MY Myocarditis in drug rash with eosinophilia and systemic symptoms Cardiol Young 2015 25 1210 1213 25234569\n\n",
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"keywords": "DRESS syndrome; carbamazepine; lymphadenopathy; myocarditis",
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"title": "Carbamazepine-induced DRESS syndrome leading to reversible myocarditis in a child.",
"title_normalized": "carbamazepine induced dress syndrome leading to reversible myocarditis in a child"
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"abstract": "BACKGROUND\nAnti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course.\n\n\nRESULTS\n6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing's sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease.\n\n\nCONCLUSIONS\nThe malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.",
"affiliations": "University of Alberta, Edmonton, Canada.;Harrison Pediatric Rheumatology & Autoimmunity Clinic, Mumbai, India.;William Osler Health System, Brampton, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON, M5G 1X8, Canada. shirley.tse@sickkids.ca.",
"authors": "Okihiro|Alexandra|A|;Hasija|Rachana|R|;Fung|Lillia|L|;Cameron|Bonnie|B|;Feldman|Brian M|BM|;Laxer|Ronald|R|;Schneider|Rayfel|R|;Silverman|Earl|E|;Spiegel|Lynn|L|;Yeung|Rae S M|RSM|;Tse|Shirley M L|SML|",
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"fulltext": "\n==== Front\nPediatr Rheumatol Online JPediatr Rheumatol Online JPediatric Rheumatology Online Journal1546-0096BioMed Central London 23310.1186/s12969-018-0233-1Short ReportDevelopment of neoplasms in pediatric patients with rheumatic disease exposed to anti-tumor necrosis factor therapies: a single Centre retrospective study Okihiro Alexandra okihiro@ualberta.ca 1Hasija Rachana rachanahasija@yahoo.com 2Fung Lillia Lillia.fung@williamoslerhs.ca 3Cameron Bonnie bonnie.cameron@sickkids.ca 4Feldman Brian M. brian.feldman@sickkids.ca 4Laxer Ronald ronald.laxer@sickkids.ca 4Schneider Rayfel rayfel.schneider@sickkids.ca 4Silverman Earl earl.silverman@sickkids.ca 4Spiegel Lynn lynn.spiegel@sickkids.ca 4Yeung Rae S. M. rae.yeung@sickkids.ca 4Tse Shirley M. L. shirley.tse@sickkids.ca 41 grid.17089.37University of Alberta, Edmonton, Canada 2 Harrison Pediatric Rheumatology & Autoimmunity Clinic, Mumbai, India 3 William Osler Health System, Brampton, Canada 4 0000 0001 2157 2938grid.17063.33Division of Rheumatology, SickKids, University of Toronto, 555 University Ave, Room 8253 Burton Wing, Toronto, ON M5G 1X8 Canada 14 3 2018 14 3 2018 2018 16 1722 11 2017 1 3 2018 © The Author(s). 2018Open Access This 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\nAnti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course.\n\nFindings\n6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing’s sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease.\n\nConclusions\nThe malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.\n\nKeywords\nAnti-TNFJuvenile idiopathic arthritisUveitisPolyarteritis nodosaMalignancyissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nThe benefit of anti-tumor necrosis factor (TNF) in refractory rheumatic disease is well established [1, 2]. However, there remains a concern for long-term safety since the United States Food and Drug Administration (FDA) reported an increased risk of malignancies in children exposed to anti-TNFs [3]. There have been extensive studies done which suggest that there is no overall increased in malignancy rate in these patients treated with biologics [4–6]. Instead, it has been suggested that the neoplasms occurring in this group have a preponderance towards hematological malignancies [7, 8] and more recently, data on children developing specific solid organ tumors is emerging [9]. As the incidence of neoplasms in rheumatic disease patients exposed to anti-TNFs is limited, characterization of neoplasms in this subset of patients is important to guide malignancy screening recommendations in anti-TNF treatment follow up care. In this study, we describe six children with rheumatic disease who developed one or more neoplasms during or following exposure to anti-TNF treatment at our centre. Additionally, a subset of patients with JIA from the biologic registry were analysed for the probability of neoplasm development after biologic treatment.\n\nFindings\nMaterials and methods\nA retrospective review was performed on the Rheumatology Biologic Registry at SickKids. Patients’ medical information, treatments and imaging were retrieved from clinical charts and the registry. The study was approved by the SickKids Ethics Review Board. A nonparametric statistical Kaplan Meier event curve was created to display the probability of neoplasms in patients with JIA exposed to anti-TNFs (confidence interval 95%).\n\nResults\nA search of our registry found 357 pediatric patients with a diagnosed rheumatic disease who were exposed to biologics between January 1997 and August 2013. Biologic exposure included etanercept (52%), infliximab (31%), adalimumab (16%), golimumab (2%), certolizumab (1%), anakinra (11%), canakinumab (4%), tocilizumab (5%), abatacept (4%) or rituximab (3%) with 21% of the patients exposed to more than one biologic. 295 of these patients had a diagnosis of JIA including: 93 RF (rheumatoid factor)-negative polyarthritis, 63 systemic JIA, 39 enthesitis related arthritis, 30 extended oligoarthritis, 29 RF-positive polyarthritis, 18 psoriatic arthritis, 14 persistent oligoarthritis, and 9 undifferentiated. The remaining patients had the following diagnoses: 23 uveitis, 10 vasculitis, 4 chronic recurrent multifocal osteomyelitis, 4 juvenile dermatomyositis, 4 systemic lupus erythematosus, 4 inflammatory bowel disease associated arthritis, 3 autoinflammatory disease/periodic fever, 3 sarcoidosis and 7 other. Six patients with one or more neoplasms during or after anti-TNF exposure were identified resulting in a malignancy rate of 1.68%. Patient demographics, medications and neoplasm characteristics are summarized in Table 1. As a group, the cohort was exposed to etanercept (n = 1), infliximab (n = 3) or both (n = 2). The median time to neoplasm from anti-TNF initiation was 5.0 years. Patients D and F were actively receiving biologic therapy right up until diagnosis of neoplasm. As a group, the median time to neoplasm from anti-TNF cessation was 4.4 years. All 6 patients received methotrexate. The median time to neoplasm from methotrexate initiation was 5.4 years. Patient D did not receive any other concomitant medication. Patient E and F received cytotoxic chemotherapies (etoposide, cyclophosphamide, azathioprine) and two patients Patient B and E received other non-anti-TNF biologic therapies (rituximab, anakinra). The neoplasms identified were 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing’s sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease. In the JIA patients, the neoplasm rate was 1.35% with a neoplasm reporting rate of 3.68 events per 1000 patient-years.Table 1 Summary of pediatric rheumatology patient demographics, neoplasms and medications\n\nPatient ID/ gender\tAge at diagnosis of rheumatologic disease (years)\tAge at diagnosis of neoplasm (years)\tNeoplasm\tAnti-TNFα (dose/Duration)\tTime from\nRheumatologic diagnosis to neoplasm (years)\tTime from start of anti-TNFα to neoplasm (years)\tConcomitant and previous DMARD, cytotoxic agent and other Biologic (years)\tOther concomitant and previous medications\tFamily history of malignancy\t\nA/Female\tExtended oligo JIA (1.6 years)\t17\tEwing’s sarcoma\tetanercept 25 mg biweekly × 2.6 years\t16.7\t5.3\tmethotrexate (7.2),\nleflunomide (0.2)\tnaprosyn, prednisone, folic acid\tUnknown\t\nB/Female\tPoly JIA (8.2 years)\t24\trenal clear cell carcinoma\tetanercept 25 mg weekly × 4.8 years,\ninfliximab 400 mg x one dose\t15.8\t10.6\nfrom etanercept,\n4.4 from infliximab\trituximaba (2 doses),\nmethotrexate (6.2),\nleflunomide (0.2), sulfasalazine (0.9), azathioprine (1.2), cyclosporine A (1.5)\tnaprosyn, prednisone, hydroxychloroquine, amitriptyline, oxycodone, depo-provera, folic acid\tUnknown\t\nC/Female\tExtended oligo JIA with anterior uveitis (2.0 years)\t14\tbenign pilo-matricoma\tinfliximab 200–500 mg monthly × 0.25 years\t12.7\t1.3\tcyclosporine A (3.2), azathioprine (4.3),\nmethotrexate (6.0), leflunomide (2.8)\thydroxychloroquine,\nacetazolamide,\nalendronate,\niron, calcium\tMultiple family members with colon cancer\t\nD/Male\tIdiopathic uveitis\n(10.8 years)\t16\tnaso-pharyngeal cancer\tinfliximab 300–400 mg monthly × 3.3 years\t5.3\t3.3\tmethotrexate (4.7)\tfolic acid\tMaternal grandfather with lung cancer; Maternal grandmother with cervical cancer\t\nE/Female\tSystemic JIA (4.7years)\t16\thepatic T-cell lymphoma\tetanercept 10 mg biweekly × 0.1 years,\ninfliximab (10 mg/kg) monthly × 1.7 years\t11.8\t9.9 from etanercept,\n8.6 from infliximab\tanakinraa (1.9),\ncyclosporine A (0.9),\nmethotrexate (3.6),\ntacrolimus (5.0), thalidomide (0.6),\netoposide (6 doses)\tprednisone\tUnknown\t\nF/Male\tPolyarteritis Nodosa (1.1 years)\t14/19\tlympho-proliferative disease (age 14);\nrenal clear cell carcinoma (age 19)\tinfliximab (100 mg) monthly × 4.8 years\t14.1 to lympho-proliferative disease;\n18.6 to renal clear cell carcinoma\t4.8 to lympho-proliferative disease;\n9.3 to renal clear cell carcinoma\tmethotrexate (1.2), azathioprine (unknown),\ncyclophosphamide (1.5)\tprednisone, enalopril, amlodipine,\nsulfamethoxazole, ranitidine, testosterone, protropin, nutropin, insulin, metformin, ferrous fumarate\tMother with breast cancer (deceased at age 31); Half-brother with suspected autoimmune lympho-proliferative disorder\t\nMedian (IQR)\t3.4 (1.7–7.3)\t16.3 (15.3–17.9)\t5.0 (3.6–7.7)\tmethotrexate: 5.4 (3.9–6.1)\t\nJIA = juvenile idiopathic arthritis\n\naOther Biologic (non-anti-TNF)\n\n\n\nCase descriptions\nPatient A is a 17-year-old female with extended oligoarticular JIA who presented with symptoms of dysphagia, hoarseness, headaches, vomiting and significant weight loss. Physical examination demonstrated left-sided facial weakness, papilledema, ataxic gait, and cerebellar signs localized to the left. Imaging and biopsy investigations revealed a small, vimentin positive, round blue cell tumour suggestive of Ewing’s sarcoma compressing the brainstem (Fig. 1). The patient had previously received etanercept for her JIA. The patient is now deceased.Fig. 1 MRI head of a 17-year-old female who developed a basal skull Ewing sarcoma 5.3 years after starting etanercept therapy\n\n\n\nPatient B is a 24-year-old female with RF-negative polyarticular JIA who presented with progressive vomiting and diarrhea. Abdominal ultrasound revealed a renal mass. Renal biopsy was positive for renal clear cell carcinoma (Fuhrman grade 2). The patient had previously received etanercept and a single dose of infliximab for her JIA.\n\nPatient C is a 14-year-old female patient with persistent oligo JIA and antinuclear antibody (ANA)-positive anterior uveitis presented with a 1 cm erythematous lesion later diagnosed as a pilomatricoma. The patient had previously received infliximab for her JIA and uveitis.\n\nPatient D is a 16-year-old male patient with idiopathic uveitis who presented with complaints of left-sided neck pain and noisy breathing. Nasal polyp and adenoid biopsy revealed a diffuse nasopharyngeal carcinoma (Epstein Barr virus positive) (Fig. 2). There was localized bony destruction and cervical lymph node involvement with no evidence of distal spread. The patient was Caucasian and denied tobacco or alcohol use. The patient had received infliximab up until diagnosis of the malignancy.Fig. 2 Head CT with contrast of a 16-year-old male who developed a nasopharyngeal carcinoma 3.3 years after starting infliximab infusions\n\n\n\nPatient E is a 16-year-old female patient with systemic arthritis and recurrent macrophage activation syndrome (MAS) who presented with fever, left upper quadrant pain, splenomegaly and thrombocytopenia. She was hypotensive and tachycardic on admission. Bone marrow aspirate and biopsy revealed hepatosplenic T-cell lymphoma. The patient had previously received etanercept and Infliximab. She died of complications shortly after a bone marrow transplant.\n\nPatient F is a 14-year-old male patient with systemic polyarteritis nodosa (PAN) who underwent a tonsillectomy due to obstructive sleep apnea. Biopsy was consistent with post-transplant lymphoproliferative disease (PTLD), even though the patient had not undergone a transplant. At age 19, echogenic renal lesions were discovered on routine imaging. He was diagnosed with left renal cell carcinoma. He had previously received infliximab up until his first malignancy diagnosis. The patient denied any tobacco or alcohol use. Of note, the patient’s half-brother was being followed for suspected autoimmune lymphoproliferative syndrome (ALPS).\n\nDiscussion\nWe report six pediatric rheumatology patients with neoplasms following anti-TNF exposure initiated during a period of more than 15 years. The neoplasms at our centre developed late after drug exposure with a median of 5.0 years from anti-TNF onset. Specifically, the patients who developed renal clear cell carcinoma and hepatic T-cell lymphoma had their malignancies develop remote from anti-TNF usage. The time to malignancy was shorter with infliximab although etanercept was trialed first in our patients receiving multiple anti-TNF treatment. One North American study involving six pediatric centres (ours included) examined the time of neoplasm in JIA patients after anti-TNF therapy [10]. Five malignancies (hepatosplenic T-cell lymphoma, polymorphic post-transplantation lymphoproliferative disease, renal cell adenocarcinoma, Ewing’s sarcoma, endometrial adenocarcinoma) were reported with the mean time to malignancy after anti-TNF exposure was 1.49 (median 0.5) years, which is shorter than our findings. These patients were also exposed to many other concomitant medications including other biologics and methotrexate. We also report a neoplasm rate in our JIA patients to be 3.68 events per 1000 patient-years. For comparison, another Canadian group summarized the findings of seven studies and reported a neoplasm risk of 1.3 events per 1000 patient-years in JIA patients exposed to anti-TNFs [11].\n\nMost of the neoplasms at our centre were unusual for the pediatric population. Benign pilomatricomas (Patient C) are quite uncommon, representing 0.12% of integument system neoplasms [12]. Nasopharyngeal carcinomas (Patient D), particularly those with EBV positive pathology, are most common in adult patients from Asian countries. When they occur in North American children, it is an extremely rare event with a reported incidence of 0.5 million person-years for patients aged 0-19 years [13]. Renal clear cell carcinomas (Patient B and F) are extremely rare in pediatrics with an overall age-adjusted incidence in the general population of 0.01/100,000 [14]. The pathology differs from adult renal cell carcinoma which is typically seen in the sixth decade of life and is associated with tobacco use. Interestingly, the FDA’s Adverse Event Reporting System (AERS) identified another pediatric patient with renal cell carcinoma following anti-TNF treatment [3]. To the best of our knowledge, this is the first report of benign pilomatricoma and nasopharyngeal carcinoma in a pediatric patient following anti-TNF exposure for rheumatic disease management.\n\nAs previously mentioned, patients who developed neoplasms from our study as well as in the literature had received multiple concomitant medications other than anti-TNFs, making establishment of causality difficult. All of our study patients were exposed to methotrexate and all but one patient (Patient D) received other concomitant medications, including other biologics in some patients. It has been speculated that methotrexate as an immunosuppressant may increase the rate of malignancy in patients with JIA, although this has yet to be proven [15]. Two of our patients received additional treatment with etoposide, cyclophosphamide and azathioprine, which have known cytotoxigenicity. Additionally, our patient who developed lymphoproliferative disorder had a second-degree relative with suspected ALPS and therefore may have had a genetic predisposition to malignancy. Also, the underlying disease process in rheumatic disease may further complicate our ability to determine any relationship in between anti-TNF and malignancy risk. It has been suggested that there may be a background incidence of malignancy in children with inflammatory disease activity, irrespective of biologic treatment. In patients with JIA, there are studies that report an approximate 2 to 4-fold increase in malignancy risk [16–19] as well as those that do not endorse this relationship [10, 20]. We are unable to comment on the overall risk of malignancy in patients with rheumatic disease, as we do not have a comparator cohort from our centre. As previously mentioned, numerous studies in patients with JIA have suggested that anti-TNF therapy does not increase the risk of neoplasm development [4–6]. Additional large-scale studies concerning infliximab therapy and pediatric inflammatory bowel disease have also shown no association with increased malignancy risk [21]. A report summarizing over 180,000 adult patients with rheumatoid arthritis treated with anti-TNFs also concluded that there is no increased cancer risk [22]. We examined patients diagnosed with JIA and the probability of developing a neoplasm at certain time periods after the start of biologic therapy (Fig. 3). For example, the survival curve demonstrated a 97% probability (Confidence Interval 92–97) of being neoplasm free 5.3 years after biologic exposure for patients of this subset, further supporting that malignancy development in this population is rare.Fig. 3 Kaplan-Meier event curve depicting probability of neoplasm development from start of biologic therapy in patients with JIA (n = 295) from the Rheumatology Biologic Registry. Dashed lines represents 95% Confidence Interval\n\n\n\nWe acknowledge that our study is limited by including patients with different underlying diagnosis with varying exposures to multiple anti-TNF agents, other biologics and concurrent medications. Also, we are unable to make conclusions about our centre’s pediatric rheumatology patients who were not exposed to biologic therapy, as we did not perform this control. Our study is further limited by the fact the both pediatric rheumatic disease and malignancies in childhood are rare events in themselves and as such, larger populations would be necessary to make any true conclusions about a causal relationship. Additionally, the Kaplan-Meier curve depicting time from biologic start to neoplasm in patients with JIA may be limited due to fewer patient numbers at longer follow up times.\n\nIn summary, we report six pediatric rheumatology patients who developed neoplasms during or after treatment with anti-TNF agents. Four of the patients had rare neoplasms for the pediatric population. The neoplasms occurred late after anti-TNF initiation, and infliximab was associated with a shorter time to malignancy compared to etanercept. Within the JIA subset, patients had an extremely favourable probability of being neoplasm free 5 years after initiation of biologics. It still remains unclear whether there is any causal relationship between anti-TNF agents and malignancy risk, as there are many potential contributing factors including the potential effect of disease activity and the contribution of concomitant medications. Additional long-term studies with larger populations should be completed to identify the types of malignancies that occur in this population. Appropriate malignancy screening at each clinical visit, including an appropriate history and physical exam especially for constitutional symptoms, masses, lymphadenopathy and new skin symptoms should continue as part of anti-TNF monitoring.\n\nAbbreviations\nALPSAutoimmune lymphoproliferative syndrome\n\nANAAntinuclear antibody\n\nJIAJuvenile idiopathic arthritis\n\nMASMacrophage activation syndrome\n\nPANPolyarteritis nodosa\n\nPTLDPost-transplant lymphoproliferative disease\n\nRFRheumatoid factor\n\nTNFTumor necrosis factor\n\nAcknowledgements\nNone.\n\nFunding\nThe study was not funded from any source.\n\nAvailability of data and materials\nPlease contact author for data requests.\n\nAuthors’ contributions\nAll authors listed above contributed to the data and review of the manuscript. AO, RH and ST contributed to the design of the study, data collection, data analysis, manuscript preparation, read and approved the final manuscript. LF, BC, RL, RS, ES, LS, RY contributed data, read and approved the final manuscript. BF performed the statistical analysis, read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe research study was approved by the Research Ethics Board, SickKids, Toronto. (REB Approval number: 1000011283).\n\nConsent for publication\nREB approval and consent for publication obtained.\n\nCompeting interests\nAll authors have no disclosures nor competing of interests related to the current research study.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Stoll ML Cron RQ Treatment of juvenile idiopathic arthritis: a revolution in care Pediatr Rheumatol Online J 2014 12 13 10.1186/1546-0096-12-13 24782683 \n2. Kessler EA Becker ML Therapeutic advancements in juvenile idiopathic arthritis Best Pract Res Clin Rheumatol 2014 28 293 313 10.1016/j.berh.2014.03.005 24974064 \n3. Diak P Siegel J La Grenade L Choi L Lemery S McMahon A Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration Arthritis Rheum 2010 62 2517 2542 10.1002/art.27511 20506368 \n4. Kok VC Horng JT Huang JL Yeh KW Gau JJ Chang CW Population-based cohort study on the risk of malignancy in east Asian children with juvenile idiopathic arthritis BMC Cancer 2014 14 634 10.1186/1471-2407-14-634 25174953 \n5. Barth S Schlichtiger J Bisdorff B Hügle B Michels H Radon K Association between drug intake and incidence of malignancies in patients with juvenile idiopathic arthritis: a nested case–control study Pediatr Rheumatol Online J 2016 14 6 10.1186/s12969-016-0066-8 26842529 \n6. Ruperto N Martini A Juvenile idiopathic arthritis and malignancy Rheumatology (Oxford) 2014 53 968 974 10.1093/rheumatology/ket318 24185766 \n7. Hodgkin IL S lymphoma associated with anti-tumor necrosis factor use in juvenile idiopathic arthritis: supplemental case report J Rheumatol 2008 35 1681 18671329 \n8. Yildirim-Toruner C Kimura Y Hodgkin RCE S lymphoma and tumor necrosis factor inhibitors in juvenile idiopathic arthritis J Rheumatol 2008 35 1680 1681 18671328 \n9. McCroskery P Wallace CA Lovell DJ Stryker S Chernyukhin N Blosch C Summary of worldwide pediatric malignancies reported after exposure to etanercept Pediatr Rheumatol Online J 2010 8 18 10.1186/1546-0096-8-18 20546618 \n10. Niaki ZO Clarke AE Ramsey-Goldman R Yeung R Hayward K Oen K Malignancy incidence in 5294 patients with juvenile arthritis RMD Open 2016 2 e000212 10.1136/rmdopen-2015-000212 27175293 \n11. Bernatsky S Rosenberg AM Oen KG Duffy CM Ramsay-Goldman R Labrecque J Malignancies in juveniole idiopatic arthritis: a preliminary report J Rheumatol 2011 38 4 760 763 10.3899/jrheum.100711 21239753 \n12. Moehlenbeck FW Pilomatrixoma (Calcifying epithelioma). A statistical study Arch Dermatol 1973 108 4 532 534 10.1001/archderm.1973.01620250020004 4745286 \n13. Sultan I Casanova M Ferrari A Rihani R Rodriguez-Galindo C Differential features of nasopharyngeal carcinoma in children and adults: a SEER study Pediatr Blood Cancer 2010 55 2 279 284 10.1002/pbc.22521 20582982 \n14. Silberstein J Grabowski J Saltzstein SL Kane CJ Renal cell carcinoma in the pediatric population: results from the California cancer registry Pediatr Blood Cancer 2009 52 2 237 241 10.1002/pbc.21779 18937317 \n15. Cleary AG McDowell H Sills JA Polyarticular juvenile idiopathic arthritis treated with methotrexate complicated by the development of non-Hodgkin’s lymphoma Arch Dis Child 2002 86 1 47 49 10.1136/adc.86.1.47 11806884 \n16. Mannion ML Beukelman T What is the background incidence of malignancy in children with rheumatic disease? Curr Rheumatol Rep 2013 15 310 10.1007/s11926-012-0310-2 23378144 \n17. Beukelman T Haynes K Curtis JR Xie F Chen L Bemrich-Stolz CJ Rates of malignancy associated with juvenile idiopathic arthritis and its treatment Arthritis Rheum 2012 64 1263 1271 10.1002/art.34348 22328538 \n18. Nordstrom BL Mines D Gu Y Mercaldi C Aquino P Harrison MJ Risk of malignancy in children with juvenile idiopathic arthritis not treated with biologic agents Arthritis Care Res 2012 64 1357 1364 10.1002/acr.21709 \n19. Simard JF Neovius M Hagelberg S Askling J Juvenile idiopathic arthritis and risk of cancer: a nationwide cohort study Arthritis Rheum 2010 62 3776 3782 10.1002/art.27741 20827782 \n20. Thomas E Brewster DH Black RJ Macfarlance GJ Risk of malignancy among patients with rheumatic conditions Int J Cancer 2000 88 497 502 10.1002/1097-0215(20001101)88:3<497::AID-IJC27>3.0.CO;2-J 11054684 \n21. Hyams JS Dubinsky MC Baldassano RN Colletti RB Cucchiara S Escher J Infliximab is not associated with increased risk of malignancy or hemophagocytic lymphohistiocytosis in pediatric patients with inflammatory bowel disease Gastroenterology 2017 152 8 1901 1914 10.1053/j.gastro.2017.02.004 28193515 \n22. Lebrec H Ponce R Preston BD Iles J Born TL Hooper M Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk Curr Med Res Opin 2015 31 3 557 574 10.1185/03007995.2015.1011778 25651481\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1546-0096",
"issue": "16(1)",
"journal": "Pediatric rheumatology online journal",
"keywords": "Anti-TNF; Juvenile idiopathic arthritis; Malignancy; Polyarteritis nodosa; Uveitis",
"medline_ta": "Pediatr Rheumatol Online J",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms; D012042:Registries; D012189:Retrospective Studies; D012216:Rheumatic Diseases; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "101248897",
"other_id": null,
"pages": "17",
"pmc": null,
"pmid": "29540190",
"pubdate": "2018-03-14",
"publication_types": "D016428:Journal Article",
"references": "23378144;18671329;11054684;24974064;20582982;24782683;22511558;27175293;26842529;20546618;18937317;22328538;18671328;28193515;24185766;25651481;20827782;21239753;20506368;25174953;11806884;4745286",
"title": "Development of neoplasms in pediatric patients with rheumatic disease exposed to anti-tumor necrosis factor therapies: a single Centre retrospective study.",
"title_normalized": "development of neoplasms in pediatric patients with rheumatic disease exposed to anti tumor necrosis factor therapies a single centre retrospective study"
} | [
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"companynumb": "CA-SA-2018SA101620",
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"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Lymphoepithelial carcinoma (LEC) is an uncommon, aggressive cancer that affects mainly the nasopharynx (a form that is closely related to the Epstein-Barr virus). LEC of the larynx/hypopharynx is extremely rare, accounting for only 0.2% of malignant tumors of the larynx. This study describes a case of locally advanced LEC of the larynx/hypopharynx with effective response to chemoradiation (an option that spares the patient from the risks of surgical resection). A 60-year-old sedentary, hypertensive male patient with a previous history of smoking and alcohol abuse received a histopathological diagnosis of locally advanced LEC of the larynx/hypopharynx in May 2018. He underwent treatment with chemoradiation and exhibited a complete clinical response. At about 3 years of follow-up, the patient is currently alive, free from disease and has not presented any tumor recurrences.",
"affiliations": "Health Science Center, State University of Piauí, Teresina, PI, Brazil. Electronic address: rafaelcosta@aluno.uespi.br.;Health Science Center, Federal University of Piauí, Teresina, PI, Brazil.;Health Science Center, State University of Piauí, Teresina, PI, Brazil.;Oncocenter, Teresina, PI, Brazil.;Oncocenter, Teresina, PI, Brazil.",
"authors": "da Costa|Rafael Everton Assunção Ribeiro|REAR|;da Silva Júnior|Raimundo Gerônimo|RG|;Magalhães|Lucio André Noleto|LAN|;Mendes|Jailson Rodrigues|JR|;Dos Reis|Cristiane Amaral|CA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.oraloncology.2021.105373",
"fulltext": null,
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"issn_linking": "1368-8375",
"issue": "118()",
"journal": "Oral oncology",
"keywords": "Case reports; Head and neck cancers; Hypopharynx; Larynx; Lymphoepithelial carcinoma",
"medline_ta": "Oral Oncol",
"mesh_terms": null,
"nlm_unique_id": "9709118",
"other_id": null,
"pages": "105373",
"pmc": null,
"pmid": "34092507",
"pubdate": "2021-07",
"publication_types": "D016422:Letter",
"references": null,
"title": "Locally advanced lymphoepithelial carcinoma of the larynx/hypopharynx: A case report.",
"title_normalized": "locally advanced lymphoepithelial carcinoma of the larynx hypopharynx a case report"
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"companynumb": "BR-ACCORD-231326",
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"abstract": "Kaposi sarcoma is a multicentric angioproliferative neoplasm of lymphatic endothelium-derived cells. Although this malignancy is relatively frequent after solid-organ transplant, it is extremely rare after bone marrow transplantation. Allogeneic stem cell transplantation is associated with severe prolonged immunosuppression; however, a few cases of Kaposi sarcoma after hematopoietic stem cell transplant were previously reported. Here, we report a case of Kaposi sarcoma after haploidentical allogeneic hematopoietic stem cell transplant. The patient was a known case of acute myelogenous leukemia and underwent transplant after relapse. Four months posttransplant, she presented with 3 dark blue or purplish small nodules on her face above the upper lip. Histopathologic study confirmed Kaposi sarcoma. Serum antibody against human herpes virus type 8 was positive. After discontinuation of immunosuppressive medication and cryotherapy for local control, Kaposi sarcoma skin nodules healed with residual pigmented skin lesions. The patient is currently in complete remission for Kaposi sarcoma and cured from acute myelogenous leukemia 36 months after stem cell transplant. Only 14 cases of Kaposi sarcoma after hematopoietic cell transplant have been previously reported in the literature (11 after allogeneic and 3 after autologous hematopoietic stem cell transplant). According to our knowledge from literature review, this case is the first report of Kaposi sarcoma after a haploidentical HLA match transplant.",
"affiliations": "From the Hematology Research Center, Department of Hematology, Medical Oncology and Stem Cell Transplantation; Shiraz University of Medical Sciences, Shiraz, Iran.",
"authors": "Ramzi|Mani|M|;Vojdani|Reza|R|;Haghighinejad|Hourvash|H|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2017.0075",
"fulltext": null,
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"issn_linking": "1304-0855",
"issue": "19(2)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": null,
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "173-175",
"pmc": null,
"pmid": "29292681",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Kaposi Sarcoma After Allogeneic Hematopoietic Stem Cell Transplant: A Rare Complication.",
"title_normalized": "kaposi sarcoma after allogeneic hematopoietic stem cell transplant a rare complication"
} | [
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"companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-310109",
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"activesubstancename": "ACYCLOVIR"
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{
"abstract": "Cholinesterase inhibitors (ChEIs) are widely used to treat mild to moderate Alzheimer's disease and related dementia. Clinical trials have focused on placebo comparisons, inadequately addressing within-class comparative safety.\nNew users of ChEIs in British Columbia were categorized into five study cohorts: low-dose donepezil, high-dose donepezil, galantamine, rivastigmine patch, and oral rivastigmine. Comparative safety of ChEIs assessed hazard ratios using propensity score adjusted Cox regression.\nCompared with low-dose donepezil, galantamine use was associated with a lower risk of mortality (adjusted hazard ratio: 0.84, 95% confidence interval: 0.60-1.18), cardiovascular serious adverse events (adjusted hazard ratio: 0.78, 95% confidence interval: 0.62-0.98), and entry into a residential care facility (adjusted hazard ratio: 0.72, 95% confidence interval: 0.59-0.89).\nGiven the absence of randomized trial data showing clinically meaningful benefit of ChEI therapy in Alzheimer's disease, our study suggests preferential use of galantamine may at least be associated with fewer adverse events than treatment with donepezil or rivastigmine.",
"affiliations": "Therapeutics Initiative, University of British Columbia, Vancouver, BC, Canada.;Therapeutics Initiative, University of British Columbia, Vancouver, BC, Canada.;Therapeutics Initiative, University of British Columbia, Vancouver, BC, Canada.;Therapeutics Initiative, University of British Columbia, Vancouver, BC, Canada.;Research and Innovation Division, B.C. Ministry of Health, Victoria, BC, Canada.;Therapeutics Initiative, University of British Columbia, Vancouver, BC, Canada.",
"authors": "Carney|Greg|G|;Bassett|Ken|K|;Wright|James M|JM|;Maclure|Malcolm|M|;McGuire|Nicolette|N|;Dormuth|Colin R|CR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.trci.2019.09.011",
"fulltext": "\n==== Front\nAlzheimers Dement (N Y)Alzheimers Dement (N Y)Alzheimer's & Dementia : Translational Research & Clinical Interventions2352-8737Elsevier S2352-8737(19)30072-110.1016/j.trci.2019.09.011Featured ArticleComparison of cholinesterase inhibitor safety in real-world practice Carney Greg greg.carney@ti.ubc.caab∗Bassett Ken abcWright James M. abdMaclure Malcolm abMcGuire Nicolette eDormuth Colin R. aba Therapeutics Initiative, University of British Columbia, Vancouver, BC, Canadab Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canadac Department of Family Practice, University of British Columbia, Vancouver, BC, Canadad Department of Medicine, University of British Columbia, Vancouver, BC, Canadae Research and Innovation Division, B.C. Ministry of Health, Victoria, BC, Canada∗ Corresponding author. Tel.: 250-388-9912; Fax: 250-590-5954. greg.carney@ti.ubc.ca25 11 2019 2019 25 11 2019 5 732 739 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nCholinesterase inhibitors (ChEIs) are widely used to treat mild to moderate Alzheimer's disease and related dementia. Clinical trials have focused on placebo comparisons, inadequately addressing within-class comparative safety.\n\nMethods\nNew users of ChEIs in British Columbia were categorized into five study cohorts: low-dose donepezil, high-dose donepezil, galantamine, rivastigmine patch, and oral rivastigmine. Comparative safety of ChEIs assessed hazard ratios using propensity score adjusted Cox regression.\n\nResults\nCompared with low-dose donepezil, galantamine use was associated with a lower risk of mortality (adjusted hazard ratio: 0.84, 95% confidence interval: 0.60–1.18), cardiovascular serious adverse events (adjusted hazard ratio: 0.78, 95% confidence interval: 0.62–0.98), and entry into a residential care facility (adjusted hazard ratio: 0.72, 95% confidence interval: 0.59–0.89).\n\nDiscussion\nGiven the absence of randomized trial data showing clinically meaningful benefit of ChEI therapy in Alzheimer's disease, our study suggests preferential use of galantamine may at least be associated with fewer adverse events than treatment with donepezil or rivastigmine.\n\nHighlights\n• Galantamine was associated with fewer adverse events than donepezil or rivastigmine.\n\n• Galantamine users experienced longer independent living.\n\n• The 3-year risk of cardiovascular events and mortality was lowest with galantamine.\n\n\n\nKeywords\nCholinesterase inhibitorAlzheimer's diseaseDementiaLog-binomial regressionCox proportional hazardPropensity scoreEpidemiology\n==== Body\n1 Introduction\nAlzheimer's disease and related dementia (ADRD) is a growing problem in Canada, affecting an estimated 747,000 people in 2012, with 25,000 new cases diagnosed every year [1]. In British Columbia, cholinesterase inhibitors (ChEIs) are commonly prescribed for treatment of ADRD, where the B.C. Ministry of Health requires a baseline cognitive assessment as part of its Special Authority process [2]. Because little data exist beyond the 6-month to one-year clinical trials and this group of medications is frequently prescribed to patients with ADRD, there is an opportunity for observational data to assess longer-term safety and effectiveness [3].\n\nChEIs increase cholinergic function by preventing the breakdown of acetylcholine, a neurotransmitter that supports communication among nerve cells when its levels are sufficiently high. Acetylcholinesterase is an enzyme involved in the rapid hydrolysis of acetylcholine. Through inhibition of acetylcholinesterase, ChEIs, such as donepezil, rivastigmine, and galantamine, allow acetylcholine to accumulate. The rationale for prescribing ChEIs for treating symptoms of ADRD is to increase acetylcholine levels, which increases neuronal activity. However, this is a strategy that has low effectiveness [4], and there is no evidence that ChEIs prevent the underlying dementing process [5].\n\nChEIs have additional pharmacological actions. Rivastigmine inhibits butyrylcholinesterase with a similar affinity to acetylcholinesterase. The therapeutic effect and resulting clinical consequences of this is unknown [6,7]. Galantamine potentiates the action of acetylcholine on nicotinic receptors, which may influence neuronal processes, such as synaptic efficacy and neuroprotection [8,9]. Evidence suggests the cholinergic adverse effects of these drugs may cause gastrointestinal, neurological, cardiovascular, and urinary disorders [10,11]. In severe instances, these drugs may increase vagal tone and, thereby, precipitate bradycardia [12]. Multiple U.S. Food and Drug Administration safety alerts have raised concerns of increased mortality and serious cardiovascular adverse events in patients taking ChEIs for mild cognitive impairment versus placebo-treated patients [13].\n\nA Cochrane database systematic review (Russ [14]) found no significant difference in progression to dementia between ChEIs and placebo at 12 months. They found ChEIs increased overall adverse events compared with placebo but found no significant differences between the groups for serious adverse events, cardiac problems, depression, or death. Earlier systematic reviews found small improvements or unchanged cognitive benefits with ChEIs versus placebo [15]. In addition, some trials within the systematic reviews showed an unexplained increased death rate.\n\nEffective October 22, 2007, the British Columbia Ministry of Health began providing financial coverage of the ChEIs through the Alzheimer's Drug Therapy Initiative to address clinical knowledge gaps around the safety and effectiveness of these drugs [16]. Patients receiving a baseline assessment score on the Standardized Mini–Mental State Examination of mild to moderate cognitive impairment are eligible for full financial coverage of a ChEI.\n\nWe investigated the risk of mortality between the ChEIs for new users during the Alzheimer's Drug Therapy Initiative. Serious cardiovascular events were investigated as a secondary outcome. We also looked at time to entry into a residential care facility. Supporting people with ADRD to function in their own homes for as long as possible is a stated priority of the B.C. Provincial Guide to Dementia Care [17].\n\n2 Methods\n2.1 Data\nWe obtained access to the B.C. Ministry of Health administrative health claims database through a secure access environment. The database contains linkable, but deidentified, health service records containing all prescriptions dispensed at community pharmacies, physician services, hospital separations, and vital statistics data in British Columbia. We assume that the completeness and accuracy of the data is comparable to other administrative databases [18,19].\n\n2.2 Study design and source population\nWe conducted a retrospective, propensity score–adjusted cohort study. The source population for the study was all B.C. residents between October 2007 and March 2016 who were registered in the provincial universal medical services plan. Federally insured patients, such as indigenous people, federal police officers, and members of the armed forces and their families, were excluded from the source population because they are not included in the data set. Excluded patients composed about 7% of the provincial population. The source population numbered 4.42 million in 2016 [20].\n\n2.3 Study cohorts\nNew users of ChEIs were identified during the study period as having no ChEI prescription in the previous 365 days. New users were categorized into 5 exposure groups based on their first prescription: (1) low-dose donepezil (≤7.5 mg/day), (2) high-dose donepezil (>7.5 mg/day), (3) galantamine, (4) rivastigmine patch, and (5) rivastigmine oral. Low-dose donepezil was defined based on receiving a dose equivalent to, or below, the World Health Organization's Defined Daily Dose. Low-dose donepezil, the most frequently prescribed ChEI, was assigned as the reference drug, providing four comparison cohorts instead of a single multinomial regression approach.\n\nThe date of each patient's first ChEI dispensing was defined as the index date. Patients were excluded from the study cohorts if they were under 50 years old on the index date, in a residential care facility in the 2-year period before index date, did not have continuous medical insurance in the 1-year period before index date, or dispensed more than one ChEI on index date.\n\n2.4 Study outcomes\nOur primary outcome was all-cause mortality. Secondary outcomes were (1) composite cardiovascular serious adverse events and (2) entry into a residential care facility. Composite cardiovascular events consisted of a hospital admission for myocardial infarction (ICD-9: 410), coronary artery disease (ICD-9: 411-414), heart failure (ICD-9: 428), arrhythmia (including atrial fibrillation) (ICD-9: 427), and peripheral arterial or vascular disease (ICD-9: 443.9, 440). Entry into a residential care facility was determined by the presence of a government-subsidized prescription under the residential care benefit plan.\n\n2.5 Data analysis\nSafety of ChEIs was compared using time-to-event Cox proportional regression. Four drug comparisons were made: (1) low-dose donepezil versus high-dose donepezil, (2) low-dose donepezil versus galantamine, (3) low-dose donepezil versus rivastigmine patch, and (4) low-dose donepezil versus oral rivastigmine. Patient follow-up was censored at the earliest occurrence of our study outcome, death, end of the study period (31 March 2016), emigration from BC, therapy discontinuation, or crossover to another study cohort. Sensitivity analyses used log-binomial regression to estimate relative risk at 6-month and 12-month fixed follow-up periods [21]. All outcome models were adjusted for history of prior cardiovascular events, smoking, and high-dimensional propensity scores meant to capture other confounding factors. The high-dimensional propensity score methods have been previously described in detail here [22].\n\n2.6 Confounders\nPotential confounders were measured before exposure to a ChEI using hospital and physician diagnostic codes, dispensed prescription records, and patient demographic records. The following covariates were included in the outcome model if they occurred within two years before index date: arrhythmia (ICD-9: 427; ICD-10: I49), myocardial infarction (ICD-9: 410; ICD-10: I21), stroke (ICD-9: 430-434, 436; ICD-10: I60, I61, I64, I63), angina (ICD-9: 413; ICD-10: I20), congestive heart failure (ICD-9: 428; ICD-10: I50), cerebrovascular disease (ICD-10: I60-I69), coronary artery disease (ICD-9: 411, 412, 414; ICD-10: I22-I25, Z95.1, Z95.5, Z98.61), peripheral arterial disease (ICD-9: 440, 443.9; ICD-10: I70, I73.9), or diabetes (ICD-9: 250; ICD-10: E10-E14). Other covariates included sex, age group (50–64, 65–74, 75–84 as reference, 85+), and smoking status (current or past smoker).\n\nThe following predefined demographic and diagnostic covariates were incorporated into the high-dimensional propensity score model: age group, sex, family income, index year, time since ADRD diagnosis, more than five distinct medications dispensed in previous year (yes/no), more than five physician visits in previous year (yes/no).\n\n3 Results\nThere were 34,338 patients from the source population who initiated a ChEI between 22 October 2007 and 31 March 2016. Of those, 29,047 patients remained eligible for the study after exclusions for not meeting medical insurance eligibility criteria (5.4%), resident of a long-term care facility in prior two years (7.9%), initiating more than one ChEI on cohort entry date (1.8%), and age under 50 years (0.4%).\n\nBaseline patient characteristics of the study cohorts (Table 1) were similar for average age of patients (80.5 years). The proportion of female patients was lowest in the oral rivastigmine (48%) cohort and highest in the low-dose donepezil (60%) cohort. Smokers, past or current, ascertained by the presence of a diagnosis of chronic obstructive pulmonary disease or use of a prescription smoking cessation therapy were similar among all cohorts. Galantamine users had the highest proportion of cardiovascular-related hospital admissions in the 2-year period before index date, including stroke, unstable angina, cerebrovascular disease, coronary artery disease, and peripheral arterial disease. Prior medication history was similar, other than prior use of antipsychotics, which was nearly double (19.5%) with oral rivastigmine compared with the low-dose donepezil cohort (10.0%).Table 1 Baseline patient characteristics\n\nCharacteristics\tDonepezil (low dose)\tDonepezil (high dose)\tGalantamine\tRivastigmine (patch)\tRivastigmine (oral)\t\nN or mean (n = 15,586)\t% or SD\tN or mean (n = 2519)\t% or SD\tN or mean (n = 5926)\t% or SD\tN or mean (n = 4286)\t% or SD\tN or mean (n = 730)\t% or SD\t\nAge (years), mean (IQR)\t80.7 (76-86)\t\t78.7 (74-85)\t\t80.8 (77-86)\t\t80.3 (76-85)\t\t79.2 (75-84)\t\t\nFemale, n (%)\t9366\t60\t1305\t52\t3400\t57\t2319\t54\t347\t48\t\nLow family income∗ (<$30k), n (%)\t3469\t22\t507\t20\t1389\t23\t1169\t27\t139\t19\t\nYear of study cohort entry, n (%)\t\t\t\t\t\t\t\t\t\t\t\n 2007 (Oct 22–Dec 31)\t323\t2\t97\t4\t229\t4\t-\t0\t64\t9\t\n 2008\t1763\t11\t437\t17\t1277\t22\t94\t2\t186\t25\t\n 2009\t1767\t11\t371\t15\t1277\t22\t558\t13\t120\t16\t\n 2010\t1966\t13\t375\t15\t1051\t18\t744\t17\t76\t10\t\n 2011\t2241\t14\t360\t14\t787\t13\t791\t18\t75\t10\t\n 2012\t2350\t15\t355\t14\t554\t9\t774\t18\t59\t8\t\n 2013\t2336\t15\t256\t10\t348\t6\t657\t15\t68\t9\t\n 2014\t2182\t14\t215\t9\t315\t5\t536\t13\t62\t8\t\n 2015 (up to March 31)\t658\t4\t53\t2\t88\t1\t132\t3\t20\t3\t\nDuration of ADRD (years), mean (SD)\t1.04\t2.3\t1.02\t2.3\t1.07\t2.4\t1.10\t2.3\t1.09\t2.2\t\nHigh-dose first prescription†, n (%)\t-\t-\t-\t-\t113\t1.9\t23\t0.5\t10\t1.4\t\nHigh-dose second prescription†, n (%)\t3471\t22\t-\t-\t134\t2.3\t11\t0.3\t11\t1.5\t\nFollow-up time (years)‡, mean (SD)\t3.41 (1.95)\t\t3.86 (2.05)\t\t4.14 (2.12)\t\t3.28 (1.76)\t\t3.95 (2.26)\t\t\nSmoker§ (past or current), n (%)\t6955\t45\t1075\t43\t2660\t45\t1967\t46\t311\t43\t\nNumber of hospital admissions in previous year\t\t\t\t\t\t\t\t\t\t\t\n 0, n (%)\t10,709\t69\t1777\t71\t4080\t69\t2768\t65\t482\t66\t\n 1–2, n (%)\t1778\t11\t288\t11\t729\t12\t523\t12\t108\t15\t\n 3+, n (%)\t3099\t20\t454\t18\t1117\t19\t995\t23\t140\t19\t\nNumber of physician visits in previous year, mean (SD)\t21 (18.2)\t\t20.9 (16.7)\t\t21 (17.2)\t\t25.2 (21.6)\t\t24.1 (19.8)\t\t\nPrior medical history¶ (2 years), n (%)\t\t\t\t\t\t\t\t\t\t\t\n Atrial fibrillation or flutter\t2393\t15.4\t336\t13.3\t982\t16.6\t704\t16.4\t105\t14.4\t\n COPD, n (%)\t2200\t14.1\t330\t13.1\t871\t14.7\t634\t14.8\t90\t12.3\t\n Diabetes mellitus\t3834\t24.6\t621\t24.7\t1467\t24.8\t1160\t27.1\t183\t25.1\t\n Myocardial infarction\t218\t1.4\t29\t1.2\t71\t1.2\t62\t1.4\t9\t1.2\t\n Hypertension\t9545\t61.2\t1420\t56.4\t3701\t62.5\t2573\t60.0\t441\t60.4\t\nPrior hospital admission (2 years), n (%)\t\t\t\t\t\t\t\t\t\t\t\n Stroke\t209\t1.3\t34\t1.3\t125\t2.1\t82\t1.9\t10\t1.4\t\n Unstable angina\t113\t0.7\t19\t0.8\t54\t0.9\t30\t0.7\t5\t0.7\t\n Congestive heart failure\t409\t2.6\t48\t1.9\t159\t2.7\t124\t2.9\t17\t2.3\t\n Cerebrovascular disease\t303\t1.9\t55\t2.2\t165\t2.8\t112\t2.6\t19\t2.6\t\n Coronary artery disease\t570\t3.7\t91\t3.6\t261\t4.4\t172\t4.0\t31\t4.2\t\n Peripheral arterial disease\t70\t0.4\t6\t0.2\t32\t0.5\t11\t0.3\t2\t0.3\t\nPrior medication history (1 year), n (%)\t\t\t\t\t\t\t\t\t\t\t\n Other anticholinergics, n (%)\t2491\t16.0\t374\t14.8\t952\t16.1\t732\t17.1\t150\t20.5\t\n Lipid-lowering agents, n (%)\t6307\t40.5\t995\t39.5\t2546\t43.0\t1804\t42.1\t298\t40.8\t\n ACE inhibitors, n (%)\t5146\t33.0\t718\t28.5\t2146\t36.2\t1375\t32.1\t268\t36.7\t\n ARBs, n (%)\t2409\t15.5\t365\t14.5\t917\t15.5\t702\t16.4\t102\t14.0\t\n Beta-blockers, n (%)\t3944\t25.3\t553\t22.0\t1563\t26.4\t1102\t25.7\t195\t26.7\t\n Antidepressants, n (%)\t4898\t31.4\t711\t28.2\t1776\t30.0\t1482\t34.6\t255\t34.9\t\n Antipsychotics, n (%)\t1565\t10.0\t235\t9.3\t569\t9.6\t592\t13.8\t142\t19.5\t\n Anxiolytics/sedatives/hypnotics, n (%)\t3717\t23.8\t605\t24.0\t1360\t22.9\t1181\t27.6\t208\t28.5\t\nAbbreviations: IQR, interquartile range; COPD, chronic obstructive pulmonary disease; ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers.\n\n∗ Net family income in Canadian dollars from the most recent income tax return (1 Canadian dollar ≈ .75 US dollar).\n\n† High-dose defined as a dispensed daily dose on the first ChEI prescription that is higher than the WHO Defined Daily Dose (DDD).\n\n‡ Follow-up time shown for primary outcome (mortality).\n\n§ Smoking status based on history of diagnosed COPD or use of a smoking cessation medication (varenicline, Zyban, or nicotine replacement products).\n\n¶ Hospital separation record or physician visit diagnosis within 2 years before the index date.\n\n\n\nCompared with low-dose donepezil, galantamine was associated with a 16% lower 3-year risk of mortality (adjusted hazard ratio [aHR]: 0.84, 95% confidence interval [CI]: 0.60–1.18). High-dose donepezil had similar risk (aHR: 0.97, 95% CI: 0.61–1.54), and the rivastigmine patch had 29% higher risk (aHR: 1.29, 95% CI: 0.93–1.79) (Table 2). The mortality differences were not statistically significant (P < .05).Table 2 Cox proportional hazards for mortality, serious cardiovascular events, and entry into a residential care facility\n\n\tN\t3 year\t\nCumulative mortality events\tCrude rate per 100 PYs\tPropensity score–adjusted hazard ratio\t\nAll-cause mortality, time-to-event, Cox proportional hazards\t\n Low-dose donepezil (reference)\t15,586\t147\t5.80\t\t\n High-dose donepezil\t2519\t23\t5.35\t0.97 (0.61–1.54)\t\n Galantamine\t5926\t51\t5.29\t0.84 (0.60–1.18)\t\n Rivastigmine—patch\t4286\t86\t10.82\t1.29 (0.93–1.79)\t\n Rivastigmine—oral\t730\t<5\t\t0.49 (0.17–1.36)\t\nSerious cardiovascular events, time-to-event, Cox proportional hazards\t\n Low-dose donepezil (reference)\t15,586\t331\t5.84\t\t\n High-dose donepezil\t2519\t50\t5.39\t1.02 (0.75–1.39)\t\n Galantamine\t5926\t106\t5.32\t0.78 (0.62–0.98)\t\n Rivastigmine—patch\t4286\t128\t10.91\t0.98 (0.77–1.25)\t\n Rivastigmine—oral\t730\t16\t3.53\t0.87 (0.51–1.48)\t\nEntry into residential care, time-to-event, Cox proportional hazards\t\n Low-dose donepezil (reference)\t15,586\t447\t5.86\t\t\n High-dose donepezil\t2519\t66\t5.41\t0.97 (0.74–1.28)\t\n Galantamine\t5926\t135\t5.34\t0.72 (0.59–0.89)\t\n Rivastigmine—patch\t4286\t182\t10.97\t1.16 (0.95–1.42)\t\n Rivastigmine—oral\t730\t22\t2.55\t0.88 (0.56–1.37)\t\n\n\nCompared with low-dose donepezil, galantamine was associated with a lower risk of serious cardiovascular events (aHR: 0.78, 95% CI: 0.62–0.98) and entry into a residential care facility (aHR: 0.72, 95% CI: 0.59–0.89) (Table 2). Comparison with the oral rivastigmine could not be completed due to small-cell data restrictions.\n\nIn the 12-month fixed follow-up sensitivity analysis of cardiovascular events, galantamine was associated with an 18% lower risk (adjusted risk ratio [RR]: 0.82 (0.72–0.93) and rivastigmine patch was associated with a 15% higher risk (RR: 1.15 [1.01–1.32]), compared with low-dose donepezil. In the 6-month fixed follow-up analysis of cardiovascular events, there was no significant difference between low-dose donepezil and any of the study medications.\n\nCompared with low-dose donepezil, galantamine was associated with a lower risk of mortality at 6 months (RR: 0.83, 95% CI: 0.69–1.01) and 12 months (RR: 0.82, 95% CI: 0.72–0.93), although the 6-month result was nonsignificant. The rivastigmine patch was associated with an increased risk of mortality at 6 months (RR: 1.21, 95% CI: 0.99–1.49) and at 12 months (RR: 1.15, 95% CI: 1.01–1.32), although the 6-month result was nonsignificant. Both formulations of rivastigmine, patch and oral, were also associated with a 12-month increased risk of entry into residential care (RR: 1.14, 95% CI: 1.03–1.26) and (RR: 1.275, 95% CI: 1.06–1.52), respectively (Tables 3 and 4).Table 3 Six-month fixed follow-up log-binomial regression\n\n\tN\tNumber of outcomes\tCrude risk ratio (95% confidence interval)\tAge-sex adjusted\tFully adjusted\t\nRisk ratio (95% confidence interval)\tP-value\tRisk ratio (95% confidence interval)\tP-value\t\nCrude and adjusted odds ratio, all-cause mortality, 6-month fixed follow-up\t\n Low-dose donepezil (reference)\t15,586\t440\t\t\t\t\t\t\n High-dose donepezil\t2519\t53\t0.75 (0.56–0.99)\t0.81 (0.61–1.08)\t0.147\t0.83 (0.62–1.11)\t0.209\t\n Galantamine\t5926\t150\t0.90 (0.75–1.08)\t0.89 (0.74–1.06)\t0.194\t0.83 (0.69–1.01)\t0.066\t\n Rivastigmine—patch\t4286\t158\t1.31 (1.09–1.56)\t1.31 (1.09–1.56)\t0.003\t1.21 (0.99–1.47)\t0.062\t\n Rivastigmine—oral\t730\t17\t0.82 (0.51–1.33)\t0.88 (0.54–1.41)\t0.585\t0.74 (0.45–1.22)\t0.243\t\nCrude and adjusted odds ratios, cardiovascular events, 6-month fixed follow-up\t\n Low-dose donepezil (reference)\t15,586\t517\t\t\t\t\t\t\n High-dose donepezil\t2519\t79\t0.95 (0.75–1.19)\t1.00 (0.80–1.27)\t0.637\t1.09 (0.85–1.38)\t0.500\t\n Galantamine\t5926\t161\t0.82 (0.69–0.98)\t0.81 (0.68–0.96)\t0.017\t0.79 (0.66–0.96)\t0.015\t\n Rivastigmine—patch\t4286\t140\t0.98 (0.82–1.18)\t0.99 (0.82–1.19)\t0.891\t0.94 (0.77–1.15)\t0.543\t\n Rivastigmine—oral\t730\t27\t1.12 (0.76–1.63)\t1.16 (0.79–1.69)\t0.447\t0.90 (0.61–1.34)\t0.606\t\nCrude and adjusted odds ratios, entry to residential care, 6-month fixed follow-up\t\n Low-dose donepezil (reference)\t15,586\t920\t\t\t\t\t\t\n High-dose donepezil\t2519\t108\t0.73 (0.60–0.88)\t0.81 (0.67–0.99)\t0.037\t0.82 (0.67–1.01)\t0.058\t\n Galantamine\t5926\t298\t0.85 (0.75–0.97)\t0.86 (0.76–0.97)\t0.017\t0.80 (0.70–0.92)\t0.001\t\n Rivastigmine—patch\t4286\t301\t1.19 (1.05–1.35)\t1.22 (1.08–1.39)\t0.002\t1.19 (1.03–1.36)\t0.015\t\n Rivastigmine—oral\t730\t63\t1.46 (1.15–1.87)\t1.62 (1.27–2.06)\t0.0001\t1.26 (0.98–1.63)\t0.077\t\nBold values indicate a confidence interval that does not include 1.\n\nTable 4 Twelve-month fixed follow-up log-binomial regression\n\n\tN\tNumber of outcomes\tCrude risk ratio (95% confidence interval)\tAge- and sex-adjusted\tProp. Score adjusted\t\nRisk ratio (95% confidence interval)\tP-value\tRisk ratio (95% confidence interval)\tP-value\t\nCrude and adjusted odds ratio, all-cause mortality, 12-month fixed follow-up\t\n Low-dose donepezil (reference)\t15,586\t990\t\t\t\t\t\t\n High-dose donepezil\t2519\t134\t0.84 (0.70–0.99)\t0.90 (0.76–1.07)\t0.244\t0.93 (0.77–1.11)\t0.408\t\n Galantamine\t5926\t335\t0.89 (0.79–1.00)\t0.88 (0.78–0.99)\t0.032\t0.82 (0.72–0.93)\t0.002\t\n Rivastigmine—patch\t4286\t329\t1.21 (1.07–1.36)\t1.21 (1.07–1.36)\t0.002\t1.15 (1.01–1.32)\t0.031\t\n Rivastigmine—oral\t730\t48\t1.04 (0.78–1.37)\t1.08 (0.82–1.43)\t0.589\t0.97 (0.72–1.29)\t0.815\t\nCrude and adjusted odds ratios, cardiovascular events, 12-month fixed follow-up\t\n Low-dose donepezil (reference)\t15,586\t914\t\t\t\t\t\t\n High-dose donepezil\t2519\t125\t0.85 (0.71–1.02)\t0.90 (0.75–1.08)\t0.264\t0.96 (0.80–1.16)\t0.708\t\n Galantamine\t5926\t300\t0.86 (0.76–0.98)\t0.86 (0.75–0.97)\t0.016\t0.83 (0.73–0.95)\t0.007\t\n Rivastigmine—patch\t4286\t240\t0.95 (0.83–1.10)\t0.96 (0.84–1.10)\t0.560\t0.94 (0.81–1.09)\t0.434\t\n Rivastigmine—oral\t730\t40\t0.93 (0.69–1.27)\t0.98 (0.72–1.33)\t0.898\t0.85 (0.61–1.16)\t0.305\t\nCrude and adjusted odds ratios, entry to residential care, 12-month fixed follow-up\t\n Low-dose donepezil (reference)\t15,586\t1702\t\t\t\t\t\t\n High-dose donepezil\t2519\t218\t0.79 (0.69–0.91)\t0.88 (0.77–1.00)\t0.051\t0.90 (0.78–1.03)\t0.117\t\n Galantamine\t5926\t659\t1.02 (0.94–1.11)\t1.02 (0.94–1.11)\t0.566\t0.95 (0.87–1.04)\t0.284\t\n Rivastigmine—patch\t4286\t529\t1.13 (1.03–1.24)\t1.16 (1.06–1.27)\t0.001\t1.14 (1.03–1.26)\t0.011\t\n Rivastigmine—oral\t730\t113\t1.42 (1.19–1.69)\t1.54 (1.30–1.83)\t<.0001\t1.27 (1.06–1.52)\t0.011\t\nBold values indicate a confidence interval that does not include 1.\n\n\n\n4 Interpretation\nThis study compares ChEIs in terms of mortality, serious cardiovascular events, and entry into a residential care facility. Donepezil users were divided into low- and high-dose exposure groups based on WHO Defined Daily Dose. Nearly all users of galantamine and rivastigmine (98%) used the single WHO Defined Daily Dose.\n\nThe 3-year risk of serious cardiovascular events was 22% lower (aHR 0.78 CI: 0.62–0.98) and all-cause mortality was 16% lower (aHR 0.84 CI: 0.60–1.18) in galantamine versus low-dose donepezil, although the mortality results were not significant at the conventional α level of 0.05. Similar results were seen in both fixed follow-up sensitivity analyses. A Danish cross-national study comparing cardiovascular safety of dementia medications found similar benefits for galantamine (29% lower risk of heart failure [aHR 0.71 CI: 0.46–1.10]) [23].\n\nPrior hospital admission for several cardiovascular conditions was highest among galantamine users. Although this usually suggests patients were at a higher risk of future cardiovascular events, an alternative explanation could be that these patients were more closely monitored and more aggressively treated for vascular risk factors, resulting in lower cardiovascular events.\n\nEntry into residential care was studied as a co-secondary outcome as a measure of net benefit over harm. Our results show a 28% lower 3-year risk of entry into a residential care facility with galantamine versus low-dose donepezil (aHR: 0.72 CI: 0.62–0.98). These findings are also consistent with a net benefit of treatment over harm for galantamine and may also be related to a previous finding of longer persistence and better adherence for patients on galantamine versus donepezil [24].\n\nResidual confounding is a possible limitation of our results because of the nonrandomized study design. Baseline characteristics of the study cohorts indicate comparable age, smoking status, and prior medical history. Low-dose donepezil had the highest proportion of females (60%). This was likely due to weight-based dosing. Rivastigmine users had the highest prior use of antipsychotics. There is a positive correlation between cognitive decline, progression of neurodegeneration, and psychosis in patients with ADRD [25]. Previous research has shown that rivastigmine users have a lower rate of antipsychotic prescriptions compared with donepezil patients in a base cohort of antipsychotic naïve patients [26]. These findings may influence physicians to preferentially prescribe rivastigmine over other ChEIs to patients with symptoms of psychosis. In addition, the Alzheimer's Drug Therapy Initiative required regular cognitive assessments; our study findings may not be generalizable to jurisdictions with alternative health care systems.\n\nA significant strength of our study was the use of the B.C. Ministry of Health administrative claims database, which captures all prescriptions dispensed at a community pharmacy regardless of payer. Dispensed prescriptions are linkable to physician services, hospital discharge abstracts, and client demographic information via an encrypted patient identifier. The comprehensiveness of the databases for the B.C. population reduces the risk of exposure misclassification, which is known to substantially affect risk estimates in observational studies [27] and allows for generalizing results to a wide population.\n\nOur study found that galantamine has a superior safety profile compared with low-dose donepezil and was associated with a lower risk of entry into a residential care facility. The rivastigmine patch was associated with a higher risk of mortality and a higher risk of entry into a residential care facility. High-dose donepezil had a similar safety and effectiveness profile compared with low-dose donepezil. Given the absence of randomized trial data showing clinically meaningful benefit of ChEI therapy in ADRD, our study suggests that preferential use of galantamine may at least be associated with fewer adverse events than treatment with donepezil or rivastigmine and may also be associated with longer independent living before requiring a residential care facility.Research in context\n1. A clinically meaningful improvement in cognitive function has not been established between cholinesterase inhibitors (ChEIs) and placebo in clinical trials of patients with Alzheimer's disease and related dementia, yet ChEIs are commonly prescribed.\n\n2. Using population-based data during a government-sponsored reimbursement program, we examined the comparative safety of ChEIs. Compared with the most common treatment, low-dose donepezil, we found galantamine was associated with a lower risk of cardiovascular events and mortality. Galantamine use was also associated with longer independent living, delaying the need for a residential care facility.\n\n3. Given the absence of randomized trial data showing clinically meaningful benefit of ChEI therapy, preferential use of galantamine may at least be associated with a superior safety profile compared with donepezil or rivastigmine.\n\n\n\n\n\nSupplementary Data\nSupplementary Fig. 1\nFlow chart of patients included in the study cohorts.\n\n Supplementary Fig. 2\nPropensity score distribution and model statistics.\n\n \n\nAcknowledgments\nThe study was funded through a contribution agreement to the University of British Columbia from the British Columbia Ministry of Health. Their support is gratefully acknowledged. Carney had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nDisclaimer: All inferences, opinions, and conclusions drawn in this manuscript are those of the authors and do not reflect the opinions or policies of the Data Stewards.\n\nEthics approval: The study received ethics approval from the University of British Columbia (UBC CREB Number H16-02922).\n\nData sharing statement: Statistical code available from the corresponding author at Greg.Carney@ti.ubc.ca\n\nConflict of interest: None declared.\n\nSupplementary data related to this article can be found at https://doi.org/10.1016/j.trci.2019.09.011.\n==== Refs\nReferences\n1 Alzheimer's Society of Canada A New Way of Looking at the Impact of Dementia in Canada 2012 Alzheimer's Society of Canada Toronto \n2 Changes to PharmaCare Coverage for Cholinesterase Inhibitors. April 2016 http://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/adti-health-professional-infosheet.pdf \n3 Hogan D.B. Long-term efficacy and toxicity of cholinesterase inhibitors in the treatment of Alzheimer disease Can J Psychiatry 59 2014 618 623 25702360 \n4 Di Santo S.G. Prinelli F. Adorni F. Caltagirone C. Musicco M. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer's disease J Alzheimer's Dis 35 2013 349 361 23411693 \n5 Sadowsky C. Galvin J. Guidelines for the management of cognitive and behavioral problems in dementia J Am Board Fam Med 25 2012 350 366 22570399 \n6 Eskander M.F. Nagykery N.G. Leung E.Y. Khelghati B. Geula C. Rivastigmine is a potent inhibitor of acetyl- and butyrylcholinesterase in Alzheimer's plaques and tangles Brain Res 1060 2005 144 152 16212945 \n7 Pohanka M. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase meet immunity Int J Mol Sci 15 2014 9809 9825 24893223 \n8 Dajas-Bailador F.A. Heimala K. Wonnacott S. The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release Mol Pharmacol 64 2003 1217 1226 14573772 \n9 Albuquerque E.X. Alkondon M. Pereira E.F. Castro N.G. Schrattenholz A. Barbosa C.T. Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function J Pharmacol Exp Ther 280 1997 1117 1136 9067295 \n10 Lanctot K. Herrmann N. Yau K.K. Khan L.R. Liu B.A. LouLou M.M. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis CMAJ 169 2003 557 564 12975222 \n11 Hansen R.A. Gartlehner G. Webb A.P. Morgan L.C. Moore C.G. Jonas D.E. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis Clin Interv Aging 3 2008 211 225 18686744 \n12 Park-Wyllie L.Y. Mamdani M.M. Li P. Gill S.S. Laupacis A. Juurlink D.N. Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study PLoS Med 6 2009 e1000157 19787032 \n13 US Food and Drug Administration [FDA] Alert for Healthcare Professionals on Galantamine Hydrochloride (marketed as Reminyl) 2005 FDA Rockville (Maryland) https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126138.pdf \n14 Russ T.C. Morling J.R. Cholinesterase inhibitors for mild cognitive impairment Cochrane Database Syst Rev 2012 CD009132 22972133 \n15 Loy C. Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment Cochrane Database Syst Rev 2006 CD001747 16437436 \n16 Fisher A. Carney G. Bassett K. Chappell N. Cholinesterase Inhibitor Utilization: the impact of provincial drug policy on discontinuation Value Health 19 2016 688 696 27565287 \n17 B.C. Ministry of Health Provincial Guide to Dementia Care in British Columbia: Achievements and Next Steps http://www.health.gov.bc.ca/library/publications/year/2016/bc-dementia-care-guide.pdf 2016 \n18 Williams J.I. Young W. Inventory of Studies on the Accuracy of Canadian Health Administrative Databases Technical report 1996 Institute for Clinical Evaluative Sciences (ICES) Toronto \n19 Fowles J.B. Lawthers A.G. Weiner J.P. Garnick D.W. Petrie D.S. Palmer R.H. Agreement between physicians' office records and Medicare Part B claims data Health Care Finance Rev 16 1995 189 199 \n20 Obtained online from B.C. Stats and reduced by 7% to account for the federally insured http://www.bcstats.gov.bc.ca/StatisticsBySubject/Demography/PopulationEstimates.aspx \n21 McNutt L.A. Wu C. Xue X. Hafner J.P. Estimating the relative risk in cohort studies and clinical trials of common outcomes Am J Epidemiol 157 2003 940 943 12746247 \n22 Schneeweiss S. Rassen J.A. Glynn R.J. Avorn J. Mogun H. Brookhart M.A. High-dimensional propensity score adjustment in studies of treatment effects using health care claims data Epidemiology 20 2009 512 522 19487948 \n23 Fosbol E.L. Peterson E.D. Holm E. Gislason G.H. Zhang Y. Curtis L.H. Comparative cardiovascular safety of dementia medications: a cross-national study J Am Geriatr Soc 60 2012 2283 2289 23176182 \n24 Fisher A. Carney G. Bassett K. Cormuth C.R. Tolerability of cholinesterase inhibitors: a population-based study of persistence, adherence, and switching Drugs Aging 34 2017 221 231 28138912 \n25 Merims D. Shabtai H. Korczyn A.D. Peretz C. Weizman N. Giladi N. Antiparkinsonian medication is not a risk factor for the development of hallucinations in Parkinson's disease J Neural Transm 111 2004 1447 1453 15480845 \n26 Scharre D.W. Vekeman F. Lefebvre P. Mody-Patel N. Kahler K.H. Duh M.S. Use of antipsychotic drugs in patients with Alzheimer's disease treated with rivastigmine versus donepezil: a retrospective, parallel-cohort, hypothesis-generating study Drugs Aging 27 2010 903 913 20964464 \n27 Rothman K.J. Greenland S. Modern Epidemiology 2nd ed. 1998 Lippincott-Raven Philadelphia, PA 347\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-8737",
"issue": "5()",
"journal": "Alzheimer's & dementia (New York, N. Y.)",
"keywords": "Alzheimer's disease; Cholinesterase inhibitor; Cox proportional hazard; Dementia; Epidemiology; Log-binomial regression; Propensity score",
"medline_ta": "Alzheimers Dement (N Y)",
"mesh_terms": null,
"nlm_unique_id": "101650118",
"other_id": null,
"pages": "732-739",
"pmc": null,
"pmid": "31921965",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "16437436;10151888;20964464;12746247;9067295;23176182;22972133;12975222;16212945;15480845;25702360;23411693;24893223;22570399;19787032;14573772;27565287;18686744;19487948;28138912",
"title": "Comparison of cholinesterase inhibitor safety in real-world practice.",
"title_normalized": "comparison of cholinesterase inhibitor safety in real world practice"
} | [
{
"companynumb": "CA-JNJFOC-20191145356",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GALANTAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "Pegfilgrastim-cbqv was developed as a biosimilar of pegfilgrastim, a pegylated form of recombinant human granulocyte colony-stimulating factor approved for decreasing febrile neutropenia-associated infection in patients receiving myelosuppressive drugs. This multicenter, randomized, single-blind, partial-reference-replicated, three-sequence crossover study assessed pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv and pegfilgrastim in healthy subjects.\n\n\n\nOne hundred twenty-two subjects were randomized to one of three treatment sequences; each included one dose of pegfilgrastim-cbqv and two doses of pegfilgrastim separated by ≥ 28 days. The primary pharmacokinetic end points were area under the curve (AUC) from 0 to infinity (AUC0-∞) and maximum concentration (Cmax). The primary pharmacodynamic end points were maximum absolute neutrophil count (ANCmax) and ANC AUC from time 0 to the last measurable observation (ANC AUC0-last). Pharmacokinetic and pharmacodynamic bioequivalences were demonstrated if the 90% CI for the geometric mean ratio (GMR) of pegfilgrastim-cbqv to pegfilgrastim was within 80-125% for the primary end points.\n\n\n\nPharmacokinetic bioequivalence criteria were met for Cmax (GMR 105.0; 90% CI 95.5-115.4) and AUC0-∞ (GMR 97.5; 90% CI 88.6-107.2). Pharmacodynamic bioequivalence criteria were met for ANCmax (GMR 99.6; 90% CI 96.2-103.2) and ANC AUC0-last (GMR 96.7; 90% CI 92.2-101.4). Adverse events occurred in 76.0%, 76.6%, and 73.1% of subjects for pegfilgrastim-cbqv, first pegfilgrastim, and second pegfilgrastim dosing periods across treatment sequences, respectively. Investigators found no drug-related serious adverse events.\n\n\n\nThis study established pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv to pegfilgrastim. The treatments displayed similar safety profiles, including immunogenicity, with no unexpected safety findings.\n\n\n\nClinicalTrials.gov, NCT02650973, February 2016.",
"affiliations": "Coherus BioSciences, Redwood City, CA, USA. bfinck@coherus.com.;Coherus BioSciences, Redwood City, CA, USA.;Coherus BioSciences, Redwood City, CA, USA.;Coherus BioSciences, Redwood City, CA, USA.;Coherus BioSciences, Redwood City, CA, USA.;Coherus BioSciences, Redwood City, CA, USA.",
"authors": "Finck|Barbara|B|0000-0002-7913-767X;Tang|Helen|H|;Civoli|Francesca|F|;Hodge|Jennifer|J|;O'Kelly|Hillary|H|;Vexler|Vladimir|V|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-020-01459-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-238X",
"issue": "37(10)",
"journal": "Advances in therapy",
"keywords": "Biosimilar; Chemotherapy-induced febrile neutropenia; Granulocyte colony-stimulating factors; Pegfilgrastim; Pegfilgrastim-cbqv; Supportive care",
"medline_ta": "Adv Ther",
"mesh_terms": "D018592:Cross-Over Studies; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D064368:Healthy Volunteers; D006801:Humans; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D016037:Single-Blind Method",
"nlm_unique_id": "8611864",
"other_id": null,
"pages": "4291-4307",
"pmc": null,
"pmid": "32789809",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacokinetic and Pharmacodynamic Equivalence of Pegfilgrastim-cbqv and Pegfilgrastim in Healthy Subjects.",
"title_normalized": "pharmacokinetic and pharmacodynamic equivalence of pegfilgrastim cbqv and pegfilgrastim in healthy subjects"
} | [
{
"companynumb": "US-AMGEN-USASP2020134775",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM-CBQV"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nTo evaluate and review the literature surrounding serotonin toxicity in patients receiving linezolid and determine the clinical relevance of this reaction.\n\n\nMETHODS\nLiterature was accessed via MEDLINE/PubMed and Google Scholar (both through February 2013) using the search terms linezolid, serotonin syndrome, serotonin toxicity, and adverse reaction.\n\n\nMETHODS\nRelevant case reports, retrospective studies, surveys, and review articles were included. Bibliographies of all relevant articles were reviewed for additional sources.\n\n\nRESULTS\nLinezolid exhibits mild, nonselective inhibition of monoamine oxidase and has been associated with serotonin toxicity when used in combination with other serotonergic agents. Based on published reports, the incidence of linezolid-associated serotonin toxicity is between 0.54% and 18.2%. Our review identified 32 documented cases, including 3 fatalities. Most cases occurred in patients concurrently receiving selective serotonin reuptake inhibitors. Receipt of multiple agents with serotonergic activity seems to increase the risk of serotonin toxicity. Both onset and resolution of symptoms varied from hours to days.\n\n\nCONCLUSIONS\nCurrent Food and Drug Administration recommendations to avoid the use of linezolid in patients receiving select serotonergic agents highlight the need to carefully balance the risk/benefit ratio in this situation. Although linezolid has been available for 12 years, reports of serotonin toxicity with this agent are uncommon. While clinicians should be aware of this potentially severe interaction and closely monitor patients who are receiving linezolid in combination with serotonergic agents, our findings show that linezolid is not contraindicated in this situation.",
"affiliations": "Wegmans School of Pharmacy, St. John Fisher College, Rochester, NY, USA. mwoytowish@sjfc.edu",
"authors": "Woytowish|Melanie R|MR|;Maynor|Lena M|LM|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1R386",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "47(3)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000081:Acetamides; D000890:Anti-Infective Agents; D006801:Humans; D000069349:Linezolid; D023303:Oxazolidinones; D020230:Serotonin Syndrome",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "388-97",
"pmc": null,
"pmid": "23424229",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clinical relevance of linezolid-associated serotonin toxicity.",
"title_normalized": "clinical relevance of linezolid associated serotonin toxicity"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-05996",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugad... |
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"abstract": "Diseases associated with immunoglobulin A (IgA) antibody include linear IgA dermatosis, IgA nephropathy, Celiac disease, Henoch-Schönlein purpura, etc. Although usually idiopathic, IgA antibody is occasionally induced by drugs (e.g., vancomycin, carbamazepine, ceftriaxone, and cyclosporine), malignancies, infections, and other causes. So far, only a few cases of IgA bullous dermatosis coexisting with IgA nephropathy have been reported. A 64-year-old female receiving intravenous ceftriaxone and metronidazole for liver abscess had purpuric macules and papules on her extremities. One week later, she had generalized edema and skin rash with bullae and was diagnosed with concurrent linear IgA dermatosis and IgA nephropathy. After steroid treatment, the skin lesion subsided within two weeks, and kidney function slowly returned to normal. As both diseases occurred after a common possible cause, we predict their pathogeneses are associated.",
"affiliations": "Department of Dermatology, Dankook University Medical College, Cheonan, Korea.;Department of Dermatology, Dankook University Medical College, Cheonan, Korea.;Department of Dermatology, Dankook University Medical College, Cheonan, Korea.;Department of Dermatology, Dankook University Medical College, Cheonan, Korea.;Department of Dermatology, Dankook University Medical College, Cheonan, Korea.;Department of Dermatology, Dankook University Medical College, Cheonan, Korea.;Department of Dermatology, Dankook University Medical College, Cheonan, Korea.",
"authors": "Kim|Ji Seok|JS|;Choi|Misoo|M|;Nam|Chan Hee|CH|;Kim|Jee Young|JY|;Park|Byung Cheol|BC|;Kim|Myung Hwa|MH|;Hong|Seung Phil|SP|",
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"country": "Korea (South)",
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"doi": "10.5021/ad.2015.27.3.315",
"fulltext": "\n==== Front\nAnn DermatolAnn DermatolADAnnals of Dermatology1013-90872005-3894Korean Dermatological Association; The Korean Society for Investigative Dermatology 10.5021/ad.2015.27.3.315Case ReportConcurrent Drug-Induced Linear Immunoglobulin A Dermatosis and Immunoglobulin A Nephropathy Kim Ji Seok Choi Misoo Nam Chan Hee Kim Jee Young Park Byung Cheol Kim Myung Hwa Hong Seung Phil Department of Dermatology, Dankook University Medical College, Cheonan, Korea.\nCorresponding author: Seung Phil Hong, Department of Dermatology, Dankook University Medical College, 201 Manghyang-ro, Dongnam-gu, Cheonan 330-715, Korea. Tel: 82-41-550-3868, Fax: 82-41-552-7541, zamoo97@naver.com6 2015 29 5 2015 27 3 315 318 15 5 2014 13 9 2014 06 11 2014 Copyright © 2015 The Korean Dermatological Association and The Korean Society for Investigative Dermatology2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Diseases associated with immunoglobulin A (IgA) antibody include linear IgA dermatosis, IgA nephropathy, Celiac disease, Henoch-Schönlein purpura, etc. Although usually idiopathic, IgA antibody is occasionally induced by drugs (e.g., vancomycin, carbamazepine, ceftriaxone, and cyclosporine), malignancies, infections, and other causes. So far, only a few cases of IgA bullous dermatosis coexisting with IgA nephropathy have been reported. A 64-year-old female receiving intravenous ceftriaxone and metronidazole for liver abscess had purpuric macules and papules on her extremities. One week later, she had generalized edema and skin rash with bullae and was diagnosed with concurrent linear IgA dermatosis and IgA nephropathy. After steroid treatment, the skin lesion subsided within two weeks, and kidney function slowly returned to normal. As both diseases occurred after a common possible cause, we predict their pathogeneses are associated.\n\nGlomerulonephritisImmunoglobulin ALinear IgA bullous dermatosisDrug eruptions\n==== Body\nINTRODUCTION\nLinear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare acquired autoimmune disease that results in subepidermal blisters, which are caused by IgA antibodies directed at target proteins within the epidermal adhesion complex. Although usually idiopathic, it is occasionally induced by drugs, internal malignancies, infection, etc1,2,3. Various drugs including acetaminophen, amiodarone, furosemide, phenytoin, ceftriaxone, and metronidazole can cause LABD. In particular, vancomycin is the most commonly associated etiologic drug4.\n\nReports of glomerulonephritis in patients with autoimmune bullous disease are increasing. However, only a few cases of LABD coexisting with IgA nephropathy have been reported. To our knowledge, no case of ceftriaxone- or metronidazole-induced LABD accompanied by IgA nephropathy has been reported. Here, we report the case of a 64-year-old woman diagnosed with concurrent drug-induced LABD (DLABD) and IgA nephropathy most probably due to ceftriaxone or metronidazole administration. We also review the relevant literature.\n\nCASE REPORT\nA 64-year-old female received intravenous ceftriaxone and metronidazole for liver abscess. One week later, she developed purpuric macules and papules on the upper and lower extremities. Because of suspected allergic vasculitis, she was treated with oral dapsone and methylprednisolone; the lesions subsided within a few days. Two weeks after purpura onset, she presented with generalized edema and consequently underwent kidney biopsy. Four days later, a pruritic diffuse morbilliform rash that clinically resembled drug eruption appeared on the trunk. Blood eosinophil percentage increased from 1.9% to 20.0% within few days after onset. One week later, bullae appeared on both the axilla and neck (Fig. 1). Skin biopsy of the bullae showed subepidermal blisters on H&E stain (Fig. 2A, B). Direct immunofluorescence showed linear depositions of IgA along basement membrane (Fig. 2C). Meanwhile, in the kidney biopsy, H&E stain showed glomeruli with mesangial proliferation (Fig. 3A), and direct immunofluorescence showed diffuse mesangial IgA deposits (Fig. 3B). On the basis of the histological findings of the kidneys and skin, the patient was diagnosed with concurrent LABD and IgA nephropathy. Intravenous ceftriaxone and metronidazole were intermittently changed with oral cefixime and oral metronidazole but were stopped owing to liver abscess at week eight after bullae formation. Therefore, intravenous dexamethasone, steroid ointment, and dressing were administered immediately after bullae formation. To treat both the skin and kidneys, which were affect by IgA antibodies, oral prednisolone 60 mg daily was administered one week after bullae formation, replacing intravenous steroid treatment. Skin lesions subsided within two weeks, and the patient underwent routine follow-up for kidney function, which recovered slowly.\n\nDISCUSSION\nDLABD differs from idiopathic LABD. For example, in DLABD, the incidence of mucosal or conjunctival lesions is relatively low, while up to 40% of patients with idiopathic LABD have mucosal involvement5. Moreover, in DLABD, spontaneous remission occurs when the causative drugs are withdrawn, and immune deposits disappear as the lesions resolve6. In contrast, only 10% to 50% of patients with idiopathic LABD achieve spontaneous remission, and immune deposits persist after lesions resolve in some cases7. Patients with DLABD also tend to be older than patients with idiopathic LABD5.\n\nThe pathogenesis of DLABD remains unclear. However, drug-specific CD4+ T lymphocytes may play an important role. Lymphocytes associated with DLABD induced by ceftriaxone and metronidazole administration exhibit significantly increased secretion of interleukin (IL)-5 and interferon (IFN)-γ cytokines8. T-cell lymphokines, including IL-4, IL-5, IL-6, IL-10, and transforming growth factor, can increase IgA synthesis, regulate IgA isotype switching, and contribute to IgA B-cell differentiation9. As a result, abnormal IgA antibodies may migrate towards the dermal-epidermal junction, causing inflammation and blisters; alternatively, they may form an immune complex with other serum proteins to become deposits in the renal mesangium, which can eventually cause glomerulonephritis.\n\nOur patient presented with concurrent LABD and IgA nephropathy. Furthermore, considering her increased blood eosinophil percentage, prior bullae formation, advanced age, the absence of mucosal involvement, and clinical remission after the cessation of drugs, we postulate the cause was drug-induced rather than idiopathic. As both ceftriaxone and metronidazole are reported to cause DLABD and had a temporal relationship with respect to onset and resolution in our patient, they could be considered the responsible drugs in the present case.\n\nThe findings of the present case suggest the pathogeneses of LABD and IgA nephropathy are likely associated, because both occurred after a common possible cause. In IgA nephropathy, IFN-γ and IL-4 gene polymorphisms with certain significantly increased genotype frequencies can influence disease susceptibility and progression in IgA nephropathy10. In addition, immune complexes from patients with IgA nephropathy can induce human mesangial cells to release factors such as tumor necrosis factor alpha, IL-6, and transforming growth factor, which can affect podocyte gene expression and glomerular permeability10. On the basis of the abovementioned pathogenesis of LABD and IgA nephropathy, IL-4, IL-6, transforming growth factor, and IFN-γ may play roles in both DLABD and IgA nephropathy. IFN-γ, which is reported to be elevated in DLABD caused by ceftriaxone and influence the disease progression of IgA nephropathy, may have played a major role in the pathogenesis of our patient. If the role of IFN-γ is clarified in further investigations, IFN-γ antibodies may be evaluated in clinical trials as an alternative treatment option for concurrent LABD and IgA nephropathy.\n\nThis case advances our understanding of the pathogenesis of concurrent LABD and IgA nephropathy, contributing to future investigations and the development of specifically targeted treatment options for these diseases.\n\nFig. 1 Multiple scattered bullae on an erythematous base on the nape (A) and back (B) (arrow: biopsy site).\nFig. 2 (A) Subepidermal blister with inflammatory cell infiltration (H&E, ×100). (B) Polymorphonuclear leukocytes and few lymphocytes along the interface of the subepidermal blister and papillary dermis (H&E, ×400). (C) Linear deposition of immunoglobulin A along basement membrane (direct immunofluorescence, ×100).\nFig. 3 (A) Glomerulus with mesangial proliferation and expansion of the mesangial matrix with mildly increased cellularity (H&E, ×400). (B) Direct immunofluorescence demonstrating diffuse mesangial immunoglobulin A deposits (×400).\n==== Refs\n1 Geissmann C Beylot-Barry M Doutre MS Beylot C Drug-induced linear IgA bullous dermatosis J Am Acad Dermatol 1995 32 296 7710511 \n2 Holló P Preisz K Nemes L Bíró J Kárpáti S Horváth A Linear IgA dermatosis associated with chronic clonal myeloproliferative disease Int J Dermatol 2003 42 143 146 12709006 \n3 Blickenstaff RD Perry HO Peters MS Linear IgA deposition associated with cutaneous varicella-zoster infection: a case report J Cutan Pathol 1988 15 49 52 2832459 \n4 Onodera H Mihm MC Jr Yoshida A Akasaka T Drug-induced linear IgA bullous dermatosis J Dermatol 2005 32 759 764 16361722 \n5 Waldman MA Black DR Callen JP Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis Clin Exp Dermatol 2004 29 633 636 15550142 \n6 Baden LA Apovian C Imber MJ Dover JS Vancomycin-induced linear IgA bullous dermatosis Arch Dermatol 1988 124 1186 1188 3041915 \n7 Wojnarowska F Marsden RA Bhogal B Black MM Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap J Am Acad Dermatol 1988 19 792 805 3056993 \n8 Yawalkar N Reimers A Hari Y Hunziker T Gerber H Müller U Drug-induced linear IgA bullous dermatosis associated with ceftriaxone- and metronidazole-specific T cells Dermatology 1999 199 25 30 10449953 \n9 Brière F Bridon JM Chevet D Souillet G Bienvenu F Guret C Interleukin 10 induces B lymphocytes from IgA-deficient patients to secrete IgA J Clin Invest 1994 94 97 104 7518836 \n10 Suzuki H Kiryluk K Novak J Moldoveanu Z Herr AB Renfrow MB The pathophysiology of IgA nephropathy J Am Soc Nephrol 2011 22 1795 1803 21949093\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1013-9087",
"issue": "27(3)",
"journal": "Annals of dermatology",
"keywords": "Drug eruptions; Glomerulonephritis; Immunoglobulin A; Linear IgA bullous dermatosis",
"medline_ta": "Ann Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8916577",
"other_id": null,
"pages": "315-8",
"pmc": null,
"pmid": "26082590",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports",
"references": "16361722;7518836;3056993;10449953;15550142;7710511;2832459;3041915;21949093;12709006",
"title": "Concurrent Drug-Induced Linear Immunoglobulin A Dermatosis and Immunoglobulin A Nephropathy.",
"title_normalized": "concurrent drug induced linear immunoglobulin a dermatosis and immunoglobulin a nephropathy"
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"abstract": "BACKGROUND\nClomiphene citrate is one of the effective drugs for infertility treatment due to oligo-ovulation or anovulation. Intrauterine insemination (IUI) is one of more adherent methods for treatment of infertile cases which is followed by controlled ovarian hyperstimulation (COH).\n\n\nOBJECTIVE\nthe aim of this study was to evaluate Clomiphene citrate versus letrozole with gonadotropins in IUI cycles.\n\n\nMETHODS\nIn this prospective randomized trial, 180 infertile women who were referred to Milad Hospital were selected. The first group received 5 mg/day letrozole on day 3-7 of menstrual cycle. The second group received 100 mg/day Clomiphene in the same way as letrozole. In both groups, human menopausal gonadotropin was administered every day starting on day between 6-8 of cycle. Ovulation was triggered with urinary Human Chorionic Gonadotropin (5000 IU) when have two follicles of ≥16 mm. IUI was performed 36 hr later.\n\n\nRESULTS\nThe number of matured follicles, cycle cancellation, and abortion were the same in both groups. Endometrial thickness was higher at the time of human menopausal gonadotropin administration in letrozole group. Chemical and clinical pregnancy rates were much higher in letrozole group. Ovarian hyperstimulation was significantly higher in clomiphene group.\n\n\nCONCLUSIONS\nLetrozole appears to be a good alternative to clomiphene citrate with fewer side effects.",
"affiliations": "Department of Obstetrics and Gynecology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Department of Obstetrics and Gynecology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Mashhad University of Medical Sciences, Mashhad, Iran.;Mashhad University of Medical Sciences, Mashhad, Iran.;Mashhad University of Medical Sciences, Mashhad, Iran.",
"authors": "Pourali|Leila|L|;Ayati|Sedigheh|S|;Tavakolizadeh|Shirin|S|;Soleimani|Hourieh|H|;Teimouri Sani|Fatemeh|F|",
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"fulltext": "\n==== Front\nInt J Reprod Biomed\nInt J Reprod Biomed\nIJRB\nInternational Journal of Reproductive Biomedicine\n2476-4108 2476-3772 Research and Clinical Center for Infertility Yazd, Iran \n\n28280800\nijrb-15-049\nOriginal Article\nClomiphene citrate versus letrozole with gonadotropins in intrauterine insemination cycles: A randomized trial\nPourali Leila M.D.1 Ayati Sedigheh M.D.1 Tavakolizadeh Shirin M.D.2 Soleimani Hourieh M.D. student.2 Teimouri Sani Fatemeh M.D. student.2 \n1 \nDepartment of Obstetrics and Gynecology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. \n\n\n2 \nMashhad University of Medical Sciences, Mashhad, Iran.\n\nCorresponding Author: Sedigheh Ayati, Department of Obstetrics and Gynecology, Ghaem Hospital, Ahmadabad Blvd., Mashhad, Iran. Postal code: 91766-99199, Tel: (+98) 9151153768 , Email: ayatis@mums.ac.ir\n1 2017 \n15 1 49 54\n30 5 2016 28 8 2016 15 10 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nClomiphene citrate is one of the effective drugs for infertility treatment due to oligo-ovulation or anovulation. Intrauterine insemination (IUI) is one of more adherent methods for treatment of infertile cases which is followed by controlled ovarian hyperstimulation (COH). \n\nObjective:\nthe aim of this study was to evaluate Clomiphene citrate versus letrozole with gonadotropins in IUI cycles. \n\nMaterials and Methods:\nIn this prospective randomized trial, 180 infertile women who were referred to Milad Hospital were selected. The first group received 5 mg/day letrozole on day 3-7 of menstrual cycle. The second group received 100 mg/day Clomiphene in the same way as letrozole. In both groups, human menopausal gonadotropin was administered every day starting on day between 6-8 of cycle. Ovulation was triggered with urinary Human Chorionic Gonadotropin (5000 IU) when have two follicles of ≥16 mm. IUI was performed 36 hr later.\n\nResults:\nThe number of matured follicles, cycle cancellation, and abortion were the same in both groups. Endometrial thickness was higher at the time of human menopausal gonadotropin administration in letrozole group. Chemical and clinical pregnancy rates were much higher in letrozole group. Ovarian hyperstimulation was significantly higher in clomiphene group. \n\nConclusion:\nLetrozole appears to be a good alternative to clomiphene citrate with fewer side effects. \n\nKey Words\nOvarian stimulationGonadotropinLetrozoleClomiphene citrate\n==== Body\nIntroduction\nInfertility is commonly defined as the failure of conception after at least twelve months of unprotected intercourse (1). According to a research in Iran, the overall prevalence of infertility was 8% (2). IUI (Intrauterine Insemination) may be recommended as a first-line treatment in young couples with different etiologies of infertility such as male factor infertility, unexplained infertility and ovulatory disorders (3). Clomiphene citrate (CC) is a selective estrogen-receptor modulator (SERM) which is the most commonly prescribed agent to induce ovulation (4). It has been widely used in treatment of infertility since its introduction into clinical practice (5). Clomiphene results in a 60-85% ovulation rate and a 10-20% pregnancy rate per cycle (6). But there are many studies which show that the clomiphene has significant adverse effects on endometrial receptivity, endocervical mucosa, fetus and ovaries (7, 8). Anti-estrogenic effects of CC on the endometrium may lead to poor pregnancy rate and significant rate of early pregnancy loss by the mechanism of estrogen receptor (ER) depletion (9). CC has a long half-life, so it accumulates in the body and has adverse effects as mentioned (4).\n\nLetrozole is a third-generation aromatase inhibitor which has been successfully used for ovulation induction in patients with polycystic ovary syndrome (PCOS) (11). Mitwally et al had reported acceptable pregnancy outcomes and lower rate of multiple gestation in letrozole group for ovarian stimulation (12). Letrozole does not deplete estrogen receptor (ER) in target tissues, so it has no persistent anti-estrogenic effect. It typically results in mono-ovulation and it may have no adverse effects on endometrium and cervical mucosa. It has a short half-life (45 hr), so it would be eliminated from the body rapidly (13). Although clomiphene is the standard drug for ovulation stimulation, clomiphene-resistance has been discovered in 15-20% of the patients (11).\n\nThe aim of this prospective randomized clinical trial was to compare the efficacy of Letrozole +HMG with Clomiphene +HMG in a group of patients with unexplained infertility that had failed to conceive after previous treatment by CC alone.\n\nMaterials and methods\nThis randomized double-blind clinical trial was performed at Milad infertility clinic, Mashhad, Iran, between April 2010 and March 2011. For sample size calculation with regard of α=0.05 and β=0.2, and data from a previous study which showed that the clinical pregnancy rate was 14 % in CC group and 32% in letrozole group, according to the formula, after assuming a 5% dropout rate, to reach the minimal statistically-acceptable figure, a minimal sample size of 90 cases was calculated in each group (13). \n\nSo, we enrolled 180 infertile women who were eligible for superovulation and IUI for the first time. Inclusion criteria were unexplained infertility and resistance to three cycles of clomiphene therapy who were candidate for IUI (Figure 1). Exclusion criteria were women with PCOS, thyroid dysfunction, hyperprolactinemia, endometriosis, ovarian hyperstimulation (more than 15 follicles in each ovary) and age more than 38 yr. Hysterosalpingography was performed for all participants to confirm tubal patency. Semen parameters were analyzed by the world health organization (2010) criteria (13). \n\nThe patients were randomized in two groups: Clomiphene group (Clomiphene +HMG) and Letrozole group (letrozole +HMG). Randomization was done by using numbers in closed envelops. The patients in the clomiphene group received CC 50 mg twice a day (BID) for 5 days starting from day 3 of menstrual cycle. In letrozole group, letrozole (Femara, Novartis, Quebec, Canada) 2.5 mg BID was given for 5 days from day 3 of the menstrual cycle. \n\nIn addition, all the patients received a daily intramuscular (IM) human menopausal gonadotropin (HMG, Pergonal, Serono, Switzerland) injection. The dosage was 75 IU starting on day 6 of menstrual cycle until hCG administration. The gynecologists, radiologists and participants were unaware of study group allocation. Drugs and treatment protocol was given by the medical consultant team to the participants. Transvaginal ultrasonography was done in the days 3, 9, 12 of the cycle and then every three days, until follicle size reached more than 16 mm in size. \n\nIf more than 15 follicles were seen in each ovary that is considered as ovarian hyperstimulation, so the cycle was cancelled and the participant was excluded from the study. When mature leading follicle(s) reached >16 mm in diameter, urinary hCG (Profasi, Serono, Italy) in a dose of 5,000 IU was given and IUI was performed 36 hr later. two weeks after the performance of IUI, if the participant was not menstruated, chemical pregnancy would be defined by the measurement of βHCG level. \n\nTransvaginal ultrasonography (TVS) was done four weeks after positive pregnancy test to confirm the presence of gestational sac with fetal pole and fetal heart pulsation, so the clinical pregnancy was identified. Finally, the therapeutic costs were calculated and compared between groups.\n\n\nEthical Consideration\n\n\nAfter approval by the medical ethics committee of Mashhad university of Medical Science; all the participants were aware of the purpose and procedures of the study and informed consent was obtained.\n\n\nStatistical analysis\n\n\nStatistical Package for Social Sciences, version 16.0, SPSS Inc, Chicago, Illinois, USA (SPSS 16) was used for statistical analysis and t test, Fisher-exact test and chi-square test were used as appropriate. P<0.05 was considered statistically significant.\n\nFigure 1. Consort flowchart of the study design\n\nResults\n180 participants were included in the analysis, 87 (51.2%) in clomiphene group and 83 (48.8%) in the letrozole group. ten women were excluded from the study due to lack of following their treatment. There were no significant differences between women in both groups in terms of age, body mass index (BMI), duration and types of infertility (Table I). \n\nThe mean endometrial thickness on the day of hCG administration was significantly higher in letrozole group (8.99±0.65 vs. 8.46±0.69 mm respectively ,p=0.001). The clinical pregnancy rate was significantly higher in letrozole group which is defined by fetal heart detection in ultrasonography (26.51 vs. 12.46% respectively, p=0.001). No twin or ectopic pregnancy occurred in this study.\n\nFour patients (5.7%) in letrozole group and five patient (4.8%) in CC group experienced abortion; there was no significant difference between two groups (p=0.80). Ovarian hyper stimulation, determined by the number of follicles more than 15, was significantly higher in clomiphene group (5.7 vs. 0%, respectively, p=0.03). \n\nThe mean number of mature follicles (≥16 mm) was not significantly different between clomiphene and letrozole group (2.17±0.13 vs. 2.28±0.1%, respectively, p=0.74). Cancelled cycles occurred due to ovarian hyperstimulation syndrome was significantly higher in clomiphene group compared to letrozole group (5.7 vs. 0 %, respectively, p=0.027). There was no significant difference between clomiphene and letrozole groups in terms of formation of at least two follicles with size of ≥16 mm (8 vs. 6%, respectively, p=0.607). Therapeutic costs including all drugs, ultrasonography, visits, and IUI costs were approximately the same between two groups (p=0.62).\n\nTable I Comparison of patients treated with Clomiphene and letrozole groups\n\n\nVariable\n\t\nClomiphene +HMG group\n\t\nLetrozole+ HMG group\n\t\np-value\n\t\nAge (yr)\t28.5 ± 1.7\t28.6 ± 1.8\t0.850*\t\nDuration of infertility (yr)\t2.5 ± 1.14\t2.5 ± 1.19\t0.902*\t\nBMI (Kg/m²)\t24.86 ± 2.6\t24.6 ± 2.7\t0.611*\t\nEndometrial thickness before treatment (mm) \t3.7 ± 0.86\t3.8 ± 0.85\t0.553*\t\nEndometrial thickness during HCG injection (mm)\t8.46 ± 0.69\t8.99 ± 0.65\t0.001*\t\nRate of pregnancy by positive βHCG\t16 (18.4%)\t26 (31.3%)\t0.059**\t\nRate of pregnancy by fetal heart detection by ultrasonography\t11 (12.64%)\t22 (26.51%)\t0.022**\t\nRate of abortion (The recent pregnancy)\t5 (5.7%)\t4 (4.8%)\t0.80**\t\nOvarian hyperstimulation (follicles more than 15)\t5 (5.7%)\t0\t0.03***\t\nTherapeutic cost (Rials)\t\t\t\t\n\t≤ 5,000,000 \t72 *(82.8%)\t71 (85.5%)\t0.62**\t\n\t10,000,000 ≥ Cost ˃ 5,000,000\t15 (17.2%)\t12 (14.5%)\t0.62**\t\nNo. of follicles ≥ 16 mm\t2.17 ± 0.13\t2.28 ± 0.1\t0.74**\t\nRate of cancelled cycles\t\t\t\t\n\tDue to OHSS\t5 (5.7%)\t0\t0.027***\t\n\tDue to non-formation of at least 2 follicles ≥ 16 mm\t7 (8%)\t5 (6%)\t0.607***\t\n* Student's t-test \n\n** Chi-square test \n\n*** Fisher-exact test\n\nDiscussion\nThe results from this study indicate that endometrial thickness was significantly higher in letrozole group; similar to some other studies (13,15,16); but in some studies, there was no significant difference in terms of endometrial thickness between two groups (14-18). This difference could be due to ovulatory dysfunction in their participants which may play a role in endometrial thickness. In the current study, there was no significant difference in the number of follicles which is more than 16 mm in size, just like as the study of Zadehmodares et al, but in the study of Badawy et al, there were more follicles ≥16 mm in clomiphene group that may be due to their larger sample size, also their study was done on patients with polycystic ovarian disease (PCOD) which were more susceptible to have higher number of follicles (17, 19). \n\nIn this study, there was a significant difference in clinical pregnancy rate which was much higher in letrozole group, similar to some studies, but in some other studies, there was no significant difference in pregnancy rate like as Zadehmodares et al and Akbari et al studies that may be due to their smaller sample size (13, 15, 16, 19, 20). The higher pregnancy rate in letrozole group can be explained by significant increase in endometrial receptivity as assessed by endometrial thickness. The lower pregnancy rate in CC may be due to antiestrogenic effects of CC on the endometrium and cervical mucusa. In the present study, there was no significant difference between two groups in terms of abortion. The systematic review which was done on this field also showed no difference in the abortion rate (21).\n\nThis study showed significantly more OHSS in clomiphene group, this important complication does not have much incidence rate in some other studies, even a systematic review in this field did not show this difference (9, 10, 21). This is a very important problem because this is a life-threatening complication and also it is the most important cause of cancelling the COH cycles in which in the current study, there was significant difference in terms of cycle cancelling in cc group; so may be the use of lower dose of cc must be considered in our protocols. \n\nThe therapeutic cost in both protocols was the same; we did not find any study in this field. Some of the strength of current study include: double blind randomization design and evaluation of treatment costs in two groups. \n\n\nLimitation\n\n\nThe limitations of this study were: 1. Short period of follow-up after pregnancy which cannot detect pregnancy outcome (after 20 weeks) and also the teratogenic effects of these drugs, 2. More than one sonologist had done the serial ultrasonography for evaluation of endometrial thickness and follicular growth, so it could be a weakness of this study.\n\nConclusion\nLetrozole has beneficial effect on endometrium which may improve the pregnancy rate in women with unexplained infertility.\n\nAcknowledgements\nThe authors would appreciate the respected research deputy of Mashhad University of Medical Sciences that supported this study financially.\n\nNote\n\nThis article extracted from M.D. thesis. (Shirin Tavakolizadeh)\n\n\n\nRegistration ID in IRCT: \nIRCT2015062422900N1\n\n\nConflict of interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Dankert T Kremer JA Cohlen BJ Hamilton CJ Pasker-de Jong PC Straatman H A randomized clinical trial of Clomiphenee citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility Hum Reprod 2007 22 792 797 17110396 \n2 Safarinejad MR Infertility among couples in a population‐based study in Iran: prevalence and associated risk factors Int J Androl 2008 31 303 314 17488339 \n3 Tomlinson MJ Amissah-Arthur JB Thompson KA Kasraie JL Bentick B Prognostic indicators for intrauterine insemination (IUI): statistical model for IUI success Hum Reprod 1996 11 1892 1896 8921060 \n4 Barroso G1 Menocal G Felix H Rojas-Ruiz JC Arslan M Oehninger S Comparison of the efficacy of the aromatase inhibitor letrozole and Clomiphenee citrate as adjuvants to recombinant follicle-stimulating hormone in controlled ovarian hyperstimulation: a prospective, randomized, blinded clinical trial Fertil Steril 2006 86 1428 1431 16978619 \n5 Greenblatt RB Barfield WE Jungck EC Ray AW Induction of ovulation with mrl/41: Preliminary report JAMA 1961 178 101 104 13901503 \n6 Fisher SA Reid RL Van Vugt DA Casper RF A randomized double-blind comparison of the effects of Clomiphenee citrate and the aromatase inhibitor letrozole on ovulatory function in normal women Fertil Steril 2002 78 280 285 12137863 \n7 Nakamura Y Ono M Yoshida Y Sugino N Ueda K Kato H Effects of Clomiphenee citrate on the endometrial thickness and echogenic pattern of the endometrium Fertil Steril 1997 67 256 260 9022599 \n8 Nelson LM1 Hershlag A Kurl RS Hall JL Stillman RJ Clomiphenee citrate directly impairs endometrial receptivity in the mouse Fertil Steril 1990 53 727 731 2318331 \n9 Ibrahim MI1 Moustafa RA Abdel-Azeem AA Letrozole versus Clomiphenee citrate for superovulation in Egyptian women with unexplained infertility: a randomized controlled trial Arch Gynecol Obstet 2012 286 1581 1587 22829102 \n10 Diamond MP Legro RS Coutifaris C Alvero R Robinson RD Casson P Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility N Engl J Med 2015 373 1230 1240 26398071 \n11 Liu A Zheng C Lang J Chen W Letrozole versus Clomiphenee citrate for unexplained infertility: A systematic review and meta-analysis J Obstet Gynaecol Res 2014 40 1205 1216 24754848 \n12 Mitwally MF Biljan MM Casper RF Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation Am J Obstet Gynecol 2005 192 381 386 15695975 \n13 Shahrokh Tehrani Nejad E Abediasl Z Rashidi BH Azimi Nekoo E Shariat M Amirchaghmaghi E Comparison of the efficacy of the aromatase inhibitor letrozole and Clomiphene citrate gonadotropins in controlled ovarian hyperstimulation: a prospective, simply randomized, clinical trial J Assist Reprod Genet 2008 25 187 190 18427974 \n14 World Health Organization WHO laboratory manual for the examination and processing of human semen 2010 5th Ed. Switzerland WHO publication 271 \n15 Ibrahim MI Moustafa RA Abdel-Azeem AA LetrozoleversusClomiphenee citrate for superovulation in Egyptianwomen with unexplained infertility: a randomized controlled trial Arch Gynecol Obstet 2012 286 1581 1587 22829102 \n16 Akbari S Ayazi Roozbahani M Ayazi Roozbahani F Comparing of letrozole versus Clomiphenee citrate combined with gonadotropins in intrauterine insemination cycles Iran J Reprod Med 2012 10 29 32 25242971 \n17 Badawy A Elnashar A Totongy M Clomiphenee citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial Fertil Steril 2009 92 1355 1359 18692823 \n18 Angel M Ghose S Gowda M A randomized trial comparing the ovulation induction efficacy of Clomiphenee citrate and letrozole J Nat Sci Biol Med 2014 5 450 452 25097433 \n19 Zadehmodares S Niyakan M Sharafy SA Yazdi MH Jahed F Comparison of treatment outcomes of infertile women by Clomiphenee citrate and letrozole with gonadotropins underwent intrauterine insemination Acta Med Iran 2012 50 18 20 22267373 \n20 Legro RS Brzyski RG Diamond MP Coutifaris C Schlaff WD Casson P Letrozole versus Clomiphenee for infertility in the polycystic ovary syndrome N Engl J Med 2014 371 119 129 25006718 \n21 Poheung C Use of letrozole versus Clomiphenee citrate for superovulation in patients undergoing intrauterine insemination: a systematic review. [MSc Thesis] 2014 China The University of Hong Kong (Pokfulam, Hong Kong)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2476-3772",
"issue": "15(1)",
"journal": "International journal of reproductive biomedicine",
"keywords": "Clomiphene citrate; Gonadotropin; Letrozole; Ovarian stimulation",
"medline_ta": "Int J Reprod Biomed",
"mesh_terms": null,
"nlm_unique_id": "101679102",
"other_id": null,
"pages": "49-54",
"pmc": null,
"pmid": "28280800",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": "17488339;8921060;17110396;22267373;12137863;16978619;18427974;22829102;25242971;24754848;26398071;18692823;9022599;25006718;15695975;2318331;25097433;13901503",
"title": "Clomiphene citrate versus letrozole with gonadotropins in intrauterine insemination cycles: A randomized trial.",
"title_normalized": "clomiphene citrate versus letrozole with gonadotropins in intrauterine insemination cycles a randomized trial"
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"companynumb": "IR-EMD SERONO-8150079",
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"abstract": "BACKGROUND\nSalvage high-dose (HD) chemotherapy with autologous stem cell transplant (ASCT), consisting of 2 to 3 sequential cycles of HD carboplatin and etoposide (CE) can achieve durable remissions in approximately half of patients with relapsed germ cell tumors. To improve on these results and based on success with paclitaxel, ifosfamide, and cisplatin (TIP) as salvage conventional-dose chemotherapy, we conducted a phase I/II trial of HD paclitaxel with ifosfamide (TI), substituting carboplatin for cisplatin to allow dose escalation.\n\n\nMETHODS\nTreatment consisted of 1 to 2 cycles of TI and granulocyte colony-stimulating factor for stem cell mobilization followed by 3 cycles of HD TI with carboplatin (TIC) with ASCT every 21 to 28 days. Twenty-six patients were enrolled. For phase I, a standard 3+3 dose-escalation design was used.\n\n\nRESULTS\nWith no dose-limiting toxicities observed, the maximum tolerated dose (MTD) was not reached and the highest prespecified dose level (paclitaxel 250 mg/m(2), ifosfamide 9990 mg/m(2), carboplatin area under the curve 24) was considered the MTD. In phase II, a Simon 2-stage design was used to estimate the complete response (CR) rate at the MTD. With 7 of 11 phase II patients who achieved a CR, efficacy was demonstrated. However, 3 patients developed delayed chronic kidney disease, resulting in premature trial closure.\n\n\nCONCLUSIONS\nTI-TIC was active in relapsed germ cell tumors but treatment-emergent chronic renal impairment, possibly from overlapping ifosfamide and carboplatin, preclude its further use. TI-CE, consisting of 2 cycles of TI with 3 cycles of HD CE remains the standard of care HD chemotherapy regimen at Memorial Sloan Kettering Cancer Center.",
"affiliations": "Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY. Electronic address: feldmand@mskcc.org.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.",
"authors": "Feldman|Darren R|DR|;Glezerman|Ilya|I|;Patil|Sujata|S|;Van Alstine|Lindsay|L|;Bajorin|Dean F|DF|;Fischer|Patricia|P|;Hughes|Amanad|A|;Sheinfeld|Joel|J|;Bains|Manjit|M|;Reich|Lilian|L|;Woo|Kaitlin|K|;Giralt|Sergio|S|;Bosl|George J|GJ|;Motzer|Robert J|RJ|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "13(5)",
"journal": "Clinical genitourinary cancer",
"keywords": "Intensive chemotherapy; Second-line; Stem cell transplant; Testicular cancer",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000328:Adult; D016190:Carboplatin; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007069:Ifosfamide; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal; D017239:Paclitaxel; D011446:Prospective Studies; D016879:Salvage Therapy; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "453-60",
"pmc": null,
"pmid": "26072101",
"pubdate": "2015-10",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23062817;9404920;17602082;8156505;20194867;8758250;1464010;21285904;2702835;8270973;18270356;22291076;1703917;21806332;16170162;10715285;17652649;8095648;10064184;10856101;1312584;9365330",
"title": "Phase I/II Trial of Paclitaxel With Ifosfamide Followed by High-Dose Paclitaxel, Ifosfamide, and Carboplatin (TI-TIC) With Autologous Stem Cell Reinfusion for Salvage Treatment of Germ Cell Tumors.",
"title_normalized": "phase i ii trial of paclitaxel with ifosfamide followed by high dose paclitaxel ifosfamide and carboplatin ti tic with autologous stem cell reinfusion for salvage treatment of germ cell tumors"
} | [
{
"companynumb": "US-PFIZER INC-2016333974",
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"abstract": "The use of meropenem, a new antibiotic from the carbapenemic family, was analyzed in the treatment of all types of serious infections in patients in critical condition. The global clinical response was satisfactory in 85.4% of the 178 assessable cases, with no significant differences being found in the form of treatment (monotherapy or combination therapy with aminoglycosides and/or glycopeptides) or in the type of infection treated, although the patients that received three or more antibiotics had more treatment failure. In the case of pneumonia, a better clinical response was observed with the use of monotherapy (38/40, 95% vs. 38/47, 80.8%, p = 0.049). The microbiological response was satisfactory in 72.7% of the 110 assessable cases. Initial pathogens persisted in just 8.2% of the cases, with superinfection in 12.7% and colonization in 6.4%. Differences relating to the form of treatment or the area of infection were not detected. The severity of the patient's condition influenced the choice of the form of meropenem treatment (monotherapy or combined therapy). Such factors as the patient's severity, the presence of hypotension or shock, and the need for mechanical ventilation were indicators for the use of two or more antibiotics. The severity also influenced the use of a larger average daily dose, as well as the length of treatment. Adverse reactions were detected in 6 of the 178 (3.37%) assessable patients, with 4 cases of nephrotoxicity, and 2 of hepatotoxicity. Global mortality was 14%, while infection-related mortality was 8.43%.",
"affiliations": "Servicio de Medicina Intensiva, Hospital del Mar, Barcelona.",
"authors": "Alverez Lerma|F|F|;Gil|C L|CL|",
"chemical_list": "D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D013845:Thienamycins; D000077731:Meropenem",
"country": "Spain",
"delete": false,
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"issue": "11(3)",
"journal": "Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia",
"keywords": null,
"medline_ta": "Rev Esp Quimioter",
"mesh_terms": "D018806:APACHE; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D003627:Data Interpretation, Statistical; D004359:Drug Therapy, Combination; D005260:Female; D006020:Glycopeptides; D006801:Humans; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D018805:Sepsis; D012772:Shock, Septic; D013845:Thienamycins",
"nlm_unique_id": "9108821",
"other_id": null,
"pages": "229-37",
"pmc": null,
"pmid": "9795309",
"pubdate": "1998-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Clinical experience with meropenem in the treatment of severe infections in critically ill patients.",
"title_normalized": "clinical experience with meropenem in the treatment of severe infections in critically ill patients"
} | [
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"companynumb": "ES-PFIZER INC-2020301596",
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"activesubstancename": "MEROPENEM"
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"abstract": "This is a case of a middle-aged woman with underlying cardiac conduction system with episodes of AV Wenckebach, who subsequently developed significant AV conduction system abnormalities after receiving one standard dose of Rituximab infusion for diffuse large B-cell lymphoma. Rituximab, being a monoclonal antibody against CD-20 antigen, is effective in treatment of B-cell lymphoma but may also cause bradyarrythmias likely due to the calcium ion channel property of CD-20 antigen.",
"affiliations": "Department of Cardiovascular Medicine, Mayo Clinic Arizona, Phoenix, AZ USA.;Department of Cardiovascular Medicine, Mayo Clinic Arizona, Phoenix, AZ USA.;Department of Cardiovascular Medicine, Mayo Clinic Arizona, Phoenix, AZ USA.",
"authors": "Ko Ko|Nway Le|NL|;Minaskeian|Nareg|N|;El Masry|Hicham Z|HZ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40959-020-00077-5",
"fulltext": "\n==== Front\nCardiooncology\nCardiooncology\nCardio-oncology\n2057-3804 BioMed Central London \n\n77\n10.1186/s40959-020-00077-5\nReview\nA case of irreversible bradycardia after rituximab therapy for diffuse large B-cell lymphoma\nKo Ko Nway Le koko.nway@mayo.edu Minaskeian Nareg El Masry Hicham Z. grid.417468.80000 0000 8875 6339Department of Cardiovascular Medicine, Mayo Clinic Arizona, Phoenix, AZ USA \n13 10 2020 \n13 10 2020 \n2020 \n6 227 7 2020 16 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.This is a case of a middle-aged woman with underlying cardiac conduction system with episodes of AV Wenckebach, who subsequently developed significant AV conduction system abnormalities after receiving one standard dose of Rituximab infusion for diffuse large B-cell lymphoma. Rituximab, being a monoclonal antibody against CD-20 antigen, is effective in treatment of B-cell lymphoma but may also cause bradyarrythmias likely due to the calcium ion channel property of CD-20 antigen.\n\nKeywords\nRituximabHigh grade AV blockComplete AV blockBradyarrythmiaDiffuse large B cell lymphomaissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nRituximab is a monoclonal antibody directed against the CD-20 antigen. The chimeric antibody has been used in the treatment of B-cell lymphoma and binds to the surface antigen activating complement-mediated cell toxicity. Cardiac complications related to Rituximab have been reported including cardiomyopathy and myocardial infarction. Rituximab-induced cardiac arrhythmias have been rarely reported.\n\nWe report a patient with sinus dysfunction and paroxysmal high-grade AV block after a single dose of Rituximab used for treatment of diffuse large B cell lymphoma.\n\nCase\nOur patient is a 56-year-old lady with no known cardiovascular condition other than controlled hypertension who presented to our hospital with an insidious onset of bilateral lower extremity lymphedema, and an obstructive uropathy with secondary acute kidney injury. Her initial work up was revealing of a large pelvic mass and extensive lymphadenopathy for which she underwent lymph node, pelvic mass and bone marrow biopsies. A confirmed diagnosis of high-grade lymphoma, most likely a follicular lymphoma transformed into diffuse large B cell lymphoma (DLBCL), required her to be started on R-ECPOCH therapy (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin). Patient reported an excellent pre-morbid functional status, and was a regular volleyball player and a walker prior to the last few months. She received the first dose of Rituximab 375 mg/m2 over 36 h along with Methylprednisolone and Doxorubicin as part of her combination chemotherapy. Patient received a total of 800 mg of Rituximab over 36 h.\n\nUpon assessment of the patient, her laboratory parameters revealed chronic microcytic anemia with hemoglobin of 6.9 mg/dl and leukocytosis with white blood cell count of 11 × 109/L with neutrophilia and lymphopenia. Her kidney function and electrolytes were normal. Her echocardiogram was evident for normal biventricular function and global longitudinal strain without any significant valvular anomalies. Initial EKG was apparent for underlying conduction system disease with episodes of AV Wenckebach. In telemetry records, the rhythm had been predominantly in 2:1 AV blocks with additional periods of transient complete AV block with a ventricular rate down to 30s with narrow QRS complexes (Fig. 1). Over the continued observation for 24 h, it was evident that with exercise, her heart rate increased with the rhythm going back into Mobitz type 1 AV block consistent with AV nodal level of conduction block. However, for most of the time, the predominant rhythm was 2:1 AV block with continued occurrence of episodes of high-grade AV block and junctional escape rhythm. Reports of occasional dizziness and an episode of near syncope with worsening bradycardia hence lead to discontinuation of Rituximab therapy as a careful review of her medications did not reveal any negative chronotropic or dromotropic agent that might explain worsening bradycardia (Fig. 2). The calculated Naranjo Adverse Drug Reaction Probability Score of 3 with Rituximab in this case indicated that her AV block was possibly caused by adverse drug effect of Rituximab, as it followed a temporal sequence after Rituximab and it could be explained by the characteristic of her AV block (Supplementary Appendix, Table 1) [1]. Her bradyarrythmia persisted more than 48 h after interruption of her infusion and a pacemaker was implanted at that point. The first time pacemaker interrogation revealed right atrial pacing percentage of 2.3% and right ventricular pacing percentage of 99.3% with the lower rate limit set at 60. The patient received another round of Rituximab in a month. The following pacemaker interrogation revealed right atrial pacing percentage of 6.96% and right ventricular pacing percentage of 99.7% with the lower rate limit set at 60 beats per minute.\nFig. 1 Showing the patient’s serial electrocardiograms: a baseline tracing demonstrating sinus rhythm with first degree AV block, b sinus rhythm with 2:1 AV block\n\nFig. 2 Showing the trend of patient’s heart rate: the arrow signified the time Rituximab therapy was initiated\n\n\n\nDiscussion\nInfusion reactions associated with Rituximab therapy have been reported including cardiac arrhythmia such as monomorphic ventricular tachycardia, supraventricular tachycardia, trigeminy, and irregular pulse [2–4]. Moreover, it can also cause bradycardia and AV blocks [2, 5, 6]. Based on our knowledge, this is the second case report of Rituximab causing high grade AV block as there has only been one case report of complete AV block after the fifth dose of Rituximab [5]. In the first reported case, the patient did not have underlying conduction system disease, but our patient did although they both received similar dose of Rituximab per cycle for the indication of DLBCL. In our case, it is likely that the underlying conduction system disease had put our patient into high grade AV block just after the first dose of Rituximab. The half-life elimination of Rituximab is proportional to dosage. After an initial dose of 375 mg/m2, the average half-life of Rituximab is 3.2 days (range, 1.3–6.4 days) [7]. For our patient, the AV block onset within 2 days of Rituximab infusion, and her conduction system failed to recover after more than 48 h of monitoring. There have been several explanations of the mechanism of Rituximab affecting the cardiac conduction system. Per Poterucha et.al., it was hypothesized that CD20 antigen may function as a calcium-ion channel. Rituximab can induce the death of CD20+ cells in many ways such as direct cytotoxicity mediated by antibody dependent cells and complement cascade as well as by indirect effects like apoptosis, structural changes and sensitization of malignant cells to chemotherapy [8]. Therefore, it is likely that Rituximab affects cardiac conduction system by inhibiting the calcium-ion-channel properties of the CD20 antigen on the cardiac myocytes. This mechanism appears to be the most plausible pathogenesis of our patient’s bradycardia: infusion initiation was associated with sinus bradycardia and worsening AV block which appears to be at the AV nodal level (improved conduction with exercise and narrow junctional escape with transient high grade AV block). A calcium channel blocking effect at both the sinus and atrioventricular node levels is a unifying explanation of those observations. Other hypotheses include elevated transforming growth factor-B promoting growth of reticulin fiber in cardiac myocytes which impairs contractility and conduction [9] as well as release of cytokines, such as interleukin-6 and tumor necrosis factor-alpha [5]. These cytokines can also mediate ventricular dysfunction, acute coronary syndrome, and myocarditis in addition to tachy-arrhythmias or brady-arrhythmias [10].\n\nConclusion\nWith this case report, we intend to highlight the effect of Rituximab on cardiac conduction due to calcium channel property of CD20 antigen. FDA has cautiously provided recommendations to discontinue infusions for serious or life-threatening cardiac arrhythmias and perform cardiac monitoring during and after each infusion of Rituximab for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia, angina or conduction system disease like our patient [10, 11]. We would also recommend telemetry monitoring for patients who demonstrate any baseline evidence of sinus node dysfunction or conduction abnormalities predisposing them to symptomatic bradycardia with Rituximab therapy and its calcium channel blocking property.\n\nAppendix\n\nTable 1 Naranjo Adverse Drug Reaction Probability Scale\n\nQuestion\tYes\tNo\tDo not know\tScore\t\nAre there previous conclusive reports on this reaction?\t+ 1\t0\t0\t+ 1\t\nDid the adverse event appear after the suspected drug was administered?\t+ 2\t− 1\t0\t+ 2\t\nDid the adverse event improve when the drug was discontinued or a specific antagonist was administered?\t+ 1\t0\t0\t0\t\nDid the adverse event reappear when the drug was readministered?\t+ 2\t−1\t0\t0\t\nAre there alternative causes that could on their own have caused the reaction?\t−1\t+ 2\t0\t0\t\nDid the reaction reappear when a placebo was given?\t−1\t+ 1\t0\t0\t\nWas the drug detected in blood or other fluids in concentrations known to be toxic?\t+ 1\t0\t0\t0\t\nWas the reaction more severe when the dose was increased or less severe when the dose was decreased?\t+ 1\t0\t0\t0\t\nDid the patient have a similar reaction to the same or similar drugs in any previous exposure?\t+ 1\t0\t0\t0\t\nWas the adverse event confirmed by any objective evidence?\t+ 1\t0\t0\t0\t\nTotal score\t\t\t\t3\t\n\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nAll authors contributed in generating the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury LiverTox: Clinical and Research Information on Drug-Induced Liver Injury 2012 Bethesda (MD) National Institute of Diabetes and Digestive and Kidney Diseases \n2. Arai Y Tadokoro J Mitani K Ventricular tachycardia associated with infusion of rituximab in mantle cell lymphoma Am J Hematol 2005 78 317 318 10.1002/ajh.20303 15795913 \n3. Coiffier B Lepage E Briere J CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med 2002 346 235 242 10.1056/NEJMoa011795 11807147 \n4. Dillman RO Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy Cancer Metastasis Rev 1999 18 465 471 10.1023/A:1006341717398 10855789 \n5. Foran JM Rohatiner AZ Cunningham D European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma J Clin Oncol 2000 18 317 324 10.1200/JCO.2000.18.2.317 10637245 \n6. Cervera Grau JM Esquerdo Galiana G Belso Candela A Llorca Ferrandiz C Juarez Marroqui A Macia ES Complete atrioventricular block induced by rituximab in monotherapy in an aged patient with non-Hodgkin's diffuse large B-cell lymphoma Clin Transl Oncol 2008 10 298 299 10.1007/s12094-008-0201-1 18490248 \n7. Maloney DG Liles TM Czerwinski DK Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma Blood 1994 84 2457 2466 10.1182/blood.V84.8.2457.2457 7522629 \n8. Cerny T Borisch B Introna M Johnson P Rose AL Mechanism of action of rituximab Anti-Cancer Drugs 2002 13 Suppl 2 S3 10 10.1097/00001813-200211002-00002 \n9. Kanamori H Tsutsumi Y Mori A Delayed reduction in left ventricular function following treatment of non-Hodgkin's lymphoma with chemotherapy and rituximab, unrelated to acute infusion reaction Cardiology 2006 105 184 187 10.1159/000091416 16490965 \n10. Cheungpasitporn W Kopecky SL Specks U Bharucha K Fervenza FC Non-ischemic cardiomyopathy after rituximab treatment for membranous nephropathy J Renal Injury Prev 2017 6 18 25 10.15171/jrip.2017.04 \n11. Rituxan official FDA information, side effects and uses [Internet]. 2007 Mar [cited 2010 Mar 2]. Available from: http://www.drugs.com/pro/rituxan.html.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2057-3804",
"issue": "6()",
"journal": "Cardio-oncology (London, England)",
"keywords": "Bradyarrythmia; Complete AV block; Diffuse large B cell lymphoma; High grade AV block; Rituximab",
"medline_ta": "Cardiooncology",
"mesh_terms": null,
"nlm_unique_id": "101689938",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "33062307",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "15795913;7522629;16490965;12710585;11807147;28487867;10855789;10637245;18490248",
"title": "A case of irreversible bradycardia after rituximab therapy for diffuse large B-cell lymphoma.",
"title_normalized": "a case of irreversible bradycardia after rituximab therapy for diffuse large b cell lymphoma"
} | [
{
"companynumb": "US-PFIZER INC-2020420419",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMalignant primary diffuse leptomeningeal gliomatosis (MPDLG) are rare central nervous system neoplasms associated with a poor outcome.\n\n\nMETHODS\nWe report the case of a 40-year-old woman who presented with unusual worsening of bilateral sciatica, headaches, diplopia and a left proptosis. MRI of the head and spine showed multiple leptomeningeal lesions with no intra parenchymal involvement. The search for a primary tumor was negative. An open surgical biopsy of the prominent intradural lumbar tumor was performed within a week. Histopathology, immunochemistry and molecular analyses revealed a malignant glioma with histone H3.3 K27M mutation. The patient was referred to the neuro-oncologist for chemotherapy and craniospinal radiotherapy. Despite aggressive therapy, she died of disseminated tumoral progression, 18 weeks after the diagnosis.\n\n\nCONCLUSIONS\nMPLG is a rare tumor which should be considered whenever a patient presents with diffuse or multinodular meningeal contrast-enhancing lesions. Some cases of MLPG share histological and immunophenotypical features with diffuse midline gliomas H3-K27M-mutant, a rapidly fatal disease. The diagnosis remains histopathological and, therefore a biopsy is obligatory without delay. Immunohistochemistry and/or molecular analyses are now currently essential for a formal classification and, to provide a better prediction of clinical outcome, particularly in this heterogeneous group of tumors.",
"affiliations": "Department of neurosurgery, Sainte-Anne hospital, 75014 Paris, France; Department of neurosurgery, Lariboisière hospital, 75010 Paris, France. Electronic address: Charles.Champeaux@gmail.com.;Réseau d'imagerie parisien, 54, avenue du Général-Leclerc, 75014 Paris, France.;Department of neurosurgery, Sainte-Anne hospital, 75014 Paris, France.;Department of neuropathology, Sainte-Anne hospital, 75014 Paris, France.",
"authors": "Champeaux|C|C|;Drier|A|A|;Devaux|B|B|;Tauziède-Espariat|A|A|",
"chemical_list": "C000609950:H3-3A protein, human; D006657:Histones",
"country": "France",
"delete": false,
"doi": "10.1016/j.neuchi.2017.12.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3770",
"issue": "64(3)",
"journal": "Neuro-Chirurgie",
"keywords": "Diffuse midline glioma; Histone H3.3; K27M mutation; Leptomeningeal gliomatosis",
"medline_ta": "Neurochirurgie",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D005260:Female; D005910:Glioma; D006657:Histones; D006801:Humans; D008577:Meningeal Neoplasms; D009154:Mutation; D018302:Neoplasms, Neuroepithelial",
"nlm_unique_id": "0401057",
"other_id": null,
"pages": "198-202",
"pmc": null,
"pmid": "29752148",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Malignant primary diffuse leptomeningeal gliomatosis with histone H3.3 K27M mutation.",
"title_normalized": "malignant primary diffuse leptomeningeal gliomatosis with histone h3 3 k27m mutation"
} | [
{
"companynumb": "FR-AMERIGEN PHARMACEUTICALS, INC-2018AMG000027",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugad... |
{
"abstract": "Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized neurological syndrome that typically presents with a severe headache. The proposed etiology is transient and segmental constriction of cerebral arteries, which in severe cases can lead to cerebral ischemia. Multiple case reports have been identified associating the use of serotonergic medications with this syndrome.\n\n\n\nA review of the literature describing RCVS in patients taking selective serotonin reuptake inhibitors and other serotonergic medications is summarized. This report also describes the case of a 32-year-old woman with a complicated psychiatric history diagnosed with RCVS who presented with progressive cerebral ischemia despite intensive medical intervention. Ischemic progression did not relent until her home medication fluoxetine was recognized as the likely etiology and discontinued. The psychiatric management of this patient is described after fluoxetine was discontinued. Other potential psychiatric treatments for patients with a history of RCVS are discussed.\n\n\n\nA literature search was performed using PubMed with the following keywords: antidepressant, selective serotonin reuptake inhibitor, serotonin, fluoxetine, reversible cerebral vasoconstriction syndrome, RCVS, and Call-Fleming syndrome.\n\n\n\nFifteen patients were identified to have RCVS with associated use of serotonergic medications from 10 case reports published between 2002 and 2019.\n\n\n\nIt is important for psychiatrists to recognize the syndrome of RCVS in patients presenting with headache and ischemia due to the possibility of this syndrome being a rare but iatrogenic complication of a common psychiatric medication class. Additionally, identification of safe alternative treatments for patients with psychiatric illness who would otherwise be candidates for serotonergic medications is an important consideration for individuals affected by this disorder.",
"affiliations": "Department of Psychiatry, The University of Oklahoma School of Community Medicine, Tulsa, OK. Electronic address: Tessa-Manning@ouhsc.edu.;Department of Psychiatry, The University of Texas at Austin Dell Medical Center, Austin, TX.;Department of Psychiatry, Duke University Medical Center, Durham, NC.;Department of Psychiatry, The University of Oklahoma School of Community Medicine, Tulsa, OK.;Warren Clinic Neurology, Tulsa, OK.;Department of Psychiatry, The University of Oklahoma School of Community Medicine, Tulsa, OK.",
"authors": "Manning|Tessa|T|;Bartow|Christine|C|;Dunlap|Michael|M|;Kiehl|Robin|R|;Kneale|Hilary|H|;Walker|Ashley|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaclp.2021.07.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2667-2960",
"issue": "62(6)",
"journal": "Journal of the Academy of Consultation-Liaison Psychiatry",
"keywords": "RCVS; SSRI; fluoxetine; headache; ischemia; reversible cerebral vasoconstriction syndrome; serotonin; stroke",
"medline_ta": "J Acad Consult Liaison Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101775059",
"other_id": null,
"pages": "634-644",
"pmc": null,
"pmid": "34371244",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Reversible Cerebral Vasoconstriction Syndrome Associated With Fluoxetine.",
"title_normalized": "reversible cerebral vasoconstriction syndrome associated with fluoxetine"
} | [
{
"companynumb": "US-Appco Pharma LLC-2123269",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "We report three patients who developed haemolysis following rifampicin treatment. Initially, autoimmune haemolytic anaemia (AIHA) of the warm type and/or an acute haemolytic transfusion reaction (AHTR) was suggested. The direct antiglobulin tests (DAT) were strongly positive for IgG and C3d, and tests for rifampicin-dependent antibodies were positive in all three cases, featuring C-specificity in one case. The outcome was fatal in two out of the three cases, presumably due to belated diagnosis. This shows that rifampicin may stimulate the production of autoantibodies (aab) and/or drug-dependent antibodies (ddab), and that the resulting haemolytic syndrome bears similarities with AIHA and AHTR.",
"affiliations": "Institute of Transfusion Medicine, Campus Virchow-Klinikum, University Hospital Charité, Humboldt-University, Augustenburger Platz 1, 13353 Berlin, Germany. norbert.ahrens@charite.de",
"authors": "Ahrens|Norbert|N|;Genth|Ramona|R|;Salama|Abdulgabar|A|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D000906:Antibodies; D001323:Autoantibodies; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1046/j.1365-2141.2002.03416.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "117(2)",
"journal": "British journal of haematology",
"keywords": null,
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000743:Anemia, Hemolytic; D000904:Antibiotics, Antitubercular; D000906:Antibodies; D001323:Autoantibodies; D003951:Diagnostic Errors; D017809:Fatal Outcome; D005260:Female; D006461:Hemolysis; D006801:Humans; D008297:Male; D012293:Rifampin; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "441-3",
"pmc": null,
"pmid": "11972531",
"pubdate": "2002-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Belated diagnosis in three patients with rifampicin-induced immune haemolytic anaemia.",
"title_normalized": "belated diagnosis in three patients with rifampicin induced immune haemolytic anaemia"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1052123",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
... |
{
"abstract": "Real-world evidence of radium 223 (Ra-223) for the treatment of men with metastatic castration-resistant prostate cancer is emerging. In this prospective single-centre service evaluation, we report for the first time in the UK, real-world quality of life (QoL) and survival outcomes, including the sequencing impact, in 228 treated patients. We aim to share our 5-year experience on how to optimise Ra-223 treatment.\n\n\n\nPatients who received Ra-223 therapy between 2014 and 2018 at the Northern Centre for Cancer Care, Newcastle upon Tyne, UK were included in this evaluation. Demographics, clinical characteristics, blood parameters, treatment sequencing and QoL data using abbreviated Functional Assessment of Cancer Therapy-Prostate questionnaires were prospectively collected and analysed.\n\n\n\nIn total, 228 patients were included; median age 72 years (51-87). The medium overall survival was 11.1 months. Overall survival in post-chemotherapy and chemotherapy-naïve patients was 8.1 and 12.3 months, respectively (P = 0.02, hazard ratio 1.52, 95% confidence interval 1.06-2.17); in pre-enzalutamide and post-enzalutamide patients was 11.3 and 10.4 months, respectively (P = 0.65, hazard ratio 0.92, 95% confidence interval 0.63-1.33); in pre-abiraterone and prednisolone and post-abiraterone and prednisolone patients was 11.8 and 10.5 months, respectively (P = 0.08, hazard ratio 0.74, 95% confidence interval 0.51-1.06); in this latter group, the fracture rate was 24% (15/63). QoL post Ra-223 (n = 101 evaluated) showed that pain scores improved in 54%, there was no change in 17% and pain scores worsened in 30% of treated patients. Overall QoL scores showed a similar trend. QoL was not significantly associated with overall survival.\n\n\n\nRa-223 palliates pain and improves disease-related QoL in most patients in the real-world setting. Our survival outcome is comparable with other real-world studies. Chemotherapy-naïve patients seemed to have better survival than those who received prior chemotherapy. No significant survival differences were observed between pre- and post-abiraterone and prednisolone or enzalutamide patients. The fracture rate in the post-abiraterone and prednisolone group seemed to be high. Bone health evaluation and protection should be incorporated as standard of care.",
"affiliations": "Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Electronic address: xue.jiang@nhs.net.;Department of Nuclear Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, UK.;Department of Clinical Oncology, James Cook University Hospital, South Tees NHS Trust, Middlesbrough, UK.;Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Department of Radiotherapy Information Technology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.",
"authors": "Jiang|X Y|XY|;Atkinson|S|S|;Pearson|R|R|;Leaning|D|D|;Cumming|S|S|;Burns|A|A|;Azzabi|A|A|;Frew|J|J|;McMenemin|R|R|;Pedley|I D|ID|",
"chemical_list": "C000615150:Radium-223; D011883:Radium",
"country": "England",
"delete": false,
"doi": "10.1016/j.clon.2020.05.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0936-6555",
"issue": "32(10)",
"journal": "Clinical oncology (Royal College of Radiologists (Great Britain))",
"keywords": "FACT-P; metastatic castration-resistant prostate cancer; quality of life; radium 223",
"medline_ta": "Clin Oncol (R Coll Radiol)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D064129:Prostatic Neoplasms, Castration-Resistant; D011788:Quality of Life; D011883:Radium; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D016896:Treatment Outcome",
"nlm_unique_id": "9002902",
"other_id": null,
"pages": "e177-e187",
"pmc": null,
"pmid": "32448724",
"pubdate": "2020-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Optimising Radium 223 Therapy for Metastatic Castration-Resistant Prostate Cancer -5-year Real-World Outcome: Focusing on Treatment Sequence and Quality of Life.",
"title_normalized": "optimising radium 223 therapy for metastatic castration resistant prostate cancer 5 year real world outcome focusing on treatment sequence and quality of life"
} | [
{
"companynumb": "GB-BAYER-2020-202675",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RADIUM RA-223 DICHLORIDE"
},
"drugadditional": nul... |
{
"abstract": "High dose corticosteroid therapy is widely used as attack therapy of inflammatory central nervous system disorders and can induce several adverse reactions. Bradycardia is an infrequent event after corticosteroids administration and is often asymptomatic. We report a case of a woman admitted to the neurological department of our hospital for paraesthesias of the lower limbs. She received adiagnosis of inflammatory myelitis and high dose corticosteroid therapy was prescribed. During the therapy she complained of chest tightness, dyspnoea, weakness and malaise. An electrocardiogram revealed sinus bradycardia. A significant increase in body weight, probably due to plasma volume expansion, was detected. Bradycardia and high blood pressure spontaneously resolved in few days. We provide a collection and a statistical analysis of literature data about steroid induced bradycardia. We found that higher total doses are associated with lower pulse rate and symptomatic bradycardia. Bradycardia is more frequent in older patients and those with underlying cardiac disease or with autonomic disturbance. However clinicians must be aware about the occurrence of symptomatic bradycardia in all patients who undergo high dose corticosteroid therapy, not only in those at risk, to early detect and treat this potentially dangerous condition.",
"affiliations": "Department of Neurological and Psychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy.;Department of Neurological and Psychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy.;Department of Neurological and Psychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy.;Department of Neurological and Psychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy.;Department of Neurological and Psychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy.;Department of Cardiology, Careggi University Hospital, Florence, Italy.;Department of Neurological and Psychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy.;Department of Neurological and Psychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy.",
"authors": "Sodero|Alessandro|A|https://orcid.org/0000-0003-4356-6912;Squitieri|Martina|M|;Mazzeo|Salvatore|S|;Pasca|Matteo|M|;Matà|Sabrina|S|;Pieri|Francesco|F|;Bessi|Valentina|V|;Sorbi|Sandro|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1179547619831026",
"fulltext": "\n==== Front\nClin Med Insights Case RepClin Med Insights Case RepICRspicrClinical Medicine Insights. Case Reports1179-5476SAGE Publications Sage UK: London, England 10.1177/117954761983102610.1177_1179547619831026Case ReportAcute Symptomatic Sinus Bradycardia in High-Dose Methylprednisolone\nTherapy in a Woman With Inflammatory Myelitis: A Case Report and Review of the\nLiterature https://orcid.org/0000-0003-4356-6912Sodero Alessandro 12Squitieri Martina 12Mazzeo Salvatore 12Pasca Matteo 12Matà Sabrina 12Pieri Francesco 3Bessi Valentina 12Sorbi Sandro 1241 Department of Neurological and\nPsychiatric sciences (NEUROFARBA), University of Florence, Florence, Italy2 Careggi University Hospital, Neurology\nunit, Florence, Italy3 Department of Cardiology, Careggi\nUniversity Hospital, Florence, Italy4 IRCCS Don Carlo Gnocchi, Florence,\nItalyAlessandro Sodero, Department of\nNeurological and Psychiatric sciences (NEUROFARBA), University of Florence,\nViale Gaetano Pieraccini, 6, 50139 Florence, Italy. Emails:\nalessandro.sodero@gmail.com;\nalessandro.sodero@unifi.it25 2 2019 2019 12 11795476198310269 1 2019 15 1 2019 © The Author(s) 20192019SAGE Publications Ltd unless otherwise noted.\nManuscript content on this site is licensed under Creative Commons\nLicensesThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).High dose corticosteroid therapy is widely used as attack therapy of inflammatory\ncentral nervous system disorders and can induce several adverse reactions.\nBradycardia is an infrequent event after corticosteroids administration and is\noften asymptomatic. We report a case of a woman admitted to the neurological\ndepartment of our hospital for paraesthesias of the lower limbs. She received\nadiagnosis of inflammatory myelitis and high dose corticosteroid therapy was\nprescribed. During the therapy she complained of chest tightness, dyspnoea,\nweakness and malaise. An electrocardiogram revealed sinus bradycardia. A\nsignificant increase in body weight, probably due to plasma volume expansion,\nwas detected. Bradycardia and high blood pressure spontaneously resolved in few\ndays. We provide a collection and a statistical analysis of literature data\nabout steroid induced bradycardia. We found that higher total doses are\nassociated with lower pulse rate and symptomatic bradycardia. Bradycardia is\nmore frequent in older patients and those with underlying cardiac disease or\nwith autonomic disturbance. However clinicians must be aware about the\noccurrence of symptomatic bradycardia in all patients who undergo high dose\ncorticosteroid therapy, not only in those at risk, to early detect and treat\nthis potentially dangerous condition.\n\nCorticosteroidbradycardiaside effectsclinical practice guidelinemyelitiscover-dateJanuary-December 2019\n==== Body\nIntroduction\nCorticosteroids (CS) have a wide range of uses, mainly related to their strong\nanti-inflammatory and immune-modulating properties. Inflammatory myelitis is\ncommonly treated with pulse corticosteroid therapy (PST) (high-dose of intravenous\nmethylprednisolone at 1000 mg daily for 3-7 days).1 The most common side-effects of high-dose PST are hyperglycemia,\ngastrointestinal intolerance, minor infections, and psychiatric symptoms. Minor\nadverse effects can be considered as transient facial flushing, a brief disturbance\nof taste, distal paresthesia, insomnia, and mild weight gain. Overall, cardiac\narrhythmias (atrial fibrillation/flutter, ventricular tachycardia, and sinus\nbradycardia) have been reported in 1% to 82%2,3 of patients undergoing high-dose\ncorticosteroid therapy. Bradycardia is a rare adverse effect1 of PST and is often asymptomatic.4,5 In this case report, we describe\nan episode of severe and symptomatic sinus bradycardia, developed after 5 days of\nPST in a 48-year-old woman with a inflammatory myelitis. We also provide a\nstatistical analysis of the published data regarding bradycardia associated with\nsteroid treatment, to identify variables related to the occurrence of this\nside-effect.\n\nCase Presentation\nA 48-year-old white woman was admitted to the neurological department of the Careggi\nHospital (Florence, Italy) for a 15-month history of paresthesias of the lower\nlimbs, in the absence of motor deterioration. Her medical history was only\nsignificant for gastric ulcer (chronically treated with proton-pump inhibitors\n[PPIs]) and smoking (about 20 cigarettes). A spinal cord magnetic resonance imaging\n(MRI) showed signal abnormalities in cervical (C2-C6) and thoracic (D6) regions;\nnone had contrast enhancement (Figure 1). A brain MRI revealed a 44-mm meningioma situated on the floor\nof left middle cranial fossa, without signs of raised intracranial pressure. A\nlumbar puncture was performed, demonstrating 2.05 g of total proteins, normal cell\ncount, link index of 0.66, and oligoclonal immunoglobulin G (IgG) with a mirror\npattern.\n\nFigure 1. The patient spinal cord MRI showing signal abnormalities in cervical (C2-C6)\nand thoracic (D6) regions. MRI indicates magnetic resonance imaging.\n\nThe patient received a diagnosis of inflammatory myelitis and then a 5-day course of\nintravenous methylprednisolone was prescribed. On Day 3 of PST, she complained of\nchest tightness, which worsened over the next 2 days. On Day 5, she also developed\ndyspnea, weakness, and malaise. Her blood pressure was 170/90 mm Hg and her pulse\nrate (PR) was ranging from 37 to 40 bpm. Pulse corticosteroid therapy was\nimmediately suspended. An increase in body weight (5 kg) was detected compared with\nDay 1. A 12-lead electrocardiogram (ECG) revealed sinus bradycardia (37 bpm),\nwithout signs of acute myocardial infarction, acute coronary syndromes,\natrio-ventricular block, or other forms of arrhythmias (Figure 2). A prior ECG, done a month earlier,\nshowed normal sinus rhythm at 76 bpm. Cardiac biomarkers were normal and blood tests\nshowed mild anemia, slight elevation of creatinine (0.95 mg/dL), potassium level of\n3.9 mEq/L, sodium level of 141 mEq/L, calcium level of 8.4 mg/dL, and a mild\ndecrease of total protein 5.6 g/dL. A normal left ventricular function was proved\nwith echocardiography. A cranial computed tomography (CT) scan was performed, which\ndid not show any significant modifications compared with prior brain MRI images. The\npatient did not receive any treatment, whereas high blood pressure and bradycardia\nspontaneously resolved in few hours and 4 days, respectively.\n\nFigure 2. The patient ECG showing isolated sinus bradycardia (37 bpm). ECG indicates\nelectrocardiogram.\n\nStatistical Analysis and Review of the Literature\nConsidering cases already reported in the literature and the one described here, we\nperformed a correlation study of demographic, clinic, and laboratory data (Table 1). Depending on the\ndistribution of data, we used t-test and non-parametric Mann–Whitney U tests for\nbetween groups’ comparisons and non-parametric Spearman ρ (rho) to evaluate\ncorrelations between groups’ numeric measures. We used chi-square test to compare\ncategorical data. We included in this analysis patients whose data were available:\n34 cases, including 27 women and 7 men.\n\nTable 1. Cases of bradycardia associated with steroids administration included in our\nanalysis.\n\nReference\tPatients\tDisease\tDaily dose*\tNo. of doses\tRoute\tSymptomatic\t\nTvede et al.6\t5 patients: 4 female (21-52 years) and 1 male (53 years)\tRheumatoid arthritis\t1250 mg\t2-3\tIV\t1 patient\t\nGuillén et al.7\t73-year-old female\tPulmonary-renal syndrome\t375 mg\t1\tIV\tYes\t\nKüçükosmanoğlu et al.8\t14-year-old male\tGlomerulonephritis\t1875 mg\t1\tIV\tYes\t\nPudil and Hrncir9\t2 female (14-28 years)\tRheumatoid arthritis, polyarticular arthritis syndrome\t156.3 mg\t4-5\tIV\tNo\t\nJain et al.10\t10 patients: 9 female (29-58 years), 1 male (39 years)\tPemphigus vulgaris\t933.3 mg\t1\tIV\tNo\t\nAl Shibli et al.11\t14-year-old female\tSteroid-sensitive nephrotic syndrome\t80 mg\t7\tOral\tNo\t\nTaylor and Gaco5\t45-year-old female\tMultiple sclerosis\t1250 mg\t5\tOral\tNo\t\nKundu and Fitzgibbons12\t48-year-old female\tMultiple sclerosis\t1250 mg\t4\tIV\tYes\t\nDomínguez-Pinilla et al.13\t15-year-old male\tJuvenile idiopathic arthritis\t312.5 mg\t3\tIV\tNo\t\nJohn et al.14\t58-year-old male\tLaryngeal edema\t50 mg\t2\tIV\tYes\t\nBeyan et al.15\t2 patients: 1 female (24 years) and 1 male (25 years)\tBehçet and LES\t1250 and 150 mg\t3-4\tIV\t1 patient\t\nDashore et al.16\t5 female patients (34-67 years)\tPemphigus vulgaris\t125 mg\t2-3\tIV\t2 patients\t\nMarinov et al.17\t51-year-old female\tPostoperative nausea and vomiting\t25 mg\t1\tIV\tYes\t\nHasan and Al-Khazraji18\t54-year-old female\tAdrenal insufficiency\t100 mg\t1\tOral\tYes\t\nAbbreviation: IV, intravenous.\n\n* steroids daily dose.\n\nIn Table 2, mean and SD\nfor age, number of doses, daily dose, total dose, systolic blood pressure before CS\n(pre-sBP), diastolic blood pressure before CS (pre-dBP), pulse rate before CS\n(pre-PR), and minimal pulse rate after CS (min-PR) are reported. Most subjects\ndeveloped bradycardia at the first day (46.7%) and at the third day (10%) of\nadministration. According to the development of symptoms of bradycardia, we divided\nthe whole sample in 2 groups, asymptomatic subjects (n = 23) and symptomatic\nsubjects (n = 11). These 2 groups had comparable sex, number of doses, pre-PR,\npre-sBP, and pre-dBP. As expected, symptomatic patients reached a lower min-PR\n(P = 0.001). Total dose, but not daily dose, was different\nbetween the 2 groups, being significantly lower in patients w developed symptoms\n(P < 0.034). There were no differences in age, pre-PR,\npre-sBP, pre-dBP, and min-PR between female and male patients. Symptomatic patients\nwere older than asymptomatic patients, although this difference was not\nstatistically significant (P = 0.07).\n\nTable 2. Demographic characteristics and steroid dosage of patients in analysis.\n\n\tWhole sample (n = 34)\tAsymptomatic (n = 23)\tSymptomatic (n = 11)\tP-value\t\nAge (±SD) years\t42.20 (±15.09)\t38.81 (±12.93)\t47.55 (±17.53)\t0.077\t\nSex (women/men)\t27/7\t19/4\t8/3\t0.505\t\nNo. of doses (±SD)\t2.23 (±1.50)\t2.43 (±1.67)\t2.36 (±1.20)\t0.856\t\nPre-sBP (±SD)\t119.27 (±15.25)\t118.05 (±9.63)\t122.11 (±24.46)\t0.859\t\nPre-dBP (±SD)\t73.90 (±9.32)\t73.05 (±7.76)\t75.89 (±12.56)\t0.449\t\nPre-PR (±SD)\t80.43 (±12.08)\t77.86 (±11.95)\t84.80 (±11.33)\t0.135\t\nMin-PR (±SD)\t46.70 (±71.73)\t49.68 (±6.00)\t38.18 (±8.01)\t\n<0.001\n\t\nDaily dose (±SD)\t687.15 (±524.98)\t778.83 (±443.85)\t495.45 (±645.25)\t0.106\t\nTotal dose (±SD)\t1435.65 (±1542.83)\t1559.23 (±1.49)\t1177.27 (±1.68)\t\n0.034\n\t\nAbbreviations: min-PR, minimal pulse rate after CS; pre-dBP, diastolic\nblood pressure before CS; pre-PR, pulse rate before CS; pre-sBP,\nsystolic blood pressure before CS.\n\nValues quoted in the table are mean (±SD); age is expressed in years;\nPre-sBP and Pre-dBP are expressed in mm Hg; Pre-PR and Minimal PR are\nexpressed in beats per minute; daily dose and total dose are expressed\nas prednisone equivalent in mg.\n\nP-value indicates level of significance for comparison\nbetween asymptomatic and symptomatic (significant differences at\nP < 0.05, in bold characters).\n\nDiscussion\nHigh-dose corticosteroid therapy is widely used as attack therapy of inflammatory\ncentral nervous system (CNS) disorders and their relapses. Tachyarrhythmia and sinus\nbradycardia have been both reported as adverse effects; however, bradycardia is\noften asymptomatic.4,5\nBradycardia is generally associated with high-dose intravenous corticosteroid\nadministration, but some cases after low-dose intravenous and oral corticosteroid\ntherapy have been reported.11,15,17,18 In a review of the literature by Stroeder et al.,19 93 cases of bradycardia attributed to PST have been reported, from 1970 to\n2014. Other cases, not included in this work, have been reported12-14,17,18 reaching a total amount of 105\ncases of bradycardia consequently to corticosteroids administration (11 case\nreports, 6 case series, 2 prospective studies, and 1 retrospective study).\n\nNowadays, the pathogenetic mechanism of CS-associated bradycardia remains unclear. An\nanimal study suggests that a single large dose of methylprednisolone may cause a\ndepression of alpha- and beta-1-receptor sensitivity in myocardial cells.20 In humans, CS work on kidneys’ mineralocorticoid receptors inducing an\nexcretion of potassium and reabsorption of sodium, leading to an expansion in\nextracellular volume and rise in blood pressure.21 Sudden changes in serum potassium levels may alter potassium flux across the\ncardiomiocyte’s cellular membrane, causing an alteration in the cardiac\nrhythms.22,23\n\nIt is possible that expansion of plasma volume induces a reflex bradycardia by\nactivation of atrial baroreceptors.24 Indeed, our patient showed a fluid accumulation attested by a 5-kg weight\ngain during the steroid therapy, which could explain the increase in the blood\npressure and the bradycardia described in our report.\n\nAccording to our analysis, we can suggest that lower total doses may be associated\nwith lower PR and with symptomatic bradycardia. This could be explained by the\nsudden treatment discontinuation that happens when symptoms appear, leading to a\nlower total dosage of steroids in these patients, if compared with asymptomatic\ngroup. Daily dose mean values instead do not differ significantly in the two groups.\nOther authors showed that bradycardia is more frequent in older patients and those\nwith underlying cardiac disease25 or with autonomic disturbance like sphincter dysfunction.26 In the absence of these conditions, corticosteroid bradycardia seems to be\nwell tolerated.4,25\n\nConsidering the analysis of the literature, as most cases of bradycardia due to PST\nare asymptomatic, it is probable that this condition is underdiagnosed. It could be\nappropriate to identify patients with risk factors for cardiac arrhythmias before\nthe first administration of PST. These patients should require close monitoring,\nrecording continuously or at least in 3 phases: at the beginning, in the middle, and\nat the end of the daily steroid treatment. An earlier detection of bradycardia could\nlead to a prompt interruption of the steroid therapy, possibly avoiding that the\narrhythmic condition became symptomatic. Moreover, early identification, and\neventually treatment of bradycardia, is crucial, especially in older patients, to\nreduce the risk of falls and to avoid the consequent injuries and\nhospitalization.\n\nOld age and the presence of underlying cardiac disease or autonomic disturbance are\nneither necessary nor sufficient to early identify patients who will develop\nsteroid-induced bradycardia, as demonstrated in the case we report. It could also be\nuseful to monitor steroid-induced fluid retention by daily weight measurement and\nserum electrolytes variations, to identify patients at risk for this adverse\nevent.\n\nConclusions\nCS therapy is a wide-ranging therapy. In many inflammatory diseases of CNS, high-dose\ncorticosteroid is used as attack therapy of relapse of the disease. Many different\nadverse effects are frequent in chronic and in PST, but only few cases of\nbradycardia are reported in the literature. Bradycardia may happen both after\nintravenous and oral administration and is asymptomatic in most of cases; moreover,\nPR generally normalizes spontaneously in few days after discontinuation of the\ntherapy. However, severe bradycardia is an uncomfortable experience and potentially\ndangerous, as described in our case. Clinicians should be aware of this adverse\neffect and consider that some patients have a higher risk.\n\nDeclaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding:The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nAuthor Contributions: AS, S Mazzeo, MP and FP initiated the project. AS and S Mazzeo were responsible\nfor design and methodology. AS, S Mazzeo, MS and MP wrote the final draft. S\nMatà, VB and SS supervised project and reviewed the final draft.\n\nORCID iD: Alessandro Sodero \nhttps://orcid.org/0000-0003-4356-6912\n==== Refs\nReferences\n1 \nWest TW. \nTransverse myelitis—a review of the presentation, diagnosis, and\ninitial management . Discov Med .\n2013 ;16 :167 –177 .24099672 \n2 \nKlein-Gitelman MS Pachman LM. \nIntravenous corticosteroids: adverse reactions are more variable\nthan expected in children . J Rheumatol .\n1998 ;25 :1995 –2002 .9779857 \n3 \nMiura M Ohki H Yoshiba S et al \nAdverse effects of methylprednisolone pulse\ntherapy in refractory Kawasaki disease . Arch Dis\nChild .\n2005 ;90 :1096 –1097 .16177169 \n4 \nAkikusa JD Feldman BM Gross GJ et al \nSinus bradycardia after intravenous pulse\nmethylprednisolone . Pediatrics .\n2007 ;119 :e778 –e782 .17308245 \n5 \nTaylor MR Gaco D. \nSymptomatic sinus bradycardia after a treatment course of\nhigh-dose oral prednisone . J Emerg Med .\n2013 ;45 :e55 –e58 .23827163 \n6 \nTvede N Nielsen LP Andersen V. \nBradycardia after high-dose intravenous methylprednisolone\ntherapy . Scand J Rheumatol .\n1986 ;15 :302 –304 .3798047 \n7 \nGuillén EL Ruiz AM Bugallo JB. \nHypotension, bradycardia, and asystole after high-dose\nintravenous methylprednisolone in a monitored patient .\nAm J Kidney Dis .\n1998 ;32 :e41 –e43 .\n8 \nKüçükosmanoğlu O Karabay A Ozbarlas N et al \nMarked bradycardia due to pulsed and oral\nmethylprednisolone therapy in a patient with rapidly progressive\nglomerulonephritis . Nephron .\n1998 ;80 :484 .9832654 \n9 \nPudil R Hrncir Z. \nSevere bradycardia after a methylprednisolone “minipulse”\ntreatment . Arch Intern Med .\n2001 ;161 :1778 –1779 .\n10 \nJain R Bali H Sharma VK et al \nCardiovascular effects of corticosteroid pulse\ntherapy: a prospective controlled study on pemphigus\npatients . Int J Dermatol .\n2005 ;44 :285 –288 .15811078 \n11 \nAl Shibli A Al Attrach I Hamdan MA \nBradycardia following oral corticosteroid use:\ncase report and literature review . Arab J Nephrol\nTransplant .\n2012 ;5 :47 –49 .22283866 \n12 \nKundu A Fitzgibbons TP. \nAcute symptomatic sinus bradycardia in a woman treated with pulse\ndose steroids for multiple sclerosis: a case report .\nJ Med Case Reports .\n2015 ;9 :216 .\n13 \nDomínguez-Pinilla N del Fresno-Valencia MR de Inocencio Arocena J et al \nBradicardia sinusal secundaria al uso de\ncorticoides en bolo . An Pediatría .\n2014 ;80 :331 –332 .\n14 \nJohn PR Khaladj-Ghom A Still KL. \nBradycardia associated with steroid use for laryngeal edema in an\nadult: a case report and literature review . Case Rep\nCardiol .\n2016 ;2016 :e9785467 .\n15 \nBeyan E Ürün Y Uzuner A. \nBradycardia due to methylprednisolone therapy .\nJ Clin Rheumatol .\n2004 ;10 :204 \nhttp://journals.lww.com/jclinrheum/Fulltext/2004/08000/Bradycardia_due_to_Methylprednisolone_Therapy.16.aspx.\nAccessed February 20, 2017 .\n16 \nDashore S Pande S Borkar M et al \nLate onset bradycardia: an unusual side-effect\nof high dose dexamethasone pulse therapy in patients of pemphigus vulgaris:\na case series of five patients . Indian J Drugs\nDermatol .\n2015 ;1 :23 –26 .\n17 \nMarinov M Fuessel M-U Unterrainer AF. \nBradycardia after dexamethasone for postoperative nausea and\nvomiting prophylaxis during induction of anaesthesia .\nBr J Anaesth .\n2013 ;111 :1025 –1026 .24233311 \n18 \nHasan AQ Al-Khazraji A \nCorticosteroids-induced bradycardia: a case\nreport & literature review . J Med Sci Clin\nRes . 4 :64 .\n19 \nStroeder J Evans C Mansell H. \nCorticosteroid-induced bradycardia . Can\nPharm J CPJ .\n2015 ;148 :235 –240 .\n20 \nHall ED Plaster M Braughler JM. \nAcute cardiovascular response to a single large intravenous dose\nof methylprednisolone and its effects on the responses to norepinephrine and\nisoproterenol . Proc Soc Exp Biol Med .\n1983 ;173 :338 –343 .6867008 \n21 \nHellal-Levy C Couette B Fagart J et al \nSpecific hydroxylations determine selective\ncorticosteroid recognition by human glucocorticoid and mineralocorticoid\nreceptors . FEBS Lett .\n1999 ;464 :9 –13 .10611474 \n22 \nParham WA Mehdirad AA Biermann KM et al \nHyperkalemia revisited .\nTex Heart Inst J .\n2006 ;33 :40 –47 .16572868 \n23 \nFujimoto S Kondoh H Yamamoto Y et al \nHolter electrocardiogram monitoring in nephrotic\npatients during methylprednisolone pulse therapy . Am\nJ Nephrol .\n1990 ;10 :231 –236 .1696428 \n24 \nAnzai Y Nishikawa T. \nHeart rate responses to body tilt during spinal\nanesthesia . Anesth Analg .\n1991 ;73 :385 –390 .1897764 \n25 \nHsu DT. \nSteroids and bradycardia: how slow can you go? \nJ Pediatr Hematol Oncol .\n2008 ;30 :119 –120 .18376262 \n26 \nVasheghani-Farahani A Sahraian MA Darabi L et al \nIncidence of various cardiac arrhythmias and\nconduction disturbances due to high dose intravenous methylprednisolone in\npatients with multiple sclerosis . J Neurol\nSci .\n2011 ;309 :75 –78 .21831398\n\n",
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"keywords": "Corticosteroid; bradycardia; clinical practice guideline; myelitis; side effects",
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"title": "Acute Symptomatic Sinus Bradycardia in High-Dose Methylprednisolone Therapy in a Woman With Inflammatory Myelitis: A Case Report and Review of the Literature.",
"title_normalized": "acute symptomatic sinus bradycardia in high dose methylprednisolone therapy in a woman with inflammatory myelitis a case report and review of the literature"
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"abstract": "As the number of cutaneous surgeries continues to increase, it is important to evaluate the safety of dermatologic surgery in the outpatient setting.\n\n\n\nThe authors sought to determine postoperative bleeding, infection, dehiscence, and necrosis rates in office-based dermatologic surgery using large flap, large graft, and interpolation flap repairs. The authors evaluated the relationship between these complications and surgical site, closure type, repair size, antibiotic use, and antithrombotic use.\n\n\n\nEligible patients were identified through searching the electronic medical records from one Mohs micrographic surgeon at University Hospitals Medical Center. Patient information, surgery characteristics, and complication information were collected. Univariate and multivariate analyses were conducted to reveal associations between each complication and closure type, repair size, repair site, antithrombotic use, and antibiotic use.\n\n\n\nThree hundred and thirty-one reconstruction procedures after Mohs micrographic surgery and excision qualified for the study. The rates of postoperative infection, hemorrhage, hematoma, necrosis, and dehiscence were 5%, 0.3%, 2.4%, 3%, and 0.9%, respectively.\n\n\n\nComplications were infrequent and non-life-threatening. The authors' results indicate that dermatologic surgery using large flaps, interpolation flaps, and large grafts is safe in the office setting.",
"affiliations": "Department of Dermatology, Mayo Clinic, Rochester, Minnesota.;Las Vegas Skin and Cancer Clinics, Las Vegas, Nevada.;Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio.;Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio.",
"authors": "Schmitt|Adam|A|;DePry|Jennifer|J|;Tsai|Sheena|S|;Bordeaux|Jeremy|J|",
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"issue": "44(12)",
"journal": "Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]",
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"medline_ta": "Dermatol Surg",
"mesh_terms": "D000368:Aged; D000556:Ambulatory Surgical Procedures; D000900:Anti-Bacterial Agents; D005260:Female; D005343:Fibrinolytic Agents; D006406:Hematoma; D006801:Humans; D008297:Male; D015580:Mohs Surgery; D009336:Necrosis; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D012867:Skin; D016038:Skin Transplantation; D013524:Surgical Flaps; D013529:Surgical Wound Dehiscence; D013530:Surgical Wound Infection; D058106:Wound Closure Techniques",
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"title": "Retrospective Evaluation of the Safety of Large Skin Flap, Large Skin Graft, and Interpolation Flap Surgery in the Outpatient Setting.",
"title_normalized": "retrospective evaluation of the safety of large skin flap large skin graft and interpolation flap surgery in the outpatient setting"
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"abstract": "DYT6 dystonia can have an unpredictable clinical course and the result of deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi) is known to be less robust than in other forms of autosomal dominant dystonia. Patients who had previous stereotactic surgery with insufficient clinical benefit form a particular challenge with very limited other treatment options available.\n\n\n\nA pediatric DYT6 patient unexpectedly deteriorated to status dystonicus 1 year after GPi DBS implantation with good initial clinical response. After repositioning the DBS electrodes the status dystonicus resolved.\n\n\n\nThis case study demonstrates that medication-resistant status dystonicus in DYT6 dystonia can be reversed by relocation of pallidal electrodes. This case highlights that repositioning of DBS electrodes may be considered in patients with status dystonicus, especially when the electrode position is not optimal, even after an initial clinical response to DBS.",
"affiliations": "Department of Neurosurgery, University of Groningen, University Medical Center Groningen, the Netherlands.;Department of Neurology, University of Groningen, University Medical Center Groningen, the Netherlands.;Department of Neurosurgery, Hannover Medical School, Germany.;Department of Neurosurgery, University of Groningen, University Medical Center Groningen, the Netherlands.;Department of Neurosurgery, Hannover Medical School, Germany.;Department of Neurology, University of Groningen, University Medical Center Groningen, the Netherlands.;Department of Neurosurgery, Hannover Medical School, Germany.;Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands.;Department of Neurosurgery, Hannover Medical School, Germany.;Department of Neurology, University of Groningen, University Medical Center Groningen, the Netherlands.;Department of Neurology, University of Groningen, University Medical Center Groningen, the Netherlands.;Department of Neurosurgery, Hannover Medical School, Germany.",
"authors": "Oterdoom|D L Marinus|DLM|;van Egmond|Martje E|ME|;Ascencao|Luisa Cassini|LC|;van Dijk|J Marc C|JMC|;Saryyeva|Assel|A|;Beudel|Martijn|M|;Runge|Joachim|J|;de Koning|Tom J|TJ|;Abdallat|Mahmoud|M|;Eggink|Hendriekje|H|;Tijssen|Marina A J|MAJ|;Krauss|Joachim K|JK|",
"chemical_list": "D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C474080:THAP1 protein, human",
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"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D82F90DXCase ReportsReversal of Status Dystonicus after Relocation of Pallidal Electrodes in DYT6 Generalized Dystonia Reversal of Status Dystonicus after Relocation of Pallidal ElectrodesOterdoom D.L. Marinus 1*†van Egmond Martje E. 23†Ascencao Luisa Cassini 4van Dijk J. Marc C. 1Saryyeva Assel 4Beudel Martijn 25Runge Joachim 4de Koning Tom J. 67Abdallat Mahmoud 4Eggink Hendriekje 2Tijssen Marina A.J. 2Krauss Joachim K. 41 Department of Neurosurgery, University of Groningen, University Medical Center Groningen, the Netherlands2 Department of Neurology, University of Groningen, University Medical Center Groningen, the Netherlands3 Ommelander Ziekenhuis Groningen, Department of Neurology, Delfzijl and Winschoten, the Netherlands4 Department of Neurosurgery, Hannover Medical School, Germany5 Department of Neurology, Isala Klinieken, Zwolle, the Netherlands6 Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands7 Department of Genetics, University of Groningen, University Medical Center Groningen, the NetherlandsLouis Elan D. Yale University, USA*To whom correspondence should be addressed. E-mail: d.l.m.oterdoom@umcg.nl†These authors contributed equally.2018 13 2 2018 8 53014 11 2017 22 1 2018 © 2018 Oterdoom et al.2018Oterdoom et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nDYT6 dystonia can have an unpredictable clinical course and the result of deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi) is known to be less robust than in other forms of autosomal dominant dystonia. Patients who had previous stereotactic surgery with insufficient clinical benefit form a particular challenge with very limited other treatment options available.\n\nCase Report\nA pediatric DYT6 patient unexpectedly deteriorated to status dystonicus 1 year after GPi DBS implantation with good initial clinical response. After repositioning the DBS electrodes the status dystonicus resolved.\n\nDiscussion\nThis case study demonstrates that medication‐resistant status dystonicus in DYT6 dystonia can be reversed by relocation of pallidal electrodes. This case highlights that repositioning of DBS electrodes may be considered in patients with status dystonicus, especially when the electrode position is not optimal, even after an initial clinical response to DBS.\n\nStatus dystonicusdeep brain stimulationDYT6\n==== Body\nIntroduction\nDystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal, often repetitive, movements, postures, or both. Childhood dystonia is often genetic,1 and DYT6 is one of the autosomal dominant forms, caused by mutations in the thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) gene.2,3 Clinically, DYT6 is characterized by an early age of onset, with symptoms that frequently start in the craniocervical region and spread to the extremities.3,4 Case series on deep brain stimulation (DBS) of the globus pallidus internus (GPi) for DYT6 suggest that improvement is to be expected, but less robust and less predictable than DYT1 dystonia.4–6 One potential reason for this is that there is often prominent oromandibular dystonia, which is less responsive to DBS.7 Furthermore, deterioration of dystonic symptoms 1–3 years after implantation has been reported in DYT6 patients.4,5\n\nStatus dystonicus (SD) represents the severe end of a deteriorating spectrum of dystonia.8 Recently, SD has been defined as “a movement disorder emergency characterized by severe episodes of generalized or focal hyperkinetic movement disorders that had necessitated urgent hospital admission because of life-threatening complications regardless of the patient’s neurological condition at baseline.”9 To date, there is no consensus on the optimal treatment protocol for SD,8,10–12 but early surgical intervention may be a valuable addition to the medical armamentarium for its cessation.8,13 Here we report the case of an 11-year-old DYT6 patient with unexpected and rapid clinical deterioration to SD, after a 1-year period of good response to GPi DB.\n\nThe SD was reversed by repositioning of the DBS electrodes.\n\nCase report\nAfter a normal birth and development, our patient developed a disturbed walking pattern at the age of 3.5 years. At age 5 he was diagnosed with dystonia and 1 year later a p.Arg29Pro mutation in the THAP1 gene was found and the diagnosis DYT6 dystonia was made. His dystonia gradually progressed to the upper limbs at age 6 and at age 9 he developed generalized dystonia. Despite pharmacological treatment with different medications his symptoms further deteriorated and he was no longer able to attend school. He became wheelchair bound with hardly intelligible speech and developed a severely impaired hand function. The neurological assessment on the Burke–Fahn–Marsden Dystonia Rating Scale Movement (BFMDRS-M) at that time was 71 (range 0–120), and on the disability part of the scale (BFMDRS-D) the score was 21 (range 0–30); see Table 1. After multidisciplinary evaluation, DBS was performed with bilateral pallidal electrodes (model 3387; Medtronic, MN, USA) using direct magnetic resonance-guided stereotactic targeting (Figure 1). A postoperative computed tomography scan showed that the actual electrode positions were more lateral than intended (Table 2). Nevertheless, the patient responded well to the DBS and 1 year after the implantation, he could walk without support, and had a clearly improved hand function and speech (BFMDRS-M 69 and BFMDRS-D 14). However, after the first year the effect of pallidal stimulation decreased and at 15 months postoperatively (age 11 years) his clinical status progressively deteriorated to SD, requiring hospital admission. Constipation was considered as a possible trigger and was treated by laxatives without success. No other possible triggers were identified. Despite symptomatic treatment with trihexyphenidyl (6 mg/day, body weight 30 kg), gabapentin (300 mg/day), and clonazepam (1.0 mg/day) and reprogramming of the DBS settings, he developed severe episodes of generalized dystonic spasms, which progressed to continuous abnormal postures and sustained contractions. This was accompanied by metabolic derangements (creatine kinase levels up to 920 IU/L), exhaustion, pain, sleep disturbance, dysphagia, and cachexia. Based on the criteria described by Allen et al.,11 he was initially diagnosed with grade 3 SD, further deteriorating towards grade 4 SD. Since this is a potentially life-threatening situation, the patient was admitted to an intensive care unit (ICU). On the ICU, pharmacological treatment with high doses of benzodiazepines (up to intravenous midazolam 1 mg/kg/hour and enteral clonazepam 3.6 mg/day, body weight 25 kg), clonidine (intravenous 105 µg/day), chloral hydrate (1,250 mg/day), baclofen (12.5 mg/day), gabapentin (900 mg/day), and trihexyphenidyl (8 mg/day) had only limited effect. Nevertheless, he experienced less discomfort, less pain, and the metabolic derangements resolved. However, he suffered from severe adverse effects, especially drowsiness. When subsequently decreasing the dosages, the dystonic movements and the discomfort became more severe. After 4 weeks on the ICU, his condition deteriorated to a total BFMDRS score of 138 (Table 1).\n\n\nTable 1 BFMDRS Scores at Different Time Points\nBFMDRS Scores\tMay 2014\tJune 2015\tDecember 2015\tJanuary 2016\tFebruary 2016\tOctober 2017\t\n\tBefore 1st Surgery\t1 Year after 1st Surgery\tStatus Dystonicus\tBefore 2nd Surgery\tAfter 2nd Surgery\t3 Years after 1st Surgery\t\nDisability\t26\t14\t29\t30\t27\t15\t\nMovement\t71\t69\t90\t108\t73\t64\t\nTotal\t97\t83\t119\t138\t100\t79\t\nThe first deep brain stimulation implantation was in May 2015, the second in February 2016. For privacy reasons, the patient and his parents did not give permission to provide supplemental videos.\n\n\n\n\nFigure 1 Schematic Depiction of the Electrode Positions. (A) Anterior coronal three-dimensional view of initial electrode positions (right 1, left 2) and electrode positions after second surgery (right 3, left 4). Note the position outside the right GPi (R) and barely inside the left GPi (L) of initial electrodes and the improved position after revision surgery. (B) Sagittal view from the right. (C) Sagittal view from the left. Note the improved position of 2 and 4 with at least two contacts within both internal parts of the globus pallidus (GPis). This is achieved by a more frontal burr hole facilitating a more oblique trajectory through the GPi. Anatomical structures and DBS electrodes were drawn into the patients using computed tomography and magnetic resonance imaging in SureTune2 software (Medtronic, MN, USA). R, GPi right; L, GPi left; OT, optic tract; 1, initial electrode right; 2, revised electrode right; 3, initial electrode left; 4, revised electrode left.\n\nTable 2 Electrode Positions Relative to the Midcommisural Point\n\tX left\tY left\tZ left\tX right\tY right\tZ right\t\nFirst surgery\t22.41\t2.7\t–2.9\t22.61\t3.1\t–2.8\t\nSecond surgery\t20\t3\t–4\t20\t3\t–4\t\nTarget coordinates relative to anterior commissure - posterior commissure line midpoint in millimeters.\n\n1 Realized lateral coordinate left 23.1 mm and right 24.4 mm.\n\n\n\n\nAfter extensive multidisciplinary and multicenter deliberation it was decided to reposition the pallidal electrodes to a more dorsal and more medial position. Target coordinates of the old and new electrodes are shown in Table 2 and the new target was further refined by microelectrode recording. After the repositioning of the DBS electrodes the SD ameliorated to a BFMDRS score of 100 after 1 week, and medication dosages were drastically reduced. Six months after the second surgery he was able to walk short distances unaided and attend school without medication (BFMDRS-M 64, BFMDRS-D 15). At present, the duration after the repositioning of the electrodes is 24 months, and the clinical condition of the patient is still gradually improving.\n\nDuring the first surgery the goal was to place electrodes in the posteroventrolateral GPi. However, Figure 1 shows that the electrodes were actually positioned within the external segment of the globus pallidus (GPe). The new electrodes were placed more medially in the posteroventrolateral GPi. The stimulation parameters after the initial implantation were bilateral monopolar stimulation of the most ventral contacts (pulse width 90 μs, frequency 130 Hz, and voltage 2.5 V). In the first year after the initial implantation, voltages were bilaterally increased to 3.5 V. Nine months after the initial implantation stimulation parameters were switched to a big bipolar stimulation field (0–/3+ and 8–/11+), with pulse width of 90 μs, a stimulation frequency of 130 Hz, and a voltage of 4.0 V on both sides. During the SD, the stimulation frequency was changed into 180 Hz on both sides without clinical effect. After the repositioning the stimulation parameters were contacts 1–/2+ and 8–/9+, pulse width 210 μs, frequency 130 Hz, and a voltage of 5.4 V for both sites.\n\nDiscussion\nThis case study demonstrates that medication-resistant SD in DYT6 dystonia can be reversed by repositioning of pallidal electrodes. This is an important finding, particularly because SD can be life-threatening.8\n\nThe exact prevalence of SD in childhood is unknown.8 Two comprehensive systematic literature studies describe a total of 133 episodes of SD in 109 patients, the majority of whom were under age 16 years.8,10 Clinically, SD is characterized by the development of increasingly frequent or continuous severe episodes of generalized dystonic spasms,10,11 often complicated by one or more of the following: bulbar weakness compromising upper airway patency; exhaustion; pain; and metabolic imbalances.12 In two-thirds of cases, a precipitating factor can be identified.8,10 Important triggers include infection, pain, constipation, or a medication change.8,10,12 Addressing these factors is the first step of a recently proposed multistaged approach to childhood SD.10 Neurosurgical intervention for SD appears to have become more frequent in the management of SD, with reported percentages ranging from 40% to 66% of SD patients.8,10 In about 70% of these cases, return to pre-SD baseline or further improvements have been reported.8,10 However, prospective blinded studies on the treatment of SD with systematic follow-up are missing.\n\nIn our case, the initial DBS placement gave some clinical benefit, despite suboptimal electrode localization. Fifteen months after surgery the patient developed severe SD and repositioning of DBS electrodes led to return to the pre-SD baseline condition. The initial response to the first DBS implantation despite the lateral position of the electrodes might be explained by extension of the electrical field into the GPi. Alternatively, it could also be the effect of GPe inhibition. As proposed in the basal-ganglia-thalamic circuit (BGTC) model for dystonia,14 DBS induced increased GPe activity might disrupt the increased BGTC synchronized oscillations in dystonia.8,9,15 However, the optimal DBS target for dystonia is the posteroventrolateral GPi.7 In the literature, target coordinates vary from 18 to 22 mm lateral from the midline.16–18 In our patient, the electrodes were placed too lateral (left 23.1 mm/right 24.4 mm). The reversal of SD by repositioning of the electrodes highlights the importance of optimal electrode placement.\n\nThe case also illustrates the unpredictable clinical effect of DBS in DYT6. This is in line with previous studies focusing on the response of DYT6 patients to pallidal DBS.4–6,19 Two of these studies describe DYT6 patients who initially responded well to pallidal stimulation, but after 1–3 years of stimulation regression occurred requiring lead reposition.4,5\n\nNoteworthy, in this case study, changes in clinical condition of the patient seem to be reflected better by the BFMDRS-D scores than by the BFMDRS-M scores. For example, the BFMDRS-M score 1 year after the first implementation (69) hardly differs from the preoperative BFMDRS-M score (71), while daily functioning was clearly improved, as is shown by a decrease in BFMDRS-D scores from 26 to 14. A possible explanation is that BFMDRS-M measures the intensity of dystonic movements, which usually fluctuate over minutes, hours, or days,8 while BFMDRS-D scores reflect disability for a longer period of time. This observation is paralleled by the results of a previous report showing that DBS may lead to a meaningful change across multiple domains of functioning and disability, even in the absence of a significant change in BFMDRS-M scores.20\n\nIn conclusion, this case study demonstrates that severe SD in DYT6 dystonia can be reversed by relocation of pallidal DBS electrodes, highlighting the importance of optimal electrode placement. Prospective multicenter studies with systematic follow-up are needed to investigate the optimal timing and patient selection for pallidal DBS in SD.\n\nFunding: None.\n\nFinancial Disclosures: M.E. van Egmond received a travel grant from Medtronic. A. Saryyeva and M. Abdallat received travel grants from Medtronic and educational support. T.J. de Koning has received research grants from Metabolic Power Foundation (non-profit) and a research grant from Actelion (for profit), and honoraria for presentations to sponsored meetings from Actelion (for profit) and for contributing to a medical advisory board meeting for Nutricia medical nutrition on the ketogenic diet. M.A.J. Tijssen received research grants from Dystonia Medical research Foundation (DMRF), Science Foundation Dystonia Society, Funds Mental Health, Phelps Foundation. In addition, she received unrestricted grants from Actelion, Merz, Ipsen, Allergan Pharmaceutics & Medtronic. J.K. Krauss is a consultant to Medtronic and to Boston Scientific. Received fees for speaking from AbbVie/St. Jude. The other authors have indicated they have no financial relationships relevant to this article to disclose.\n\nConflicts of Interest: The authors report no conflict of interest.\n\nEthics Statement: This study was reviewed by the authors' institutional ethics committee and was considered exempted from further review.\n==== Refs\nReferences\n1 van Egmond ME Kuiper A Eggink H Sinke RJ Brouwer OF Verschuuren-Bemelmans C Dystonia in children and adolescents: a systematic review and a new diagnostic algorithm J Neurol Neurosurg Psychiatry 2015 86 774 781 doi: 10.1136/jnnp-2014-309106 25395479 \n2 Fuchs T Gavarini S Saunders-Pullman R Raymond D Ehrlich ME Bressman SB Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia Nat Genet 2009 41 286 288 doi: 10.1038/ng.304 19182804 \n3 Djarmati A Schneider SA Lohmann K Winkler S Pawlack H Hagenah J Mutations in THAP1 (DYT6) and generalized dystonia with prominent spasmodic dysphonia: a genetic screening study Lancet Neurol 2009 8 447 452 doi: 10.1016/S1474-4422(09)70083-3 19345148 \n4 Panov F Tagliati M Ozelius LJ Fuchs T Gologorsky Y Cheung T Pallidal deep brain stimulation for DYT6 dystonia J Neurol Neurosurg Psychiatry 2012 83 182 187 doi: 10.1136/jnnp-2011-300979 21949105 \n5 Groen JL Ritz K Contarino MF van de Warrenburg BP Aramideh M Foncke EM DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation Mov Disord 2010 14 2420 2427 doi: 10.1002/mds.23285 \n6 Zittel S Moll CK Bruggemann N Tadic V Hamel W Kasten M Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families Mov Disord 2010 25 2405 2412 doi: 10.1002/mds.23279 20687193 \n7 Vidailhet M Jutras MF Grabli D Roze E Deep brain stimulation for dystonia J Neurol Neurosurg Psychiatry 2013 84 1029 1042 doi: 10.1136/jnnp-2011-301714 23154125 \n8 Lumsden DE King MD Allen NM Status dystonicus in childhood Curr Opin Pediatr 2017 29 674 682 doi: 10.1097/MOP.0000000000000556 28937508 \n9 Ruiz-Lopez M Fasano A Rethinking status dystonicus Mov Disord 2017 32 1667 1676 doi: 10.1002/mds.27207 29144565 \n10 Fasano A Ricciardi L Bentivoglio AR Canavese C Zorzi G Petrovic I Status dystonicus: predictors of outcome and progression patterns of underlying disease Mov Disord 2012 27 783 788 doi: 10.1002/mds.24981 22488948 \n11 Allen NM Lin JP Lynch T King MD Status dystonicus: a practical guide Dev Med Child Neurol 2014 56 105 112 doi: 10.1111/dmcn.12339 24304390 \n12 Manji H Howard RS Miller DH Hirsch NP Carr L Bhatia K Status dystonicus: the syndrome and its management Brain 1998 121 243 252 doi: 10.1093/brain/121.2.243 9549503 \n13 Ben-Haim S Flatow V Cheung T Cho C Tagliati M Alterman RL Deep brain stimulation for status dystonicus: a case series and a review of the literature Stereotact Funct Neurosurg 2016 94 207 215 doi: 10.1159/000446191 27504896 \n14 Hendrix CM Vitek JL Toward a network model of dystonia Ann NY Acad Sci 2012 1265 46 55 doi: 10.1111/j.1749-6632.2012.06692.x 22823747 \n15 Chiken S Nambu A Mechanism of deep brain stimulation: inhibition, excitation, or disruption? Neuroscientist 2016 22 313 322 doi: 10.1177/1073858415581986 25888630 \n16 Laitinen LV Bergenheim AT Hariz MI Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease J Neurosurg 1992 76 53 61 doi: 10.3171/jns.1992.76.1.0053 1727169 \n17 Starr PA Vitek JL DeLong M Bakay RAE Magnetic resonance imaging-based stereotactic localization of the globus pallidus and subthalamic nucleus Neurosurg 1999 44 303 313 doi: 10.1097/00006123-199902000-00031 \n18 Krauss JK Yianni J Loher TJ Aziz TZ Deep brain stimulation for dystonia J Clin Neurophysiol 2004 21 18 30 doi: 10.1097/00004691-200401000-00004 15097291 \n19 Miyamoto R Koizumi H Morino H Kawarai T Maruyama H Mukai Y DYT6 in Japan-genetic screening and clinical characteristics of the patients Mov Disord 2014 29 278 280 doi: 10.1002/mds.25745 24227593 \n20 Gimeno H Tustin K Selway R Lin JP Beyond the Burke-Fahn-Marsden Dystonia Rating Scale: deep brain stimulation in childhood secondary dystonia Eur J Paediatr Neurol 2012 16 501 508 doi: 10.1016/j.ejpn.2011.12.014 22258088\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2160-8288",
"issue": "8()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "DYT6; Status dystonicus; deep brain stimulation",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D051017:Apoptosis Regulatory Proteins; D002648:Child; D004268:DNA-Binding Proteins; D046690:Deep Brain Stimulation; D004421:Dystonia; D020821:Dystonic Disorders; D005917:Globus Pallidus; D006801:Humans; D008297:Male; D009687:Nuclear Proteins; D012086:Reoperation",
"nlm_unique_id": "101569493",
"other_id": null,
"pages": "530",
"pmc": null,
"pmid": "29520331",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1727169;22488948;24304390;22823747;9932883;20687191;19345148;29144565;28937508;19182804;9549503;27504896;23154125;25395479;22258088;21949105;20687193;24227593;15097291;25888630",
"title": "Reversal of Status Dystonicus after Relocation of Pallidal Electrodes in DYT6 Generalized Dystonia.",
"title_normalized": "reversal of status dystonicus after relocation of pallidal electrodes in dyt6 generalized dystonia"
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