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"abstract": "The aim of our study was to investigate glue properties of a fibrin sealant in cases of septoplasty and conchotomy.\n\n\n\nDouble-blind prospective randomized study.\n\n\n\nA study of 146 patients (80 M, 66 F) who underwent septoplasty and conchotomy was performed in Assaf Harofeh Medical Center Tzrifin, Israel. The patients were divided randomly into two groups: Group I (n = 74) underwent septoplasty with transseptal suturing, and conchotomy with glue as a haemostatic. Group II (n = 72) underwent septoplasty and conchotomy with glue as a haemostatic as well as septal cartilage and mucoperichodrial flaps sealant (no transseptal suturing). The glue was based on a concentrate of human clottable proteins and purified native human thrombin.\n\n\n\nOur results showed complete healing in both groups without significant differences. One late postoperative nasal bleeding occurred in group I, and none in group II.\n\n\n\nWe conclude that the use of second-generation glue in endonasal surgery is well suited to stop nasal bleeding and seal intranasal flaps. Moreover, it might help to avoid transseptal suturing.",
"affiliations": "Department of Otolaryngology, Head and Neck Surgery, Assaf Harofeh Medical Center, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel. vaimed@yahoo.com",
"authors": "Vaiman|Michael|M|;Sarfaty|Shlomo|S|;Eviatar|Ephraim|E|",
"chemical_list": "D006490:Hemostatics",
"country": "Netherlands",
"delete": false,
"doi": "10.4193/Rhin08.156",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0729",
"issue": "47(3)",
"journal": "Rhinology",
"keywords": null,
"medline_ta": "Rhinology",
"mesh_terms": "D004311:Double-Blind Method; D005260:Female; D006490:Hemostatics; D006801:Humans; D008297:Male; D009300:Nasal Septum; D014420:Turbinates",
"nlm_unique_id": "0347242",
"other_id": null,
"pages": "297-300",
"pmc": null,
"pmid": "19839254",
"pubdate": "2009-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "The use of fibrin sealant as a glue for septoplasty and conchotomy.",
"title_normalized": "the use of fibrin sealant as a glue for septoplasty and conchotomy"
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"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
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"abstract": "Whole-genome sequencing was used to compare longitudinal isolates of Staphylococcus aureus that developed resistance to oxacillin (MIC up to 16 μg/ml). The mecA gene was absent. A novel 5-bp TATCC frameshift insertion in a gene encoding an ABC transporter similar to that of the teichoic acid translocation ATP-binding protein TagH and a 3-bp GCT nonframeshift insertion in the pdhA pyruvate dehydrogenase gene were detected in the oxacillin-resistant isolates.",
"affiliations": "Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA eburd@emory.edu.;Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.",
"authors": "Burd|Eileen M|EM|;Alam|Mohammad Tauqeer|MT|;Passalacqua|Karla D|KD|;Kalokhe|Ameeta S|AS|;Eaton|Molly E|ME|;Satola|Sarah W|SW|;Kraft|Colleen S|CS|;Read|Timothy D|TD|",
"chemical_list": "D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D010068:Oxacillin",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.00615-14",
"fulltext": null,
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"issn_linking": "0095-1137",
"issue": "52(8)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D018528:ATP-Binding Cassette Transporters; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D004269:DNA, Bacterial; D024881:Drug Resistance, Bacterial; D016368:Frameshift Mutation; D016680:Genome, Bacterial; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010068:Oxacillin; D012008:Recurrence; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "3114-7",
"pmc": null,
"pmid": "24850355",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23027967;19321725;19307172;7125630;20080505;20644199;1759816;20807471;23300474;17517606;21278185;17391376;20668911;8585719;2610497;22827703;22932400;1624119",
"title": "Development of oxacillin resistance in a patient with recurrent Staphylococcus aureus bacteremia.",
"title_normalized": "development of oxacillin resistance in a patient with recurrent staphylococcus aureus bacteremia"
} | [
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"companynumb": "PHHY2014US105518",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"abstract": "OBJECTIVE\nA vector force model for the determination of upper eyelid position in the setting of a trabeculectomy bleb is presented. The model is used to explain the clinical courses of 5 patients with bleb-induced upper eyelid malposition and the efficacy of modalities previously described for the treatment of bleb-induced upper eyelid retraction. The novel use of botulinum toxin in the treatment of bleb-induced eyelid retraction and unique surgical considerations in patients with trabeculectomy blebs undergoing upper eyelid surgery are discussed.\n\n\nMETHODS\nA vector force analysis was conducted and a force diagram constructed. The clinical and surgical courses of 5 patients with trabeculectomy blebs and upper eyelid malposition were reviewed. The vector force model was applied to these cases and the previously described treatment modalities for bleb-induced upper eyelid retraction.\n\n\nRESULTS\nVector force analysis demonstrates that in the case of trabeculectomy bleb-induced upper eyelid retraction, the net force vector, which represents the sum of all the individual forces acting on the eyelid, has a positive vertical component resulting in superior displacement of the eyelid. In contrast, bleb-induced ptosis results when the net force vector has a negative vertical component. In 3 patients, alterations in the bleb resulted in resolution of upper eyelid malposition. Botulinum toxin was used to achieve a normal upper eyelid position in 1 patient with lateral canthal tendon disinsertion and unilateral eyelid retraction and 1 patient with bilateral eyelid retraction. One patient developed unilateral ptosis in concert with the emergence of a large Tenon cyst that resolved with the treatment of the cyst via eyelid massage. One patient with unilateral ptosis and an ipsilateral bleb underwent external levator advancement but was unable to achieve the desired upper eyelid height as retraction over the bleb occurred with any attempt to elevate the eyelid above a marginal reflex distance of 1.5 mm. The efficacy of previously reported modalities for the treatment of trabeculectomy bleb-induced upper eyelid retraction can be explained by either a reduction in the positive vertical component of the net force vector or augmentation of the negative vertical component.\n\n\nCONCLUSIONS\nA vector force model systematically accounts for the multiple determinants of upper eyelid position in the setting of a trabeculectomy bleb. This model provides a framework for the evaluation of bleb-induced upper eyelid malposition and offers a logical, mathematical explanation for the occurrence of bleb-induced upper eyelid retraction and the usefulness of previously reported treatment modalities for this clinical entity.",
"affiliations": "*Department of Ophthalmology and Visual Sciences, Carver College of Medicine and †Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa, U.S.A.; ‡Department of Ophthalmology, Colorado Permanente Medical Group, Denver, Colorado, U.S.A.; §Laser Center, Santo Domingo, Dominican Republic; and ‖Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, University of Miami, Miami, Florida, U.S.A.",
"authors": "Clark|Thomas J E|TJ|;Rao|Karan|K|;Quinn|Carolyn D|CD|;Batlle|Juan F|JF|;Alward|Wallace L M|WL|;Wester|Sara T|ST|;Shriver|Erin M|EM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/IOP.0000000000000444",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-9303",
"issue": "32(2)",
"journal": "Ophthalmic plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Ophthalmic Plast Reconstr Surg",
"mesh_terms": "D000368:Aged; D001696:Biomechanical Phenomena; D005141:Eyelid Diseases; D005143:Eyelids; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009801:Oculomotor Muscles; D014130:Trabeculectomy",
"nlm_unique_id": "8508431",
"other_id": null,
"pages": "127-32",
"pmc": null,
"pmid": "25794022",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Vector Force Model of Upper Eyelid Position in the Setting of a Trabeculectomy Bleb.",
"title_normalized": "a vector force model of upper eyelid position in the setting of a trabeculectomy bleb"
} | [
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"companynumb": "ALCN2016US003052",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "TIMOLOL"
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"abstract": "Niacin or tryptophan deficiency causes pellagra. Isoniazid interferes with the absorption of niacin and individuals on Isoniazid (INH) are at risk of pellagra. Isoniazid preventive therapy (IPT) is the administration of isoniazid to immunosuppressed individuals to prevent active tuberculosis (TB). IPT, in sub-Saharan Africa, the region worst hit by HIV and with a high TB prevalence, is recommended. A 40-year-old, HIV+ Zambian woman on Antiretroviral therapy for five years and IPT for three months presented with a four-day history of constipation, generalised body weakness and irrelevant talk. She complained of a generalised rash, sloughing off, and darkening of the skin on the face, neck, forearms, and dorsum of both feet. A physical examination revealed features of pellagra, and rapid response to oral niacin reaffirmed the diagnosis of pellagra. Unlike typical cases of pellagra presenting with the classic 3 Ds of Diarrhoea, Dementia and Dermatitis, our patient presented with constipation instead of diarrhoea. A consideration of Pellagra in HIV+ patients on IPT whose diet is mostly maize-based will be beneficial, even if the classic 3 Ds of diarrhoea, dementia, and dermatitis are not wholly present. A timely diagnosis and prompt treatment of pellagra can be lifesaving.",
"affiliations": "Research Physician-Rwanda Zambia Health Research Group, Lusaka, Zambia.;Medical Residency, Mazabuka General Hospital, Mazabuka, Zambia.;Registered Nurse, Mazabuka General Hospital, Mazabuka, Zambia.;Dermatology and Venereology Unit, Department of Internal Medicine, Livingstone Central Hospital, Livingstone, Zambia.",
"authors": "Kabengele|Chishiba|C|;M'hango|Hellen|H|;Mweemba|Diana|D|;Malumani|Malan|M|",
"chemical_list": "D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D009525:Niacin; D007538:Isoniazid",
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2021.39.73.28072",
"fulltext": "\n==== Front\nPan Afr Med J\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688\nThe African Field Epidemiology Network\n\nPAMJ-39-73\n10.11604/pamj.2021.39.73.28072\nCase Report\nA peculiarly characterised case of isoniazid-induced pellagra- 2 Ds and a C: a case report\nKabengele Chishiba 123https://orcid.org/0000-0003-0087-8596\n\nM’hango Hellen 34\nMweemba Diana 5\nMalumani Malan 67&https://orcid.org/0000-0002-9149-002X\n\n1 Research Physician-Rwanda Zambia Health Research Group, Lusaka, Zambia,\n2 Research Fellow-Sub-Saharan Network for TB and HIV Research Excellence (SANTHE), Durban, South Africa,\n3 Medical Residency, Mazabuka General Hospital, Mazabuka, Zambia,\n4 Registrar, Children´s Hospital- The University Teaching Hospitals, Lusaka, Zambia,\n5 Registered Nurse, Mazabuka General Hospital, Mazabuka, Zambia,\n6 Dermatology and Venereology Unit, Department of Internal Medicine, Livingstone Central Hospital, Livingstone, Zambia,\n7 Mulungushi University, School of Medicine and Health Sciences, Kabwe, Central Province, Zambia\nCorresponding author: Malan Malumani, Dermatology and Venereology Unit, Department of Internal Medicine, Livingstone Central Hospital, Livingstone, Mulungushi University, School of Medicine and Health Sciences, Kabwe, Central Province, Zambia. drmalumani@yahoo.com\n26 5 2021\n2021\n39 7326 1 2021\n10 2 2021\nCopyright: Chishiba Kabengele et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nNiacin or tryptophan deficiency causes pellagra. Isoniazid interferes with the absorption of niacin and individuals on Isoniazid (INH) are at risk of pellagra. Isoniazid preventive therapy (IPT) is the administration of isoniazid to immunosuppressed individuals to prevent active tuberculosis (TB). IPT, in sub-Saharan Africa, the region worst hit by HIV and with a high TB prevalence, is recommended. A 40-year-old, HIV+ Zambian woman on Antiretroviral therapy for five years and IPT for three months presented with a four-day history of constipation, generalised body weakness and irrelevant talk. She complained of a generalised rash, sloughing off, and darkening of the skin on the face, neck, forearms, and dorsum of both feet. A physical examination revealed features of pellagra, and rapid response to oral niacin reaffirmed the diagnosis of pellagra. Unlike typical cases of pellagra presenting with the classic 3 Ds of Diarrhoea, Dementia and Dermatitis, our patient presented with constipation instead of diarrhoea. A consideration of Pellagra in HIV+ patients on IPT whose diet is mostly maize-based will be beneficial, even if the classic 3 Ds of diarrhoea, dementia, and dermatitis are not wholly present. A timely diagnosis and prompt treatment of pellagra can be lifesaving.\n\nPellagra\nniacin deficiency\nisoniazid-induced pellagra\nphotosensitive dermatitis\ncase report\n==== Body\nIntroduction\n\nGasper Casal first described pellagra in 1735 in Spain [1]. It is the archetypal clinical exhibition of niacin deficiency or its precursor amino acid tryptophan and is depicted by erythema and hyperpigmentation of the skin in sun-exposed areas. Niacin (vitamin B3) is a combination of two compounds: nicotinamide and nicotinic acid [2]. Niacin plays a significant role in the metabolism of alcohol, fats, carbohydrates, and proteins. It is also essential in cell signalling, nucleic acid repair, and the detoxification of drugs and reactive oxygen species [3]. The systemic disease that results from niacin deficiency clinically manifests as the 4 Ds: photosensitive dermatitis, dementia, diarrhoea, and death in severe cases [4].\n\nGlobally, tuberculosis (TB) is the leading cause of death from a single infectious agent and accounted for 1.4 million deaths in 2019. Human Immunodeficiency Virus (HIV) infection is the most substantial risk factor for tuberculosis (TB) disease and people living with HIV (PLHIV) are eighteen (18) times more likely to develop active TB than those that do not have HIV [5]. To prevent the evolution of latent tuberculosis to active disease, isoniazid (INH) preventive therapy (IPT) is commonly indicated in PLHIV and other immunosuppressed individuals. The duration of IPT is usually six months. Despite being classically associated with distorted pyridoxine metabolism, INH also indirectly affects tryptophan conversion to nicotinamide. Pellagra may, therefore, result from INH despite pyridoxine supplementation [6].\n\nHIV infection provokes a pellagra-like condition; plasma tryptophan levels are reduced in patients with HIV infection, and elevated dosages of nicotinamide treatment could effectively reverse this HIV-associated metabolic irregularity [7]. HIV infection may induce niacin depletion. Adding INH preventive therapy may worsen the deficit of plasma niacin levels, especially in the malnourished and in those whose staple food is maize-based. We report a case of isoniazid-induced pellagra in an HIV positive patient on isoniazid prophylaxis in Zambia with constipation rather than the expected and traditional diarrhoea.\n\nPatient and observation\n\nPatient information: a 40-year-old female presented to the outpatient department with a four-day history of constipation, generalised body weakness, irrelevant talk, and inability to walk. She was unable to feed orally for two days before presenting to the hospital. She also complained of a generalised rash, sloughing off, and darkening of the skin on the face, neck, forearms, and dorsum of both feet. The rash was itchy and started on the forehead and spread to the cheeks and chin. The patient is HIV positive and has been on antiretroviral therapy for five (5) years now (lamivudine, tenofovir, and efavirenz). She was also on Isoniazid prophylactic therapy (300 mg) and pyridoxine (50 mg) for three months at the time of presentation. She was treated for bacteriologically confirmed TB 5 years before she presented with the above symptoms. She had quit alcohol when she was diagnosed with TB. Her main diet was corn-based, with little protein and occasional vegetables, and she lived with her two children and her cousins and was widowed.\n\nClinical findings: when examined, she was weak and had vital signs within normal limits: blood pressure 110/61mmHg; temperature 36.5°C; pulse 98/min; respiratory rate 18/min. Her speech was slurred. Her tongue was smooth on the oral cavity examination. She appeared distressed and had hyperpigmented lesions with fissures on the forehead, nose, zygomatic and perizygomatic regions, around the neck (Casal's necklace), on both forearms, on the dorsal areas of both feet, as seen in Figure 1. Digital Rectal Examination revealed hard, impacted stool. The rectal mucosa was smooth, and no other masses were noted. Examination of the other systems was unremarkable.\n\nFigure 1 pre-treatment appearance of the patient showing photodermatitis, hyperpigmentation in sun-exposed areas and casal’s necklace (courtesy of Dr Chishiba Kabengele)\n\nDiagnostic assessment: laboratory tests that were done are shown in Table 1. She had microcytic, normochromic anaemia, elevated ESR and HIV-1 viral load and a low CD4 count. The rest of the parameters were within reference ranges. A clinical diagnosis of isoniazid-induced pellagra in an HIV patient with constipation was entertained based on the appearance, distribution, and time frame over which the rash developed.\n\nTable 1 results of laboratory investigations that were done\n\nLaboratory test\tResults\tReference range\t\nWhite blood cell (*109/L)\t3.32\t3.5-10.0\t\nLymphocytes (*109/L)\t0.9\t0.9-5.0\t\nGranulocytes (*109/L)\t2.25\t1.2-8.0\t\nHemoglobin (g/dl)\t10\t11.5-16.5\t\nMean cell hemoglobin (pg)\t26.7\t25.0-35.0\t\nMean corpuscular volume (fl)\t73.9\t75.0-100.0\t\nPlatelets (*109/L)\t286\t150-450\t\nErythrocyte sedimentation rate (ESR)\t18\t< 15\t\nHepatitis B surface antigen\tNegative\t\t\nViral load\t250 copies/ml\t< 50 copies\t\nTreponema pallidum test (RPR)\tNegative\t\t\nCD 4 Count (cells/UI)\t368\t400-1200\t\nAST (U/L)\t20.4\t8.0-45.0\t\nALT (U/L)\t23.3\t8.0-45.0\t\nCreatinine (mmol/L)\t32\t60-120\t\nUrea\t2.4\t2.0-7.0\t\n\nTherapeutic intervention: the patient was hospitalised, and the management plan initially included intravenous vitamin B complex (2mls OD), rectal evacuation with a soap enema, and lactulose syrup. Isoniazid was temporarily withdrawn and reintroduced later after dietary counselling and niacin supplements. Vitamin B3 was introduced on the second day of admission. After dermatological consultation, the entertained diagnosis of pellagra was maintained, and niacin capsules for eight weeks were prescribed. Due to the high cost of niacin, vitamin B complex tablets were instead used by the patient, and Pyridoxine dose was adjusted upwards to 50 mg twice a day for 12 weeks.\n\nFollow-up and outcomes: the patient opened their bowels, on her own, after 48 hours of treatment with lactulose. After two weeks, the patient was reviewed, there was marked improvement of the rash, as shown in Figure 2. Her bowel habits had returned to normal after discharge from the hospital. The patient continued a high protein diet of High energy protein supplement (HEPS) and animal protein, and the generalised body weakness had resolved after a week of treatment. She was scheduled to return for review after a month but did not return.\n\nFigure 2 two weeks post-treatment, showing resolving lesions (courtesy of Dr Chishiba Kabengele)\n\nPatient perspective: during the time she was hospitalized and after the treatment, the patient was delighted with the care she received and was optimistic about the outcome of her condition.\n\nInformed consent: the patient was informed about the case report, why her case was peculiar and the authors’ interest in publishing her case. She willingly gave informed consent to allow the authors to use her photos for this case report.\n\nPatient´s consent: informed consent was obtained from the client for us to use the pictures.\n\nDiscussion\n\nPellagra can be primary or secondary [8]. It is termed primary pellagra when it is a result of deficiency of niacin or vitamin B3. If it occurs, when dietary intake of niacin is adequate, as a result of conditions that affect tryptophan or niacin metabolisms such as alcoholism and use of drugs such as isoniazid, it is termed as secondary. Isoniazid is structurally similar to niacin and therefore competes, biochemically, with niacin resulting in inhibition of niacin's absorption at the intestinal level. The competitive absorption of niacin and isoniazid results in the accumulation of isoniazid, which then inhibits niacin's endogenous production, leading to pellagra [8]. In our patient's case, we contemplate that isoniazid, coupled with her poor diet and HIV infection, was the direct cause of pellagra.\n\nNiacin is an essential component in coenzyme I and coenzyme II, which either donate or accept hydrogen ions in vital oxidation-reduction reactions and, therefore, is needed for adequate cellular function and metabolism. Nicotinamide, the amide form of niacin to which it is converted in the body, on the other hand, has immunomodulatory and anti-inflammatory effects. These essential cellular functions and roles that niacin performs in multiple organs and tissues lead to a diversity in the symptoms and signs associated with pellagra.\n\nThe gastrointestinal disturbances that arise include epigastric discomfort, reduced appetite, nausea, vomiting, and abdominal pain [8]. Although used as one of the characteristic features of pellagra, diarrhoea occurs in only half the cases of pellagra and is due to intestinal mucosal inflammation and atrophy [9]. Diarrhoea was not present in our patient´s case. Out of the traditional three Ds that typically characterise pellagra, only photosensitive dermatitis, and features of dementia were present in our patient. This presentation could have been due to a patchy involvement of the mucosal surface of the GI tract. A quick review of the literature revealed a paucity of data and a dearth of knowledge concerning the mechanism of constipation in pellagra, with only one paper, according to our knowledge reporting constipation in pellagra [10].\n\nFunding:this work was supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative [grant # DEL-15-006]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)´s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa´s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [grant # 107752/Z/15/Z] and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Welcome Trust or the UK government.\n\nConclusion\n\nINH preventive therapy in latent tuberculosis patients is commonly indicated in HIV patients who reside in high TB prevalence settings. A consideration of pellagra in patients on INH therapy whose diet is mostly maise-based will be beneficial, even if the classic 3 Ds of diarrhoea, dementia, and dermatitis are not wholly present. A timely diagnosis and prompt treatment of pellagra in this population can be lifesaving.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nAuthors’ contributions\n\nCK, HM, and DM were responsible for the diagnosis and clinical management of the patient. CK drafted the manuscript. MM participated in the analysis, supervision, writing of the original draft, reviewing and editing of the manuscript for intellectual content. All authors read and approved the final manuscript.\n\nCite this article: Chishiba Kabengele et al. A peculiarly characterised case of isoniazid-induced pellagra- 2 Ds and a C: a case report. Pan African Medical Journal. 2021;39(73). 10.11604/pamj.2021.39.73.28072\n==== Refs\n1 Usman AB Pembi Emmanuel Dogo Belmont Manchan Akoma Chinyere Ovansa Emmanuel Onimisi Mava Yakubu et al Pellagra, a re-emerging disease: a case report of a girl from a community ravaged by insurgency Pan Afr Med J 2019 7 12 33 195 31692657\n2 Kchir H Yacoub H Hassine H Maamouri N Isoniazid-induced pellagra in a patient with Crohn´s disease Clin Case Reports 2020 2 19 8 5 815 818 eCollection 2020 May\n3 Kipsang JK Choge JK Marinda PA Khayeka-Wandabwa C Pellagra in isoniazid preventive and antiretroviral therapy IDCases 2019 5 3 17 e00550 31193074\n4 Matapandeu G Dunn SH Pagels P An outbreak of pellagra in the kasese catchment area, dowa, Malawi Am J Trop Med Hyg 2017 5 96 5 1244 1247 28219990\n5 World Health Organization Global tuberculosis report 2020 2020 Geneva\n6 Coates SJ Blasini AW Musinguzi P Laker-Oketta M Drug-related pellagra in a Ugandan woman on isoniazid preventative therapy IDCases 2020 3 29 20 e00750 32337156\n7 Murray MF Niacin as a potential AIDS preventive factor Med. Hypotheses 1999 11 53 5 375 9 10616035\n8 Hegyi RA Vladimir Schwartz Dermatologic Manifestations of Pellagra Background, Pathophysiology, Etiology [Online] Accessed on 24 Dec 2020\n9 Lule VK Garg S Gosewade SC Tomar SK Khedkar CD Niacin Encycl Food Heal 2015 9 63 72\n10 Hampl JS Hampl WS Pellagra and the origin of a myth: evidence from European literature and folklore JR Soc Med 1997 90 11 636 639\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "39()",
"journal": "The Pan African medical journal",
"keywords": "Pellagra; case report; isoniazid-induced pellagra; niacin deficiency; photosensitive dermatitis",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D003248:Constipation; D003704:Dementia; D003872:Dermatitis; D005260:Female; D015658:HIV Infections; D006801:Humans; D007538:Isoniazid; D009525:Niacin; D010383:Pellagra; D014376:Tuberculosis",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "73",
"pmc": null,
"pmid": "34422196",
"pubdate": "2021",
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"abstract": "Primary breast lymphoma (PBL) in males is a rare clinical entity and has been reported in anecdotal case reports up until now. We report two cases of PBL from a tertiary care centre in Southern India. A 46-year-old male presented with a lump in the right breast with right axillary lymphadenopathy; a biopsy with immunohistochemistry showed neoplastic cells positive for CD 20 and negative for CD 30, epithelial membrane antigen, anaplastic lymphoma kinase, suggestive of diffuse large B cell lymphoma stage IIEA. He received three cycles of CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) chemotherapy, then developed a cerebrovascular accident, and died. The other patient was a 60-year-old male with a left breast lump with left axillary lymphadenopathy. The biopsy with immunohistochemistry showed neoplastic cells positive for CD 23 and CD 5, suggestive of small lymphocytic lymphoma stage IIEA. Initially he received three cycles of cyclophosphamide, vincristine, and prednisolone (COP) and defaulted. One year later, he received six cycles of COP chemotherapy, developed progressive disease, and was lost to follow-up. The literature on PBL in males was reviewed. To conclude, PBL in males is an extremely rare disease and can mimic breast cancer. A strong index of suspicion with early diagnosis by biopsy with immunohistochemistry and treatment with rituximab- and anthracycline-based chemotherapy followed by radiotherapy will improve overall survival.",
"affiliations": "Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, India.",
"authors": "Lokesh|Kn|K|;Sathyanarayanan|Vishwanath|V|;Lakshmaiah|Kc|K|;Suresh|Tm|T|;Lokanatha|D|D|;Govinda Babu|K|K|;Jacob|Linu Abraham|LA|;Babu|Suresh|S|",
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"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2013.347can-7-347Case ReportPrimary breast lymphoma in males—a report of two cases with a review of the literature Lokesh KN Sathyanarayanan Vishwanath Lakshmaiah KC Suresh TM Lokanatha D Govinda Babu K Jacob Linu Abraham Babu Suresh Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka 560029, IndiaCorrespondence to: Vishwanath Sathyanarayanan. vishsathya@gmail.com2013 05 9 2013 7 34721 4 2013 © the authors; licensee ecancermedicalscience.2013This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary breast lymphoma (PBL) in males is a rare clinical entity and has been reported in anecdotal case reports up until now. We report two cases of PBL from a tertiary care centre in Southern India. A 46-year-old male presented with a lump in the right breast with right axillary lymphadenopathy; a biopsy with immunohistochemistry showed neoplastic cells positive for CD 20 and negative for CD 30, epithelial membrane antigen, anaplastic lymphoma kinase, suggestive of diffuse large B cell lymphoma stage IIEA. He received three cycles of CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) chemotherapy, then developed a cerebrovascular accident, and died. The other patient was a 60-year-old male with a left breast lump with left axillary lymphadenopathy. The biopsy with immunohistochemistry showed neoplastic cells positive for CD 23 and CD 5, suggestive of small lymphocytic lymphoma stage IIEA. Initially he received three cycles of cyclophosphamide, vincristine, and prednisolone (COP) and defaulted. One year later, he received six cycles of COP chemotherapy, developed progressive disease, and was lost to follow-up. The literature on PBL in males was reviewed. To conclude, PBL in males is an extremely rare disease and can mimic breast cancer. A strong index of suspicion with early diagnosis by biopsy with immunohistochemistry and treatment with rituximab- and anthracycline-based chemotherapy followed by radiotherapy will improve overall survival. \n\nbreastdiffuse large B cell lymphomasmall lymphocytic lymphoma\n==== Body\nIntroduction\nAround 1% of all malignant breast tumours occur in males, and primary breast lymphoma (PBL) in males is an extremely rare clinical entity and can masquerade as breast cancer in its clinical presentation. Early diagnosis and treatment with a combination of radiotherapy and chemotherapy are important.\n\nCase description\nWe describe two cases of PBL in males from Kidwai Memorial Institute of Oncology, a tertiary care oncology centre in Southern India.\n\nCase 1\nA 46-year-old male presented with a palpable mass in the right breast of one month duration. He denied B symptoms such as fever, weight loss, or drenching night sweats. On examination, he had an Eastern co-operative oncology group performance status (ECOG PS) of 1.5. The right breast lump was 3 × 4 cm with 1 × 1 cm right axillary lymphadenopathy. The breast lump and axillary lymph node biopsy with immunohistochemistry revealed large B cells positive for CD 20 and negative for CD 30, epithelial membrane antigen (EMA), and anaplastic lymphoma kinase (ALK), suggestive of diffuse large B cell lymphoma (DLBCL) of right breast (Ann-Arbor stage IIEA). He was not able to afford rituximab and received three cycles of chemotherapy with cyclophosphamide 750 mg/m2, adriamycin 50 mg/m2, vincristine 1.4 mg/m2, and prednisolone 100 mg/day for five days (CHOP), following which he developed a cerebrovascular accident with right hemiparesis and died.\n\nCase 2\nA 60-year-old male presented with a palpable mass in the left breast of four months duration. He denied B symptoms. On examination, ECOG PS was 2. He had a 5 × 4 cm palpable mass in the left breast and 2 × 2 cm left axillary lymphadenopathy. Examinations of the heart, lungs, and abdomen were normal. The breast lump and axillary lymph node biopsy with immunohistochemistry revealed neoplastic cells positive for CD 23 and CD 5, suggestive of a small lymphocytic lymphoma (SLL) of the left breast (Ann-Arbor stage IIEA). He received chemotherapy with cyclophosphamide, vincristine, prednisolone (COP) for two cycles and defaulted for one year. He then received six cycles of COP, following which he developed a progressive disease with bilateral supraclavicular lymphadenopathy. He was scheduled for further second-line chemotherapy but was lost to follow-up.\n\nThe clinical profile of our patients and a review of the literature have been outlined in Table 1.\n\nDiscussion\nPBL is a rare neoplasm of the breast with an incidence of less than 0.5% of primary breast malignancies [1]. The incidence of PBL in men is extremely low, with around 25 cases reported so far [2]. PBL is defined as those who had no evidence of disease beyond the breast or ipsilateral axillary lymph nodes as seen in both of our cases [3]. DLBCL is the most frequent histological type, while mucosa-associated lymphoid tissue-type lymphoma and follicular lymphoma are seen rarely. However, SLL of the breast as seen in one of our cases is an extremely rare type of PBL [4]. Ryan, in his study on PBL, concluded that the use of anthracycline-containing chemotherapy and radiotherapy is strongly associated with longer overall survival, especially in early-stage disease [5]. Our patients also received anthracycline-based chemotherapy. One of our patients (46-year-old male with DLBCL) received three cycles of chemotherapy and died of a cerebrovascular accident with hemiparesis, and the other patient with SLL was lost to follow-up after six cycles of chemotherapy with progressive disease. Studies have also shown that mastectomy is not of any benefit [6]. Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for patients with good-prognosis DLBCL, but our patients with DLBCL could not afford rituximab therapy [7]. To the best of our knowledge and following our literature search, SLL of the breast has not been reported in males; Park et al reported a case of SLL in the female breast in his case series of nine patients who were treated with CHOP chemotherapy and radiotherapy [8].\n\nConclusion\nPBL in males is an extremely rare entity and can mimic breast cancer. A strong index of suspicion with early diagnosis by biopsy with immunohistochemistry and treatment with rituximab-based chemotherapy followed by radiotherapy will improve overall survival.\n\nConflicts of interest\nThe authors have no conflicts of interest to declare.\n\nAcknowledgments\nWe would like to thank the staff in the Department of Medical Oncology at Kidwai Memorial Institute of Oncology for their help and support in preparing this manuscript.\n\nTable 1. The clinical profile, treatment, and outcome of PBL in males, with a review of the literature.\n\tAge/sex\tPresentation\tHistology\tStage\tTreatment\tOutcome\t\nMpallas et al (2004) [3]\t67 years/M\tMass (R) breast + (R) ALN\tDLBCL\tN.A.\tN.A\tDied\t\nMiura et al (2009) [11]\t64 years/M\tMass (L) breast\tDLBCL\tIEA\tR-CHOP six cycles + IFRT 50 Gy\tCR EFS – 12 months\t\nRathod et al (2011) [9]\t48 years/M\tMass (L) breast\tDLBCL\tN.A.\tCHOP six cycles\tPR\t\nMahmood et al (2011) [10]\t50 years/M\tMass (L) breast + (L) ALN\tDLBCL\tIIIA\tN.A.\tN.A.\t\nMantia et al (2012) [4]\t54 years/M\tMass in (L) breast initially, followed by (R) breast mass two years later\tFL grade 3\tIII A\tR-CHOP six cycles + lumpectomy\tDied of AML\t\nKo et al (2012) [12]\t51 years/M\tMass (L) breast\tALK negative ALCL\tN.A\tCHOP five cycles\tOne year EFS\t\nPresent study (2013)\t46 years/M\tMass (R) breast + (R) ALN\tDLBCL\tII EA\tCHOP three cycles\tDied\t\nPresent study (2013)\t60 years/M\tMass (L) breast + (L) ALN\tSLL\tIIEA\tThree cycles of COP and defaulted, six cycles COP one year later\tLost to follow-up\t\nALK, anaplastic large cell kinase; ALCL, anaplastic large cell lymphoma; AML, acute myeloid leukaemia; ALN, axillary lymphadenoapthy; CR, complete remission; CHOP, cyclophosphamide, H, doxorubicin, O, vincristine, P, prednisolone; DLBCL, diffuse larger B cell lymphoma; EFS, event-free survival; IFRT, involved field radiotherapy; R, CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; FL, follicular lymphoma; L, left; M, male; N.A, not available; R, right.\n==== Refs\nReferences\n1. Espinosa LA Daniel BL Jeffrey SS Nowels KW Ikeda DM MRI features of mucosa-associated lymphoid tissue lymphoma in the breast AJR Am J Roentgenol 2004 185 199 202 10.2214/ajr.185.1.01850199 15972423 \n2. Duman BB Sahin B Guvenç B Ergin M Lymphoma of the breast in a male patient Med Oncol 2011 28 490 3 10.1007/s12032-010-9675-0 \n3. Mpallas G Simatos G Tasidou A Patra E Galateros G Lakiotis G Papanicolaou S Mpallas E Anagnostou D Primary breast lymphoma in a male patient Breast 2004 13 436 8 10.1016/j.breast.2003.11.002 15454203 \n4. La Mantia E Cantile M Liguori G Di Bonito M De Chiara A D’Aiuto M Pannone G Franco R Botti G Breast systemic follicular lymphoma in a man: a case report J Med Case Rep 2012 6 217 10.1186/1752-1947-6-217 22823980 \n5. Ryan G Martinelli G Kuper-Hommel M Tsang R Pruneri G Yuen K Roos D Lennard A Devizzi L Crabb S Hossfeld D Pratt G Dell’Olio M Choo SP Bociek RG Radford J Lade S Gianni AM Zucca E Cavalli F Seymour JF Primary diffuse large B-cell lymphoma of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma Study Group Ann Oncol 2008 19 233 41 10.1093/annonc/mdm471 17932394 \n6. Jennings WC Baker RS Murray SS Howard CA Parker DE Peabody LF Vice HM Sheehan WW Broughan TA Primary breast lymphoma: the role of mastectomy and the importance of lymph node status Ann Surg 2007 245 784 10.1097/01.sla.0000254418.90192.59 17457172 \n7. Pfreundschuh M Kuhnt E Trümper L Osterborg A Trneny M CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group Lancet Oncol 2011 12 1013 22 10.1016/S1470-2045(11)70235-2 21940214 \n8. Park YH Kim SH Choi SJ Ryoo BY Kang YK Lee SS Primary malignant lymphoma of the breast: clinicopathological study of nine cases Leuk Lymphoma 2004 45 327 30 10.1080/10428190310001597892 15101719 \n9. Rathod J Taori K Disawal A Gour P Dhakate S A rare case of male primary breast lymphoma J Breast Cancer 2011 14 333 6 10.4048/jbc.2011.14.4.333 22323922 \n10. Mahmood S Sabih Z Sabih D Lymphoma presenting as gynaecomastia Biomed Imaging Interv J 2011 7 e10 10.2349/biij.7.2.e10 22287984 \n11. Miura Y Nishizawa M Kaneko H Watanabe M Tsudo M A male with primary breast lymphoma Am J Hematol 2009 84 191 2 10.1002/ajh.21292 18932237 \n12. Ko ES Seol H Shin JH Ko EY Primary anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma of the breast in a male patient Br J Radiol 2012 85 e79 82 10.1259/bjr/23296454 22457412\n\n",
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"abstract": "The Protecting Canadians from Unsafe Drugs Act will eventually require institutions to report all serious adverse drug reactions (ADRs), although the proposed regulations do not yet define what will need to be reported and by whom. Knowledge about the occurrence of serious ADRs in the hospital setting is needed to optimize the effectiveness of reporting and to determine the potential implications of mandatory reporting.\nTo quantify and characterize suspected serious ADRs in patients admitted to a general medicine service, to assess the likelihood of causality, and to determine inter-rater agreement for identification of ADRs and assessment of their likelihood.\nThis prospective observational study involved 60 consecutive patients admitted to a general medicine service at a tertiary care teaching centre starting on March 28, 2016. The primary outcome was the number of serious ADRs, defined by Health Canada as ADRs that result in hospital admission, congenital malformation, persistent or significant disability or incapacity, or death; that are life-threatening; or that require significant intervention to prevent one of these outcomes. Medical records were reviewed independently by pairs of pharmacists for serious ADRs, and the likelihood of causality was assessed using the World Health Organization-Uppsala Monitoring Centre system. Inter-rater agreement was calculated using the kappa score, and disagreements were resolved by discussion and consensus.\nTwenty-three serious ADRs occurred in the sample of 60 patients. The proportion of patients experiencing a serious ADR that contributed to the original hospital admission was 19/60 (32%, 95% confidence interval [CI] 20%-43%), and 4 patients (7%, 95% CI 0%-13%) experienced a serious ADR during their hospital stay. Inter-rater agreement for occurrence of serious ADRs was moderate (kappa 0.58, 95% CI 0.35-0.76).\nReportable serious ADRs were common among patients admitted to a general medicine service. Canadian hospitals would face difficulties reporting all serious ADRs because of the frequency of their occurrence and the subjectivity of their identification.",
"affiliations": ",BScPharm, ACPR, was, at the time of this study, a pharmacy resident at The Ottawa Hospital, Ottawa, Ontario. She is now a Pharmacist with the Centre de santé Saint-Boniface, My Health Team, St Boniface/St Vital, Winnipeg, Manitoba.;,BScPharm, ACPR, BCOP, is a Pharmacist with The Ottawa Hospital and a Clinician Investigator with The Ottawa Hospital Research Institute, Ottawa, Ontario.;,BScPharm, ACPR, PharmD, is a Clinical Pharmacy Specialist with The Ottawa Hospital and an Associate Scientist with The Ottawa Hospital Research Institute, Ottawa, Ontario.;,BScPharm, ACPR, BCOP, is a Pharmacist with The Ottawa Hospital and a Clinician Investigator with The Ottawa Hospital Research Institute, Ottawa, Ontario.;,MD, FRCPC, MSc, is a Staff Physician with the Department of Medicine, The Ottawa Hospital; a Clinician Investigator with The Ottawa Hospital Research Institute; and an Assistant Professor with the University of Ottawa, Ottawa, Ontario.;,BScPharm, ACPR, MSc, is the Professional Practice Coordinator and a Pharmacist with The Ottawa Hospital and a Clinician Investigator with The Ottawa Hospital Research Institute, Ottawa, Ontario.",
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"abstract": "Mastocytosis is a myeloproliferative neoplasm characterized by clonal expansion of abnormal mast cells, ranging from the cutaneous forms of the disease to mast cell leukemia. In a significant proportion of patients, systemic mastocytosis (SM) coexists with another hematologic malignancy, termed systemic mastocytosis with an associated hematologic nonmast cell lineage disorder (SM-AHNMD). Despite the pronounced predominance of concomitant myeloid neoplasms, the much more unusual coexistence of lymphoproliferative diseases has also been reported. Imatinib mesylate (IM) has a role in the treatment of SM in the absence of the KITD816V mutation. In the setting of SM-AHNMD, eradicating the nonmast cell malignant clone greatly affects prognosis. We report a case of an adult patient with SM associated with B-lineage acute lymphoblastic leukemia (B-ALL). Three cases of concurrent adult ALL and mastocytosis have been reported in the literature, one concerning SM and two concerning cutaneous mastocytosis (CM), as well as six cases of concomitant CM and ALL in children.",
"affiliations": "Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Department of Pathology, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pathology, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pathology, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pathology, National and Kapodistrian University of Athens, Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.;Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece.",
"authors": "Iliakis|Theodoros|T|;Rougkala|Niki|N|;Diamantopoulos|Panagiotis T|PT|0000-0003-2692-5944;Papadopoulou|Vasiliki|V|;Kalala|Fani|F|;Zervakis|Konstantinos|K|;Giannakopoulou|Nefeli|N|;Chatzinikolaou|Polixeni|P|;Levidou|Georgia|G|0000-0002-1398-178X;Lakiotaki|Eleftheria|E|;Korkolopoulou|Penelope|P|;Patsouris|Efstratios|E|;Variami|Eleni|E|;Viniou|Nora-Athina|NA|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/526129Case ReportAn Adult Patient with Systemic Mastocytosis and B-Acute Lymphoblastic Leukemia Iliakis Theodoros \n1\n\n*\nRougkala Niki \n1\nhttp://orcid.org/0000-0003-2692-5944Diamantopoulos Panagiotis T. \n1\nPapadopoulou Vasiliki \n1\nKalala Fani \n1\nZervakis Konstantinos \n1\nGiannakopoulou Nefeli \n1\nChatzinikolaou Polixeni \n1\nhttp://orcid.org/0000-0002-1398-178XLevidou Georgia \n2\nLakiotaki Eleftheria \n2\nKorkolopoulou Penelope \n2\nPatsouris Efstratios \n2\nVariami Eleni \n1\nViniou Nora-Athina \n1\n1Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma Street, 11527 Athens, Greece2Department of Pathology, National and Kapodistrian University of Athens, Athens, Greece*Theodoros Iliakis: drcab@hotmail.comAcademic Editor: Lothar Bergmann\n\n2014 6 11 2014 2014 5261297 7 2014 9 10 2014 14 10 2014 Copyright © 2014 Theodoros Iliakis et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Mastocytosis is a myeloproliferative neoplasm characterized by clonal expansion of abnormal mast cells, ranging from the cutaneous forms of the disease to mast cell leukemia. In a significant proportion of patients, systemic mastocytosis (SM) coexists with another hematologic malignancy, termed systemic mastocytosis with an associated hematologic nonmast cell lineage disorder (SM-AHNMD). Despite the pronounced predominance of concomitant myeloid neoplasms, the much more unusual coexistence of lymphoproliferative diseases has also been reported. Imatinib mesylate (IM) has a role in the treatment of SM in the absence of the KITD816V mutation. In the setting of SM-AHNMD, eradicating the nonmast cell malignant clone greatly affects prognosis. We report a case of an adult patient with SM associated with B-lineage acute lymphoblastic leukemia (B-ALL). Three cases of concurrent adult ALL and mastocytosis have been reported in the literature, one concerning SM and two concerning cutaneous mastocytosis (CM), as well as six cases of concomitant CM and ALL in children.\n==== Body\n1. Introduction\nMastocytosis is a clonal myeloproliferative disorder characterized by dysregulation of various organs infiltrated with abnormal mast cells and by symptoms attributed to histamine release. According to the location of mast cell proliferation it is classified into cutaneous mastocytosis (CM), affecting solely the skin, and to systemic mastocytosis (SM), involving at least one extracutaneous organ with more severe clinical manifestations. SM is further divided to six subtypes, according to the recent World Health Organization (WHO) classification, reflecting progressive mast cell clonal expansion and severity of symptoms [1].\n\nIn up to 40% of cases, SM is accompanied by a nonmast cell hematologic disorder (SM-AHNMD) [1], resulting in a combination of symptoms, related to each separate component [2]. A form of reactive mast cell hyperplasia, which is observed in other hematologic neoplasms, such as lymphoplasmacytic lymphoma and hairy cell leukemia (HCL) must be excluded [3]. A predominance of associated myeloid disorders, especially chronic myelomonocytic leukemia (CMML) is reported in SM-AHNMD [4, 5]. Lymphoproliferative neoplasms are much less commonly implicated [4, 5], referring to 10 reported cases of non-Hodgkin lymphomas (NHL), 3 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 1 case of HCL, 6 cases of multiple myeloma (MM), and 1 case of Hodgkin lymphoma (HL). SM associated with adult acute lymphoblastic leukemia (ALL) has been documented in the case of a patient with SM associated with B-ALL carrying the (13;13) (q12;q22) translocation [6]. Two other cases concerning adults with concurrent CM and ALL have also been reported [7, 8]. Among children with ALL, six cases of concomitant CM have been described [8–11].\n\nIdentification of the KITD816V mutation comprising almost 80% of c-kit mutations [5] is of major importance in SM-AHNMD. Cases of SM with wild type c-kit or those who carry c-kit mutations other than D816V may respond to therapy with imatinib mesylate (IM). D816V mutation, with rare exceptions, confers resistance to tyrosine kinase inhibitors (TKI) [12]. We present the case of a young woman with B-ALL and concurrent SM lacking the KITD816V mutation.\n\n2. Case Report\nA 40-year-old Caucasian female was admitted displaying symptoms of weakness and fatigue, being febrile (37.9°C) with moderate pallor. Her liver was palpable, as well as a slightly enlarged left inguinal lymph node. She also manifested diffuse cutaneous brown macular lesions on her trunk. Her complete blood count (CBC) revealed normocytic normochromic anemia with a normal leukocyte count and moderate thrombocytopenia. Bone marrow (BM) trephine biopsy and immunophenotype showed extensive infiltration from B-ALL expressing the surface markers CD10, CD19, CD22, CD79a, CD34, CD123, CD38, and Tdt, with an aberrant coexpression of the myeloid markers CD13, CD33. Eosinophilia was noted and spindle-shaped mast cells were present, scattered or in small aggregates, being positive in c-kit and negative in CD2 staining (Figure 1). Polymerase chain reaction (PCR) for KITD816V mutation, fibroblast growth factor receptor 1 and platelet derived growth factor receptor (FGFR1, PDGFR) rearrangements, and breakpoint cluster region/Abelson tyrosine kinase (BCR/ABL) fusion gene was negative. Conventional cytogenetics was normal in all studied metaphases.\n\nThe patient received induction therapy for B-ALL, consisting of dexamethasone, vincristine, idarubicin, cyclophosphamide, cytarabine, and thioguanine, along with intrathecal methotrexate. During induction, she developed severe low respiratory tract infections. BM immunophenotyping and trephine biopsy following induction revealed residual leukemic disease consisting of 10% lymphoblasts and an extensive mast cell infiltration exceeding 50% of nucleated BM cells (Figure 2). The majority of mast cells (>25%) were spindle-shaped, distributed either in a diffuse pattern or forming dense aggregates of more than 15 cells, synchronously expressing the surface markers c-kit (CD117) and CD2. Serum tryptase levels were normal. Thus, the major criterion and two out of the four minor recent diagnostic WHO criteria for SM were fulfilled, unequivocally establishing the diagnosis of SM-AHNMD, in terms of the preexisting B-lymphoid neoplasm [1]. A subsequent skin biopsy revealed only sparse mast cells in the dermis.\n\nIM was administered orally to our patient in a daily dose of 100 mg, due to its previously outlined effectiveness in wild type c-kit and other than D816V mutated cases of SM [12]. Hematological response was temporarily obtained, with CBC values reaching near normal levels in 8 days but it had short duration (Table 1). Since our patient failed to achieve ALL complete remission (CR), she received a salvage regimen consisting of idarubicin, fludarabine, and cytarabine.\n\nFollowing two cycles of the salvage regimen, the patient experienced disease progression. Infusion of clofarabine, a purine nucleoside antimetabolite, was ineffective. IM administration was interrupted, because of elevated liver enzymes. Subsequent BM immunophenotyping and trephine biopsy indicated extensive lymphoblastic marrow infiltration up to fifty percent, with concurrent mast cell infiltration (Figure 3). Palliative care was administered to the patient, who died after a severe low respiratory tract infection.\n\n3. Discussion\nSM-AHNMD is a distinct form of SM characterized by synchronous evolution of two separate clonal populations, one consisting of mast cells and one as a second hematologic malignancy. CMML is the most prevalent concomitant hematologic disorder, followed by other myelodysplastic/myeloproliferative syndromes (MPN/MPDs), MPNs, MDS, and acute myeloid leukemia (AML) [4, 5]. Lymphoproliferative neoplasms are much less frequently found in this setting with reported cases of CLL/SLL, HCL, plasma cell dyscrasias, and lymphomas [3–5]. Among the latter, HL, splenic marginal zone lymphoma, diffuse large B-cell lymphoma, hepatosplenic T-cell γ/δ lymphoma, and cutaneous B-cell lymphoma have rarely been described. We are currently aware of a sole published case of an adult with KITD816V mutated SM associated with B-ALL carrying a (13;13) (q12;q22) translocation [6]. The authors reported that B-ALL was cured by alloHSCT, while SM persisted for more than a decade. The other two reported adult patients suffered from concomitant ALL with cutaneous forms of mastocytosis [7, 8].\n\nSM-AHNMD constitutes about 30%–40% of all SM cases [4, 5] and harbors certain difficulties in terms of diagnosis, therapeutic management, and response assessment. The diagnosis of occult SM associated with ALL is highly demanding, due to its rarity along with shared clinical manifestations between the two entities. In our patient, initial BM biopsy revealed only a 15% infiltration of mast cells, whereas constitutional symptoms and hepatomegaly were attributed to the lymphoid neoplasm.\n\nThe combined nature of SM-AHNMD underlies the need to confront each malignant entity separately but simultaneously. Both its clinical course and prognosis strongly correlate with those of the associated nonmast cell neoplasm and standard regimens are required for the latter. Management of histamine related symptoms, such as anaphylaxis, pruritus, flashing, or malabsorption, lies on relevant pharmaceutical agents. Interferon-α, corticosteroids, and cytoreductive therapies, mostly cladribine, have been used to treat the SM component, with minor responses [13]. Data on the beneficial role of allo-HSCT are scarce and conflicting, due to the rarity of relevant cases [14]. In addition, leukemias arising in the context of SM are considered of poor risk [13]. This was also the case for our patient, who was primarily refractory to all treatment modalities.\n\nIM has demonstrated effectiveness only in c-kit wild type SM cases or when mutations in c-kit outside exon 17 are present [12]. In contrast to CMML cases and other myeloid neoplasms which usually exhibit KITD816V positivity that is not a prominent feature in the category of concomitant lymphoid neoplasms with SM [5], our patient, who did not carry the KITD816V mutation, was treated with IM.\n\nThe duration of response is a prerequisite for its estimation according to the recent International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus criteria, taking into account ascites and pleural effusions, spleen size, liver function, serum tryptase, albumin and CBC values, and mast cell infiltrates in tissue biopsy sections [15]. Prior to duration of response, assessing organ damage is the most crucial parameter in order to apply the previously mentioned criteria in SM-AHNMD cases and may prove difficult due to shared clinicopathological features between the two components of the disease [15]. In our case, response to IM administration could not be assessed because of chemotherapy-related toxicity. Eligible organ damage mostly consisted of transfusion dependent anemia and thrombocytopenia, due to BM infiltration from both diseases. Infiltration from the ALL clone in the performed BM biopsy was around 10% and, thus, not compatible with the severity and duration of cytopenias. Liver biopsy was not carried out due to the patient's poor performance status. As anticipated, the clinical course and prognosis of our patient were principally determined by her poor response to all applied antileukemic treatment modalities, failing to achieve CR. We should acknowledge that the concurrent SM complicated the chemotherapy related marrow and liver toxicities. IM administration enhanced transient hematologic improvement and permitted the administration of subsequent chemotherapeutic agents for ALL. In conclusion, the diagnosis of SM-AHNMD requires careful consideration of both clinical and laboratory findings. The choice of treatment depends on the nature and clinical behaviour of both disorders [13].\n\nOff-label drug use: clofarabine for acute lymphoblastic leukemia in adults.\n\nConflict of Interests\nThe authors have no conflict of interests to disclose.\n\nFigure 1 Initial bone marrow trephine biopsy showing infiltration by an immature blastoid population in H&E stain (a), which immunohistochemically was positive for CD79a (b) and TDT (c). The presence of a small aggregate consisting of spindle shaped mast cells is also illustrated (d).\n\nFigure 2 Bone marrow trephine biopsy after induction with an extensive infiltration by spindle shaped mast cells as illustrated in H&E stain (a) as well as c-KIT immunostaining (b). Immunohistochemical expression for TDT also revealed the presence of infiltration by TDT (+) lymphoblasts (c), which however was lower than that observed initially.\n\nFigure 3 Final bone marrow trephine biopsy in which there is extensive infiltration by medium sized lymphoblasts (a), which were immunohistochemically positive for TDT (b). Concurrent mast cell infiltration is also observed (c-KIT immunohistochemical analysis (c)).\n\nTable 1 Hematological response of our patient to imatinib mesylate (IM).\n\n \tDay of assessment of response following induction (concurrent G-CSF usage)\tInitiation of IM 6 days later (cessation of G-CSF)\t5 days following introduction of IM (without G-CSF or transfusional support)\t8 days following introduction of IM (without G-CSF or transfusional support)\t15 days following introduction of IM (initiation of salvage therapy)\t\nHemoglobin (gr/dL)\t7.2\t8.6\t11.7\t12.3\t11.2\t\nNeutrophils (/μL)\t0.0\t1100\t3600\t4180\t2900\t\nPlatelets (/μL)\t11000\t16000\t91000\t180000\t170000\t\nG-CSF; granulocyte-colony stimulating factor.\n==== Refs\n1 Horny H. P. Akin C. Metcalfe D. D. Swerdlow S. Campo E. Lee Harris N. etal Mastocytosis WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008 Lyon, France IARC Press 53 63 \n2 Lim K.-H. Tefferi A. Lasho T. L. Finke C. Patnaik M. Butterfield J. H. McClure R. F. Li C.-Y. Pardanani A. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors Blood 2009 113 23 5727 5736 10.1182/blood-2009-02-205237 2-s2.0-67651120132 19363219 \n3 Kim Y. Weiss L. M. Chen Y.-Y. Pullarkat V. Distinct clonal origins of systemic mastocytosis and associated B-cell lymphoma Leukemia Research 2007 31 12 1749 1754 10.1016/j.leukres.2007.04.008 2-s2.0-35748965598 17544505 \n4 Sperr W. R. Horny H.-P. Lechner K. Valent P. Clinical and biologic diversity of leukemias occurring in patients with mastocytosis Leukemia and Lymphoma 2000 37 5-6 473 486 10.3109/10428190009058500 2-s2.0-0034050944 11042508 \n5 Sotlar K. Colak S. Bache A. Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD) The Journal of Pathology 2010 220 5 586 595 10.1002/path.2677 2-s2.0-77949865698 20112369 \n6 Tzankov A. Sotlar K. Muhlematter D. Theocharides A. Went P. Jotterand M. Horny H.-P. Dirnhofer S. Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving FLT3 Journal of Clinical Pathology 2008 61 8 958 961 10.1136/jcp.2008.058073 2-s2.0-49149127176 18663058 \n7 Raj S. Khopkar U. Wadhwa S. L. Kapasi A. Urticaria-pigmentosa-like lesions in acute lymphoblastic leukaemia (2 cases) Dermatology 1993 186 3 226 228 10.1159/000247352 2-s2.0-0027403581 8453153 \n8 Fromer J. L. Jaffe N. Urticaria pigmentosa and acute lymphoblastic leukemia. Archives of Dermatology 1973 107 2 283 284 10.1001/archderm.107.2.283 2-s2.0-0015578899 4510082 \n9 Masserot C. Adjaoud D. Haouy S. Deswarte C. Ballerini P. Landman-Parker J. Acute lymphoblastic leukemia and cutaneous mastocytosis in two children Pediatric Blood and Cancer 2008 51 3 444 445 10.1002/pbc.21640 2-s2.0-48249135110 18491374 \n10 Athanassiadou F. Fidani L. Papageorgiou T. Hadjistylianou M. Catriu D. Acute lymphoblastic leukemia and urticaria pigmentosa in an infant Medical and Pediatric Oncology 2000 34 5 368 369 10797364 \n11 Lewis H. M. Winter E. Darbyshire P. Yoong A. Marsden J. R. Moss C. Urticaria pigmentosa and acute lymphoblastic leukaemia Journal of the Royal Society of Medicine 1995 88 9 530 531 2-s2.0-0029160095 \n12 Pardanani A. Elliott M. Reeder T. Li C.-Y. Baxter E. J. Cross N. C. P. Tefferi A. Imatinib for systemic mast-cell disease The Lancet 2003 362 9383 535 537 10.1016/S0140-6736(03)14115-3 2-s2.0-0041656424 \n13 Valent P. Sperr W. R. Akin C. How I treat patients with advanced systemic mastocytosis Blood 2010 116 26 5812 5817 10.1182/blood-2010-08-292144 2-s2.0-78650673033 20855864 \n14 Nakamura R. Chakrabarti S. Akin C. A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis Bone Marrow Transplantation 2006 37 4 353 358 10.1038/sj.bmt.1705245 2-s2.0-32844466631 16400343 \n15 Gotlib J. Pardanani A. Akin C. Reiter A. George T. Hermine O. Kluin-Nelemans H. Hartmann K. Sperr W. R. Brockow K. Schwartz L. B. Orfao A. Deangelo D. J. Arock M. Sotlar K. Horny H.-P. Metcalfe D. D. Escribano L. Verstovsek S. Tefferi A. Valent P. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis Blood 2013 121 13 2393 2401 10.1182/blood-2012-09-458521 2-s2.0-84878423607 23325841\n\n",
"fulltext_license": "CC BY",
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"issue": "2014()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
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"nlm_unique_id": "101512910",
"other_id": null,
"pages": "526129",
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"pmid": "25431599",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "20855864;12932387;18491374;17544505;8453153;23325841;18663058;7562854;10797364;20112369;19363219;4510082;16400343;11042508",
"title": "An adult patient with systemic mastocytosis and B-acute lymphoblastic leukemia.",
"title_normalized": "an adult patient with systemic mastocytosis and b acute lymphoblastic leukemia"
} | [
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"companynumb": "GR-MYLANLABS-2016M1053114",
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"abstract": "OBJECTIVE\nTo describe posterior uveal cleft and chronic hypotony occurring in association with a fluocinolone acetonide implant (Retisert) that was successfully treated by vitrectomy, removal of the implant, and cryotherapy.\n\n\nMETHODS\nA 57-year-old female patient with idiopathic uveitis, well-controlled with cyclosporine, developed chronic hypotony with maculopathy after insertion of a fluocinolone acetonide implant. Visual acuity in the affected eye was counting fingers, and intraocular pressure was 0 mmHg. Wound leakage, cyclodialysis cleft, and cyclitic membrane were excluded. Ultrasound biomicroscopy demonstrated a posterior uveal cleft at the site of implant, which was presumed to have created a channel for passage of intraocular fluid to the suprachoroidal space. The patient was treated with pars plana vitrectomy, removal of the implant, cryotherapy at the implant site, and intravitreal triamcinolone acetonide injection.\n\n\nRESULTS\nThe procedure was well tolerated. Intraoperative appearance suggested incarceration of the implant, which did not show on ultrasound biomicroscopy. Intraocular pressure was normalized 5 days after the surgery. Postoperative visual acuity improved to 20/200 at 2 weeks after the surgery and remained stable through 1 year of follow-up. Uveitis remains well controlled with cyclosporine at 1 year after the procedure.\n\n\nCONCLUSIONS\nPosterior uveal cleft may cause hypotony as a complication of insertion of a fluocinolone acetonide implant. The ultrasound biomicroscopy is a crucial investigation to establish the diagnosis and to exclude other pathologies including cyclodialysis cleft and cyclitic membrane. It may fail to demonstrate incarceration of an implant, however. Proper surgical technique may prevent this complication.",
"affiliations": "From the Casey Eye Institute, Oregon Health and Science University, Portland, Oregon.",
"authors": "Pasadhika|Sirichai|S|;Smith|Justine R|JR|;Flaxel|Christina J|CJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0b013e31819955aa",
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"issn_linking": "1935-1089",
"issue": "4(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "137-9",
"pmc": null,
"pmid": "25390386",
"pubdate": "2010",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Posterior uveal cleft and hypotony complicating insertion of a fluocinolone acetonide implant.",
"title_normalized": "posterior uveal cleft and hypotony complicating insertion of a fluocinolone acetonide implant"
} | [
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"companynumb": "US-BAUSCH-BL-2015-012304",
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"abstract": "Appendicovesical fistula is a rare entity, with only 116 cases reported to date. It is an uncommon form of enterovesical fistula and often associated with a history of appendicitis. It can present as pneumaturia, fecaluria, and recurrent urinary tract infections, not unlike symptoms of enterovesical fistulas. We present a novel case of appendicovesical fistula developing after transurethral resection of bladder tumor and instillation of mitomycin C. Treatment included laparoscopic appendectomy and bladder repair.",
"affiliations": "Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address: Tom.feng@cshs.org.;Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA.;Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, CA.;Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, CA.",
"authors": "Feng|Tom S|TS|;Rusnack|Susan|S|;Kaminski|Jan|J|;Fleshner|Phillip|P|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D016685:Mitomycin",
"country": "United States",
"delete": false,
"doi": null,
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"issue": "89()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D001065:Appendix; D002429:Cecal Diseases; D015653:Cystectomy; D006801:Humans; D007412:Intestinal Fistula; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D001747:Urinary Bladder Fistula; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0366151",
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"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Appendicovesical Fistula Following Transurethral Resection of Bladder Tumor With Mitomycin C.",
"title_normalized": "appendicovesical fistula following transurethral resection of bladder tumor with mitomycin c"
} | [
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"companynumb": "US-ACCORD-037028",
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"activesubstancename": "MITOMYCIN"
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"abstract": "In recent years, anti-CD20 antibodies have been increasingly used to treat lymphoproliferative and immune disorders. Chronic viral infections are infrequently reported in patients receiving these therapies. Enteroviral infection can cause life-threatening meningoencephalitis and other systemic chronic syndromes in immune deficient patients. We describe the clinical courses and outcomes of 6 patients from 2 tertiary care institutions who developed chronic enteroviral infection with neurological manifestations, after combined chemoimmunotherapy with rituximab for B-cell lymphoma. We review the literature that includes 10 sporadic reported cases of chronic enteroviral meningoencephalitis attributed to rituximab therapy. It is a rare disease, and its diagnosis is often elusive. We propose that low immunoglobulin G levels are the main risk factor for developing chronic enteroviral infection and emphasize the need for a high index of suspicion, early diagnosis, and intervention in this iatrogenic and potentially fatal complication.",
"affiliations": "Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Hematology Division Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Hematology Division Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Israel.;Hematology Division Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Israel.;Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.",
"authors": "Grisariu|S|S|;Vaxman|I|I|;Gatt|M|M|;Elias|S|S|;Avni|B|B|;Arad|A|A|;Pasvolsky|O|O|;Raanani|P|P|;Paltiel|O|O|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D016756:Immunoglobulins, Intravenous; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2365",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": "35(4)",
"journal": "Hematological oncology",
"keywords": "enterovirus; lymphoma; review; rituximab",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D001706:Biopsy; D001853:Bone Marrow; D003520:Cyclophosphamide; D004317:Doxorubicin; D004769:Enterovirus Infections; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "591-598",
"pmc": null,
"pmid": "27734521",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Enteroviral infection in patients treated with rituximab for non-Hodgkin lymphoma: a case series and review of the literature.",
"title_normalized": "enteroviral infection in patients treated with rituximab for non hodgkin lymphoma a case series and review of the literature"
} | [
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"companynumb": "IL-TEVA-2018-IL-853378",
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"occurcountry": "IL",
"patient": {
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"actiondrug": "6",
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"activesubstancename": "VINCRISTINE"
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"drugadditional": null,
... |
{
"abstract": "Cutaneous xanthomas are the result of dermal deposition of lipid, mostly caused by disorders of lipid metabolism. Less commonly, they occur in the setting of cholestatic liver disease, leading to accumulation of lipoprotein X, a rare form of dyslipidemia that does not respond well to conventional treatments. We describe an atypical presentation of sudden diffuse xanthomas secondary to lipoprotein X dyslipidemia in the context of cholestatic fulminant hepatitis caused by trimethoprim-sulfamethoxazole hypersensitivity. Histopathology was also atypical and showed an unusual verrucous appearance consisting of overlying epidermal hyperplasia with hyperkeratosis. Our patient had significant improvement, after normalization of her lipid panel under cholestyramine and 13 sessions of apheresis, with topical corticosteroids offering some relief. This rare case shows the importance of recognizing atypical presentations of xanthomas, particularly when they do not respond to conventional dyslipidemia treatments.",
"affiliations": "Division of Dermatology, Department of Medicine, Université de Montréal, Montreal, QC, Canada.;Division of Dermatology, Department of Medicine, Université de Montréal, Montreal, QC, Canada.;Department of Pathology, McGill University Health Center, Montreal, QC, Canada.;Department of Medical Biochemistry, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada.;Division of Hemato-Oncology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada.;Division of Internal Medicine, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada.;Division of Dermatology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada.",
"authors": "Dang|Julie|J|https://orcid.org/0000-0001-5624-2779;Lim|Darosa|D|;Watters|Kevin|K|;Simard|Olivier|O|;Doyon|Karine|K|;Rhéaume|Maxime|M|;Mereniuk|Alexandra|A|https://orcid.org/0000-0002-4090-7833",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X211057937",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211057937\n10.1177_2050313X211057937\nJCMS Case Report\nVerrucous plane xanthomas secondary to lipoprotein X dyslipidemia in the context of cholestatic fulminant hepatitis: A case report\nhttps://orcid.org/0000-0001-5624-2779\nDang Julie 12\nLim Darosa 1\nWatters Kevin 3\nSimard Olivier 4\nDoyon Karine 5\nRhéaume Maxime 6\nhttps://orcid.org/0000-0002-4090-7833\nMereniuk Alexandra 2\n1 Division of Dermatology, Department of Medicine, Université de Montréal, Montreal, QC, Canada\n2 Division of Dermatology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada\n3 Department of Pathology, McGill University Health Center, Montreal, QC, Canada\n4 Department of Medical Biochemistry, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada\n5 Division of Hemato-Oncology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada\n6 Division of Internal Medicine, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada\nJulie Dang, Division of Dermatology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Boul Gouin O, Montreal, QC H4J 1C5, Canada. Email: julie.dang@umontreal.ca\n9 11 2021\n2021\n9 2050313X211057937© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nCutaneous xanthomas are the result of dermal deposition of lipid, mostly caused by disorders of lipid metabolism. Less commonly, they occur in the setting of cholestatic liver disease, leading to accumulation of lipoprotein X, a rare form of dyslipidemia that does not respond well to conventional treatments. We describe an atypical presentation of sudden diffuse xanthomas secondary to lipoprotein X dyslipidemia in the context of cholestatic fulminant hepatitis caused by trimethoprim-sulfamethoxazole hypersensitivity. Histopathology was also atypical and showed an unusual verrucous appearance consisting of overlying epidermal hyperplasia with hyperkeratosis. Our patient had significant improvement, after normalization of her lipid panel under cholestyramine and 13 sessions of apheresis, with topical corticosteroids offering some relief. This rare case shows the importance of recognizing atypical presentations of xanthomas, particularly when they do not respond to conventional dyslipidemia treatments.\n\nXanthoma\nlipoprotein X\napheresis\ndyslipidemia\ncholestasis\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\npmcIntroduction\n\nCutaneous xanthomas are the result of dermal deposition of lipid. They are mostly caused by disorders of lipid metabolism that can be primary or secondary to obesity, diabetes mellitus, cholestatic liver disease and certain medications. The major forms of xanthomas associated with hyperlipidemia are eruptive, tuberous, tendinous and plane (including xanthelasma). Monoclonal gammopathies or lymphoproliferative disorders are other causes of plane xanthomas.\n\nCase report\n\nA 27-year-old Caucasian woman presented with a 2 week onset of diffuse itchy papules, initially on the eyelids, then on the trunk and extremities. Her medical history included mild atopic dermatitis and 3 month previous fulminant hepatitis with cholestasis and multi-organ involvement secondary to trimethoprim and sulfamethoxazole hypersensitivity. A hepatology consultation and liver biopsy confirmed the diagnosis. For this reason, prior to appearance of the cutaneous lesions, the patient was taking prednisone 7.5 mg PO daily (initially started at 60 mg PO daily 3 months prior) and cholestyramine 12 g PO daily. Family history was negative for dyslipidemia or early cardiovascular events.\n\nOn physical examination, she presented diffuse icterus of sclera and skin as well as numerous 1 to 2 cm scaly mildly erythematous papules and plaques on the abdomen, back, limbs and face, mimicking pityriasis rosea (Figure 1). Furthermore, she had palmar xerosis and discrete yellowish papules in the palmar creases, suggestive of xanthoma striatum palmare (Figure 2).\n\nFigure 1. Numerous 1 to 2 cm scaly mildly erythematous papules and plaques on the abdomen.\n\nFigure 2. Palmar xerosis and discrete yellowish papules in the palmar creases.\n\nThe patient was concurrently under investigation for hyponatremia; plasma sodium was very low at 123 mmol/L (normal: 134–144) with normal plasma osmolality at 298 mOsm/kg. Workup revealed extremely elevated total cholesterol at 46.84 mmol/L (normal: 3.8–5.2), elevated triglycerides at 5.47 mmol/L (normal: 0.6–2.3), low high-density lipoprotein at 0.19 mmol/L (normal: 0.9–2.2), elevated alanine aminotransferase at 72 U/L (normal: 3.5–50), and elevated conjugated bilirubin at 136 µmol/L (normal: 1.7–8.6), thus confirming a pseudohyponatremia secondary to hypercholesterolemia in the context of hepatic cholestasis. A lipoprotein electrophoresis demonstrated abnormal migration of beta and pre-betalipoproteins in only one band as well as absence of alpha-lipoproteins, which was compatible with lipoproteinemia X dyslipidemia.\n\nA skin biopsy on the flank revealed mild verrucous epidermal hyperplasia with hyperkeratosis and a prominent papillary dermal infiltrate of xanthomatous cells, compatible with verrucous xanthomas (Figure 3).\n\nFigure 3. Mild verrucous epidermal hyperplasia with hyperkeratosis and a prominent papillary dermal infiltrate of xanthomatous cells.\n\nA trial of topical corticosteroids prior to confirmation of diagnosis provided mild relief of itch. Given the development of dyslipidemia while already on cholestyramine for 3 months, decision was made to initiate weekly apheresis. As lipid apheresis was not available at our center, conventional apheresis (1 plasma volume exchange per procedure with albumin) was used and still lowered her total cholesterol from 46.84 to 5.74 mmol/L in 10 weeks. It was administered every week for 6 weeks, then every 2 weeks for 6 weeks. After the second procedure, the patient already noticed improvement of the pruritus. After 10 weeks, her lesions improved greatly, leaving residual hyperpigmented macules (Figure 4). To this date, the patient was free of relapse 2 months after discontinuation of apheresis.\n\nFigure 4. Residual hyperpigmented macules after 10 weeks of apheresis.\n\nDiscussion\n\nWe describe an atypical presentation of rapidly occurring diffuse plane xanthomas that were clinically squamous without the classic yellow hue, as well as concomitant xanthoma striatum palmare. In addition, the histopathology presents an unusual verrucous appearance consisting of epidermal hyperplasia with hyperkeratosis, reminiscent of verruciform xanthomas, but with the clinical presentation of plane xanthomas. In fact, verruciform xanthomas are rather solitary plane or verrucous plaques in the mouth or anogenital site. They are not caused by dyslipidemia, but can be associated to lymphedema or epidermolysis bullosa.1,2\n\nAnother noteworthy feature is that our patient developed these lesions in the setting of lipoproteinemia X secondary to cholestatic hepatitis caused by trimethoprim-sulfamethoxazole hypersensitivity. The diagnosis of hyperlipoproteinemia X was made a few weeks earlier through investigation of sudden-onset hyponatremia with normal plasma osmolality. Lipoprotein X accumulation is a rarely described complication of severe cholestatic liver diseases and is a rare cause of pseudohyponatremia as it interferes with plasma sodium measurements. It is possibly caused by biliary proteins reflux into the systemic circulation. 3 Therefore, lipid profiles show important elevations of total cholesterol and triglycerides, and low high-density lipoprotein levels. 4 Because lipoprotein X lacks apoB structure, its accumulation does not respond well to conventional treatments such as statins, fibrates and PCSK9 inhibitors. 5\n\nA few case reports showed temporary resolution of xanthomas secondary to lipoprotein X with LDL plasmapheresis, but the ultimate treatment remains addressing the underlying condition such as liver transplantation for persisting liver diseases.3,4,6 Combination with ursodeoxycholic acid and cholestyramine may also help lower lipoprotein X. 3 For xanthelasma, destructive methods include surgical excision, cryotherapy, trichloroacetic acid and laser, though the effects are temporary with a risk of scarring.1,4 For diffuse plane xanthomas, there are rare case reports of treatments with erbium:YAG laser, 7 topical simvastatin 8 and systemic probucol. 9 We describe a rare case of lipoproteinemia X with complete resolution of xanthomas and normalization of the lipid panel after 18 weeks of conventional apheresis, even without a specific LDL filter.\n\nThis rare case highlights the importance of recognizing this atypical clinical presentation and histopathological findings of xanthomas. In the presence of hyperlipidemia, cholestasis and pseudohyponatremia, it is important to perform a lipoprotein electrophoresis to rule out lipoproteinemia X. Investigating possible underlying causes and promptly initiating apheresis can significantly improve the patient’s condition.\n\nAuthor Note: Darosa Lim is now affiliated to Division of Dermatology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada.\n\nAlexandra Mereniuk is now affiliated to Division of Dermatology, Department of Medicine, Université de Montréal, Montreal, QC, Canada.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Informed consent was obtained from the patient.\n\nORCID iDs: Julie Dang https://orcid.org/0000-0001-5624-2779\n\nAlexandra Mereniuk https://orcid.org/0000-0002-4090-7833\n==== Refs\nReferences\n\n1. Massengale WT . Xanthomas (chapter 92). In: Bolognia J Schaffer JV Cerroni L (eds) Dermatology. 4th ed. Philadelphia, PA: Elsevier, 2018, pp. 1634–1643.\n2. Flynn PD . Xanthomas and abnormalities of lipid metabolism and storage (chapter 62). In: Griffiths C Barker J Bleiker T , et al . (eds) Rook’s textbook of dermatology. 9th ed. New York: Wiley, 2016, pp. 1–13.\n3. Brandt EJ Regnier SM Leung EK , et al . Management of lipoprotein X and its complications in a patient with primary sclerosing cholangitis. Clin Lipidol 2015; 10 (4 ): 305–312.26413163\n4. Harris J Cao S Hile G , et al . Diffuse xanthomas in a patient with primary biliary cholangitis and lipoprotein X. JAAD Case Rep 2021; 7 : 30–32.33318998\n5. Kattah L Gómez A Gutiérrez S , et al . Hypercholesterolemia due to lipoprotein X: case report and thematic review. Clin Med Insights Endocrinol Diabetes 2019; 12 : 1179551419878687.31632171\n6. Suzuki L Hirayama S Fukui M , et al . Lipoprotein-X in cholestatic patients causes xanthomas and promotes foam cell formation in human macrophages. J Clin Lipidol 2017; 11 (1 ): 110–118.28391876\n7. Lorenz S Hohenleutner S Hohenleutner U , et al . Treatment of diffuse plane xanthoma of the face with the Erbium:YAG laser. Arch Dermatol 2001; 137 (11 ): 1413–1415.11708942\n8. Yu X Yang L Gu Y , et al . Simvastatin ointment in the treatment of seven childhood diffuse plane xanthomas. J Dermatol 2021; 48 : 223–227.33180983\n9. Miyagawa F Fukumoto T Kobayashi N , et al . Successful treatment of diffuse normolipemic plane xanthoma with probucol. Case Rep Dermatol 2013; 5 (2 ): 148–151.23741215\n\n",
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"medline_ta": "SAGE Open Med Case Rep",
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"title": "Verrucous plane xanthomas secondary to lipoprotein X dyslipidemia in the context of cholestatic fulminant hepatitis: A case report.",
"title_normalized": "verrucous plane xanthomas secondary to lipoprotein x dyslipidemia in the context of cholestatic fulminant hepatitis a case report"
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"abstract": "Plasma and unbound concentrations and hemodynamic and CNS effects were monitored in a patient after overdose of 2 g of lidocaine HCl infused during 1 h. Hypotension, decreased heart rate, tremors, and nonresponsiveness to stimuli were observed at plasma and unbound concentrations of 17.7 and 12.0 micrograms/ml. The half-lives of decline of plasma and unbound concentrations were 3.8 and 2.7 h; the difference in half-lives was due to nonlinear plasma protein binding.",
"affiliations": "Laboratory of Applied Pharmacokinetics, University of Southern California School of Medicine, Los Angeles.",
"authors": "Armstrong|D K|DK|;Bremseth|D L|DL|;Lima|J J|JJ|",
"chemical_list": "D008012:Lidocaine",
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"mesh_terms": "D000368:Aged; D006207:Half-Life; D006339:Heart Rate; D006801:Humans; D007022:Hypotension; D007118:Immunoassay; D008012:Lidocaine; D008297:Male; D014202:Tremor",
"nlm_unique_id": "7909660",
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"title": "Clinical response and total and unbound plasma concentrations after lidocaine overdose.",
"title_normalized": "clinical response and total and unbound plasma concentrations after lidocaine overdose"
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"abstract": "OBJECTIVE\nMethotrexate (MTX) is an important agent for the treatment of primary central nervous system lymphomas (PCNSL) but needs to be given in big doses by intravenous infusions to achieve therapeutic concentrations in the cerebrospinal fluid. However, co-administration with many drugs may delay the excretion of MTX which may cause serious adverse effects if the serum concentration exceeds 0.1 µmol/L 72 h after an intravenous infusion.\n\n\nMETHODS\nA 67-year-old Japanese female with PCNSL was treated with high-dose MTX-based chemotherapy. The serum MTX concentration 72 h post-infusion was 0.153 µmol/L when she was taking levofloxacin (LVFX) but <0.1 µmol/L 72 h after 4 subsequent infusions when she was not taking LVFX. She was given many other drugs but the timing of the short course of LVFX and the fact that ciprofloxacin also delays MTX excretion suggests that LVFX was the cause.\n\n\nCONCLUSIONS\nCo-administration of LVFX may delay the excretion of MTX. Therefore, serum concentrations of MTX should be monitored to help prevent and improve the management of potentially serious MTX drug-drug interaction.",
"affiliations": "Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.;Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.;Department of Neurosurgery, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.;Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.;Department of Neurosurgery, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.",
"authors": "Urata|Shuhei|S|https://orcid.org/0000-0003-1118-4952;Yoshikawa|Naoki|N|https://orcid.org/0000-0002-4928-0395;Saito|Kiyotaka|K|;Tazaki|Tomoya|T|;Ohno|Rie|R|;Takeshima|Hideo|H|;Ikeda|Ryuji|R|",
"chemical_list": null,
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"issue": "46(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "delayed elimination; drug-drug interaction; methotrexate; primary central nervous system lymphoma; therapeutic drug monitoring",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "1796-1799",
"pmc": null,
"pmid": "34008211",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Delayed methotrexate elimination in a patient with primary central nervous system lymphoma: A case report.",
"title_normalized": "delayed methotrexate elimination in a patient with primary central nervous system lymphoma a case report"
} | [
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"companynumb": "JP-ACCORD-227206",
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"abstract": "BACKGROUND\nLoperamide is a mu-opioid receptor agonist that is available as an over-the-counter anti-motility agent in the US and UK; recommended maximum doses of 12-16 mg/day. Anecdotal reports of non-medical use (NMU) have increased over the past decade with supra-therapeutic doses (70-800 mg/day) associated with cardiotoxicity. Little data exists on the prevalence of loperamide NMU.\n\n\nOBJECTIVE\nThe aim of this study was to determine the prevalence of loperamide NMU in the UK and US and to describe characteristics of non-medical loperamide users.\n\n\nMETHODS\nThe Researched, Abuse, Diversion and Addiction Related Surveillance (RADARS® ) Survey of Nonmedical Use of Prescription Drugs (NMURx) was utilized to study NMU of loperamide among the adult population in the UK and US in 2017. The RADARS® NMURx is anonymous and self-administered online.\n\n\nMETHODS\nA total of 40,029 completed surveys were included (10,019 from the UK and 30,010 from the US). Respondents were asked questions about medical and NMU of loperamide, frequency of and reasons for NMU, route of use problematic drug use markers, and demographics.\n\n\nRESULTS\nPrevalence of lifetime loperamide use (95% CI) and lifetime NMU of loperamide were: UK 28.5% (27.67-29.4), and 0.66% (0.5-0.8), respectively; US 33.7% (33.1-34.2), and 5.19% (4.9-5.5), respectively. Problematic drug use markers were elevated in those who reported NMU of loperamide in both the UK and US, however high-risk use was more prevalent in the UK than in the US.\n\n\nCONCLUSIONS\nNMU of loperamide is common. In the current international environment of opioid addiction involving both therapeutic and illicit opioids, awareness of the NMU of loperamide is important.",
"affiliations": "Clinical Toxicology Department, St Thomas' Hospital, Westminster Bridge Road London, London, UK.;Clinical Toxicology Department, St Thomas' Hospital, Westminster Bridge Road London, London, UK.;Rocky Mountain Poison and Drug Center, 1391 Speer Boulevard, Suite 600, Denver, CO, USA.;Rocky Mountain Poison and Drug Center, 1391 Speer Boulevard, Suite 600, Denver, CO, USA.;Rocky Mountain Poison and Drug Center, 1391 Speer Boulevard, Suite 600, Denver, CO, USA.;Clinical Toxicology Department, St Thomas' Hospital, Westminster Bridge Road London, London, UK.",
"authors": "Webb|N E|NE|;Wood|D M|DM|;Black|J C|JC|;Amioka|E|E|;Dart|R C|RC|;Dargan|P I|PI|",
"chemical_list": "D000930:Antidiarrheals; D013287:Illicit Drugs; D055553:Prescription Drugs; D008139:Loperamide",
"country": "England",
"delete": false,
"doi": "10.1093/qjmed/hcz215",
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"issn_linking": "1460-2393",
"issue": "113(1)",
"journal": "QJM : monthly journal of the Association of Physicians",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000930:Antidiarrheals; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D008139:Loperamide; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D063487:Prescription Drug Misuse; D055553:Prescription Drugs; D015995:Prevalence; D011795:Surveys and Questionnaires; D006113:United Kingdom; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "9438285",
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"pmc": null,
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"pubdate": "2020-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Non-medical use of loperamide in the UK and the USA.",
"title_normalized": "non medical use of loperamide in the uk and the usa"
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"activesubstancename": "HYDROMORPHONE HYDROCHLORIDE"
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{
"abstract": "We present a boy with a genetically proven congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. While massively elevated 17-hydroxyprogesterone (17-OHP) concentrations after birth led to the diagnosis, 17-OHP concentrations became immeasurable starting with the second year of life even though the dose of hydrocortisone was continuously decreased to ∼7 mg/m2/day. Furthermore, 17-OHP levels were immeasurable during the ACTH test and after withdrawing hydrocortisone medication. In contrast, ACTH levels increased after cessation of hydrocortisone treatment suggesting complete primary adrenal cortex failure. We discuss this case based on the differential diagnosis of complete adrenal cortex failure including other genetic causes in addition to CAH, prednisolone treatment, autoimmune adrenalitis, adrenoleukodystrophy, CMV infection, and adrenal hemorrhage infarction. The most likely disease in our boy is autoimmune adrenalitis, which is difficult to prove years after the onset of the disease. Treatment of CAH had masked the classical symptoms of complete adrenal cortex insufficiency leading to delayed diagnosis in this case.",
"affiliations": "Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Witten, Germany.;Department of Pediatric Endocrinology, Diabetes, and Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Witten, Germany.;Department of Pediatric Radiology and Sonography, Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Witten, Germany.;Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany.;Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany.;Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University Hospital of Schleswig-Holstein, UKSH, Campus Kiel/Christian Albrecht University of Kiel, CAU, Kiel, Germany.",
"authors": "Reinehr|Thomas|T|;Rothermel|Juliane|J|;Wegener-Panzer|Andreas|A|;Hartmann|Michaela F|MF|;Wudy|Stefan A|SA|;Holterhus|Paul-Martin|PM|",
"chemical_list": "D019326:17-alpha-Hydroxyprogesterone; D006854:Hydrocortisone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000487927",
"fulltext": null,
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"issn_linking": "1663-2818",
"issue": "90(2)",
"journal": "Hormone research in paediatrics",
"keywords": "17-Hydroxyprogesterone ; Adrenal cortex insufficiency ; Autoimmune adrenalitis ; Congenital adrenal hyperplasia ; Hypoglycemia",
"medline_ta": "Horm Res Paediatr",
"mesh_terms": "D019326:17-alpha-Hydroxyprogesterone; D000015:Abnormalities, Multiple; D000303:Adrenal Cortex Diseases; D000312:Adrenal Hyperplasia, Congenital; D000309:Adrenal Insufficiency; D000359:Aftercare; D002648:Child; D002675:Child, Preschool; D057210:Delayed Diagnosis; D006801:Humans; D006854:Hydrocortisone; D007223:Infant; D007231:Infant, Newborn; D008297:Male",
"nlm_unique_id": "101525157",
"other_id": null,
"pages": "138-144",
"pmc": null,
"pmid": "29694951",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vanishing 17-Hydroxyprogesterone Concentrations in 21-Hydroxylase Deficiency.",
"title_normalized": "vanishing 17 hydroxyprogesterone concentrations in 21 hydroxylase deficiency"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1084272",
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"occurcountry": "DE",
"patient": {
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"activesubstancename": "HYDROCORTISONE"
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{
"abstract": "Angioedema is characterized by marked swelling of the subcutaneous or submucosal tissue and may affect various parts of the body, including the face, mouth, and extremities. Angioedema has specifically been associated with the use of several antipsychotic agents, including clozapine, olanzapine, iloperidone, haloperidol, quetiapine, paliperidone, ziprasidone, risperidone, and chlorpromazine. A 67-year-old African American male with a past medical history significant for hypertension, coronary artery disease requiring stent placement, mitral insufficiency, hyperlipidemia, tobacco use disorder, and schizophrenia presented with altered mental status and disorientation in the setting of clozapine nonadherence, which prompted acute hospitalization for clozapine reinitiation. During clozapine titration, the patient developed edema, erythema, and pruritus on his face and arms along with lip swelling characteristic of angioedema. Upon discontinuation of clozapine, the patient was trialed on several other antipsychotic medications to help manage acute psychosis and subsequently developed angioedema symptoms with trials of both olanzapine and quetiapine. Following these 3 distinct events of angioedema, the clinical decision was made to no longer trial atypical antipsychotics for the patient, and loxapine was cautiously initiated. The patient responded well to loxapine and continued to tolerate loxapine therapy for years. This case report identifies angioedema cross-reaction linked with 3 second-generation antipsychotics. Given the potentially life-threatening nature of angioedema, awareness of recurrent angioedema should be undertaken when trialing antipsychotics following an episode of angioedema correlated to antipsychotic use, particularly when trialing antipsychotics from the same generation and with similar chemical structures.",
"affiliations": null,
"authors": "Williams|Gabriela D|GD|https://orcid.org/0000-0001-8768-8706",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.9740/mhc.2019.09.315",
"fulltext": "\n==== Front\nMent Health ClinMent Health ClinmhclMent Health ClinThe Mental Health Clinician2168-9709College of Psychiatric & Neurologic Pharmacists 10.9740/mhc.2019.09.315mhcl-09-05-05MHC-D-19-00007Case ReportsCross-reaction of angioedema with clozapine, olanzapine, and quetiapine: A case report Williams Gabriela D. PharmD, BCPS, BCPPhttps://orcid.org/0000-0001-8768-87061 Clinical Pharmacy Specialist – Psychiatry, Eskenazi Health, Indianapolis, Indiana, gabriela.dimitrievski@gmail.comDisclosures: The author has no actual or potential conflicts of interest related to the content of this article.\n\n9 2019 4 9 2019 9 5 315 317 © 2019 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Angioedema is characterized by marked swelling of the subcutaneous or submucosal tissue and may affect various parts of the body, including the face, mouth, and extremities. Angioedema has specifically been associated with the use of several antipsychotic agents, including clozapine, olanzapine, iloperidone, haloperidol, quetiapine, paliperidone, ziprasidone, risperidone, and chlorpromazine. A 67-year-old African American male with a past medical history significant for hypertension, coronary artery disease requiring stent placement, mitral insufficiency, hyperlipidemia, tobacco use disorder, and schizophrenia presented with altered mental status and disorientation in the setting of clozapine nonadherence, which prompted acute hospitalization for clozapine reinitiation. During clozapine titration, the patient developed edema, erythema, and pruritus on his face and arms along with lip swelling characteristic of angioedema. Upon discontinuation of clozapine, the patient was trialed on several other antipsychotic medications to help manage acute psychosis and subsequently developed angioedema symptoms with trials of both olanzapine and quetiapine. Following these 3 distinct events of angioedema, the clinical decision was made to no longer trial atypical antipsychotics for the patient, and loxapine was cautiously initiated. The patient responded well to loxapine and continued to tolerate loxapine therapy for years. This case report identifies angioedema cross-reaction linked with 3 second-generation antipsychotics. Given the potentially life-threatening nature of angioedema, awareness of recurrent angioedema should be undertaken when trialing antipsychotics following an episode of angioedema correlated to antipsychotic use, particularly when trialing antipsychotics from the same generation and with similar chemical structures.\n\nangioedemaantipsychotic agentsclozapinecross-reactivityCitationHow to cite: Williams GD. Cross-reaction of angioedema with clozapine, olanzapine, and quetiapine: A case report. Ment Health Clin [Internet].\n==== Body\nBackground\nAngioedema is an event characterized by marked swelling of the subcutaneous or submucosal tissue and may affect various parts of the body, including the face, mouth, and extremities. This reaction is often mild and overall self-limiting but can be life-threatening, particularly in cases in which airway patency is threatened.1,2 Angioedema has been linked to a variety of medications and has specifically been associated with the use of several antipsychotic agents, including clozapine, olanzapine, iloperidone, haloperidol, quetiapine, paliperidone, ziprasidone, risperidone, and chlorpromazine.2-8\n\nLimited prior case reports have identified angioedema cross-reactivity among antipsychotic medications. In one published case,2 a 27-year-old female taking clozapine for 5 years presented with facial swelling and periorbital eruption, prompting a diagnosis of acute angioedema. Clozapine therapy was discontinued, and upon resolution of angioedema, olanzapine was initiated; however, angioedema symptoms recurred within several days of initiation of olanzapine. Similarly, a 24-year-old male patient presented with tongue and facial swelling 24 hours after the initiation of haloperidol, prompting haloperidol discontinuation.3 Iloperidone was then initiated, also leading to the formation of an erythematous rash, lip swelling, shortness of breath, and speech difficulty within 3 days.\n\nThe following case report details the development of angioedema following trials of clozapine, olanzapine, and quetiapine in a patient with a long-standing history of schizophrenia. This patient case prompts a need for further awareness of and caution for recurrent angioedema following an initial episode linked to antipsychotic medication.\n\nCase Report\nThe patient is a 67-year-old African American male with a past medical history significant for hypertension, coronary artery disease requiring stent placement, mitral insufficiency, hyperlipidemia, tobacco use disorder, and schizophrenia. The patient was initially brought in for hospitalization by family secondary to altered mental status and disorientation. Upon presentation, an extensive medical workup was undertaken, including laboratory analysis (basic metabolic panel, complete blood count, urinalysis, urine drug screen, ammonia concentration, vitamin B12 concentration, folate concentration, thyroid stimulating hormone, liver function tests, and venereal disease research laboratory), computed tomography of the head, and electroencephalography. All workup for a general medical cause of that patient's acute presentation was negative, and a psychiatric consult was subsequently requested given the patient's chronic history of schizophrenia. Upon consultation and assessment by psychiatric services, the patient endorsed nonadherence to clozapine therapy, with which he had been effectively treated for numerous years. As a result of the negative medical workup and medication nonadherence, the patient was subsequently transferred to the acute care psychiatric unit for reinitiation of clozapine. Concurrent scheduled medications at this time included aspirin 81 mg by mouth daily, atorvastatin 80 mg by mouth at bedtime, buspirone 10 mg by mouth every morning and 20 mg by mouth every night, clopidogrel 75 mg by mouth daily, metoprolol succinate 25 mg by mouth daily, and thiamine 100 mg by mouth daily.\n\nClozapine was titrated up to a dose of 375 mg by mouth nightly over a 14-day period with the ultimate goal of achieving the previously prescribed dose of 450 mg by mouth nightly; however, it was at this time the patient developed edema, erythema, and pruritus to his face and arms along with lip swelling characteristic of and concerning for angioedema. Clozapine was discontinued upon development of this reaction, and the patient was symptomatically treated with hydroxyzine and ranitidine for suspected angioedema. A single 40-mg dose of prednisone was also given to the patient; however, due to resolution of symptoms, further glucocorticoid treatment was not found to be warranted. A complete blood count was drawn and noted to be significant for increased eosinophils to 1.1 10×3/uL, consistent with an inflammatory response. A probability score for this reaction was calculated utilizing the methods described by Naranjo et al,9 which identified the described as a probable drug reaction to clozapine.\n\nAll scheduled antipsychotic therapy was held for 8 days, during which all allergic sequelae improved; all other nonpsychotropic medications were continued without change. Given resolution of the allergic reaction and continued symptoms of uncontrolled psychosis, the decision was made to initiate olanzapine 10 mg by mouth nightly with plans to cautiously increase the dose as tolerated. Two days following the initiation of olanzapine, the patient had a re-emergence of facial edema, and olanzapine was immediately discontinued. Treatment with an antihistamine was again initiated, and the patient was transitioned to haloperidol 5 mg by mouth twice daily for continued treatment of schizophrenia symptoms. A repeat complete blood count indicated a continued increase in eosinophils to 2.9 10×3/uL. Over the next week, haloperidol was titrated to a dose of 5 mg by mouth every morning and 10 mg by mouth nightly, which was well tolerated and appropriately controlled the patient's psychosis, allowing for discharge.\n\nFifteen days after discharge, the patient presented to acute care services again, this time with complaints of disorganization, confusion, and substantial extrapyramidal symptoms. Haloperidol was promptly discontinued and replaced with quetiapine 100 mg by mouth nightly in an attempt to minimize extrapyramidal symptoms. Yet again, following 2 days of quetiapine therapy, the patient re-experienced facial edema. Following this reaction, the decision was made by the treatment team to no longer trial atypical antipsychotics, and loxapine was cautiously initiated. Over the next 2 weeks, loxapine therapy was maintained and slowly titrated to a final dose of 25 mg by mouth each morning and 50 mg by mouth at bedtime. The patient responded well to loxapine, so much so that, at the time of discharge, he was logical, organized, and had a sustained reduction in auditory hallucinations. Additionally, the patient continued to tolerate loxapine therapy with no further emergence of allergic sequelae. A review of the patient's medical record identified continued treatment with loxapine for an additional 2 years following the events reported above, at which time the patient was transitioned to paliperidone due to a sustained unavailability of loxapine at local pharmacies.\n\nDiscussion\nDrug-induced angioedema has been reported1,10,11 with numerous medications and is thought to promote edema via inflammation caused by immunoglobulin E-related hypersensitivity, kinin-dependent processes, or C1-esterase inhibition deficiencies. Angioedema presents as swelling of the subcutaneous and/or submucosal tissue, and although, in many cases, it is mild and self-limiting, it has the potential to cause severe complications, particularly when swelling involves compromise to airway structures.1,2 In various cases, symptoms of angioedema present within the first several weeks of drug therapy; however, cases of angioedema developing after months or years of medication use have also been previously reported.2\n\nPublished reports2-8 have identified cases of angioedema related to antipsychotic use, particularly related to clozapine, olanzapine, iloperidone, haloperidol, quetiapine, paliperidone, ziprasidone, risperidone, and chlorpromazine. Although cases of angioedema have been fairly well documented with a number of antipsychotic medications, very limited information is available regarding the potential cross-reactivity of antipsychotics as it relates to angioedema events. To date, only 2 other cases of cross-reactivity have been published, 1 documenting cross-reactivity between clozapine and olanzapine2 and the other between haloperidol and iloperidone.3 In the case report of cross-reactivity between clozapine and olanzapine,2 the patient presented with a delayed angioedema reaction to clozapine after 5 years of therapy, followed by a similar reaction to olanzapine several days after initiation; similarly, the case report identifying cross-reactivity between haloperidol and iloperidone3 noted reactions within several days of drug initiation. The course of these previously published reports is consistent with the currently presented case in which the patient developed angioedema following years of clozapine therapy with similar reactions occurring several days after the initiation of olanzapine and quetiapine. At the present time, angioedema cross-reaction among 3 antipsychotic medications has not been described elsewhere in the literature.\n\nA potential explanation of the recurrent swelling seen with trials of clozapine and quetiapine, both dibenzodiazepine antipsychotics, and olanzapine, a thienobenzodiazepine antipsychotic, may be related to the structural similarities shared by these 3 medications although this does not explain the lack of reaction seen when the patient was trialed on loxapine, another dibenzodiazepine antipsychotic medication structurally similar to clozapine. Additionally, one cannot rule out other unknown confounding factors that may have contributed to the occurrence of angioedema related specifically to the trials of clozapine, olanzapine, and quetiapine within this patient's course of treatment.\n\nConclusion\nThe presented case report identifies angioedema cross-reaction linked with three atypical antipsychotics: clozapine, olanzapine, and quetiapine. Although usually mild, angioedema may result in life-threatening complications and warrants further awareness regarding the potential recurrence and cross-reactivity of medications. Awareness of and caution for recurrent angioedema should be undertaken when trialing antipsychotics following an episode of angioedema correlated to antipsychotic use, particularly when trialing antipsychotics from the same generation and with similar chemical structures.\n==== Refs\nReferences\n1 Salih I Causes Thomas S and management of drug-induced angioedema Prescriber 2006 17 7 14 8 10.1002/psb.358 \n2 Tatar ZB Oflaz S Baran B A case of late-onset angioedema associated with clozapine and redevelopment of angioedema with olanzapine J Clin Psychopharmacol 2014 34 4 523 5 DOI: 10.1097/JCP.0000000000000153 PubMed PMID: 24911442 24911442 \n3 Muzyk AJ Cvelich RG Kincaid BR Preud'homme XA Angioedema occurring in patient prescribed iloperidone and haloperidol: a cross-sensitivity reaction to antipsychotics from different chemical classes J Neuropsychiatry Clin Neurosci 2012 24 2 E40 1 DOI: 10.1176/appi.neuropsych.11040094 PubMed PMID: 22772698 \n4 Tuman TC Tuman BA Şereflican B Yildirim O Quetiapine associated with angioedema J Clin Psychopharmacol 2016 36 3 289 90 DOI: 10.1097/JCP.0000000000000503 PubMed PMID: 27035491 27035491 \n5 Yucel A Yucel N Ozcan H Saritemur M Dose-dependent paliperidone associated with angioedema J Clin Psychopharmacol 2015 35 5 615 6 DOI: 10.1097/JCP.0000000000000368 PubMed PMID: 26125544 26125544 \n6 Mohan T Bastiampillai T Dhillon R Ziprasidone-induced angioedema J Clin Psychiatry 2009 70 7 1054 DOI: 10.4088/JCP.07l04657 PubMed PMID: 19653983 \n7 Cooney C Nagy A Angio-edema associated with risperidone BMJ 1995 311 7014 1204 DOI: 10.1136/bmj.311.7014.1204c PubMed PMID: 7488898 \n8 Hine FR Severe angioneurotic edema during chlorpromazine therapy Am J Psychiatry 1958 114 10 942 DOI: 10.1176/ajp.114.10.942 PubMed PMID: 13508935 13508935 \n9 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 45 DOI: 10.1038/clpt.1981.154 PubMed PMID: 7249508 7249508 \n10 Lamer V Lipozencic J Turcic P Adverse cutaneous reactions to psychopharmaceuticals Acta Dermatovenerol Croat 2010 18 1 56 67 PubMed PMID: 20361889 20361889 \n11 Inomata N Recent advances in drug-induced angioedema Allergol Int 2012 61 4 545 57 DOI: 10.2332/allergolint.12-RAI-0493 PubMed PMID: 23183389 23183389\n\n",
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"abstract": "We describe 4 cases in which patients with coagulopathies, an absolute contraindication to epidural/paravertebral blocks, received an erector spinae plane block to manage severe thoracic pain with respiratory impairment. Intubation was avoided in 2 cases, and weaning from the ventilator was facilitated in 2 cases. Ultrasound-guided erector spinae plane block is simple to perform, has a low risk profile, and provides an excellent analgesic alternative.",
"affiliations": "Department of Anesthesiology, Kingston Health Sciences Centre, Queen's University, Kingston, Ontario, Canada.;Department of Anesthesiology, Kingston Health Sciences Centre, Queen's University, Kingston, Ontario, Canada.;Department of Anesthesiology, Kingston Health Sciences Centre, Queen's University, Kingston, Ontario, Canada.;Department of Anesthesiology, Kingston Health Sciences Centre, Queen's University, Kingston, Ontario, Canada.;Department of Anesthesiology, Kingston Health Sciences Centre, Queen's University, Kingston, Ontario, Canada. Electronic address: gregory.klar@kingstonhsc.ca.",
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"abstract": "BACKGROUND\nEarly hepatic artery thrombosis (HAT) after liver transplantation is a serious complication that frequently results in graft loss and the need for retransplantation. Although studies have reported on various operative and endovascular treatment approaches, pharmacologic strategies for the prevention or management of HAT are not well defined. Patients with blood clotting disorders, those with a contraindication to heparin, and those who have previously developed HAT represent unique challenges in management.\n\n\nMETHODS\nWe present the case of a 9-month-old male with a hypercoagulable state who developed early HAT after two liver transplants, despite the use of postoperative therapeutic heparin infusion.\n\n\nCONCLUSIONS\nThe patient successfully underwent a third liver transplant using intraoperative and postoperative bivalirudin infusion, a direct thrombin inhibitor. Rotational thromboelastometry (ROTEM) was used to guide anticoagulation and blood product administration in the perioperative period. At 1.5 years post-transplant, the patient has good graft function with patent hepatic vasculature. This case demonstrates the innovative use of bivalirudin anticoagulant therapy and viscoelastic methodologies to improve outcomes in hypercoagulable liver transplant recipients.",
"affiliations": "Division of Transplant Surgery, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Division of Hematology and Oncology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Division of Transplant Surgery, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Division of Transplant Surgery, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.",
"authors": "Craig-Schapiro|Rebecca|R|https://orcid.org/0000-0003-1083-5063;Banc-Husu|Anna M|AM|https://orcid.org/0000-0001-8399-8870;Taylor|Sarah A|SA|;Bercovitz|Rachel S|RS|;Lemoine|Caroline P|CP|https://orcid.org/0000-0002-3422-6740;Superina|Riccardo A|RA|https://orcid.org/0000-0003-3076-2244",
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"title": "Bivalirudin for the prevention of hepatic artery thrombosis in pediatric liver transplantation.",
"title_normalized": "bivalirudin for the prevention of hepatic artery thrombosis in pediatric liver transplantation"
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"abstract": "Systemic lupus erythematosus (SLE) is known to cause neuropsychiatric symptoms (NPSLE). While not formally recognized as a syndrome associated with NPSLE, catatonia has frequently been reported.\n\n\n\nIt is important for clinicians to recognize and treat catatonia as a potential manifestation of NPSLE. We present 2 cases of SLE with catatonia and review the cases reported in the literature.\n\n\n\nWe performed a PubMed search for reported cases of catatonia in SLE. Case reports that met Diagnostic and Statistical Manual of Mental Disorders-5th ed. diagnostic criteria for catatonia were summarized to assess common diagnostic tests and treatments.\n\n\n\nTwenty-six articles describing a total of 35 patients (all female), in addition to our 2 patients, were included in the report. All but one of the patients received immunosuppressive therapy for treatment of SLE. To treat catatonia symptoms, 81% of the patients received benzodiazepines, and 38% received electroconvulsive therapy.\n\n\n\nCatatonia can be a manifestation of NPSLE, particularly in the presence of serologies and symptoms indicative of an active lupus flare. Management of catatonia involves management of the underlying condition, in this case immunomodulatory treatments for NPSLE; avoidance of treatments, such as antipsychotics, which can worsen catatonia; and symptomatic treatments for catatonia, for which benzodiazepines are a first-line treatment, and electroconvulsive therapy when catatonia is refractory to benzodiazepines.",
"affiliations": "Department of Psychiatry (A.B.), NewYork-Presbyterian Hospital, New York, NY.;Department of Psychiatry (A.B.), NewYork-Presbyterian Hospital, New York, NY.;Department of Psychiatry (A.B.), NewYork-Presbyterian Hospital, New York, NY.;Department of Psychiatry (A.B.), NewYork-Presbyterian Hospital, New York, NY.;Department of Psychiatry (A.B.), NewYork-Presbyterian Hospital, New York, NY. Electronic address: acboeke@gmail.com.",
"authors": "Boeke|Annabel|A|;Pullen|Bianca|B|;Coppes|Lucas|L|;Medina|Michel|M|;Cooper|Joseph J|JJ|",
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"title": "Catatonia Associated With Systemic Lupus Erythematosus (SLE): A Report of Two Cases and a Review of the Literature.",
"title_normalized": "catatonia associated with systemic lupus erythematosus sle a report of two cases and a review of the literature"
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"abstract": "The main purpose of this article was to report the incidence of neonatal neutropenia or leukopenia after chemotherapy exposure during pregnancy according to the time elapsed between treatment during pregnancy and birth.\n\n\n\nA single study reports 33% of infants exposed to chemotherapy within the last month of pregnancy are born with neutropenia, which can place the newborn at risk for nosocomial infections. On the basis of this report, chemotherapy is typically stopped by 34 weeks of pregnancy to avoid maternal or neonatal myelosuppression at delivery. Such a pause in treatment may affect maternal health. Determining the true incidence of neutropenia after chemotherapy in relation to the time of this lapse in treatment is important to support this practice.\n\n\n\nComplete blood counts are collected for newborn whose mothers were treated for cancer during pregnancy and enrolled in the Cancer and Pregnancy Registry. Neutropenia was defined as absolute neutrophil count<1000 mm3 and leukopenia was defined as white blood cells <5000 cells/μL. Incidence of neutropenia was calculated according to the time elapsed from last chemotherapy treatment until birth. Fisher's exact test is used to determine if neutropenia or leukopenia is related to the time elapsed between chemotherapy during pregnancy and newborn birth. A Bayesian analysis evaluated the occurrence of neutropenia and leukopenia according to the number of days between the initiation of chemotherapy and birth.\n\n\n\nA total of 135 infants exposed to chemotherapy in utero with a complete blood count collected at birth were identified from the database. Only 7.3% and 2.9% of infants were born with neutropenia or leukopenia, respectively. The highest incidence of newborn neutropenia occurred in infants delivered 22 to 28 days after chemotherapy.\n\n\n\nThe incidence of neutropenia peaks when chemotherapy is given 22 to 28 days before birth, while leukopenia is highest if delivery is <7 days from chemotherapy.",
"affiliations": "Cooper Medical School at Rowan University, Camden, NJ.",
"authors": "La Nasa|Maria|M|;Gaughan|John|J|;Cardonick|Elyce|E|",
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"title": "Incidence of Neonatal Neutropenia and Leukopenia After In Utero Exposure to Chemotherapy for Maternal Cancer.",
"title_normalized": "incidence of neonatal neutropenia and leukopenia after in utero exposure to chemotherapy for maternal cancer"
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... |
{
"abstract": "Prescription drug abuse ranks as the second most common class of illicit drug use in the United States, and one mechanism of opiate abuse involves intravenous injection of enteral narcotics such as oxycodone or hydrocodone. The authors describe a patient who sustained significant soft tissue necrosis after intravenously injecting a solution made from crushed enteral narcotics, with a focus on the operative course that resulted due to a delay in initial definitive treatment. The patient's wounds encompassed 8% total body surface area and covered 247 cm2. A 55-year-old female was admitted to the burn unit (West Penn Burn Center, Western Pennsylvania Hospital, Pittsburgh, PA) after she initially presented with infection and cellulitis to her bilateral upper extremities 3 weeks after intravenously injecting herself with crushed oxycodone/acetaminophen. She underwent numerous sequential operative repairs including initial debridement, placement of dermal replacement templates, and several split-thickness autografts and xenografts. Her total length of stay was 59 days, broken into an initial 47-day stay, and a subsequent 12-day readmission due to graft failure secondary to poor follow-up. As the number of prescription drug abusers rises, it is possible that an increase in attempts to intravenously abuse enteral narcotics may also rise. As such, burn centers should be prepared for the extent of potential limb necrosis and the operative treatment that may ensue.",
"affiliations": "Lake Erie College of Osteopathic Medicine, Erie, PA.;Lake Erie College of Osteopathic Medicine, Erie, PA.;University of Pittsburgh School of Medicine, Department of Plastic and Reconstructive Surgery, Pittsburgh, PA.;West Penn Burn Center, Western Pennsylvania Hospital, Pittsburgh, PA.;West Penn Burn Center, Western Pennsylvania Hospital, Pittsburgh, PA.;West Penn Burn Center, Western Pennsylvania Hospital, Pittsburgh, PA; email: AAballay@wpahs.org.",
"authors": "Baskin|Sean M|SM|;Abboud|Christine|C|;Chen|Wendy|W|;Tolchin|Eric|E|;Kelly|Robert W|RW|;Aballay|Ariel M|AM|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D004338:Drug Combinations; D009294:Narcotics; C514822:oxycodone-acetaminophen; D000082:Acetaminophen; D010098:Oxycodone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-7946",
"issue": "27(7)",
"journal": "Wounds : a compendium of clinical research and practice",
"keywords": null,
"medline_ta": "Wounds",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D002481:Cellulitis; D003646:Debridement; D004338:Drug Combinations; D003875:Drug Eruptions; D005260:Female; D006084:Graft Rejection; D006801:Humans; D008875:Middle Aged; D009294:Narcotics; D009336:Necrosis; D010098:Oxycodone; D063487:Prescription Drug Misuse; D016038:Skin Transplantation; D018461:Soft Tissue Infections; D017695:Soft Tissue Injuries; D015819:Substance Abuse, Intravenous",
"nlm_unique_id": "9010276",
"other_id": null,
"pages": "174-9",
"pmc": null,
"pmid": "26192735",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subcutaneous Injection of Percocet: A Case of Severe Soft Tissue Loss.",
"title_normalized": "subcutaneous injection of percocet a case of severe soft tissue loss"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201602536",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null... |
{
"abstract": "Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed.",
"affiliations": "Division of Cardiology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan. t.oyakawa@scchr.jp.;Division of Cardiology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.;Division of Cardiology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.;Research Institute, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.",
"authors": "Oyakawa|Takuya|T|;Muraoka|Nao|N|;Iida|Kei|K|;Kusuhara|Masatoshi|M|;Kawamura|Takahisa|T|;Naito|Tateaki|T|;Takahashi|Toshiaki|T|",
"chemical_list": "D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D000077547:Crizotinib",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-018-0605-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "36(5)",
"journal": "Investigational new drugs",
"keywords": "Cardiac toxicity; Cardio-oncology; Crizotinib; Lung cancer; MET",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000230:Adenocarcinoma; D000970:Antineoplastic Agents; D001145:Arrhythmias, Cardiac; D066126:Cardiotoxicity; D000077547:Crizotinib; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008175:Lung Neoplasms; D008875:Middle Aged; D010493:Pericarditis; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "949-951",
"pmc": null,
"pmid": "29717400",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27567406;26561593;26169611;22241953;25264305",
"title": "Crizotinib-induced simultaneous multiple cardiac toxicities.",
"title_normalized": "crizotinib induced simultaneous multiple cardiac toxicities"
} | [
{
"companynumb": "JP-PFIZER INC-2019020565",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CRIZOTINIB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nAbuse of prescription opioid pain relievers continues to be a serious public health concern. In contrast to opioids such as oxycodone or morphine, tapentadol, a prescription analgesic, has two mechanisms of action: μ-opioid receptor agonism and norepinephrine reuptake inhibition. As a result of differences in its receptor pharmacology, there may be differences in its abuse profile. As an initial step toward testing this hypothesis, we present a postmarketing examination of tapentadol's abuse liability relative to comparators.\n\n\nMETHODS\nA sentinel sample of 113,914 individuals assessed for substance abuse treatment as part of the NAVIPPRO ASI-MV(®) surveillance system at 624 facilities in 38 states from January 2011 to September 2012 was examined for prevalence and prescription-adjusted prevalence of past 30-day abuse of tapentadol as a compound and its immediate-release (IR) and extended-release (ER) formulations with oxymorphone, hydromorphone, hydrocodone, morphine, fentanyl, oxycodone, tramadol, and buprenorphine as comparators.\n\n\nRESULTS\nTapentadol abuse was reported significantly less often (P < 0.001) than all comparator compounds. Tapentadol IR abuse prevalence was significantly lower than all comparators except fentanyl IR, which had the next lowest unadjusted abuse prevalence. Prevalence of tapentadol ER abuse was lower than comparators except hydromorphone ER. Low prescription-adjusted estimates were observed for tapentadol as a compound as well as its IR and ER formulations, which were among the lowest observed and the lowest of the Schedule II comparators. Prescription-adjusted risk for tapentadol ER was less than comparators except hydromorphone ER (P = 0.06).\n\n\nCONCLUSIONS\nTapentadol abuse was seen infrequently in this study and, on a prescription basis, was less likely to be abused than most of the examined Schedule II analgesics.",
"affiliations": "Health Analytics, Inflexxion, Inc., Newton, Massachusetts.",
"authors": "Butler|Stephen F|SF|;McNaughton|Emily C|EC|;Black|Ryan A|RA|",
"chemical_list": "D000701:Analgesics, Opioid; D010636:Phenols; D000077432:Tapentadol",
"country": "England",
"delete": false,
"doi": "10.1111/pme.12524",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-2375",
"issue": "16(1)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "ASI-MV; Abuse Liability; Abuse Risk; NAVIPPRO; Opioid; Tapentadol",
"medline_ta": "Pain Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D010636:Phenols; D015995:Prevalence; D011358:Product Surveillance, Postmarketing; D000077432:Tapentadol; D055815:Young Adult",
"nlm_unique_id": "100894201",
"other_id": null,
"pages": "119-30",
"pmc": null,
"pmid": "25243972",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment.",
"title_normalized": "tapentadol abuse potential a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment"
} | [
{
"companynumb": "US-DEP_07982_2015",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"druga... |
{
"abstract": "Renal involvement is a rare occurrence in juvenile rheumatoid arthritis (JRA). We report on two JRA patients with kidney disease. The first was a 14-year-old African-American female with a 12-month history of polyarthritis. On presentation she was found to have an ESR of 127 mm/h and a positive ANA, rheumatoid factor (RF), perinuclear antineutrophil cytoplasmic antibodies (pANCA), haematuria, proteinuria with normal BUN and creatinine. Renal biopsy showed focal segmental glomerulosclerosis. Her renal function deteriorated to end-stage renal failure requiring dialysis within a few months, despite aggressive treatment with steorids and monthly i.v. pulses of cyclophosphamide. The second patient presented with a 6-week history of polyarthritis and intermittent fever, and had a salmon-coloured evanescent rash. On presentation his laboratory evaluation was significant for elevated ESR and negative ANA, RF and ANCA tests. Within 8 months the patient had developed a persistent microscopic haematuria. Renal biopsy showed mild mesangial glomerulonephritis. On low-dose methotrexate therapy his JRA went into remission and his renal function remained normal. The haematuria persisted for 1 year and then resolved spontaneously. This is the first time that focal segmental glomerulosclerosis and mesangial glomerulonephritis have been described in JRA. Although the association may be just coincidental, further studies are needed to define the role of JRA in these renal conditions. In patients with JRA, urinalysis and renal function should be routinely monitored.",
"affiliations": "Department of Pediatrics, LSU Health Sciences Center, New Orleans, Louisiana 70112-2822, USA. a61543@pol.net",
"authors": "Gedalia|A|A|;Mendez|E A|EA|;Craver|R|R|;Vehaskari|M|M|;Espinoza|L R|LR|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/pl00011196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "20(2)",
"journal": "Clinical rheumatology",
"keywords": null,
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000293:Adolescent; D019268:Antibodies, Antineutrophil Cytoplasmic; D001171:Arthritis, Juvenile; D003520:Cyclophosphamide; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative; D005923:Glomerulosclerosis, Focal Segmental; D006417:Hematuria; D006801:Humans; D007166:Immunosuppressive Agents; D007678:Kidney Glomerulus; D008297:Male; D008727:Methotrexate",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "153-6",
"pmc": null,
"pmid": "11346232",
"pubdate": "2001",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal involvement in juvenile rheumatoid arthritis: report of two cases.",
"title_normalized": "renal involvement in juvenile rheumatoid arthritis report of two cases"
} | [
{
"companynumb": "US-PFIZER INC-202101649178",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3... |
{
"abstract": "Vitamin K antagonists are advised in pulmonary arterial hypertension patients despite a lack of safety data. We reviewed major bleeding in three classes of pulmonary hypertension patients, all receiving vitamin K antagonists. Bleeding event rates were 5.4 per 100 patient-years for patients with idiopathic pulmonary arterial hypertension, 19 per 100 patient-years for connective tissue disease related pulmonary arterial hypertension patients and 2.4 per 100 patient-years for chronic thromboembolic pulmonary hypertension patients. Life tables analysis showed that event-free survival was worse in patients with connective tissue disease related pulmonary hypertension than in patients with idiopathic pulmonary arterial hypertension (Wilcoxon=12.8; p<0.001), and patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=23.2; p<0.001). Patients with idiopathic pulmonary arterial hypertension suffered more events than patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=7.2; p<0.01). Major bleeding was independent of age, sex, target international normalised ratio (INR) range, documented INR, vitamin K antagonist type, or right atrial pressure, but was associated with use of prostacyclin analogues. Major bleeding risk during vitamin K antagonist therapy differs among groups of patients with pulmonary hypertension. Further research regarding optimal anticoagulant therapy is needed, as well as risk-benefit analyses for pulmonary hypertension patients with a higher bleeding propensity.",
"affiliations": "Dept of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.",
"authors": "Henkens|Ivo R|IR|;Hazenoot|Thomas|T|;Boonstra|Anco|A|;Huisman|Menno V|MV|;Vonk-Noordegraaf|Anton|A|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D014812:Vitamin K",
"country": "England",
"delete": false,
"doi": "10.1183/09031936.00039212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0903-1936",
"issue": "41(4)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants; D018572:Disease-Free Survival; D005260:Female; D005343:Fibrinolytic Agents; D006470:Hemorrhage; D006801:Humans; D006976:Hypertension, Pulmonary; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D012189:Retrospective Studies; D014812:Vitamin K",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": "872-8",
"pmc": null,
"pmid": "22936704",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension.",
"title_normalized": "major bleeding with vitamin k antagonist anticoagulants in pulmonary hypertension"
} | [
{
"companynumb": "NL-ACTELION-A-CH2018-180056",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPOPROSTENOL SODIUM"
},
"drugadditional": "... |
{
"abstract": "Evolocumab is a relatively new monoclonal antibody designed to decrease low-density lipoproteins via the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). It is used alone or in combination with other lipid-lowering agents. Evolocumab was associated with adverse events of skin rashes in clinical trials. We describe a rare case of maculopapular exanthema in a female patient with hyperlipidemia, which was treated with evolocumab. The patient was a 60-year-old female with hyperlipidemia who experienced a maculopapular rash after she was administered the second dose of evolocumab subcutaneously. The rash occurred on her torso and upper extremities and was associated with pruritus and mild wheezing. The hypersensitivity reaction was treated with antihistamines and with the discontinuation of evolocumab. The skin eruption cleared within 10 days. In conclusion, medical professionals should be aware of evolocumab skin hypersensitivity reactions, which could demand the cessation of the evolocumab treatment.",
"affiliations": "Internal Medicine, Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals/Queens, New York, USA.;Research, NYC Health+Hospitals/Queens, New York, USA.;Internal Medicine, Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals/Queens, New York, USA.",
"authors": "Ghernautan|Victoria|V|;Amini|Masoud|M|;Sachmechi|Issac|I|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.15249",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.15249\nEndocrinology/Diabetes/Metabolism\nInternal Medicine\nMaculopapular Exanthema After the Second Dose of Evolocumab\nMuacevic Alexander\nAdler John R\nGhernautan Victoria 1\nAmini Masoud 2\nSachmechi Issac 1\n1 Internal Medicine, Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals/Queens, New York, USA\n2 Research, NYC Health+Hospitals/Queens, New York, USA\nVictoria Ghernautan vicutag@yahoo.com\n26 5 2021\n5 2021\n13 5 e1524926 5 2021\nCopyright © 2021, Ghernautan et al.\n2021\nGhernautan et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/60054-maculopapular-exanthema-after-the-second-dose-of-evolocumab\nEvolocumab is a relatively new monoclonal antibody designed to decrease low-density lipoproteins via the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). It is used alone or in combination with other lipid-lowering agents. Evolocumab was associated with adverse events of skin rashes in clinical trials. We describe a rare case of maculopapular exanthema in a female patient with hyperlipidemia, which was treated with evolocumab. The patient was a 60-year-old female with hyperlipidemia who experienced a maculopapular rash after she was administered the second dose of evolocumab subcutaneously. The rash occurred on her torso and upper extremities and was associated with pruritus and mild wheezing. The hypersensitivity reaction was treated with antihistamines and with the discontinuation of evolocumab. The skin eruption cleared within 10 days. In conclusion, medical professionals should be aware of evolocumab skin hypersensitivity reactions, which could demand the cessation of the evolocumab treatment.\n\nevolocumab\nhyperlipidemia\nhypersensitivity reactions\nadverse effect\nmaculopapular exanthema\ndrug rash\ndrug hypersensitivity reactions\nmonoclonal antibodies\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nDrug hypersensitivity reactions have various presentations such as transient and benign erythema, maculopapular exanthema (MPE), fixed drug eruption, as well as severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) [1,2]. MPE is a mild skin eruption and is characterized by generalized macular and/or papular rash [1,2]. We present the case of a 60-year-old female with hyperlipidemia who developed a hypersensitivity skin eruption manifested as MPE and associated wheezing after receiving the second dose of evolocumab, which resulted in the discontinuation of the medication.\n\nCase presentation\n\nThis is the case of a 60-year-old female with prediabetes, obesity, hypothyroidism, and hyperlipidemia, who was recently started on evolocumab. The patient was on statin therapy (pravastatin 40 mg daily, then switched to rosuvastatin 10 mg daily) for hyperlipidemia; however, it was discontinued due to the side effect of myalgia. Her lipid panel before starting the statins was not available, as she had different providers before joining our clinic. Evolocumab was started at the dose of 140 mg/ml subcutaneously every two weeks. The patient tolerated the first dose well. However, a day after the second evolocumab dose, the patient manifested MPE on the upper extremities, neck, and chest, associated with pruritus and mild wheezing (Figures 1, 2). There was no local reaction at the injection site, and the patient did not have any dyspnea, hypotension, or tongue swelling. The patient had not had any prior history of allergies or asthma. She was on levothyroxine 125 mcg daily for hypothyroidism and did not start new medications or had allergen exposure. The rash cleared within 10 days with oral and topical antihistamines. An inhaled steroid/long-acting β₂ adrenergic receptor agonist was given for wheezing. Evolocumab was discontinued, and the patient was prescribed bempedoic acid for hyperlipidemia.\n\nFigure 1 Maculopapular exanthema on the upper extremity secondary to evolocumab.\n\nFigure 2 Papular rash on the dorsal aspect of the forearms secondary to evolocumab.\n\nDiscussion\n\nAdverse drug reactions can affect 10% to 15% of patients taking medications, and the skin is involved in approximately 20% of cases [3]. Patients at risk of experiencing drug hypersensitivity reactions include those with a previous history of such reactions, patients on multiple drugs, and patients with concomitant diseases such as HIV, autoimmune disorders, and asthma [3]. Most cutaneous drug eruptions are delayed type IV hypersensitivity reactions. A sub-classification of this reaction type was proposed, as the traditional Gell and Coombs model does not include all the various presentations of hypersensitivity to medications. It is based on the specific cell, which becomes activated, monocytes (type IVa), eosinophils (type IVb), and neutrophils (type IVd) [1]. Cytotoxicity (type IVc) predominates in many drug reactions [1].\n\nDrugs are foreign substances that are precepted as antigens that bind the T-cell receptors to induce immune responses [2]. This is especially valid for biological drugs since they have non-self proteins in their component, which can potentially promote immune-mediated side effects [4,5]. There are several differences in the structure, molecular weight, and technology of traditional drugs and biologics; therefore, the side effects of biologics are expected to have distinct mechanisms. Adverse effects of biologic drugs, such as hypersensitivity, are encountered less frequently compared to infusion reactions, although they share common features [5].\n\nEvolocumab is a biological agent, a human monoclonal antibody (mAb) designed to decrease low-density lipoprotein (LDL) cholesterol. It works by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), which prevents it from degrading LDL receptors, leading to enhanced removal of LDL. It is the second PCSK9 inhibitor approved by the U.S. Food and Drug Administration (FDA) on August 27, 2015, for the treatment of hyperlipidemia in heterozygous and homozygous familial hypercholesterolemia and clinical atherosclerotic cardiovascular disease [6].\n\nThe safety of evolocumab was assessed in eight placebo-controlled trials and revealed several adverse events such as nasopharyngitis (10.5%), upper respiratory tract infections (9.3%), back pain (6.2%), and myalgias (4.0%). Rash and urticaria were encountered; however, their incidence was not reported [6]. According to the manufacturer, hypersensitivity reactions occurred in 0.4%-1% of patients receiving evolocumab [7].\n\nIn the OSLER-1 (Open Label Study of Long Term Evaluation Against LDL-C Trial) study, an open-label study, which evaluated the effectiveness and safety profile of evolocumab over a five-year period, hypersensitivity reactions were noticed in 10.2 % of patients in the first year of use. However, their incidence decreased over time by 5.6% of cases in the fourth year [8]. The GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) randomized clinical trial, which compared the efficacy and tolerability of evolocumab versus ezetimibe in patients with muscle-related statin intolerance, revealed the adverse events in the form of a rash in 3.4% of 145 patients receiving evolocumab. The skin eruptions, along with nausea, insomnia, and acid reflux were the least encountered side effects in that study [9]. There was a case published in 2019, which reported a rash mimicking atopic dermatitis associated with high-dose evolocumab therapy [10].\n\nA large study, which published real-world data of evolocumab and alirocumab safety using a hospital registry and two pharmacovigilance databases, revealed influenza-like illness (27.3% and 28.6%, respectively) and myalgia (7.8% and 9.4%, respectively) to be among the most common side effects [11]. Myalgia was the main reason for discontinuation of both mAbs. Rash was reported in four (5.9%) of 68 patients [11]. In the randomized, controlled, open-label DE LAVAL study, one patient discontinued the evolocumab treatment due to worsening rash on the face and neck, which was attributed to evolocumab [12].\n\nOur patient developed a pruritic MPE a day after she received the second dose of evolocumab, which prompted us to suspect a cutaneous drug reaction. This case adds valuable knowledge about the adverse event of MPE secondary to evolocumab treatment.\n\nConclusions\n\nClinicians should be vigilant regarding potential hypersensitivity reactions during evolocumab therapy. It could require immediate termination of evolocumab administration and subsequent application of alternative treatments. Our case urges providers to share their experience on unexpected drug reactions to contribute to the postmarketing surveillance of drug adverse effects.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Clinical heterogeneity of drug hypersensitivity Toxicology Roujeau JC 123 129 15 2005\n2 Severe cutaneous adverse drug reactions J Dermatol Chung WH Wang CW Dao RL 758 766 43 2016 27154258\n3 Danger signs in drug hypersensitivity Med Clin North Am Scherer K Bircher AJ 681 689 94 2010 20609857\n4 Drug allergy and hypersensitivity: still a hot topic Allergy Bousquet PJ Demoly P Romano A 179 182 64 2009\n5 Adverse reactions to biologic therapy Immunol Allergy Clin North Am Patel SV Khan DA 397 412 37 2017 28366484\n6 Repatha (evolocumab): second PCSK9 inhibitor approved by the FDA for patients with familial hypercholesterolemia Am Health Drug Benefits Fala L 136 139 9 2016 27668060\n7 Evolocumab (Repatha) for the treatment of hyperlipidemia Am Fam Physician Erlich DR 843 846 94 2016 https://pubmed.ncbi.nlm.nih.gov/27929280/ 27929280\n8 Long-term efficacy and safety of evolocumab in patients with hypercholesterolemia J Am Coll Cardiol Koren MJ Sabatine MS Giugliano RP 2132 2146 74 2019 31648705\n9 Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial JAMA Nissen SE Stroes E Dent-Acosta RE 1580 1590 315 2016 27039291\n10 Atopic dermatitis-like rash during evolocumab treatment of familial hypercholesterolemia J Nippon Med Sch Kanda N Okajima F 187 190 86 2019 31292332\n11 Adverse events associated with PCSK9 inhibitors: a real-world experience Clin Pharmacol Ther Gürgöze MT Muller-Hansma AHG Schreuder MM Galema-Boers AMH Boersma E Roeters van Lennep JE 496 504 105 2019 30053327\n12 Effect of evolocumab on lipoprotein apheresis requirement and lipid levels: results of the randomized, controlled, open-label DE LAVAL study J Clin Lipidol Baum SJ Sampietro T Datta D 901 909 13 2019 31759938\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(5)",
"journal": "Cureus",
"keywords": "adverse effect; drug hypersensitivity reactions; drug rash; evolocumab; hyperlipidemia; hypersensitivity reactions; maculopapular exanthema; monoclonal antibodies",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pmc": null,
"pmid": "34188988",
"pubdate": "2021-05-26",
"publication_types": "D002363:Case Reports",
"references": "31759938;27668060;27039291;27154258;30053327;15767024;31648705;20609857;27929280;19178397;31292332;28366484",
"title": "Maculopapular Exanthema After the Second Dose of Evolocumab.",
"title_normalized": "maculopapular exanthema after the second dose of evolocumab"
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"abstract": "Clinical experience of perampanel overdoses is markedly limited and the relevant literature is sparse. Perampanel is a novel antiepileptic drug (an amino-3-hydroxy-5-methyl-4-isoxazlepropionic acid glutamate receptor antagonist) with a long half-life, which is used for the adjunctive treatment of epilepsy. The literature available identifies a potential for prolonged unconsciousness in overdose. We report a case of prolonged unconsciousness for 14 days following a perampanel overdose of 3.5 times the maximum daily dose, requiring protracted intubation and ventilation on intensive care, with eventual complete neurological recovery. This represents the longest known period of unconsciousness with full recovery and the first reported in a perampanel naïve patient. This case helps to inform decision-making in critical care, particularly the early consideration of admission and intubation. It highlights that while perampanel overdose may not initially cause systemic effects such as cardiac toxicity, it can cause protracted altered consciousness with secondary compromise requiring prolonged intensive care management.",
"affiliations": "Critical Care, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, UK guy.parsons@nhs.net.;Critical Care, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, UK.;Critical Care, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, UK.;Critical Care, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, UK.",
"authors": "Parsons|Guy|G|http://orcid.org/0000-0001-5786-2750;Bailey|Jon|J|;Bailey|Frederick|F|;Brzezicki|Max|M|",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232517",
"fulltext": null,
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"issue": "12(11)",
"journal": "BMJ case reports",
"keywords": "drugs: CNS (not psychiatric); epilepsy and seizures; intensive care; mechanical ventilation; neurology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D062787:Drug Overdose; D006801:Humans; D008297:Male; D009570:Nitriles; D011728:Pyridones; D013997:Time Factors; D014474:Unconsciousness",
"nlm_unique_id": "101526291",
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"pmid": "31791997",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23772853;23663001;29467570;27904300;29299938;30809502",
"title": "Prolonged unconsciousness in perampanel overdose.",
"title_normalized": "prolonged unconsciousness in perampanel overdose"
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"abstract": "Staphylococcus-associated glomerulonephritis (SAGN) occurs as a complication of staphylococcal infection elsewhere in the body. Dermatomyositis (DM) can be associated with glomerulonephritis due to the disease per se. We report a case of a 40-year-old male patient with DM who presented with acute kidney injury, and was initially pulsed with methylprednisolone for 3 days, followed by dexamethasone equivalent to 1 mg/kg/day prednisolone. He was subsequently found to have SAGN on kidney biopsy along with staphylococcus bacteraemia and left knee septic arthritis. With proof of definitive infection, intravenous immunoglobulin 2 g/kg over 2 days was given and steroids were reduced. He was treated with intravenous vancomycin. With treatment, the general condition of the patient improved. On day 38, he developed infective endocarditis and died of congestive heart failure subsequently. Undiagnosed staphylococcal sepsis complicating a rheumatological disease course can lead to complications like SAGN, infective endocarditis and contribute to increased morbidity and mortality, as is exemplified by our case.",
"affiliations": "Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India anupamwakhlu@gmail.com.",
"authors": "Sahoo|Rasmi Ranjan|RR|http://orcid.org/0000-0001-6616-4989;Pradhan|Sourav|S|;Goel|Akhil Pawan|AP|;Wakhlu|Anupam|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236695",
"fulltext": null,
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"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; connective tissue disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D016470:Bacteremia; D003882:Dermatomyositis; D004697:Endocarditis, Bacterial; D017809:Fatal Outcome; D005921:Glomerulonephritis; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008297:Male; D013203:Staphylococcal Infections; D014640:Vancomycin",
"nlm_unique_id": "101526291",
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"pmid": "33472800",
"pubdate": "2021-01-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20837496;27082609;23557013;24378741;15854195;17699345;25984152;19343367",
"title": "Staphylococcus-associated acute glomerulonephritis in a patient with dermatomyositis.",
"title_normalized": "staphylococcus associated acute glomerulonephritis in a patient with dermatomyositis"
} | [
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"abstract": "Talimogene laherparepvec (T-VEC) is a intralesional oncolytic virotherapy, licensed in the European Union for locoregional advanced melanoma of American Joint Committee on Cancer stages IIIB, IIIC and IVM1a. Organ transplant recipients are currently excluded from all clinical trials dealing with immunotherapies due to the risk of transplant rejection. A 58-year-old white man with a history of heart and kidney transplantation in 2014 was diagnosed with melanoma (Breslow thickness 1·6 mm, stage pT2a) on the left arm in September 2015. In March 2016 he developed in transit metastases, and local therapy with a combination of topical imiquimod (5%) and cryotherapy of individual lesions was initiated. However, in November 2016 therapy was stopped following local progression of the metastases. An interdisciplinary decision to treat the patient with T-VEC was taken. After 11 cycles of T-VEC, the patient showed a complete response. As of June 2018, 11 months after the last treatment cycle of T-VEC, the patient continues to be tumour free. The patient tolerated the therapy well with only mild adverse events and did not show any sign of graft rejection or loss of function of the transplanted organs. We conclude that T-VEC can be a potentially effective and safe treatment in patients with a history of organ transplantation. Nevertheless, due to this special situation, the risks and benefits should always be discussed with an interdisciplinary tumour board.",
"affiliations": "Departments of Dermatology, Medical University of Vienna, Vienna, Austria.;Departments of Dermatology, Medical University of Vienna, Vienna, Austria.;Departments of Dermatology, Medical University of Vienna, Vienna, Austria.;Departments of Dermatology, Medical University of Vienna, Vienna, Austria.;Departments of Dermatology, Medical University of Vienna, Vienna, Austria.;Departments of Surgery, Medical University of Vienna, Vienna, Austria.;Departments of Dermatology, Medical University of Vienna, Vienna, Austria.",
"authors": "Ressler|J|J|0000-0001-8602-0878;Silmbrod|R|R|;Stepan|A|A|;Tuchmann|F|F|;Cicha|A|A|;Uyanik-Ünal|K|K|;Hoeller|C|C|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; C000629782:talimogene laherparepvec",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.17783",
"fulltext": "\n==== Front\nBr J DermatolBr. J. Dermatol10.1111/(ISSN)1365-2133BJDThe British Journal of Dermatology0007-09631365-2133John Wiley and Sons Inc. Hoboken 10.1111/bjd.17783BJD17783Case Report: TherapyCase ReportTherapyTalimogene laherparepvec (T‐VEC) in advanced melanoma: complete response in a heart and kidney transplant patient. A case report Ressler J. https://orcid.org/0000-0001-8602-0878\n1\njulia.ressler@meduniwien.ac.at Silmbrod R. \n1\nStepan A. \n1\nTuchmann F. \n1\nCicha A. \n1\nUyanik‐Ünal K. \n2\nHoeller C. \n1\n\n1 \nDepartments of Dermatology\nMedical University of Vienna\nVienna\nAustria\n\n2 \nDepartments of Surgery\nMedical University of Vienna\nVienna\nAustria\n* \nCorrespondence\n\nJulia Ressler.\n\nE‐mail: julia.ressler@meduniwien.ac.at\n26 3 2019 7 2019 181 1 10.1111/bjd.2019.181.issue-1186 189 11 2 2019 © 2019 The Authors British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of DermatologistsThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Summary\nTalimogene laherparepvec (T‐VEC) is a intralesional oncolytic virotherapy, licensed in the European Union for locoregional advanced melanoma of American Joint Committee on Cancer stages IIIB, IIIC and IVM1a. Organ transplant recipients are currently excluded from all clinical trials dealing with immunotherapies due to the risk of transplant rejection. A 58‐year‐old white man with a history of heart and kidney transplantation in 2014 was diagnosed with melanoma (Breslow thickness 1·6 mm, stage pT2a) on the left arm in September 2015. In March 2016 he developed in transit metastases, and local therapy with a combination of topical imiquimod (5%) and cryotherapy of individual lesions was initiated. However, in November 2016 therapy was stopped following local progression of the metastases. An interdisciplinary decision to treat the patient with T‐VEC was taken. After 11 cycles of T‐VEC, the patient showed a complete response. As of June 2018, 11 months after the last treatment cycle of T‐VEC, the patient continues to be tumour free. The patient tolerated the therapy well with only mild adverse events and did not show any sign of graft rejection or loss of function of the transplanted organs. We conclude that T‐VEC can be a potentially effective and safe treatment in patients with a history of organ transplantation. Nevertheless, due to this special situation, the risks and benefits should always be discussed with an interdisciplinary tumour board.\n\n\nWhat's already known about this topic?\n\n\n\nTalimogene laherparepvec (T‐VEC) is a intralesional oncolytic virotherapy, licensed in the European Union for locoregional advanced melanoma of American Joint Committee on Cancer stages IIIB, IIIC and IVM1a.\n\nOrgan transplant recipients have so far been excluded from all clinical trials dealing with immunotherapies due to the risk of transplant rejection.\n\n\n\n\n\nWhat does this study add?\n\n\n\nWe conclude that T‐VEC can be a potentially effective and safe treatment in patients with a history of organ transplantation.\n\nNevertheless, due to this special situation, the risks and benefits should always be discussed with an interdisciplinary tumour board.\n\n\n\n\n\nLinked Comment: https://doi.org/10.1111/bjd.18103.\n\n source-schema-version-number2.0cover-dateJuly 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:12.11.2019\nFunding sources\n\n\n\nNone.\n\n\nConflicts of interest\n\n\n\nNone to declare.\n==== Body\nTalimogene laherparepvec (T‐VEC) is an intralesional oncolytic virotherapy. It has been licensed in the European Union since December 2015 for locoregional advanced melanoma of American Joint Committee on Cancer (AJCC) stages IIIB, IIIC and IV M1a. T‐VEC is a modified double‐stranded DNA herpes simplex virus type 1, and its ability to mediate tumour regression is dependent on two different mechanisms.1, 2, 3, 4 Firstly, viral replication leads to preferential lysis of tumour cells, due to disrupted protein kinase R activity and disrupted type I interferon signalling.4 Secondly, the release of new viral particles induces continuous inflammation, which is amplified by expression of human granulocyte colony‐stimulating factor from the altered viral genome.\n\nBesides T‐VEC, other approved drugs like checkpoint inhibitors and targeted therapies can also be used to treat locoregional metastatic disease.5, 6 However, none of these treatments has been formally tested in organ transplant recipients (OTRs), as these patients have been excluded from all pivotal clinical studies. To date only one previous case of administration of T‐VEC in a heart transplant patient with inoperable recurrent melanoma has been described,7 but no cases of patients with double organ transplantation have been reported so far.\n\nCase report\nA 58‐year‐old white man had a history of heart and kidney transplantation in 2014, due to dilated cardiomyopathy and consecutive renal failure. He was diagnosed with melanoma (Breslow thickness 1·6 mm, stage pT2a) on the left arm in September 2015. Following a positive sentinel lymph node biopsy, a left axillary lymph node dissection was performed in October 2015 (26 negative nodes). In March 2016 the patient progressed to AJCC stage IIIC with multiple small epidermotropic metastases along his left arm, confirmed by five punch biopsies. Local therapy with a combination of topical imiquimod (5%) and cryotherapy of individual lesions was initiated. However, in November 2016 the therapy was stopped following local progression of the metastases (Fig. 1).\n\nFigure 1 In November 2016, before the first therapy with talimogene laherparepvec, there were multiple epidermotropic cutaneous metastases confirmed by histopathology. The findings showed atypical melanoma cells limited to the epidermis.\n\nA positron emission tomography scan performed at this time did not show any sign of metastases in any other part of the body. A multidisciplinary tumour board was held, including members of the patient's heart and kidney transplant team. As the tumour did not carry mutations in BRAF, c‐kit or NRAS, and as the risk of graft rejection was assumed to be higher with treatment with systemic checkpoint inhibitors, it was decided to treat the patient with the intralesional oncolytic virotherapy T‐VEC. The immunosuppressive regimen, which at this time consisted of mycophenolate mofetil 2 g per day, tacrolimus 7·5 mg per day and prednisolone 10 mg per day, was changed to mycophenolate mofetil 2 g per day and sirolimus 1 mg per day before starting therapy with T‐VEC.\n\nIn June 2017, after 11 cycles of intralesional infiltration with T‐VEC [first dose of 106 plaque‐forming units (PFU) mL−1, followed 3 weeks later by 10 doses of 108 PFU mL−1 in 2‐week intervals] the patient presented complete regression of all lesions, including those that were not injected, confirmed by representative punch biopsies (Fig. 2). The patient tolerated the therapy well, with mild adverse events. According to the Common Terminology Criteria for Adverse Events these were grade II pyrexia, grade I local erythema and grade I lesional hypopigmentation.\n\nFigure 2 In June 2017, 8 months after 11 cycles of talimogene laherparepvec, there was complete regression of all melanoma metastases on the patient's left arm. Histopathology showed melanophages and plasma cells, with no sign of melanoma residua.\n\nIn addition to regular dermato‐oncological follow‐up, the patient was checked by his transplant team every 3 months, including laboratory tests, transthoracic echocardiography (showing stable left ventricular function), electrocardiography, coronary angiography and coronary computer tomography. During the entire treatment period, the patient did not show any sign of graft rejection or changes in the function of the transplanted organs. As of September 2018, 13 months after the last dose of T‐VEC in June 2017, the patient remains well and tumour free.\n\nDiscussion\nCompared with the general population, OTRs have an estimated 2·4 times higher risk of developing melanoma.8 Additionally, immunosuppressive drugs increase the risk of developing skin cancer.9 Patients treated with calcineurin inhibitors show a higher risk of developing skin cancer after transplantation than those receiving mammalian target of rapamycin inhibitors like sirolimus.10 Therefore, we changed the patient's concomitant immunosuppressive therapy from tacrolimus to sirolimus in order to minimize a possible tumour‐promoting effect.\n\nOnly a few cases of OTRs treated with checkpoint inhibitors have been published,9, 11, 12 as immunotherapies are often considered ineffective due to the existing immunosuppressive medication,13 and they could at the same time pose a risk of transplant rejection.9 BRAF–mitogen‐activated protein kinase kinase (MEK) inhibitors can also be considered as a treatment option for BRAF‐positive melanoma in OTRs.14 In murine models, post‐transplant MEK inhibition resulted in delayed onset of graft‐versus‐host disease, associated mortality and a decreased risk of alloreactivity. Therefore, the combination of BRAF and MEK inhibitors in OTRs may prevent acquired resistance to these agents and could help reduce the risk of allograft rejection.14 Regarding oncolytic virotherapy in OTRs, Schvartsman et al. reported successful treatment of a patient with an inoperable, recurrent melanoma after therapy with T‐VEC.7 While it is currently unknown how robust and long lasting this immune response is in OTRs under concurrent immunosuppressive therapy, the 13‐month relapse‐free period observed in our patient treated with T‐VEC is a hint that durable responses can be possible.\n\nWe conclude that oncolytic virotherapy can be considered as a potentially effective treatment in OTRs with locoregionally advanced melanoma, but treatment decisions should always be based on a thorough discussion with an interdisciplinary tumour board.\n\nSupporting information\n\nPowerpoint S1 Journal Club Slide Set.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nAndtbacka \nRH \n, \nRoss \nM \n, \nPuzanov \nI \n\net al\nPatterns of clinical response with talimogene laherparepvec (T‐VEC) in patients with melanoma treated in the OPTiM phase III clinical trial . Ann Surg Oncol \n2016 ; 23 :4169 –77 .27342831 \n2 \n\nAppleton \nES \n, \nTurnbull \nS \n, \nRalph \nC \n\net al\nTalimogene laherparepvec in treatment of melanoma . Expert Opin Biol Ther \n2015 ; 15 :1517 –30 .26629575 \n3 \n\nHarrington \nKJ \n, \nAndtbacka \nRH \n, \nCollichio \nF \n\net al\nEfficacy and safety of talimogene laherparepvec versus granulocyte–macrophage colony‐stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase III OPTIM trial . Onco Targets Ther \n2016 ; 9 :7081 –93 .27895500 \n4 \n\nKohlhapp \nFJ \n, \nKaufmann \nHL \n. Molecular pathways: mechanism of action for talimogene laherparepvec, a new oncolytic virus immunotherapy . Clin Cancer Res \n2016 ; 22 :1048 –54 .26719429 \n5 \n\nLong \nG \n. Targeted therapy for the adjuvant treatment of stage III BRAF‐mutated melanoma . Clin Adv Hematol Oncol \n2018 ; 16 :25 –7 .29741501 \n6 \n\nMenshawy \nA \n, \nEltonob \nAA \n, \nBarkat \nSA \n\net al\nNivolumab monotherapy or in combination with ipilimumab for metastatic melanoma: systematic review and meta‐analysis of randomized controlled trials . Melanoma Res \n2018 ; 28 :371 –9 .29957656 \n7 \n\nSchvartsman \nG \n, \nPerez \nK \n, \nFlynn \nJE \n\net al\nSafe and effective administration of T‐VEC in a patient with heart transplantation and recurrent locally advanced melanoma . J Immunother Cancer \n2017 ; 5 :45 .28642816 \n8 \n\nDahlke \nE \n, \nMurray \nCA \n, \nKitchen \nJ \n\net al\nSystematic review of melanoma incidence and prognosis in solid organ transplant recipients . Transplant Res \n2014 ; 3 :10 .24834346 \n9 \n\nSpain \nL \n, \nHiggins \nR \n, \nGopalakrishnan \nK \n\net al\nAcute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma . Ann Oncol \n2016 ; 27 :1135 –7 .26951628 \n10 \n\nSmith \nA \n, \nNiu \nW \n, \nDesai \nA \n\net al\nThe effect of conversion from a calcineurin inhibitor to sirolimus on skin cancer reduction in post‐renal transplantation patients . Cureus \n2017 ; 9 :1564 .\n11 \n\nKittai \nAS \n, \nOldham \nH \n, \nCetnar \nJ \n\net al\nImmune checkpoint inhibitors in organ transplant patients . J Immunother \n2017 ; 40 :277 –81 .28719552 \n12 \n\nWinkler \nJK \n, \nGutzmer \nR \n, \nBender \nC \n\net al\nSafe administration of an anti‐PD‐1 antibody to kidney‐transplant patients: 2 clinical cases and review of the literature . J Immunother \n2017 ; 40 :341 –4 .29028789 \n13 \n\nMin \nL \n, \nHodi \nFS \n, \nKaiser \nUB \n. Corticosteroids and immune checkpoint blockade . Aging (Albany NY) \n2015 ; 7 :521 –2 .26298620 \n14 \n\nChae \nYK \n, \nGalvez \nC \n, \nAnker \nJF \n\net al\nCancer immunotherapy in a neglected population: the current use and future of T‐cell‐mediated checkpoint inhibitors in organ transplant patients . Cancer Treat Rev \n2018 ; 63 :116 –21 .29276997\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0007-0963",
"issue": "181(1)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; D006084:Graft Rejection; D016027:Heart Transplantation; D018259:Herpesvirus 1, Human; D006801:Humans; D015552:Injections, Intralesional; D016030:Kidney Transplantation; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009367:Neoplasm Staging; D050130:Oncolytic Virotherapy; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "186-189",
"pmc": null,
"pmid": "30776080",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29057176;27895500;26298620;29741501;26629575;28642816;29276997;29957656;29028789;26951628;24834346;27342831;26719429;28719552",
"title": "Talimogene laherparepvec (T-VEC) in advanced melanoma: complete response in a heart and kidney transplant patient. A case report.",
"title_normalized": "talimogene laherparepvec t vec in advanced melanoma complete response in a heart and kidney transplant patient a case report"
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... |
{
"abstract": "OBJECTIVE\nTo evaluate a signal of acute pulmonary oedema (APO) due to nicardipine used off-label as tocolytic in pregnant women.\n\n\nMETHODS\nAll the suspected cases of APO recorded in EudraVigilance database up to 31/01/2013 and associated with nicardipine containing medicinal products were retrieved. The Proportional Reporting Ratio was considered as measure of disproportionality. Individual cases evaluation was conducted.\n\n\nRESULTS\nThirty-four spontaneous cases regarding pregnancy women who experienced APO following nicardipine treatment as tocolytic were collected. The detected proportional reporting ratio was 50.96 (95% confidence interval lower bound equal to 36.75). The analysis focused on 10 serious cases. Most women, aged between 27 and 39 years, were treated with intravenous nicardipine. The most of the suspected adverse reactions occurred between 24 and 96 hours.\n\n\nCONCLUSIONS\nA potentially causal association between APO and off-label use of nicardipine as tocolytic has been detected during a periodic signal detection activity. The Pharmacovigilance Risk Assessment Committee confirmed our findings, recommending an update of the summary of the product characteristics for medicines containing nicardipine for both intravenous and oral formulations. Then European Medicines Agency reaffirmed that nicardipine use in other indications is no longer recommended.",
"affiliations": "Department of Medical and Surgical Sciences - Unit of Pharmacology, University of Bologna, Bologna, Italy.;Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA)Pharmacovigilance Office, Rome, Italy.;Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA)Pharmacovigilance Office, Rome, Italy.;Department of Medical and Surgical Sciences - Unit of Pharmacology, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences - Unit of Pharmacology, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences - Unit of Pharmacology, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences - Unit of Pharmacology, University of Bologna, Bologna, Italy.",
"authors": "Melis|Mauro|M|;Cupelli|Amelia|A|;Sottosanti|Laura|L|;Buccellato|Elena|E|;Biagi|Chiara|C|;Vaccheri|Alberto|A|;Motola|Domenico|D|",
"chemical_list": "D015149:Tocolytic Agents; D009529:Nicardipine",
"country": "England",
"delete": false,
"doi": "10.1002/pds.3782",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "24(11)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "Eudra Vigilance; acute pulmonary oedema; nicardipine; pharmacoepidemiology; signal detection",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000208:Acute Disease; D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D016208:Databases, Factual; D005260:Female; D006801:Humans; D009529:Nicardipine; D056687:Off-Label Use; D060735:Pharmacovigilance; D011247:Pregnancy; D011358:Product Surveillance, Postmarketing; D011654:Pulmonary Edema; D013997:Time Factors; D015149:Tocolytic Agents",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "1220-4",
"pmc": null,
"pmid": "25845714",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Off-label use of nicardipine as tocolytic and acute pulmonary oedema: a post-marketing analysis of adverse drug reaction reports in EudraVigilance.",
"title_normalized": "off label use of nicardipine as tocolytic and acute pulmonary oedema a post marketing analysis of adverse drug reaction reports in eudravigilance"
} | [
{
"companynumb": "IT-MYLANLABS-2016M1017304",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "We report a case of a 34-year-old drunken male, who was found dead in his apartment. On scene inspection, the deceased body was found in the sitting position on a chair, and a massive arterial blood pattern was observed at the scene. First responders and the coroner visited the scene considered this case as a criminally suspicious due to arterial blood pattern on walls and excessive blood pool at the scene. At autopsy, a laceration was present on the left side of the scalp with an underlying transection of the left superficial temporalis artery. Subsequent histological examination of the arterial section established its transection and cellular response to injury. After careful perusal of CCTV camera footages, pre-autopsy CT, macroscopic examination of injury, histological examination of the transected artery, and toxicological analysis report, cause of death was given as exsanguination due to laceration of a superficial temporal artery following blunt force head trauma. The manner of death was accidental. Although it is not uncommon to see deaths of alcoholics following scalp trauma, the peculiarity of this case lies in the fact that no evidence of fatal accidental superficial temporal artery has ever been reported in the forensic literature. We also suggest that a thorough analysis of history, circumstances, and histologic examination, even of a transacted artery can provide medicolegal relevant data.",
"affiliations": "Deen Dayal Upadhyay Hospital,Department of Forensic Medicine, Saheed Mangal Pandey Marg,Nanak Pura, Hari Nagar, New Delhi, 110064, India; Department of Pathobiology and Laboratory Medicine, University of Toronto & Ontario Forensic Pathology Service, Toronto, Ontario, Canada. Electronic address: jatinfsm@gmail.com.;Ontario Forensic Pathology Service, Toronto and Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Bodwal|Jatin|J|;Herath|Jayantha|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jflm.2020.102054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-928X",
"issue": "75()",
"journal": "Journal of forensic and legal medicine",
"keywords": "Alcoholic; Blunt force head injury; Laceration; Superficial temporal artery",
"medline_ta": "J Forensic Leg Med",
"mesh_terms": "D000059:Accidents; D000328:Adult; D000435:Alcoholic Intoxication; D058734:Exsanguination; D017809:Fatal Outcome; D016489:Head Injuries, Closed; D006470:Hemorrhage; D006801:Humans; D022125:Lacerations; D008297:Male; D013699:Temporal Arteries",
"nlm_unique_id": "101300022",
"other_id": null,
"pages": "102054",
"pmc": null,
"pmid": "32927258",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal bleeding from a laceration of superficial temporal artery: A rare case.",
"title_normalized": "fatal bleeding from a laceration of superficial temporal artery a rare case"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-264035",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PAROXETINE"
},
"drug... |
{
"abstract": "DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is a severe delayed type IV hypersensitivity drug reaction by T helper cell 2 (Th2) and Interleukin 5 (IL-5) resulting in activation of eosinophils. It is mostly reported with antiepileptic drugs (AEDs), antibiotics, and allopurinol. Here, we present the second case of myocarditis secondary to DRESS syndrome caused by amoxicillin. Most of the case reports present with cross-reactivity among the anticonvulsants and beta-lactams, which is also rarely been reported. Amoxicillin could reactivate human herpesvirus 6 (HHV 6) and Epstein-Barr virus (EBV) with a presentation similar to DRESS syndrome, but our patient was neither taking the anticonvulsants nor have any viral infection in the recent past. His RegiSCAR score was 6, consistent with definite DRESS syndrome. Management includes identification and prompt withdrawal of the offending drug and supportive care for patients without severe organ involvement and systemic corticosteroids for patients with severe organ involvement.",
"affiliations": "Internal Medicine, Bronx Care Health System, Bronx, USA.;Internal Medicine, Bronx Care Health System, Bronx, USA.;Internal Medicine, Bronx Care Health System, Bronx, USA.;General Internal Medicine, Bronx Care Health System, Bronx, USA.",
"authors": "De La Cruz|Angel C|AC|;Ashraf|Shoaib|S|;Shrestha|Nikee|N|;Saad|Muhammad|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.13496",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13496\nCardiology\nDermatology\nInternal Medicine\nMyocarditis and Drug Rash With Eosinophilia and Systemic Symptoms Syndrome: A Deadly Combination\nMuacevic Alexander\nAdler John R\nDe La Cruz Angel C 1\nAshraf Shoaib 1\nShrestha Nikee 1\nSaad Muhammad 2\n1 Internal Medicine, Bronx Care Health System, Bronx, USA\n2 General Internal Medicine, Bronx Care Health System, Bronx, USA\nAngel C. De La Cruz adlcruz@bronxleb.org\n22 2 2021\n2 2021\n13 2 e1349621 2 2021\nCopyright © 2021, De La Cruz et al.\n2021\nDe La Cruz et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/44678-myocarditis-and-drug-rash-with-eosinophilia-and-systemic-symptoms-syndrome-a-deadly-combination\nDRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is a severe delayed type IV hypersensitivity drug reaction by T helper cell 2 (Th2) and Interleukin 5 (IL-5) resulting in activation of eosinophils. It is mostly reported with antiepileptic drugs (AEDs), antibiotics, and allopurinol. Here, we present the second case of myocarditis secondary to DRESS syndrome caused by amoxicillin. Most of the case reports present with cross-reactivity among the anticonvulsants and beta-lactams, which is also rarely been reported. Amoxicillin could reactivate human herpesvirus 6 (HHV 6) and Epstein-Barr virus (EBV) with a presentation similar to DRESS syndrome, but our patient was neither taking the anticonvulsants nor have any viral infection in the recent past. His RegiSCAR score was 6, consistent with definite DRESS syndrome. Management includes identification and prompt withdrawal of the offending drug and supportive care for patients without severe organ involvement and systemic corticosteroids for patients with severe organ involvement.\n\nmyocarditis\ndress syndrome\nlymphadenopathy\nechocardiography\namoxicillin\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nDRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms), also known as drug-induced hypersensitivity syndrome, is a severe idiosyncratic drug reaction. It is a delayed-type IV hypersensitivity reaction by T helper cell 2 (Th2), and Interleukin 5 (IL-5) resulting in activation of eosinophils [1]. DRESS is most commonly reported with antiepileptic drugs (AEDs), antibiotics, and allopurinol [2]. It affects the skin and various internal organs anywhere from two to eight weeks after exposure to a culprit medication [3]. DRESS syndrome typically presents with widespread skin rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia, atypical lymphocytosis), and end-organ damage, most commonly to the kidneys, lungs, and liver. We present the second case of myocarditis secondary to DRESS syndrome caused by amoxicillin. Cardiac involvement varies considerably between 4% and 21%, which can be fatal and therefore requires prompt diagnosis and treatment [4]. RegiSCAR scoring system helps clinicians in confirming or excluding the diagnosis of DRESS syndrome [5]. Management includes identification and prompt withdrawal of the offending drug and supportive care for patients without severe organ involvement. For patients with severe organ involvement, treatment with systemic corticosteroids is suggested but has not been evaluated in randomized trials [6].\n\nCase presentation\n\nA 33-year-old Hispanic man, with a recent dental procedure presented to our hospital complaining of right-sided neck pain and swelling for three days. He also complained of fever, chills, headache, and non-pruritic deep red blanching macular eruption on the trunk and extremities which extends to palms and soles. He is from the Dominican Republic, immigrated to the United States three months ago. A week before the presentation, the patient had a dental procedure for which he was treated with the amoxicillin antibiotic and a nonsteroidal anti-inflammatory drug (NSAID) for three days. Later on, he developed fever, malaise, headache, and macular eruption on the trunk and extremities. \n\nIn the emergency department, he was ill-appearing and was in moderate distress. His vital signs on admission included a body temperature of 102.3 °F, blood pressure of 122/76 mmHg, heart rate of 120 beats/min, respiratory rate of 15 breaths/minute, and oxygen saturation of 99% on room air. The patient’s cardiovascular examination revealed a regular heart rate without audible heart murmurs or an elevated jugular venous pressure. He had no peripheral edema of the lower extremities with normal peripheral pulses. The respiratory examination revealed normal vesicular breath sounds, no wheezing. His skin showed non-pruritic deep red blanching macular eruption on the trunk and extremities which extends to palms and soles. The rest of the physical examination was within normal limits (Figure 1). The Nikolsky sign and Koplik spots were negative.\n\nFigure 1 Cutaneous manifestations in patient\n\nErythematous macules and papules on the entire body\n\nLaboratory investigations showed a white blood cell (WBC) count of 13.6 × 103/µL, with 2.8% eosinophils and 81.3% neutrophils, and a platelet count of 345 ×103/μL. Blood chemistry results showed blood urea nitrogen (BUN) of 10 mg/dL, serum creatinine of 0.9 mg/dL, aspartate aminotransaminase (AST) of 63 U/mL, and alanine aminotransferase (ALT) of 66 U/mL.\n\nSerological tests for the presence of hepatitis B surface antigen (HbsAg), surface antibody (anti-HBs), total hepatitis B core antibody (anti-HBc), hepatitis C antibody and its polymerase chain reaction (PCR) test, varicella-zoster IgM antibody, and cytomegalovirus IgM antibody were all negative, indicating that these viruses were unlikely to be the cause of his condition. Serological testing for Epstein-Barr virus (EBV) was negative for EBV DNA, serum heterophile agglutination, EBV viral capsid antigen IgG, and EBV viral capsid antigen IgM. Serological testing for herpes simplex virus (HSV) 1 and 2 DNA and IgM screen was negative but HSV Ab types 1 and 2 were positive indicating a history of HSV infection. Serological testing for measles Ab IgM (EIA) was negative but measles (rubeola) antibodies, IgG was positive, indicating a history of rubeola infection. The results of serological tests for the presence of cytomegalovirus (CMV) IgM (EIA), varicella-zoster virus (VZV) IgM, human parvovirus B19 IgM, and human immunodeficiency virus (HIV) antibody were negative.\n\nBlood cultures, aerobic throat culture, and blood fungal culture resulted in normal; serologic tests for an acute viral infection by adenovirus, human rhinovirus, Influenza (A and B), Influenza A virus H1/H3 subtype by PCR, human metapneumovirus (hMPV), human respiratory syncytial virus (RSV A and B), and human parainfluenza (1, 2, 3) resulted negative according to the cutoffs of our laboratory. Among autoantibodies, rheumatoid factor, antinuclear antibody (ANA), antibody to antiscleroderma-70, anti-cyclic citrullinated antibody, anti-SM, antistreptolysin O, myeloperoxidase, proteinase-3 Ab, anti-Ro/SSA, and anti-La/SSB antibodies, anti-Jo-1 antibody, anti-Sm, anti-RNP antibodies, anti-DNA antibodies, and lupus anticoagulants were negative. Tests for syphilis, including the rapid plasma reagin (RPR) test were negative. Skin biopsy and histopathology showed superficial perivascular dermatitis with lymphocyte and eosinophils infiltrates (Figure 2). The changes are consistent with hypersensitivity reactions such as drugs or orthropodocytes.\n\nFigure 2 Skin biopsy and histopathology of the patient\n\nSkin biopsy showed superficial perivascular dermatitis with lymphocyte and eosinophils infiltrate\n\nThe first chest X-ray showed no evidence of active chest disease (Figure 3A). Repeat chest x-ray on the floor demonstrating cardiomegaly, left basilar infiltrate versus atelectasis (Figure 3B).\n\nFigure 3 Chest X-ray of the patient\n\n(A) chest X-ray showed no evidence of active chest disease; (B) chest x-ray demonstrating cardiomegaly, left basilar infiltrate versus atelectasis\n\nA head computed tomography (CT) scan showed no acute infarct, intracranial bleeding, or mass effect. A neck CT scan showed a retropharyngeal abscess and enlarged right posterior triangle lymph nodes (Figure 4).\n\nFigure 4 Neck computed tomography\n\n(A) Axial section showed a retropharyngeal abscess and enlarged right posterior triangle lymph nodes; (B) coronal image showed a retropharyngeal abscess\n\nThe patient was initially started on ceftriaxone and clindamycin for the retropharyngeal abscess but due to persistent fever, high erythrocyte sedimentation rate (ESR) 90.0 mm/hour, and C-reactive protein (CRP) 285.84 mg/L antibiotics were changed to vancomycin, aztreonam, metronidazole, and doxycycline for broader coverage.\n\nFour days after admission, the rash became more confluent with annular and polycyclic lesions with dusky centers, but fever persisted. We used the RegiSCAR scoring system that grades our patient was definite DRESS syndrome (Table 1). Five days after admission, he developed intermittent chest discomfort and malaise with persistent fever despite antibiotics. Electrocardiography (ECG) showed normal sinus rhythm with 88 beats/minute, first-degree atrioventricular (AV) block, and moderate voltage criteria for left ventricular hypertrophy.\n\nTable 1 RegiSCAR scoring system\n\nAccording to the original publication, cut-off points include: <2 No DRESS, 2-3 Possible, 4-5 Probable, ≥6 Definite\t\nFever ≥38.5 °C\tYes\t0\t\nEnlarged lymph nodes ≥2 sites, ≥1 cm\tYes\t1\t\nAtypical lymphocytes\tNo\t0\t\nEosinophilia\tNo\t0\t\nSkin rash\tYes\t \t\n- Extend >50%\tYes\t1\t\n- At least two of the following: edema, infiltration, purpura, scaling\tYes\t1\t\n- Biopsy suggesting DRESS\tYes\t0\t\nInternal organ involved\t≥2 organs\t2\t\nResolution delay\t>15 days\t0\t\nAt least three biological investigations done and negative to exclude the alternative diagnosis\tYes\t1\t\nRegiSCAR score\t\nAssessment\tDefinite DRESS\t6\t\n\nThe patient was found to have troponin of 447 ng/ml and repeat 562 ng/ml with a delta of 115 ng/ml, N-terminal pro-B-type Natriuretic Peptide (Pro BNP) was 4835 pg/ml, and CRP 285.84 mg/L. Echocardiography following admission showed a concentric remodeling with global hypokinesis and grade 2 diastolic dysfunction, and pericardial effusion was seen without echocardiographic signs of tamponade. Left ventricular systolic function was diffusely reduced with left ventricular ejection fraction (LVEF) of 49.29% (Figure 5), right ventricular systolic pressure 41.58 mmHg consistent with mildly elevated pulmonary artery pressure. Endomyocardial biopsy was discussed with the patient but he refused the biopsy.\n\nFigure 5 Echocardiography\n\nConcentric remodeling with global hypokinesis, grade 2 diastolic dysfunction, and left ventricular ejection fraction of 49.29%\n\nHe was started on a standard heart failure regimen consisting of carvedilol, lisinopril but the diuretic was not started as the patient was euvolemic. He was placed on intravenous immune globulin (IVIG) and began triamcinolone 0.1% ointment applied to his whole body. High-dose glucocorticoids were avoided because of myocarditis. Repeat neck CT scan showed resolution of a retropharyngeal abscess, blood cultures came back negative, so antibiotics were stopped. Troponin and N-terminal pro-B-type natriuretic peptide (BNP) levels came to normal limits. Repeat echocardiogram showed improvement in ejection fraction (EF). He slowly improved, became afebrile with a gradual central clearing of the rashes and clinical improvement.\n\nDiscussion\n\nDRESS is a distinct type of drug-induced hypersensitivity syndrome caused by a wide variety of drugs, although it is most commonly associated with anticonvulsants and antibiotics [6]. It carries about 10% mortality, with an incidence that ranges from 1 in 1000 to 10,000 drug exposures [6,7]. Most cases of DRESS occur in adults, and the female to male ratio is around 1:1.\n\nThe pathogenesis of this syndrome is unclear. Many hypotheses have been proposed, including genetic mutations involving deficient drug metabolism, an immunologic mechanism involving activation of drug-specific T cells, reactivation of herpesviruses-HHV6, CMV, and EBV, and many more. Anticonvulsant drugs such as phenytoin, carbamazepine, phenobarbital, and sulfonamides such as dapsone and sulfasalazine are the most common agents known to cause DRESS. During the initial phase of the syndrome, there is an expansion of regulatory T cells as well as cytotoxic and helper T cells. These cells will cross-react with the offending drug, and the activated cytotoxic T cells will cause tissue damage through secretion of interferon-gamma, interleukin-5, and tumor necrosis factor-alpha. Interleukin-5 will also mediate the eosinophilic infiltrate in the involved tissues.\n\nGenetic deficiencies causing a deficiency in enzymes involved in drug catabolism have also been reported. Because of that, the buildup of drug metabolites can occur. These metabolites can bind to macromolecules inducing cell death in the involved organs. It has been reported that individuals with HLA-B1502, HLA-B1508, and HLA-B1502 are at increased risk of developing DRESS [8-10]. Generally, clinical signs and symptoms begin within two to six weeks after drug intake and include fever preceding various cutaneous manifestations - most commonly morbilliform rash and systemic findings. The most common systemic findings involve lymphatic, hematologic, and hepatic systems followed by renal, pulmonary, and cardiac systems. Patients may present with fever, skin rash, facial edema, extremity swelling, abdominal pain, chest pain, cervical lymphadenopathy, eosinophilia, atypical lymphocytosis, and multi-organ failure [11]. Several diagnostic criteria have been used for the diagnosis of DRESS, such as RegiSCAR and J-SCAR. The severity of DRESS depends upon the systemic involvement, which can result in multi-organ failure.\n\nTo the best of our understanding, we report the second case of amoxicillin-induced DRESS syndrome [12]. Potentially, amoxicillin can, directly and indirectly, cause DRESS syndrome. Multiple case reports of amoxicillin triggering DRESS syndrome through reactivation of HHV 6 and EBV [13,14] and through cross-reactivity to carbamazepine, sulfasalazine, and benzylpenicillin [7,15,16], have been reported. Nevertheless, DRESS syndrome directly caused by amoxicillin has been previously reported only once. In regards to the cases related to amoxicillin, few observations are notably in our case, the fact that the symptoms of DRESS flared within around five days later after the introduction of the antibiotic instead of a universally accepted time frame of two weeks to two months after the introduction of culprit drugs. A rash that appeared within two to five days after amoxicillin treatment is also observed in many related case reports [15,17,18]. Our patient neither had any active viral infection like HHV 6 and EBV nor was taking any medications that commonly are considered being causative agents for DRESS syndrome except amoxicillin. We believe that DRESS would obviously be related to amoxicillin in view of these arguments: (1) a clear-cut temporal relationship between the administration of amoxicillin and the symptoms onset (five days, typically two to five days [15,17,18]); (2) remission of the symptomatological pattern after the withdrawal of this drug and introduction of IVIG therapy and topical steroids; (3) the association of different symptoms evoking a clinical picture of DRESS syndrome. RegiSCAR scoring system grades our patient was probable DRESS syndrome (Table 1). There is no available gold standard for diagnosis of DRESS syndrome, but the RegiSCAR scoring system helps clinicians in the probability of diagnosis and inclusion criteria for hospitalization for the management of patients [19]. Our patient met six of seven RegiSCAR criteria.\n\nCardiac involvement in DRESS syndrome has been reported in only 4% to 21 % of cases of DRESS and it usually presents with myocarditis. Patients can present with no symptoms or can present with chest pain, dyspnea, and hypotension. Cardiomegaly and pleural effusions can be seen on the chest radiograph. EKG changes of ST and T wave changes and arrhythmias can be found, and decreased ejection fraction in echocardiogram can be seen. In addition, patients can present with elevation of cardiac enzymes. It is a very intriguing fact that there are two described forms of myocarditis in DRESS: hypersensitivity and acute necrotizing eosinophilic myocarditis (ANEM). ANEM is associated with more than 50% mortality, which is one of the reasons why this topic is important [20]. A definitive diagnosis is made by a cardiac biopsy. Management involves the removal of the offending drug. Beta-blockers and renin-angiotensin-aldosterone system modulators can also be used. Given the fact that DRESS can present with variable manifestations- with or without eosinophilia, with a variety of skin manifestations and a vast range of systemic involvement, one should have a high suspicion for diagnosis, especially with the fact that mortality in DRESS syndrome is around 10% with hepatic and cardiac involvement mortality rate increase significantly. \n\nFor the most part, patients with DRESS recover entirely after about one month after the offending drug is withdrawn. About 10% of patients may develop complications that can include renal failure and the development of an autoimmune disease, such as Graves’ disease and diabetes mellitus type 1. Based on our experience, we recommend patient education and counseling about myocarditis, congestive cardiac failure, and pericarditis along with routine screens for cardiac enzymes in patients with DRESS. It is also essential to follow-up patients with signs and symptoms of heart failure with an echocardiogram and assesses them clinically, especially in the first six months after the DRESS syndrome because cardiac involvement can be quickly fatal.\n\nAmoxicillin is believed to result in DRESS syndrome, but how amoxicillin can trigger DRESS syndrome is a topic of debate. Better knowledge of DRESS may contribute to understanding pathophysiology, improve the diagnosis and management of this syndrome in clinical practice.\n\nConclusions\n\nDRESS is a complex clinical syndrome associated with multiple medications and may involve many organs. Myocarditis is an uncommon complication of DRESS. When suspected, immediate action should be taken because it increases mortality significantly. In this document, we described a unique case of DRESS syndrome due to amoxicillin confirmed with a skin biopsy, clinical presentation, and RegiSCAR scoring system. The patient developed myocarditis, which makes this case to be even more unique. We strongly recommend patient and healthcare personnel education about the possible presentations of myocarditis along with routine screens for cardiac enzymes in patients with DRESS. Early identification of myocarditis and removal of the offending agent is key to reduce mortality in patients with DRESS and myocarditis. We highlight the importance of a structured approach to evaluate and investigate DRESS syndrome.\n\nHuman Ethics\n\nThe authors thank Dr. Muhammad Saad for academic support to Dr. Masooma Niazi for providing pathology slides and to Dr. Saria Jamshaid for manuscript preparation and editing.\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Drug-induced hypersensitivity syndrome with myocardial involvement treated with tofacitinib JAAD case reports Damsky WE Vesely MD Lee AI 1018 1026 5 2019 31763425\n2 Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study Br J Dermatol Kardaun SH Sekula P Valeyrie-Allanore L 1071 1080 169 2013 23855313\n3 Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome J Clin Aesthet Dermatol Choudhary S McLeod M Torchia D Romanelli P 31 37 6 2013 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718748/ 23882307\n4 Cardiac involvement in DRESS syndrome Asian Pac J Allergy Immunol Thongsri T Chularojanamontri L Pichler WJ 3 10 35 2017 27996289\n5 Diagnostic criteria for drug rash and eosinophilia with systemic symptoms J Family Med Prim Care Pannu AK Saroch A 693 694 6 2017 29417040\n6 The DRESS syndrome: a literature review Am J Med Cacoub P Musette P Descamps V Meyer O Speirs C Finzi L Roujeau JC 588 597 124 2011 21592453\n7 DRESS syndrome due to benzylpenicillin with cross-reactivity to amoxicillin J Allergy Clin Immunol Pract Watts TJ Li PH Haque R 1766 1768 6 2018 29408014\n8 Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome Br J Dermatol Choquet-Kastylevsky G Intrator L Chenal C Bocquet H Revuz J Roujeau JC 1026 1032 139 1998 9990366\n9 Medical genetics: a marker for Stevens-Johnson syndrome Nature Chung WH Hung SI Hong HS 486 428 2004 15057820\n10 HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol Proc Natl Acad Sci U S A Hung SI Chung WH Liou LB 4134 4139 102 2005 15743917\n11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with cefotaxime and clindamycin use in a 6 year-old boy: a case report Pan Afr Med J Karakayali B Yazar AS Cakir D 218 28 2017 29629004\n12 Association of DRESS syndrome with chylous ascites Nephrol Dial Transplant Yu MK Yu MC Lee F 3301 3303 21 2006 16954168\n13 Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro Eur J Dermatol Mardivirin L Valeyrie-Allanore L Branlant-Redon E 68 73 20 2010 19822481\n14 Virus reactivation and intravenous immunoglobulin (IVIG) therapy of drug-induced hypersensitivity syndrome Toxicology Kano Y Inaoka M Sakuma K Shiohara T 165 167 209 2005 15767030\n15 Drug rash with eosinophilia and systemic symptoms syndrome induced by sulfasalazine Joint Bone Spine Bahat G Celik HG Tufan F Saka B 87 88 77 2010 19854669\n16 Amoxicillin-induced hypersensitivity after DRESS To carbamazepine World Allergy Organ J Aouam K Fredj Nadia B Amel C Naceur B 220 222 3 2010 23282653\n17 The rest of the story of the patient described in the letter to the editors: 'Hypersensitivity to amoxicillin after… (DRESS) to carbamazepine…: a possible co-sensitization' Br J Clin Pharmacol Chadli Z Ben Fredj N Youssef M Chaabane A Boughattas NA Zili JE Aouam K 784 785 81 2016 26594014\n18 DRESS syndrome in a patient on sulfasalazine for rheumatoid arthritis Joint Bone Spine Michel F Navellou J-C Ferraud D Toussirot E Wendling D 82 85 72 2005 15681256\n19 Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in two young children: the importance of an early diagnosis Ital J Pediatr Castellazzi ML Esposito S Claut LE Daccò V Colombo C 93 44 2018 30111350\n20 Refractory cardiac myocarditis associated with drug rash with eosinophilia and systemic symptoms syndrome due to anti-bipolar disorder drugs: a case report Eur Heart J Case Rep Hagiwara H Fukushima A Iwano H Anzai T 100 2 2018\n\n",
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"issue": "13(2)",
"journal": "Cureus",
"keywords": "amoxicillin; dress syndrome; echocardiography; lymphadenopathy; myocarditis",
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"title": "Myocarditis and Drug Rash With Eosinophilia and Systemic Symptoms Syndrome: A Deadly Combination.",
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"abstract": "We present a case of a 79-year-old male who presented with retroperitoneal hematoma a week after motor vehicle accident. Prior history and family history of bleeding were nonsignificant. His activated partial thromboplastin time was found to be prolonged in the emergency department. Further workup with coagulation studies showed decreased factor VIII, vWF antigen, and vWF:ristocetin cofactor assay, and negative Bethesda assay, indicating acquired von Willebrand disease. Immunofluorescence to find an underlying etiology was suggestive of MGUS. Management of AvWD depends on controlling active bleeding and treating the underlying cause. He was treated with factor VIII, haemate-p, rituximab, two cycles of IVIg, and three weeks of oral steroids.",
"affiliations": "Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA.;Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA.;Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA.;Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA.;Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA.;Maharajgunj Medical Campus, Tribhuvan University, Kathmandu, Nepal.;Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA.;Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA.",
"authors": "Basnet|Sijan|S|0000-0002-8324-2827;Lin|Catherine|C|;Dhital|Rashmi|R|;Mir|Izza|I|0000-0002-6704-2331;Mohanty|Elan|E|;Tharu|Biswaraj|B|;Ghimire|Sushil|S|;Poudel|Dilli Ram|DR|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2017/9295780Case ReportAcquired von Willebrand Disease Associated with Monoclonal Gammopathy of Unknown Significance http://orcid.org/0000-0002-8324-2827Basnet Sijan sijan.basnet@readinghealth.org\n1\nLin Catherine \n1\nDhital Rashmi \n1\nhttp://orcid.org/0000-0002-6704-2331Mir Izza \n1\nMohanty Elan \n1\nTharu Biswaraj \n2\nGhimire Sushil \n1\nPoudel Dilli Ram \n1\n\n1Department of Medicine, Reading Hospital, 420 S. Fifth Avenue, West Reading, PA 19611, USA\n2Maharajgunj Medical Campus, Tribhuvan University, Kathmandu, NepalAcademic Editor: Josep M. Ribera\n\n2017 1 11 2017 2017 92957801 8 2017 16 10 2017 Copyright © 2017 Sijan Basnet et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a case of a 79-year-old male who presented with retroperitoneal hematoma a week after motor vehicle accident. Prior history and family history of bleeding were nonsignificant. His activated partial thromboplastin time was found to be prolonged in the emergency department. Further workup with coagulation studies showed decreased factor VIII, vWF antigen, and vWF:ristocetin cofactor assay, and negative Bethesda assay, indicating acquired von Willebrand disease. Immunofluorescence to find an underlying etiology was suggestive of MGUS. Management of AvWD depends on controlling active bleeding and treating the underlying cause. He was treated with factor VIII, haemate-p, rituximab, two cycles of IVIg, and three weeks of oral steroids.\n==== Body\n1. Introduction\nAcquired von Willebrand disease (AvWD) is a rare bleeding disorder [1, 2]. It is characterized by hemorrhagic events later in life without personal or family history of bleeding events [3]. A number of acquired conditions have been associated with AvWD [4]. We report a patient diagnosed with acquired von Willebrand disease secondary to monoclonal gammopathy with unknown significance after initial presentation with retroperitoneal hematoma.\n\n2. Case Description\nA 79-year-old man presented to the emergency department with severe left hip and groin pain with overlying hematoma. He had a prior admission one week before with arrhythmia-induced syncope leading to a motor vehicle accident. He received a dual-chamber automatic implantable cardioverter-defibrillator after inducible ventricular fibrillation/ventricular tachycardia during electrophysiology study. CT scan at the time was unremarkable except for a 2 cm area of suspected hematoma in the left trochanteric region. His past medical history and medications were not significant except for aspirin use. The patient denied significant prior or family history of bleeding or easy bruising. He had undergone an appendectomy and bilateral hip replacements in the past without significant bleeding.\n\nThe patient was hypotensive on presentation. His hemoglobin had dropped from 11.7 g/dl to 6.2 g/dl within one week. CT scan of his chest/abdomen/pelvis revealed a large left retroperitoneal hematoma measuring approximately 14.2 × 6.8 × 14.1 cm (Figure 1). The patient's PTT was 48 s, which increased from 38 s a week ago (Table 1). His prothrombin time was 13.9 s with INR of 1.1. His white blood count and platelet count were normal. Serum fibrinogen, fibrin degradation products and d-dimer, and liver function tests were normal. His factor VIII activity was 12%, and von Willebrand factor antigen was 4%. vWF had normal multimeric distribution. His vWF:ristocetin cofactor assay was < 20. The Bethesda assay (factor VIII inhibitor screening) was negative for an inhibitor. Circulating anticoagulant screening (mixing study) failed to correct his PTT which suggested the possibility of an inhibitor or lupus anticoagulant. Although he was positive for lupus anticoagulant (anti-LA 67), dilute Russell viper venom time (DRVVT) ratio was 1. Thus, we ruled out antiphospholipid antibody syndrome and diagnosed the patient's condition as acquired von Willebrand factor deficiency. The patient was resuscitated with 3 units of packed red blood cells and prothrombin complex concentrate. He underwent factor VIII 50% replacement, one dose of haemate-p (3976 units), one cycle of rituximab, and three weeks of oral steroids. He also received two cycles of IVIg which normalized vWF antigen or factor VIII activity. His aPTT was 34.9 s, factor VIII activity was 114%, von Willebrand factor antigen was 95%, and vWF:ristocetin cofactor assay was 81%.\n\nEvaluation of underlying etiology showed decreased albumin and IgG with normal IgA and IgM on serum electrophoresis. Immunofluorescence showed a band in IgG lambda suggestive of an early monoclonal protein (0.34 g/dL of the total 0.68 g/dL of protein in the gamma region). Kappa/lambda ratio was 0.70 (normal reference range 0.26–1.65). He was diagnosed with monoclonal gammopathy of unknown significance. Bone marrow biopsy to rule out myeloma was not done. CT scans of head, chest, abdomen, and pelvis done were negative for lytic bone lesions or lymphadenopathy. He had normal renal function and normal serum calcium. Iron profile showed ferritin of 925 ng/ml (27–300 ng/dl), iron of 25 mcg/dl (40–175 mcg/dl), and transferrin of 125 mg/dl (193–378 mg/dl). Ferritin was most likely elevated from blood transfusions. Folate and vitamin B12 were normal. ANA, hepatitis B, and hepatitis C were negative. Thyroid function test was normal. Echocardiogram showed mild aortic stenosis. He was discharged on 40 mg prednisone daily after bleeding was controlled. His hemoglobin level on discharge was 9.8 gm/dl.\n\nOn follow-up after a month on prednisone, his aPTT was 34.9, factor VIII activity was 114%, von Willebrand factor antigen was 95%, and vWF:ristocetin cofactor assay was 81%. His hemoglobin was 11.8 g/dl. Repeat iron studies were not done.\n\n3. Discussion\nAcquired vWS is a rare condition [5]. It is associated with a multitude of conditions, including lymphoproliferative disorders (most common: 48%), myeloproliferative disorders (chronic granulocytic leukemia, essential thrombocythemia, and polycythemia vera), neoplasms (Wilms tumor), immunological disorders, cardiovascular diseases, hypothyroidism, hemoglobinopathies, drugs (valproate, ciprofloxacin, and hydroxyethyl starch), and infections [1, 2, 4–7]. Among lymphoproliferative disorders, MGUS is the most commonly associated with AvWD, including in 23% of registered patients [1]. Other lymphoproliferative disorders associated with acquired vWD are MM, Waldenstrom macroglobulinemia, CLL, HCL, NHL, and lymphosarcoma [3]. There are two proposed mechanisms for acquired vWD. Immune mechanism is believed to be the responsible mechanism in patients with lymphoproliferative or autoimmune diseases. Nonspecific antibodies bind to vWF; this complex gets cleared by FC-bearing cells or autoantibodies directed against the vWF [5, 8]. In MGUS, as in our patient, paraproteins bind to vWF resulting in accelerated clearance and low circulating levels [2]. Immune-mediated cause most likely mediates the disease process in our patient, as he had significant response to IVIg. Nonimmune-mediated mechanisms are thought to be due to loss of large vWF multimers under high shear stress conditions (congenital heart defects, aortic stenosis, artificial heart valves, or left ventricular assist device), absorption of vWF onto tumor cells, decreased synthesis (hypothyroidism and valproic acid) or release from endothelial cells, or increased proteolysis of vWF (ciprofloxacin) [2, 4, 5].\n\nPresentation in acquired vWD is similar to congenital vWD. However, AvWD presents later in life with no previous or family history of bleeding [9, 10]. Routine recommended tests in acquired von Willebrand disease are vWF:Ag assay, vWF:Ag activity assay, and ristocetin cofactor assay (vWF:RCo/Ag ratio) (normal = 1) [2, 7]. Among them, ristocetin cofactor assay is the recommended test [7]. vWF:RCo/Ag ratio < 0.6–0.7 indicates inhibitory antibodies or a selective loss or decrease in high molecular weight multimers [2]. Circulating inhibitors are rarely detected in this condition [4]. vWF multimer analysis is the gold standard test. It is particularly useful if other tests are negative [2]. A multimeric pattern with decreased levels of high molecular weight vWF multimers is seen because the inhibitors tend to attack the large multimers of vWF. Serum protein electrophoresis or immunofluorescence tests and thyroid function test can be done to establish etiology [4]. Congenital vWD and AvWD can be differentiated by measurement of vWF propeptide (vWFAg II). vWF propeptide is a marker of vWF synthesis. Since AvWD is associated with clearance of vWF, vWF propeptide will be normal [4].\n\n4. Management\nManagement is based on correction of acute bleeding episode and treatment of associated underlying conditions. The acute bleeding can be controlled by infusion of cryoprecipitate, vWF-containing factor VIII (FVIII) concentrates (haemate-p), or desmopressin. This will result in immediate and transient rise in serum FVIII-vWF complex levels [4]. IVIg can correct vWF activity for 2–3 weeks [2]. IVIg is the preferred to minimize bleeding risk during elective procedures [1]. A combination of IVIg, vWF-containing factor VIII (FVIII) concentrates (haemate-p), and desmopressin is effective in some patients [5]. FVIII and vWF levels return to baseline within 2 hours of transfusion of haemate-p [11]. In patients with MGUS, steroids and rituximab have been used to treat AvWD [5]. Rituximab, which is effective in acquired hemophilia, has been used in treatment for a few cases. However, it has been reported to be ineffective in them [12]. Management of aortic stenosis, hypothyroidism, and discontinuation of medications has resulted in correction of the bleeding disorder [2].\n\n5. Conclusion\nAvWD should be considered in cases with abnormal bleeding and prolonged PTT. It can be asymptomatic in mild conditions for decades [2]. Further workup for an etiology is important as treatment of the underlying cause can prevent future bleeding episodes.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 CT scan of the abdomen with retroperitoneal hematoma.\n\nTable 1 Lab tests done during presentation, treatment, and a month after treatment.\n\nLab test\tPresentation\tDuring treatment (3 days)\t1 month after treatment\tReference range\t\nINR\t1.1\tN/A\t1.1\t0.9–1.1\t\nPTT (sec)\t48\tN/A\t34.9\t23–34 s\t\nFactor VIII activity (%)\t12\t33\t114\t50–160%\t\nFactor IX activity (%)\t166\tN/A\tN/A\t60–150%\t\nFactor XI activity\t98\tN/A\tN/A\t50–150%\t\nFactor XII activity\t54\tN/A\tN/A\t50–150%\t\nvWF antigen (%)\t6\t10\t95\t60–150%\t\nRistocetin cofactor assay (%)\t< 20\t< 20\t81\t50–160%\t\nvWF multimer analysis\tNormal\tN/A\tN/A\tNormal multimeric distribution\t\nBethesda assay\t0\tN/A\tN/A\t0\t\nINR: international normalized ratio; PTT: partial thromboplastin time; vWF: von Willebrand factor; N/A: not available.\n==== Refs\n1 Federici A. B. Rand J. H. Bucciarelli P. Subcommittee on von Willebrand factor. Acquired von Willebrand syndrome: data from an international registry Thrombosis and Haemostasis 2000 84 2 345 349 10959711 \n2 Tiede A. Diagnosis and treatment of acquired von Willebrand syndrome Thrombosis Research 2012 130 2 S2 S6 10.1016/S0049-3848(13)70003-3 2-s2.0-84874621807 23439003 \n3 Mital A. Acquired von Willebrand syndrome Advances in Clinical and Experimental Medicine 2016 25 6 1337 1344 10.17219/acem/64942 2-s2.0-85006830412 28028990 \n4 Nitu-Whalley I. C. Lee C. A. Acquired von Willebrand syndrome–report of 10 cases and review of the literature Haemophilia 1999 5 5 318 326 10.1046/j.1365-2516.1999.00340.x 2-s2.0-0032749035 10583513 \n5 Gavva C. Patel P. Shen Y.-M. Frenkel E. Sarode R. A case of autoimmune severe acquired von Willebrand syndrome (type 3-like) Transfusion and Apheresis Sciences 2017 56 3 431 433 10.1016/j.transci.2017.04.006 \n6 Shetty S. Kasatkar P. Ghosh K. Pathophysiology of acquired von Willebrand disease: a concise review European Journal of Haematology 2011 87 2 99 106 10.1111/j.1600-0609.2011.01636.x 2-s2.0-79960391165 21535159 \n7 Tefferi A. Nichols W. L. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis, and treatment American Journal of Medicine 1997 103 6 536 540 10.1016/s0002-9343(97)00239-8 2-s2.0-0031460262 9428838 \n8 Ghosh K. Shetty S. Jijina F. Mohanty D. Development of anti-VWF antibody in a patient with severe haemophilia A following the development of high-grade non-Hodgkin’s lymphoma Clinical and Laboratory Haematology 2002 24 3 191 193 10.1046/j.1365-2257.2002.00432.x 2-s2.0-0036283856 12067287 \n9 Qamar H. Lee A. Valentine K. Skeith L. Jimenez-Zepeda V. H. Acquired von Willebrand syndrome associated to secondary IgM MGUS emerging after autologous stem cell transplantation for AL amyloidosis Mediterranean Journal of Hematology and Infectious Diseases 2017 9 1 p. e2017034 10.4084/MJHID.2017.034 \n10 Saif M. A. Thachil J. Brown R. Is it congenital or acquired von Willebrands disease? Haemophilia 2015 21 1 e113 e115 10.1111/hae.12588 2-s2.0-84921500969 25381916 \n11 Maddox J. M. Anderson J. A. M. Plews D. Ludlam C. A. Management of acquired von Willebrand’s syndrome in a patient requiring major surgery Haemophilia 2005 11 6 633 637 10.1111/j.1365-2516.2005.01150.x 2-s2.0-27744434517 16236115 \n12 Mazoyer E. Fain O. Dhote R. Laurian Y. Is rituximab effective in acquired von Willebrand syndrome? British Journal of Haematology 2009 144 6 967 968 10.1111/j.1365-2141.2008.07538.x 2-s2.0-60649109915 19120364\n\n",
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"title": "Acquired von Willebrand Disease Associated with Monoclonal Gammopathy of Unknown Significance.",
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"abstract": "The hepatic complications of sickle cell disease (SCD) are associated with increased morbidity and mortality in adults; children usually survive but may suffer significant sequelae. Few diagnostic tools differentiate the various hepatic manifestations of SCD. Why patients exhibit one hepatic pathology versus another is unclear. We report four pediatric patients with hemoglobin SS disease with diverse manifestations of acute hepatic involvement including acute sickle hepatic crisis, hepatic sequestration, sickle cell intrahepatic cholestasis, and a non-SCD cause of hepatopathy in a patient with viral hepatitis. These complications require a systematic approach to extensive evaluation and coordinated multidisciplinary care.",
"affiliations": "Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California.;Center for Innovation in Pediatric Practice, Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, Ohio.;Division of Gastroenterology, Hepatology, and Nutrition, Children's National Health System, Washington, District of Columbia.;Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana.;Division of Hematology, Children's National, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.;Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.",
"authors": "Pecker|Lydia H|LH|0000-0002-8371-9752;Patel|Nidhi|N|;Creary|Susan|S|;Darbari|Anil|A|;Meier|Emily Riehm|ER|;Darbari|Deepika S|DS|;Fasano|Ross M|RM|",
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"keywords": "sickle cell anemia; sickle cell disease; sickle hepatopathy",
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"mesh_terms": "D000293:Adolescent; D000755:Anemia, Sickle Cell; D002648:Child; D005260:Female; D006801:Humans; D008107:Liver Diseases; D008297:Male; D055815:Young Adult",
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"title": "Diverse manifestations of acute sickle cell hepatopathy in pediatric patients with sickle cell disease: A case series.",
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"abstract": "Lawsonella clevelandensis is a recently described anaerobic and partially acid-fast bacterium within the order Corynebacterineae. It is a fastidious microorganism that has been identified as part of the oral microbiota and is rarely associated with human infections. We describe the case of a 70-year-old man with a history of rheumatoid arthritis that developed liver abscesses and pylephlebitis. Gram stain of purulent material obtained by percutaneous drainage of the hepatic collection revealed gram-positive bacilli that stained acid-fast by the Kinyoun method. The patient was initially treated with imipenem, moxifloxacin and clarithromycin for possible Nocardia and/or nontuberculous mycobacterial infection. Cultures failed to grow the organism seen on the stains, and broad-spectrum 16S rRNA PCR gene sequencing analysis identified it as Lawsonella clevelandensis. Treatment was de-escalated to amoxicillin/clavulanic acid. The hepatic abscesses resolved completely after 4 weeks of treatment. There are only 8 documented cases of human infection caused by Lawsonella clevelandensis reported in the literature. Conventional microbiological methods do not reliably detect this bacterium, and the diagnosis relies on molecular methods. Excellent outcomes are obtained with a combined treatment approach that includes abscess drainage and prolonged antibiotic therapy.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, 33136, United States.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, 33136, United States.;The AIDS Healthcare Foundation, Northpoint Health Center, Fort Lauderdale, FL, 33308, United States.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, 33136, United States.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, 33136, United States.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, 33136, United States.",
"authors": "Gonzales Zamora|Jose A|JA|;Romero Alvarez|Maria|M|;Henry|Zachary|Z|;Baracco|Gio J|GJ|;Dickinson|Gordon|G|;Lichtenberger|Paola|P|",
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"doi": "10.1016/j.idcr.2020.e00734",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30042-1\n10.1016/j.idcr.2020.e00734\ne00734\nArticle\nLiver abscess caused by Lawsonella clevelandensis in a patient with rheumatoid arthritis: A case report and literature review\nGonzales Zamora Jose A. jxg1416@med.miami.edua⁎ Romero Alvarez Maria maria.romeroalvarez@jhsmiami.orga Henry Zachary zachary.henry@aidshealth.orgb Baracco Gio J. gbaracco@med.miami.eduac Dickinson Gordon gdickins@med.miami.eduac Lichtenberger Paola plichtenberger@med.miami.eduac a Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, 33136, United States\nb The AIDS Healthcare Foundation, Northpoint Health Center, Fort Lauderdale, FL, 33308, United States\nc Department of Infectious Diseases, Miami Veterans Affairs Healthcare System, Miami, FL, 33125, United States\n⁎ Corresponding author at: 1120 NW 14th Street, Suite 863B, Miami, FL, 33136, United States. jxg1416@med.miami.edu\n28 2 2020 \n2020 \n28 2 2020 \n20 e007347 2 2020 26 2 2020 26 2 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Lawsonella clevelandensis is a recently described anaerobic and partially acid-fast bacterium within the order Corynebacterineae. It is a fastidious microorganism that has been identified as part of the oral microbiota and is rarely associated with human infections. We describe the case of a 70-year-old man with a history of rheumatoid arthritis that developed liver abscesses and pylephlebitis. Gram stain of purulent material obtained by percutaneous drainage of the hepatic collection revealed gram-positive bacilli that stained acid-fast by the Kinyoun method. The patient was initially treated with imipenem, moxifloxacin and clarithromycin for possible Nocardia and/or nontuberculous mycobacterial infection. Cultures failed to grow the organism seen on the stains, and broad-spectrum 16S rRNA PCR gene sequencing analysis identified it as Lawsonella clevelandensis. Treatment was de-escalated to amoxicillin/clavulanic acid. The hepatic abscesses resolved completely after 4 weeks of treatment.\n\nThere are only 8 documented cases of human infection caused by Lawsonella clevelandensis reported in the literature. Conventional microbiological methods do not reliably detect this bacterium, and the diagnosis relies on molecular methods. Excellent outcomes are obtained with a combined treatment approach that includes abscess drainage and prolonged antibiotic therapy.\n\nKeywords\nLawsonella clevelandensisLiver abscessAnaerobeAcid-fast bacilli\n==== Body\nIntroduction\nLawsonella clevelandensis is an anaerobic, partially acid-fast bacillus recently recognized as a human pathogen. It is difficult to isolate in conventional cultures, thus diagnosis relies on molecular techniques based on gene sequencing analysis [1]. Human infections are extremely rare. To our knowledge, there are only 8 cases of infection caused by this organism documented in the English literature. Abscesses in the abdominal cavity, breast, and spine have been described [2]. We present a case of Lawsonella clevelandensis liver abscess with pylephlebitis and review the existing literature.\n\nCase description\nA 70-year-old man was admitted to the hospital with two months of abdominal pain, fatigue, unintentional 40-pound weight loss, and one week of subjective fevers and shortness of breath. He described his abdominal pain as diffuse, non-radiating, and constant, without aggravating or relieving factors. His shortness of breath started a week prior to admission and progressed to being able to walk only a few steps. His past medical history was significant for rheumatoid arthritis, for which he was on treatment with methotrexate and adalimumab for 1 year. He also suffered of hypertension, hyperlipidemia, diverticulosis, and sleep apnea. Three months before onset of symptoms, the patient had an uneventful dental procedure. The patient was a retired marine who went to Vietnam in 1961 and stayed there for 13 months. He denied any sick contacts.\n\nUpon admission, his temperature was 37.8 °C, pulse was 98 beats/min, respiratory rate was 14 breaths/min, and blood pressure was 87/53 mmHg. His abdominal exam revealed a distended and diffusely tender abdomen with guarding and normal bowel sounds. No hepatosplenomegaly was noted. Laboratory studies showed 19,300 leukocytes/uL with 91 % neutrophils, hemoglobin of 12.2 g/dL, platelet count of 245,000/uL, elevated transaminases (AST: 136 IU/L, ALT: 96 IU/L), mild hyperbilirubinemia (2.1 mg/dL), and elevated alkaline phosphatase (415 IU/L). His creatinine was 1.6 mg/dL, up from his baseline of 0.9 mg/dL one month prior. A computed tomography with contrast of the abdomen showed numerous low-density lesions within the liver (Fig. 1A). There was also thrombosis of the hepatic veins in the right lobe of the liver that extend to involve the entire portal vein and the central portion of the splenic vein, which was later confirmed by Doppler ultrasound (Fig. 2A,B). Other significant findings included cholelithiasis, ascites (Fig. 1B) and bowel wall edema involving the small bowel, cecum, ascending colon and transverse colon. A paracentesis was performed with removal of 2.3 liters of cloudy fluid. Analysis of ascitic fluid revealed albumin of 0.9 g/dL, total protein of 2.5 g/dL, and 1734 leukocytes/uL with 77 % of neutrophils. Approximately 55 mL of purulent material were obtained by percutaneous drainage of the hepatic collections, and a Jackson-Pratt (JP) drain was placed in right upper quadrant. Piperacillin/tazobactam, vancomycin, and metronidazole were administered empirically for a suspected polymicrobial liver abscess.Fig. 1 Contrast CT scan showing numerous low-density lesions within the liver, likely representing hepatic abscesses (A) and abdominal/pelvic ascites probably due to venous congestion (B).\n\nFig. 1Fig. 2 Doppler ultrasound demonstrating portal vein (A) and splenic vein (B) thrombosis.\n\nFig. 2\n\nMicrobiological studies of the liver drainage and ascitic fluid revealed beaded gram-positive rods, which also stained acid-fast on Kinyoun stain (Fig. 3), raising the concern for non-tuberculous mycobacteria and Nocardia. Antimicrobial treatment was modified to imipenem, moxifloxacin, and clarithromycin. He remained afebrile and clinically stable and was discharged home on this antimicrobial regimen. One week later, the culture remained negative, but 16S rRNA gene sequencing (752 bp) showed 100 % identity to Lawsonella clevelandensis. Antimicrobial therapy was de-escalated to oral amoxicillin/clavulanic acid 875 mg twice a day based on our literature review for similar cases. At one-month follow up, CT scan showed complete resolution of abscesses (Fig. 4). The JP drain was removed, and antimicrobial therapy was discontinued at that time. After 3-months of follow-up, there was no evidence of recurrent infection. The patient has been kept off immunosuppressants and has not developed any flares of his rheumatologic condition.Fig. 3 Direct microscopy showing acid-fast bacilli by Kinyoun method (x200).\n\nFig. 3Fig. 4 Contrast CT scan showing resolution of hepatic abscesses at 1-month follow-up.\n\nFig. 4\n\nDiscussion\nLawsonella clevelandensis is an anaerobic, partially acid fast-bacterium that belongs to the suborder Corynebacterineae. It was named Lawsonella to honor Paul A. Lawson (English microbiologist from University of Oklahoma), and clevelandensis after Cleveland, Ohio, the city of origin of the type strain. The presence of mycolic acids in its cell wall makes it structurally related to the aerobic actinomycetales [2]. This fastidious microorganism requires a prolonged incubation period and is sometimes confounded with other organisms (mainly Nocardia spp.) due to their morphologic similarities. The microbiologic identification of this organism relies on 16S rRNA gene sequencing most times [1]. Documented infections caused by Lawsonella clevelandensis are extremely rare, but it has been reported to cause abscesses in the abdominal cavity, breast, and spine in post-surgical and immunocompromised patients [2].\n\nWe searched MEDLINE via OVID and EMBASE via Scopus for the relevant Medical Subject Headings terms in English-language literature. The terms included in our search were “Lawsonella” and “clevelandensis”. We considered only those cases in whom the organism was identified as the cause of infection. We also reviewed the references of these reports for additional relevant literature. We found 8 case reports fitting our search criteria [[3], [4], [5], [6], [7]] (Table 1). The mean age of afflicted patients was 43.3 years, ranging from 2 to 81 years. The male to female ratio was 1:1. The majority of cases were described in USA and Canada (75 %), with only 2 cases reported from Europe (Portugal and United Kingdom). Five (63 %) patients presented certain degree of immunosuppression that included neoplastic conditions, rheumatologic diseases, and diabetes mellitus. In addition, two patients reported taking prednisone. Our patient’s clinical characteristics were similar to the ones described in the literature. He was immunocompromised due to his history of rheumatoid arthritis and was on chronic treatment with methotrexate and adalimumab.Table 1 Summary of Cases Reported in the Literature for Lawsonella clevelandensis infection.\n\nTable 1Ref\tAge(y)sex\tCountry of origin\tUnderlying disease\tImmunosuppressive medications\tInfection\tProcedure to control the infection\tAntibiotic therapy\tOutcome\t\n[3]\t65/M\tCleveland, Ohio, USA\tMetastatic prostate cancer\tPrednisone\tAbscess in thoracic spine, osteomyelitis with hardware\tIncision and drainage, partial hardware removal, debridement\tVAN -> SAM -> MPM -> SXT -> AMC\tDeath\t\n[3]\t44/F\tWinnipeg, Manitoba, Canada\tDiabetes mellitus, liver steatosis, obesity\tNone\tBreast abscess\tIncision and drainage\tVAN -> CLOXA -> AMC\tCure\t\n[3]\t23/F\tWinnipeg, Manitoba, Canada\tDiabetes mellitus, recurrent furunculosis\tNone\tBreast abscess\tIncision and drainage\tCIP + MTZ -> SXT\tCure\t\n[3]\t81/M\tNew York, USA\tPolymyalgia rheumatica, coronary artery disease, aortic stenosis\tPrednisone\tLiver abscess\tPercutaneous aspiration, drain placement\tLVX + MTZ + VAN + CLI + SXT -> CLI + SXT -> SXT\tCure\t\n[4]\t64/M\tOhio, USA\tNeuroendocrine tumor s/p distal pancreatectomy and splenectomy, Diabetes mellitus, obesity\tNone\tIntraabdominal abscess\tPercutaneous drainage, catheter placement, exploratory laparotomy\tCIP + MTZ -> VAN + MPM -> TGC -> ETP + SXT\tCure\t\n[5]\t29/F\tLisbon, Portugal\tNone\tNone\tBreast abscess\tSurgical drainage\tSXT -> AMC\tCure\t\n[6]\t38/M\tMaryland, USA\tUlcerative colitis s/p total proctocolectomy\tNone\tIntraabdominal abscess\tLaparoscopy and percutaneous drain placement\tBroad spectrum antibiotics -> Antitubercular treatment -> AMC\tCure\t\n[7]\t2/F\tNottingham, United Kingdom\tBeckwith-Weidemann syndrome, infected dermoid cyst\tNone\tSpinal subdural empyema\tSurgical drainage\tCXM + MTZ -> AMC -> CXM -> LZD\tCure\t\nPresent report\t70/M\tMiami, USA\tRheumatoid arthritis, cirrhosis, diverticulosis\tMethotrexate, adalimumab\tLiver abscess\tPercutaneous drainage and drain placement\tTZP + VAN + MTZ -> IPM + MXF + CLR -> AMC\tCure\t\nRef, reference; y, years; M, male; F, female; s/p, status post; VAN, vancomycin; SAM, ampicillin/sulbactam; MPM, meropenem; SXT, trimethoprim-sulfamethoxazole; AMC, amoxicillin/clavulanic acid; CLOXA, cloxacillin; CIP, ciprofloxacin; MTZ, metronidazole; LVX, levofloxacin; CLI, clindamycin; TGC, tigecycline; ETP, ertapenem; CXM, cefuroxime; LZD, linezolid; TZP, piperacillin/tazobactam; IPM, imipenem; MXF, moxifloxacin; CLR, clarithromycin.\n\n\n\nHarrington et al. reported a patient with polymyalgia rheumatica receiving prednisone who developed multiple liver abscesses. No history of prior surgical intervention was reported in this patient [3]. This case is very similar to the one described in the present report, since both manifested as liver abscesses and occurred in immunocompromised patients with no surgical history. Two (25 %) cases presented with intra-abdominal abscesses after abdominal surgery [4,6]. One of them was a patient who underwent distal pancreatectomy and splenectomy for resection of a pancreatic neuroendocrine tumor and developed a peri-pancreatic abscess one-month post-surgery [4]. The other case had a recent history of total proctocolectomy with ileal pouch-anal anastomosis and developed an intra-abdominal abscess in the right lower quadrant [6]. Three of the eight cases of Lawsonella clevelandensis infection presented as breast abscesses [3,5]. Two of these patients were diabetic, and one of them did not have any relevant medical history. The presentation was subacute or chronic in all of them, with a slow progression over the course of 3 weeks to 3 months. Other infections documented in the literature included a case of thoracic spine abscess with osteomyelitis that developed as a complication of surgical spinal stabilization, and a case of spinal subdural empyema resulting from an infected spinal dermoid cyst [3,7]. The patient with osteomyelitis reported a history of immunosuppression due to metastatic prostate cancer and chronic treatment with prednisone [3].\n\nThe environmental niche for Lawsonella clevelandensis is still unknown; however, recent studies have isolated Lawsonella in the oral human microbiome [8]. It is uncertain if this organism is part of the skin flora, but this possibility has been suggested by cases of breast abscess and post-surgical infections which originated most likely from the skin [[3], [4], [5], [6]]. In some cases, the relationship with abdominal surgeries has raised the possibility that this microorganism is part of the normal gut flora [4]. In the present case, we postulate that the organism reached the liver by hematogenous spread from an oral source. Our patient’s history of a prior dental procedure may support this hypothesis. However, another potential source is the bowel, which is plausible due to our patient’s history of diverticulosis. Although no signs of diverticular abscesses or intestinal perforation were noted on imaging, our patient could have developed microperforations in the large bowel that led to portal vein pyemia and resulted in seeding of the liver and development of pylephlebitis. Our patient’s ascitic fluid, consistent with secondary peritonitis (low serum-ascites albumin gradient (SAAG) and high total protein in ascitic fluid) makes bowel microperforations highly possible in this setting. Although there are no reported cases of Lawsonella clevelandensis infection related to the use of tumor necrosis factor blockers (adalimumab), previous reports suggest a relationship between this organism and an immunosuppressed state [3]. We believe that the use of immune-modulators for the treatment of the rheumatoid arthritis in this case played an important role on the pathophysiology of the infection.\n\nThe morphologic appearance of Lawsonella makes this microorganism easily confounded with other related strains such as Nocardia and Actinomyces. In the case described by Chudy-Onwugaje et al., as well as in our case, the infection was attributed initially to a mycobacterial infection given the presence of acid-fast bacilli on smear, and in our case to the fact that the patient was on a tumor necrosis factor inhibitor (adalimumab). In both cases, the patients were eventually switched to amoxicillin/clavulanic acid after identification of Lawsonella by molecular techniques [6].\n\nDrainage of infected collections has been crucial to successfully treat all the cases reported. In our patient, percutaneous aspiration and drain placement aided in the complete resolution of liver abscess. There is no standardized antibiotic therapy for this organism, and the selection of antimicrobials is entirely based on case reports. Given its poor growth in liquid media, antibiotic susceptibility testing has never been accomplished. The most common antibiotics used for definitive treatment have been amoxicillin/clavulanic acid (5 patients) and trimethoprim/sulfamethoxazole (3 patients) [[3], [4], [5], [6], [7]]. In most cases, treatment was initiated with broad-spectrum antibiotics and then de-escalated based on gram-stain results, growth in anaerobic cultures, or gene sequencing analysis.\n\nRegarding the duration of treatment, most authors favor prolonged antibiotic therapy, ranging from 2 to 17 months [[3], [4], [5], [6], [7]]. Our patient received 6 weeks of antibiotics that included 2 weeks of broad-spectrum antibiotics and 4 weeks of monotherapy with oral amoxicillin/clavulanic acid. Completion of treatment was reached when there was complete radiological resolution of the liver collections and the JP drain was removed.\n\nThe outcomes of patients with Lawsonella clevelandensis infection are generally favorable, and most of them achieve cure after abscess drainage and prolonged antibiotic therapy. Only one fatal case has occurred in a patient who developed abscess of the spine and osteomyelitis with hardware involvement; however, the patient’s death was attributed to complications of his underlying condition (metastatic prostate cancer) and not to the infection itself [3]. Based on these reports, we hypothesize that Lawsonella clevelandensis is a low-virulent species that becomes pathogenic in immunocompromised hosts and in patients with recent surgical interventions.\n\nConclusions\nLawsonella clevelandensis is a novel anaerobic, partially acid-fast bacterium that morphologically can mimic other organisms such as mycobacteria and actinomycetes. The diagnosis is challenging due to the limitations of conventional methods for isolating this microorganism. Our case highlights the importance of obtaining molecular identification of unidentified organisms causing culture-negative collections, especially in immunocompromised patients. The treatment is not standardized; however, we have obtained excellent outcomes with abscess drainage and prolonged antibiotic therapy with amoxicillin/clavulanic acid.\n\nFunding\nThis research received no external funding.\n\nCredit author statement\nJose A. Gonzales Zamora participated in the conceptualization of the article and wrote the manuscript. Zachary Henry, Maria Romero, Paola Lichtenberger, Gio Baracco, and Gordon Dickinson were involved in direct patient care. Paola Lichtenberger and Gio Baracco reviewed and edited the manuscript. All the authors reviewed and approved the final version of the article.\n\nDeclaration of Competing Interest\nSource of financial support: PL, GB, and GD receive salary support from the U.S. Department of Veterans Affairs\n\nNo potential conflict of interest was reported by the authors\n==== Refs\nReferences\n1 Nicholson A.C. Bell M. Humrighouse B.W. McQuiston J.R. Complete genome sequences for two strains of a novel fastidious, partially acid-fast, gram-positive Corynebacterineae bacterium, derived from human clinical samples Genome Announc 3 December (6) 2015 pii: e01462-15 \n2 Bell M.E. Bernard K.A. Harrington S.M. Patel N.B. Tucker T.A. Metcalfe M.G. Lawsonella clevelandensis gen. nov., sp. nov., a new member of the suborder Corynebacterineae isolated from human abscesses Int J Syst Evol Microbiol 66 August (8) 2016 2929 2935 27130323 \n3 Harrington S.M. Bell M. Bernard K. Lagacé-Wiens P. Schuetz A.N. Hartman B. Novel fastidious, partially acid-fast, anaerobic Gram-positive bacillus associated with abscess formation and recovered from multiple medical centers J Clin Microbiol 51 November (11) 2013 3903 3907 24025902 \n4 Navas M.E. Jump R. Canaday D.H. Wnek M.D. SenGupta D.J. McQuiston J.R. Can anaerobes be acid fast? A novel, clinically relevant acid fast anaerobe JMM Case Rep 3 August (4) 2016 e005036 \n5 Favila Menezes M. Sousa M.J. Paixão P. Atouguia J. Negreiros I. Simões M.J. Lawsonella clevelandensis as the causative agent of a breast abscess IDCases 12 March (21) 2018 95 96 29942760 \n6 Chudy-Onwugaje K. Vandermeer F. Quezada S. Mimicking abdominal tuberculosis: abdominal abscess caused by Lawsonella clevelandensis in inflammatory bowel disease Clin Gastroenterol Hepatol 17 July (8) 2019 e92 29913279 \n7 Kumaria A. Lucas E.K. Crusz S.A. Howarth S.P.S. Cartmill M. Lawsonella clevelandensis causing spinal subdural empyema Br J Neurosurg November (19) 2018 1 3 \n8 Escapa I.F. Chen T. Huang Y. Gajare P. Dewhirst F.E. Lemon K.P. New insights into human nostril microbiome from the expanded human oral microbiome database (eHOMD): a resource for the microbiome of the human aerodigestive tract mSystems 3 December (6) 2018 pii: e00187-18\n\n",
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"keywords": "Acid-fast bacilli; Anaerobe; Lawsonella clevelandensis; Liver abscess",
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"title": "Liver abscess caused by Lawsonella clevelandensis in a patient with rheumatoid arthritis: A case report and literature review.",
"title_normalized": "liver abscess caused by lawsonella clevelandensis in a patient with rheumatoid arthritis a case report and literature review"
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"abstract": "Nowadays, schizophrenia is treated with atypical antipsychotics that can determine neuroleptic malignant syndrome or rhabdomyolysis appearance. In addition to trauma and muscular hypoxia, there are some drugs and toxins associated with rhabdomyolysis development, among which olanzapine. A case of severe rhabdomyolysis syndrome, with extremely high levels of serum creatine kinase (CK), followed by acute kidney failure, secondary to olanzapine overdose and prolonged immobilization is outlined. Continuous renal replacement therapy was performed, with a slow clearance of serum CK levels. Under supportive therapy, systemic alkalinisation with volume resuscitation and corticotherapy, patient's general condition was improved, as well as his lower limb paresis. He followed frequent psychiatric evaluations and psychotherapies, before and after being transferred to a medical service. Rhabdomyolysis diagnosis is difficult in mild cases due to non-specific signs and symptoms, but it also has some typical manifestation, generically called \"the rhabdomyolysis syndrome triad\". The treatment is usually supportive; renal replacement therapy is required in the presence of acute kidney injury unresponsive to aggressive volume resuscitation. The systemic myoglobin release is responsible for renal injury. Olanzapine muscle toxicity can lead to severe rhabdomyolysis syndrome complicated with acute kidney injury and multiple organ dysfunction syndrome. Rapid identification and aggressive therapeutic management are essential for improving patients' outcome and prevent the occurrence of irreversible injuries.",
"affiliations": "\"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;Emergency Clinical Hospital, Bucharest, Romania.;Emergency Clinical Hospital, Bucharest, Romania.;\"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;\"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;\"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.",
"authors": "Tiglis|Mirela|M|;Hurmuzache|Tudor|T|;Bologa|Cristina|C|;Neagu|Tiberiu Paul|TP|;Mirea|Liliana|L|;Grintescu|Ioana Marina|IM|",
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"doi": "10.2478/jccm-2020-0032",
"fulltext": "\n==== Front\nJ Crit Care Med (Targu Mures)\nJ Crit Care Med (Targu Mures)\njccm\njccm\nThe Journal of Critical Care Medicine\n2393-1809 2393-1817 Sciendo \n\njccm-2020-0032\n10.2478/jccm-2020-0032\nCase Report\nRhabdomyolysis-Induced Acute Renal Injury in a Schizophrenic Patient\nTiglis Mirela 12 Hurmuzache Tudor 2 Bologa Cristina 2 Neagu Tiberiu Paul *12 Mirea Liliana 1 Grintescu Ioana Marina 12 1 \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania\n2 Emergency Clinical Hospital, Bucharest, Romania\n* E-mail: drneagupaul@gmail.com\n10 2020 \n07 11 2020 \n6 4 249 252\n16 6 2020 07 9 2020 © 2020 Mirela Tiglis, Tudor Hurmuzache, Cristina Bologa, Tiberiu Paul Neagu, Liliana Mirea, Ioana Marina Grintescu, published by Sciendo2020Mirela Tiglis, Tudor Hurmuzache, Cristina Bologa, Tiberiu Paul Neagu, Liliana Mirea, Ioana Marina Grintescu, published by SciendoThis work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Abstract\nNowadays, schizophrenia is treated with atypical antipsychotics that can determine neuroleptic malignant syndrome or rhabdomyolysis appearance. In addition to trauma and muscular hypoxia, there are some drugs and toxins associated with rhabdomyolysis development, among which olanzapine. A case of severe rhabdomyolysis syndrome, with extremely high levels of serum creatine kinase (CK), followed by acute kidney failure, secondary to olanzapine overdose and prolonged immobilization is outlined. Continuous renal replacement therapy was performed, with a slow clearance of serum CK levels. Under supportive therapy, systemic alkalinisation with volume resuscitation and corticotherapy, patient’s general condition was improved, as well as his lower limb paresis. He followed frequent psychiatric evaluations and psychotherapies, before and after being transferred to a medical service. Rhabdomyolysis diagnosis is difficult in mild cases due to non-specific signs and symptoms, but it also has some typical manifestation, generically called “the rhabdomyolysis syndrome triad”. The treatment is usually supportive; renal replacement therapy is required in the presence of acute kidney injury unresponsive to aggressive volume resuscitation. The systemic myoglobin release is responsible for renal injury. Olanzapine muscle toxicity can lead to severe rhabdomyolysis syndrome complicated with acute kidney injury and multiple organ dysfunction syndrome. Rapid identification and aggressive therapeutic management are essential for improving patients’ outcome and prevent the occurrence of irreversible injuries.\n\nKeywords\nrhabdomyolysisacute renal injuryolanzapineprolonged immobilizationschizophrenia\n==== Body\nBackground\nSchizophrenia, a significant psychiatric disorder, is usually treated with atypical antipsychotics, among which olanzapine. The use of these substances is favoured compared with the typical agents due to the lower risk of extrapyramidal adverse events [1]. However, olanzapine is associated with significant side effects, especially weight gain, somnolence or mild fever and studies showed an increasing number of cases of neuroleptic malignant syndrome (NMS), severe rhabdomyolysis and acute kidney injury [2, 3].\n\nRhabdomyolysis, the destruction of striated muscle fibres and leakage of intracellular content into the systemic circulation, can be a life-threatening syndrome [4]. It is caused principally by trauma and exertion, but also by infectious agents or toxins, medications, various diseases (especially body-temperature extreme changes), electrolyte abnormalities, muscle enzyme deficiencies (genetic defects) and endocrinopathies [5, 6]. There are also some reported cases of idiopathic rhabdomyolysis, sometimes recurrent [7, 8]. Epidemiological reports show that non-traumatic causes are about five times more frequent [9, 10]. It can present itself as an asymptomatic increase in serum creatine kinase (CK) levels, or it can manifest through intensively high CK levels, subsequent myoglobinuria, hyperkalaemia and acute renal injury [11].\n\nA case is described of severe rhabdomyolysis syndrome, with high levels of serum CK, followed by acute kidney failure, secondary to olanzapine overdose and prolonged immobilization.\n\nCase Presentation\nA 32-year-old man, under treatment by his general practitioner for schizophrenia and type III obesity, was referred to the Emergency Clinical Hospital, Bucharest, Romania, due to multiple organ dysfunction syndrome (MODS) secondary to severe rhabdomyolysis. At the time of referral, he was being treated with 20 mg oral olanzapine (Olanzapină Actavis©, Actavis Group PTC, Hafnarfjörður, Islanda) once daily.\n\nOn admission to the hospital, he was conscious, sleepy, temporal and spatial disoriented, presenting with lower limb paresis, without no signs of compartment syndrome, and a temperature of 38.5°C.\n\nIn the emergency department (ED), a series of examinations were performed, which suggested a diagnosis of multiple organ dysfunction syndrome (MODS). The laboratory results showed CK levels > 160.000 U/L (reference range 30-135 U/L), creatine kinase myocardial band level (CK-MB) 15.000 U/L (reference range 10-16 U/L), severe leucocytosis 27.89 x 103/μL, haemo-concentration (haemoglobin 18.65 g/dL), serum creatinine 5.70 mg/dL (normal range 0.70-1.40 mg/dL), blood urea 87 mg/dL (normal range 19-43 mg/dL), serum aminotransferase (AST (TGO) 3421 U/L – normal range 14-50 U/L, ALT (TGP) 530 U/L – normal range 10-50 U/L), mild hyponatremia and severe hyperkalaemia (potassium 6.72 mmol/L). The computed tomography examination revealed no acute pathological modification. After 3 hours in the ED the patient remained anuric.\n\nIn the presence of severe rhabdomyolysis, with subsequent MODS, the patient was admitted directly into the Intensive Care Unit. Based on above laboratory findings and persistent anuria, the diagnostic of acute kidney injury (AKI) was established (AKIN Classification: Stage 3), and continuous veno-venous haemodiafiltration was started in order to prevent further kidney damage and to clear the serum creatine kinase, additionally using a CytoSorb® cartridge.\n\nA toxicologist had evaluated the patient, in the first hours after ICU admission, and according to DMS-5 diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders), NMS was excluded.\n\nFrom the time of admission and continuing over the following days, the patient received systemic alkalinization with volume resuscitation and short-term high corticosteroids doses.\n\nAccording to the hospital’s protocol, at admission, full bacteriologic and viral screening were performed, and despite persistent hyperthermia, which had persisted for three days after ICU hospitalization, all the results were negative.\n\nThe variation over time of different laboratory findings is presented in Figure 1 and Figure 2.\n\nFig. 1 Evolution of CK and CK-MB levels\n\nFig. 2 Variations of different laboratory findings\n\nContinuous renal replacement therapy (CRRT) was performed for six days, with frequent changes of the dialysis filter in the first 72 hours, to ensure optimum mediator reduction in the face of this extremely severe rhabdomyolysis.\n\nAfter six days, the serum CK values gradually decreased, the renal function progressively improved with a progressive resumption of diuresis, continuous veno-venous haemodiafiltration was stopped. Intermittent haemodialysis therapy was initiated, in the dialysis department, for another week (four sessions), until creatinine and blood urea levels remained within the normal range (serum creatinine 1.37 mg/dL and urea 39 mg/dL), with a spontaneous urinary flow of around 1mL/kg/hr.\n\nAfter a few sessions of psychotherapy, started in the sixth day after ICU admission, and frequent psychiatric evaluations, the patient, revealed the fact that he consumed 15 tablets of olanzapine in the last 48 hours before hospital admission. During that period he admitted to losing consciousness and probably compressing his lower limbs under his body weight.\n\nAlthough on admission to the ICU he presented lower limb paresis, there was no motor deficit after a few days, and the patient started physical therapy.\n\nThe evolution was favourable with a gradual remission of the clinical picture of MODS. After two weeks of hospitalization in the ICU, he was transferred to the internal medicine department, where he was kept under psychiatric surveillance. He was discharged home after another three days.\n\nThe particularity of this case is that, in the absence of NMS and rigidity, it remains unclear if the cause of the extremely severe rhabdomyolysis was the prolonged immobilization, the olanzapine overdose and its toxicity or both.\n\nDiscussion\nThis case shows the development of rhabdomyolysis in the absence of NMS, rigidity or tremor, with extremely high levels of CK. Like other reported cases, olanzapine seems to be the causative agent, by direct muscular toxicity, as there was no evidence of infection, myocardial infarct or important dyselectrolytemia, but only paresis, persistent muscle weakness and hypotonia [2].\n\nSevere rhabdomyolysis syndrome is frequently associated with electrolyte imbalance, acute renal failure and cardiac arrhythmia. There are reported cases complicated with disseminated intravascular coagulation (CID) [5, 10]. Diagnosis is difficult in mild cases due to non-specific signs and symptoms. However, it has also some typical manifestations, which were present as well in our case, like muscle weakness, myalgia and urinary hyperpigmentation, so-called by some authors “the rhabdomyolysis syndrome triad” [4, 12].\n\nThe treatment for rhabdomyolysis syndrome is usually supportive of allowing the patient a safe return to baseline levels, without invasive manoeuvres. Nevertheless, in severe cases, as it was the case of our patient, renal replacement therapy is required in order to save a patient’s life and to prevent extensive damage to renal function. It is of greater importance in patients with chronic kidney disease or concomitant cardiovascular diseases for improving the outcome [13, 14]. There are three different mechanisms responsible for renal injury, secondary to myoglobin release: severe renal vasoconstriction, intratubular casts formation and direct toxicity on the renal tubular cells [15, 16].\n\nTherefore, AKI is one of the most severe complications of this syndrome, appearing secondary to myosin accumulation in the renal tubular system with subsequent necrosis. When CK levels overcome 15.000 U/L, the rate of AKI development is greater than 70% [17]. The mortality rate associated with rhabdomyolysis is 8-10% in mild cases, exceeding 42% of AKI develops [18], prompt and proper therapeutic management being the key to success.\n\nOther severe complications of rhabdomyolysis syndrome, also present in our case, are acute liver failure and MODS. Acute liver failure, probably due to drug-induced cytolysis, appears because of liver inflammation, secondary to liver protease leakage. It has an overall incidence of 25% in patients with olanzapine-induced rhabdomyolysis [17]. MODS, the leading cause of death in severe rhabdomyolysis, results secondary to a massive release of cytokines and inflammatory mediators into the systemic circulation [19]. Early prompt and proper treatment with aggressive volume resuscitation, systemic alkalinization, haemodialysis in the face of AKI, correction of electrolyte imbalance and corticosteroids can improve patients’ outcome and limit the long-term disabilities [20, 21, 22].\n\nWaring et al. published a study about the olanzapine overdose and subsequent acute muscle toxicity, and they discovered that > 17% of patients presenting for olanzapine ingestion had developed dose-dependent muscle toxicity, with increased levels of CK. Like in our case, a significant limitation is due to the impossibility of determining serum olanzapine concentration [23]. More studies pointed out the fact that CK values elevation appears after 12-hours post ingestion [2, 14, 17]. Therefore, repeated laboratory determinations are required for proper management.\n\nConclusion\nOlanzapine muscle toxicity can lead to severe rhabdomyolysis syndrome complicated with AKI and MODS. Rapid identification, periodic monitoring of CK levels changes and aggressive therapeutic management are essential for improving patients’ outcome and prevent the occurrence of irreversible injuries. When AKI develops, renal replacement is frequently required even in the presence of rapid and prompt volume resuscitation and systemic alkalinization.\n\nAcknowledgement\nThe authors declare no conflict of interest regarding this article. All the procedures of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed written consent was obtained.\n==== Refs\nReferences\n1 Joshi K Lin J Lingohr-Smith M Fu DJ Muser E Treatment patterns and antipsychotic medication adherence among commercially insured patients with schizoaffective disorder in the United States Journal of clinical psychopharmacology 2016 36 5 429 27525965 \n2 Jiang Y McCombs JS Park SH A retrospective cohort study of acute kidney injury risk associated with antipsychotics CNS drugs 2017 Apr 1 31 4 319 26 28290080 \n3 Sood L Owen A Saini M Olanzapine-induced rhabdomyolysis Irish Journal of psychological medicine 2006 23 3 114 5 30290514 \n4 Khan FY Rhabdomyolysis: a review of the literature Neth J Med 2009 Oct 1 67 9 272 83 19841484 \n5 Huerta-Alardín AL Varon J Marik PE. Bench-to-bedside review: Rhabdomyolysis–an overview for clinicians Critical care 2004 Apr 1 9 2 158 15774072 \n6 Virupannavar S Volkov S An Unusual Presentation of Rhabdomyolysis in a Newly Diagnosed Sjögren’s Syndrome Associated Polymyositis Archives of rheumatology 2016 31 3 281 29900949 \n7 Savage DC Forbes M Pearce GW Idiopathic rhabdomyolysis Archives of disease in childhood 1971 Oct 1 46 249 594 607 4107384 \n8 Rodríguez-Quintero JH Ramos-Pineda A Salas-Villela R Gotés-Palazuelos J. Refractory hypercalcemia after idiopathic rhabdomyolysis Clinical Cases in Mineral & Bone Metabolism 2018 Sep 1 15 3 358 363 \n9 Watson JD Gifford SM Clouse WD Biochemical markers of acute limb ischemia, rhabdomyolysis, and impact on limb salvage In Seminars in vascular surgery. WB Saunders 2014 27 3-4 176 181 \n10 Jiang W Wang X Zhou S Rhabdomyolysis induced by antiepileptic drugs: characteristics, treatment and prognosis Expert opinion on drug safety 2016 Mar 3 15 3 357 65 26750987 \n11 Bosch X Poch E Grau JM Rhabdomyolysis and acute kidney injury New England Journal of Medicine 2009 Jul 2 361 1 6272 \n12 Cervellin G Comelli I Lippi G Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features Clinical chemistry and laboratory medicine 2010 Jun 1 48 6 749 56 20298139 \n13 Onofrei SD Radulescu D Peride I Niculae A Checherita IA Fibroblast Growth Factor 23 and Cardiovascular Outcome in Acute Kidney Injury Revista de Chimie 2019 Apr 1 70 4 126871 \n14 Zutt R Van Der Kooi AJ Linthorst GE Wanders R.J. De Visser M. Rhabdomyolysis: review of the literature Neuromuscular Disorders 2014 Aug 1 24 8 651 9 24946698 \n15 Petejova N Martinek A Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review Critical Care 2014 18 3 224 25043142 \n16 Ronco C Bellomo R Kellum JA Critical care nephrology Philadelphia, USA Saunders \n17 Veenstra J Smit WM Krediet RT Arisz L Relationship between elevated creatine phosphokinase and the clinical spectrum of rhabdomyolysis Nephrology Dialysis Transplantation 1994 Jan 1 9 6 637 41 \n18 Chatzizisis YS Misirli G Hatzitolios AI Giannoglou GD The syndrome of rhabdomyolysis: complications and treatment European journal of internal medicine 2008 Dec 1 19 8 56874 \n19 Pinkston R Walker LA Multiorgan system failure caused by valproic acid toxicity The American journal of emergency medicine 1997 Sep 1 15 5 504 6 9270391 \n20 Altintepe L Guney I Tonbul Z Türk S Mazi M Ağca E Yeksan M Early and intensive fluid replacement prevents acute renal failure in the crush cases associated with spontaneous collapse of an apartment in Konya Renal failure 2007 Jan 1 29 6 737 41 17763170 \n21 Checheriţă IA David C Ciocalteu A Lascăr I Budală LA. Oral treatment of metabolic acidosis in hemodialyzed patients and the implications on the hemodynamic status Rom J Morphol Embryol 2013 54 3 539 43 24068401 \n22 Antoon JW Chakraborti C Corticosteroids in the treatment of alcohol-induced rhabdomyolysis Elsevier. In Mayo Clinic Proceedings 2011 Oct 1 86 10 1005 1007 \n23 Waring WS Wrate J Bateman DN Olanzapine overdose is associated with acute muscle toxicity Human & experimental toxicology 2006 25 12 735 40 17286152\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "6(4)",
"journal": "Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures)",
"keywords": "acute renal injury; olanzapine; prolonged immobilization; rhabdomyolysis; schizophrenia",
"medline_ta": "J Crit Care Med (Targu Mures)",
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"nlm_unique_id": "101706934",
"other_id": null,
"pages": "249-252",
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"publication_types": "D002363:Case Reports",
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"title": "Rhabdomyolysis-Induced Acute Renal Injury in a Schizophrenic Patient.",
"title_normalized": "rhabdomyolysis induced acute renal injury in a schizophrenic patient"
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"abstract": "Although spontaneous spinal epidural hematoma is a rare entity with an unknown origin, it may occur secondary to the use of anticoagulant and/or antiplatelet agents, which are particularly used for the treatment of cardiovascular and cerebrovascular diseases. Since it occurs rarely and its initial symptoms are usually non-specific, early and accurate diagnosis can be challenging which affects survival rate and the quality of life. Herein, we present a 65-year-old male case who developed acute severe neck pain and headache on the third day of acute coronary syndrome treatment, followed by neurological deficits in bilateral upper and lower extremities.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Kahta State Hospital, Adıyaman, Turkey.;Department of Neurosurgery, Kahta State Hospital, Adıyaman, Turkey.;Department of Cardiology, Kahta State Hospital, Adıyaman, Turkey.;Department of Physical Medicine and Rehabilitation, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Çorum|Mustafa|M|;Uysal|İsmail|İ|;Afşin|Abdulmecit|A|;Aksoy|Cihan|C|",
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"fulltext": "\n==== Front\nTurk J Phys Med Rehabil\nTurk J Phys Med Rehabil\ntftrd\nTurkish Journal of Physical Medicine and Rehabilitation\n2587-0823 2587-1250 Bayçınar Medical Publishing \n\n10.5606/tftrd.2020.3971\nCase Report\nA spontaneous cervical spinal epidural hematoma in a male patient receiving treatment for acute coronary syndrome: A case report\nÇorum Mustafa 1 Uysal İsmail 2 Afşin Abdulmecit 3 Aksoy Cihan 4 \n1 \nDepartment of Physical Medicine and Rehabilitation, Kahta State Hospital, Adıyaman, Turkey\n\n\n2 \nDepartment of Neurosurgery, Kahta State Hospital, Adıyaman, Turkey\n\n\n3 \nDepartment of Cardiology, Kahta State Hospital, Adıyaman, Turkey\n\n\n4 \nDepartment of Physical Medicine and Rehabilitation, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey\n\nMustafa Çorum, MD. Kahta Devlet Hastanesi Fizik Tedavi ve Rehabilitasyon Kliniği, 02400 Kahta, Adıyaman, Türkiye.\nmustafacorum@gmail.com.\n\n9 2020 \n18 8 2020 \n66 3 360 363\n25 11 2018 12 2 2019 Copyright © 2020, Turkish Society of Physical Medicine and Rehabilitation2020Turkish Society of Physical Medicine and RehabilitationThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Although spontaneous spinal epidural hematoma is a rare entity with an unknown origin, it may occur secondary to the use of anticoagulant and/or antiplatelet agents, which are particularly used for the treatment of cardiovascular and cerebrovascular diseases. Since it occurs rarely and its initial symptoms are usually non-specific, early and accurate diagnosis can be challenging which affects survival rate and the quality of life. Herein, we present a 65-year-old male case who developed acute severe neck pain and headache on the third day of acute coronary syndrome treatment, followed by neurological deficits in bilateral upper and lower extremities.\n\nAnticoagulantslaminectomyneck pain\n==== Body\nIntroduction\nSpontaneous spinal epidural hematoma (SSEH) is a very rare disease warranting early diagnosis and treatment. Although its prevalence is predicted to be 1 in 100,000, it has a high risk of morbidity and mortality.[1] Despite its uncertain pathogenesis, predisposing factors have been reported to be coagulation disorders, vascular malformations, hypertension, cancer, pregnancy and, most commonly, anticoagulant and antiplatelet treatments.[2] However, no predisposing factor can be detected in 40% of the patients reported in the literature.[3]\n\nThe most common clinical presentation is the emergence of nerve root and spinal cord compression symptoms accompanying or following sudden-onset spinal pain.[4] On the other hand, initial symptoms can appear in a wide range and can be atypical. The severity of clinical symptoms is significantly associated with the size of hemorrhage, degree of hematoma, and length of onset time.[5] It is most commonly encountered in the lower cervical and upper thoracic spinal levels, although it may occur across the whole spine. Favorable neurological and functional outcomes can be achieved with early, accurate diagnosis, and emergent surgical treatment. In addition, early and individualized rehabilitation program can prevent long-term disability in SSEH patients.[6]\n\nIn this report, we present a male case who developed quadriparesis during acute coronary syndrome (ACS) treatment and underwent emergency surgery and received early rehabilitation to prevent neurological sequelae.\n\nCase Report\nA 65-year-old male patient was admitted to our hospital with chest pain in the coronary intensive care unit. Upon the detection of instable angina pectoris, 60 mg low-molecular-weight heparin (LMWH) and 300 mg clopidogrel were initiated. The patient was on antihypertensive treatment for 15 years due to essential hypertension and he also used acetylsalicylic acid 100 mg/day. The patient did not have any a recent head or spinal trauma and surgical treatment, and he did not smoke.\n\nFigure 1 A preoperative magnetic resonance imaging showing a posterior spontaneous spinal epidural hematoma located from C4 to T1 level. (a) The mass having isointensity to spinal cord on T1-weighted and (b) heterogeneous signal intensity to spinal cord on T2-weighted sagittal scanning images and (c) spinal cord compression on dorsal and left lateral sides on T2-weighted axial scanning image.\n\n\n\nHe experienced sudden-onset severe neck pain and occipital headache on the third day of ACS treatment and felt muscle weakness and numbness in bilateral upper and lower extremities about 24 h after the onset of pain. On his physical examination, the patient was alert, orientated, and afebrile with a blood pressure of 140/90 mmHg. The muscle strength of upper extremities was 2/5 proximally and 1/5 distally, while that of the lower extremities was 0/5 proximally and distally. There was anesthesia below the C4 dermatome. Also, no deep tendon reflex could be elicited. The rectal examination revealed reduced anal sphincter tone and anesthesia in the perineal region. Routine laboratory and coagulation parameters (prothrombin time and activated partial thromboplastin time, and the international normalized ratio) were within normal limits. Neurology and neurosurgery consultations were requested, and urgent spinal magnetic resonance imaging (MRI) was performed. The MRI showed a space occupying formation extending from the level of C4 to T1 in the cervical spine which did not cause abnormal signal changes in the spinal cord and which was isointense in the T1-weighted images and heterogeneous signal intensity in the T2-weighted images. Spinal cord injury was assessed as Grade A complete injury according to the American Spinal Injury Association (ASIA) Impairment Scale. The patient underwent emergency decompressive laminectomy and hematoma evacuation with the diagnosis of SSEH approximately 40 h after the onset of symptoms. On the postoperative Day 1, no neurological recovery was noted, while the muscle strength of the lower extremities was 1/5 after two weeks. The range of motion exercises for upper and lower extremities, muscle strength enhance training, seat balancing training, transfer training (from the bed to a wheelchair), and respiratory function training were given to the patient as the early rehabilitation program. Also, clean intermittent self-catheterization was initiated for him in whom urinary retention persisted. After 60 sessions of rehabilitation program, neurological recovery was achieved in the upper (proximal 3/5, distal 1/5) and lower (proximal 2/5, distal 1/5) extremities. A written informed consent was obtained from the patient.\n\nDiscussion\nThe sole use or various combinations of anticoagulant and antiplatelet drugs used for the treatment of cardiovascular and cerebrovascular diseases are one of the most common factors regarding the development of SSEH. Antiplatelet agents associated SSEH is quite rare, whereas 25 to 70% of SSEH patients were reported to have the history of anticoagulation use.[1] Unlike anticoagulants, the risk of major hemorrhage is also lower for antiplatelet agents. However, Harker et al.[7] reported that the incidence of hemorrhagic events did not differ significantly among the groups receiving clopidogrel and acetylsalicylic acid treatments. The patients receiving a combination of acetylsalicylic acid and clopidogrel were also demonstrated to have a higher prevalence of major hemorrhage than those treated with only clopidogrel or acetylsalicylic acid.[8,9] In addition, the risk of major hemorrhagic complications increases, when concurrent antiplatelet agents are used in combination with LMWH.[10] Our case used acetylsalicylic acid 100 mg/day and was on antihypertensive treatment for 15 years due to essential hypertension treatment. It can be speculated that adding LMWH and clopidogrel to the treatment due to ACS may have had a direct impact on the development of SSEH.\n\nThe pathophysiology of SSEH has not been completely understood yet, and it is still controversial whether the origin of epidural hematomas is arterial or venous. Since spinal epidural venous plexuses which do not contain any valves drain to abdominal and thoracic venous systems, vigorous physical activity enough to cause changes in the abdominal or thoracic pressure may lead to rupture by causing a sudden increase in the spinal venous pressure.[11] However, since cervical epidural venous pressure is lower than the intrathecal pressure, venous hemorrhage cannot cause compression in the dural sac. Therefore, particularly cervical SSEHs may be considered to originate from epidural arteries.[3] The fact that our patient had a hematoma in the cervical region, that he had a history of hypertension, and that there was no severe physical strain or trauma prior to his symptoms suggests that the hematoma may be of arterial origin.\n\nAlthough SSEH has a characteristic clinical presentation, its early and accurate diagnosis still remains a challenge due its rare prevalence and usually varying and atypical initial symptoms. In case of sudden spinal pain accompanied by a neurological deficit, a potential hemorrhagic disease of the spinal cord should be considered. The differential diagnosis highly depends on a pertinent clinical and radiological correlation. A heterogeneous signal intensity or hyperintensity appearance on T2-weighted MRIs and homogeneous hypointensity or isointense appearance on T1-weighted images are typical for SSEH.[5] Early diagnosis plays an important role for the prognosis of SSEH and probability of initiating surgical treatment.\n\nThe prognosis of SSEH can be associated with the size of hematoma, severity of preoperative paresis, and time interval between the onset of symptom and surgical treatment.[4] Groen[12] reported that the size of hematoma was larger in patients with conservative follow-up treatment, compared to patients treated surgically, suggesting that hematoma size does not affect prognosis and should not be used in treatment selection. On the contrary, examining SSEH patients treated surgically, Liao et al.[13] found that the large size of hematoma and a hematoma extending over two or more segments caused an increase in postoperative relapse rate and resulted in worse functional recovery. The early surgical treatment of SSEHs, particularly in the cervical and thoracic region, yielded more favorable neurological and functional outcomes in patients with incomplete spinal cord injury than those with complete injury.[13] Previous studies indicated that the surgical treatment outcomes of SSEH were inversely associated with the time interval between the onset of symptoms and surgical treatment. Shin et al.[14] suggested that more favorable neurological outcomes were observed in patients operated within 12 h. In the study by Groen and van Alphen,[15] evaluating 330 patients with SSEH, surgical treatment produced more favorable outcomes, when performed before 36 h in patients with complete injury and before 48 h in patients with incomplete injury. Although the clinical presentation of our case was typical, administering surgical intervention after the emergence of neurological deficits that may affect long-term outcomes (>36 h), the presence of severe paresis (ASIA A) and a hematoma extending over two or more segments (four segments) might have affected prognosis adversely and caused a limited postoperative neurological and functional recovery in our case.\n\nThe gold standard treatment of SSEH is urgent decompressive laminectomy and hematoma evacuation. Early decompressive surgical treatment was shown to affect neurological recovery and functional outcomes positively.[4] According to Liao et al.,[5] complete recovery in the postoperative first year was 88.9% in patients with incomplete injury, while it was only 37.5% in those with complete injury. However, conservative treatment may be considered for patients with rapid spontaneous recovery of neurological deficits in the early period or patients with mild neurological deficits (ASIA D or E).[16] It can also be used in case of advanced cardiovascular disease, progressive and irreversible spinal cord injury, or for high-risk patients for hemorrhagic tendency.\n\nIn conclusion, non-traumatic hematomas of the spinal column are rare and severe, and they can cause severe neurological sequelae. Spontaneous spinal epidural hematoma should be suspected in case of spinal pain accompanied by motor or sensorial deficit in any patient receiving anticoagulation and/or antiplatelet therapy. Early diagnosis and urgent surgical decompression are warranted for reducing neurological sequelae.\n\nConflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.\n\nFinancial Disclosure: The authors received no financial support for the research and/or authorship of this article.\n==== Refs\n1 Liu Z Jiao Q Xu J Wang X Li S You C Spontaneous spinal epidural hematoma: analysis of 23 cases Surg Neurol 2008 69 253 260 17900669 \n2 Kirazli Y Akkoc Y Kanyilmaz S Spinal epidural hematoma associated with oral anticoagulation therapy Am J Phys Med Rehabil 2004 83 220 223 15043358 \n3 Kreppel D Antoniadis G Seeling W Spinal hematoma: a literature survey with meta-analysis of 613 patients Neurosurg Rev 2003 26 1 49 12520314 \n4 Matsumura A Namikawa T Hashimoto R Okamoto T Yanagida I Hoshi M Clinical management for spontaneous spinal epidural hematoma: diagnosis and treatment Spine J 2008 8 534 537 17434807 \n5 Liao CC Lee ST Hsu WC Chen LR Lui TN Lee SC Experience in the surgical management of spontaneous spinal epidural hematoma J Neurosurg 2004 100 1 Suppl Spine 38 45 14748572 \n6 New PW Functional outcomes and disability after nontraumatic spinal cord injury rehabilitation: Results from a retrospective study Arch Phys Med Rehabil 2005 86 250 261 15706551 \n7 Harker LA Boissel J-P Pilgrim AJ Gent M Comparative safety and tolerability of clopidogrel and aspirin Drug Saf 1999 21 325 335 10514023 \n8 Diener HC Bogousslavsky J Brass LM Cimminiello C Csiba L Kaste M Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial Lancet 2004 364 331 337 15276392 \n9 Bhatt DL Fox KA Hacke W Berger PB Black HR Boden WE Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events N Engl J Med 2006 354 1706 1717 16531616 \n10 Horlocker TT Wedel DJ Benzon H Brown DL Enneking KF Heit JA Regional anesthesia in the anticoagulated patient: defining the risks Reg Anesth Pain Med 2004 29 1 12 \n11 Bakker NA Veeger NJ Vergeer RA Groen RJ Prognosis after spinal cord and cauda compression in spontaneous spinal epidural hematomas Neurology 2015 84 1894 1903 25862799 \n12 Groen RJ Non-operative treatment of spontaneous spinal epidural hematomas: a review of the literature and a comparison with operative cases Acta Neurochir (Wien) 2004 146 103 110 14963742 \n13 Liao CC Hsieh PC Lin TK Lin CL Lo YL Lee SC Surgical treatment of spontaneous spinal epidural hematoma: a 5-year experience J Neurosurg Spine 2009 11 480 486 19929346 \n14 Shin JJ Kuh SU Cho YE Surgical management of spontaneous spinal epidural hematoma Eur Spine J 2006 15 998 1004 16758110 \n15 Groen RJ van Alphen HA Operative treatment of spontaneous spinal epidural hematomas: a study of the factors determining postoperative outcome Neurosurgery 1996 39 494 508 8875479 \n16 Dziedzic T Kunert P Krych P Marchel A Management and neurological outcome of spontaneous spinal epidural hematoma J Clin Neurosci 2015 22 726 729 25677879\n\n",
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"title": "A spontaneous cervical spinal epidural hematoma in a male patient receiving treatment for acute coronary syndrome: A case report.",
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"abstract": "Giant cell arteritis with ocular involvement is an ocular emergency. Arteritic anterior ischaemic optic neuropathy (AAION) is the most common ophthalmological manifestation associated with this disease. Visual loss is usually permanent with rare cases showing visual recovery. Visual improvement, if it occurs, is generally limited, and the visual field defects are persistent and severe. The main goal of AAION treatment is the preservation of vision in the fellow eye. In patients with neurophthalmological manifestations, high-dose corticosteroids should be initiated immediately and aggressively, and maintained thereafter. We present a case of AAION and severe vision loss where significant visual recovery was seen after treatment.",
"affiliations": "Department of Ophthalmology, Hospital de Santa Maria, Lisbon, Portugal.;Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisbon, Portugal Department of Internal Medicine, Hospital de Santa Maria, Lisbon, Portugal.;Department of Pathology, Hospital de Santa Maria, Lisbon, Portugal.;Department of Ophthalmology, Hospital de Santa Maria, Lisbon, Portugal.",
"authors": "Pinto Ferreira|Nuno G|NG|;Menezes Falcão|Luiz|L|;Alves|Antonio T|AT|;Campos|Fatima|F|",
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"title": "Giant cell arteritis: a closer look at its ophthalmological manifestations.",
"title_normalized": "giant cell arteritis a closer look at its ophthalmological manifestations"
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"abstract": "BACKGROUND Trigger-point injection (TPI) therapy is an effective modality for symptomatic treatment of myofascial pain. Serious adverse effects are rarely observed. In this report, we present the case of a 39-year-old man who experienced severe, transient hypokalemic paralysis in the context of TPI therapy with methylprednisolone, bupivacaine, and epinephrine. He was successfully treated with electrolyte replacement in a closely monitored setting. CASE REPORT A 39-year-old man with no past medical history except for chronic left hip pain from a work-related injury received a TPI with methylprednisolone and bupivacaine. The TPI targeted the left iliopsoas tendon and was administered using ultrasound guidance. There were no immediately perceived complications, but within 12 h he presented with severe hypokalemic paralysis with a serum potassium 1.7 mmol/L. Judicious potassium repletion was initiated. Repeated tests after 6 h consistently showed normal potassium levels of 4.5 mmol/L. CONCLUSIONS Severe hypokalemic paralysis in the context of trigger-point injection is an incredibly rare occurrence and this is the first case report in English literature. A high index of clinical suspicion and a systematic approach are therefore required for prompt diagnosis and management of this obscure iatrogenic entity. Clinicians can enhance patient safety by allowing the primary pathology to guide them.",
"affiliations": "Department of Internal Medicine, Southern Illinois University, Springfield, IL, USA.;Department of Internal Medicine, Southern Illinois University, Springfield, IL, USA.;Department of Pharmacy Practice, Southern Illinois University School of Pharmacy, Edwardsville, IL, USA.;Department of Internal Medicine, Southern Illinois University, Springfield, IL, USA.",
"authors": "Soriano|Paolo K|PK|;Bhattarai|Mukul|M|;Vogler|Carrie N|CN|;Hudali|Tamer H|TH|",
"chemical_list": "D000779:Anesthetics, Local; D005938:Glucocorticoids; D008775:Methylprednisolone; D002045:Bupivacaine",
"country": "United States",
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"doi": "10.12659/ajcr.903139",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2844270110.12659/AJCR.903139903139ArticlesA Case of Trigger-Point Injection-Induced Hypokalemic Paralysis Soriano Paolo K. ABCDEFG1Bhattarai Mukul ABCDFG1Vogler Carrie N. CDF2Hudali Tamer H. ABCDFG11 Department of Internal Medicine, Southern Illinois University, Springfield, IL,U.S.A.2 Department of Pharmacy Practice, Southern Illinois University School of Pharmacy, Edwardsville, IL, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nThe case was presented as a poster presentation at the national meeting of the Society of Hospital Medicine, March 6–9, 2016, San Diego, CA, U.S.A.\n\nConflict of interest: None declared\n\nCorresponding Author: Tamer Hudali, e-mail: thudali39@siumed.edu2017 26 4 2017 18 454 457 02 1 2017 09 2 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 39\n\nFinal Diagnosis: Trigger-point induced hypokalemia\n\nSymptoms: Bilateral lower extremity weakness\n\nMedication: Epinephrine • Bupivacaine • Methylprednisolone\n\nClinical Procedure: Trigger-point Injection\n\nSpecialty: Nephrology and Radiology\n\nObjective:\nUnknown etiology\n\nBackground:\nTrigger-point injection (TPI) therapy is an effective modality for symptomatic treatment of myofascial pain. Serious adverse effects are rarely observed. In this report, we present the case of a 39-year-old man who experienced severe, transient hypokalemic paralysis in the context of TPI therapy with methylprednisolone, bupivacaine, and epinephrine. He was successfully treated with electrolyte replacement in a closely monitored setting.\n\nCase Report:\nA 39-year-old man with no past medical history except for chronic left hip pain from a work-related injury received a TPI with methylprednisolone and bupivacaine. The TPI targeted the left iliopsoas tendon and was administered using ultrasound guidance. There were no immediately perceived complications, but within 12 h he presented with severe hypokalemic paralysis with a serum potassium 1.7 mmol/L. Judicious potassium repletion was initiated. Repeated tests after 6 h consistently showed normal potassium levels of 4.5 mmol/L.\n\nConclusions:\nSevere hypokalemic paralysis in the context of trigger-point injection is an incredibly rare occurrence and this is the first case report in English literature. A high index of clinical suspicion and a systematic approach are therefore required for prompt diagnosis and management of this obscure iatrogenic entity. Clinicians can enhance patient safety by allowing the primary pathology to guide them.\n\nMeSH Keywords:\nHypokalemia Hypokalemic Periodic Paralysis Trigger Points\n==== Body\nBackground\nTrigger points are symptomatic irritable foci in taut bands of a skeletal muscle or its fascia [1]. They are the hallmark physical examination signs of myofascial pain [2,3]. Trigger-point injection (TPI) is an effective modality for symptomatic treatment of myofascial pain syndrome [4–6]. Steroids and anesthetics are thought to inactivate tight muscular bands, thereby relieving nerve irritation and referred pain [7]. The use of ultrasound-guided injection improves efficacy of drug delivery and enhances safety [8,9]. Site injury is common, but serious complications are rare [8,10]. We present a case of TPI therapy-induced hypokalemic paralysis. To the best of our knowledge, this is the first such case report in the English literature [11].\n\nCase Report\nA 39-year-old man, with no known past medical history except for chronic left hip pain from a work- related injury, received a TPI with methylprednisolone, bupivacaine, and epinephrine. He had received the same drug cocktail 3 months prior without incident, and the intervention was effective in relieving his hip pain. The TPI targeted the left iliopsoas tendon and was administered using ultrasound guidance. He went to sleep that night without perceived complications. Approximately 12 h after therapy, he awoke with shortness of breath and functional quadriplegia. His mental faculties were intact and he did not experience chest pressure, vomiting, abdominal discomfort, or diarrhea.\n\nHe was brought to the Emergency Department with the following vital signs: BP 162/92 mmhg, HR 94 bpm, RR 22 cpm, T 97.9°F (36.6°C), and SaO2 95% on room air. He appeared calm and conversational. He was in mild respiratory distress with shallow respirations. Results of cardiovascular, pulmonary, and gastrointestinal examinations were unremarkable. A neurologic exam revealed intact cerebral and cognitive function, GCS 15, normal pupillary light reflex and extraocular muscle movements, and no nystagmus. Cranial nerves and cerebellar function test results were also normal. He had severe paresis of the upper extremities, 1/5 bilateral motor strength, and nearly choreiform in movement. Both lower limbs were paraplegic. Sensory perception and deep-tendon reflexes were normal in all extremities.\n\nElectrocardiography (EKG) demonstrated sinus arrhythmia, flat T waves, and small U waves, with a normal QT interval. He was in metabolic acidosis with a base deficit of −7 (pH 7.31, HCO3 19 mmol/L, PCO2 38 mmHg). The patient’s serum potassium was 1.7 mmol/L, magnesium 2.1 mg/dl, and calcium 9.8 mg/dl. Urine K/Cr ratio was 0.067, creatinine kinase levels were moderately elevated (523 IU/L), and thyroid function was normal (Table 1).\n\nHe immediately received judicious potassium repletion with a combined total of 150 milliequivalents of IV and PO KCl administered, which resolved the EKG abnormalities and muscle weakness within 2 h. Repeated potassium tests after 6 h consistently showed normal levels of 4.5 mmol/L\n\nUpon revisiting the patient’s history, he knew of no family members with periodic paralyses, muscle defects, or kidney disease. Personal history is negative for adrenal or thyroid disorder.\n\nDiscussion\nThe etiology of hypokalemia can often be gleaned from the patient history. Diuretic use and gastrointestinal losses from vomiting and diarrhea are among the common causes [12]. Although a decrease in intake can lower serum potassium levels, it is rarely sufficient to cause significant hypokalemia. A study by Gallen et al. (1998) restricted potassium intake to 20 meq per day, resulting in only a 0.6 meq/L reduction of potassium levels from the baseline [13].\n\nIn cases where the cause of hypokalemia is not readily apparent, assessment of renal potassium excretion is the next step in evaluation. The most accurate method is a 24-h urine collection. However, in the clinical setting, this is not the best test, as patients will need immediate repletion, which will invariably alter the results. The urine potassium-to-creatinine ratio (U. K-Cr) from a single random sample supplies comparable point-of-care information. Since more potassium is excreted in relation to constant creatinine excretion, higher U. K-Cr values reflect renal potassium wasting. Values less than 1.5 meq/mmol creatinine (13 meq/g creatinine) are seen in transcellular potassium shifts, gastrointestinal losses, diuretic use, and poor intake [14,15].\n\nA study of 43 patients with severe hypokalemia (range, 1.5–2.6 mmol/L) associated with paralysis demonstrated the efficacy of U.K-Cr in distinguishing between hypokalemia from renal potassium wasting and that from potassium redistribution. The 30 patients with periodic paralysis (whose hypokalemia was caused by transcellular shifts) had significantly lower levels than the 13 patients with hypokalemia, due mostly to renal potassium wasting (11 vs. 36 meq/g creatinine or 1.3 vs. 4.1 meq/mmol creatinine) [15].\n\nThe trans-tubular potassium gradient (TTKG) gauges the renal potassium secretion by the cortical collecting duct.\n\nAlthough this measurement cannot be made in humans, it was proposed that potassium concentration at this site could be estimated clinically [16–18]. However, in a later publication, the authors of the original studies found that these assumptions were not valid [19]. It was concluded that TTKG is not reliable in evaluating this condition.\n\nIn our patient, the U. K-Cr ratio was normal and did not reflect renal potassium wasting syndromes such as Bartter, Gittelman’s, or renal tubular acidosis. Normal renal potassium handling, the absence of extra-renal losses, and rapid return to normal-high potassium levels with minimal repletion all support that the effect was transient and redistributive. The only remaining explanation is a “relative” decrease in serum potassium secondary to transcellular shifting.\n\nThe normal potassium distribution between and cells and the extracellular fluid is primarily maintained by the Na-KATPase pump in the cell membrane. Factors that increase the pump’s activity and potassium entry into the cells are outlined in Table 2. The exact trigger in this case is unclear. The proposed mechanism is an exaggerated response to the epinephrine component of the TPI. Another theory is that the increased stress of the procedure lead to epinephrine release. In trauma patients, high levels of circulating epinephrine are negatively correlated with serum potassium [20], which is known as post-traumatic hypokalemia.\n\nThe Naranjo nomogram estimates the causality of this event as a probable adverse drug reaction with a score of 6 [21]. A clinical review of the medications administered in the TPI show that methylprednisolone and epinephrine have the potential to cause hypokalemia, via mineralocorticoid effects by the former, and the latter through B2 adrenoreceptors linked to Na-K ATPase upregulation. The prevalence of hypokalemia in methylprednisolone therapy is 18% (95% CI 10.5–25.8) and causes only a mild reduction in serum potassium [22]. Bupivacaine, when used alone, does not cause significant hypokalemia. In 1994, Lofgren and Hahn studied the effects on plasma potassium levels when adding epinephrine to the local anesthetic solution for intercostal nerve block in patients undergoing upper abdominal surgery. When used in combination, bupivacaine and epinephrine produced a modest decrease in plasma potassium compared to bupivacaine used alone, especially after surgery (0.58 mmol/L vs. 0.10 mmol/L P<0.03) [23].\n\nUncommon causes of sporadic (periodic) paralyses were also considered. Patients with hypokalemic periodic paralysis (HPP) generally have a family history of the disorder. Its onset appears early (during childhood and late teenage years) and is triggered by stress and high-carbohydrate meals. Thyrotoxic paralysis presents with abnormal thyroid hormone levels during the acute attack. Lastly, Andersen-Tawil syndrome and para-myotonia congenita are rare genetic disorders evident during early childhood. Our patient’s case profile was inconsistent with all of these possibilities. The diagnosis of hypokalemia secondary to TPI medications was made after excluding all other possible etiologies.\n\nRapid onset of severe symptomatic hypokalemia warrants urgent investigation and requires immediate treatment [14]. It is critical to distinguish hypokalemia caused by redistribution from that caused by depletion. In contrast to those with marked depletion, patients with hypokalemia due to potassium redistribution have little or no potassium deficit and are at risk for rebound hyperkalemia after minimal potassium repletion [24,25]. As seen in a study by Lin et al. (2004), 19 out of 30 patients with periodic paralysis developed rebound hyperkalemia (serum potassium greater than 5 meq/L) after administration of a mean of 63 meq of potassium chloride [15].\n\nThe importance of prompt treatment cannot be overstated. Apart from life-threatening arrhythmias, “judicious” early repletion precludes the clinician from having to face the potential diagnostic and therapeutic dilemma once ischemic rhabdomyolysis has set in. The release of potassium from injured myocytes will mask the severity of the underlying hypokalemia or even lead to normal or high values. Although treatment for hypokalemia seems straightforward, keeping in mind the primary pathology will appropriately guide the clinician and enhance patient safety.\n\nConclusions\nTranscellular shifting is a common cause of hypokalemia. Severe hypokalemic paralysis in the context of trigger-point injection is an incredibly rare occurrence and this is the first case report in English literature. A high index of clinical suspicion and a systematic approach are therefore required for prompt diagnosis and management of this obscure iatrogenic entity.\n\nWe thank Lydia Howes MSI and Carol Gordon MLIS, AHIP of Southern Illinois University School of Medicine Library for proofreading and for their comments, which greatly improved the manuscript.\n\nTable 1. Laboratory evaluation.\n\nSerum labs\tUrinary labs\t\nNa\t140 (136–145meq/L)\tOsmolality\t637 (300–1000 mosmkg)\t\nK\t1.7 (3.5–4.5 meq/L)\tpH\t6.0 (5.0–7.0)\t\nCl\t110 (98–107 meq/L)\tNa\t131 mmol/L\t\nHCO3\t20 (22–29 mmol/L)\tK\t12 mmol/L\t\nGlucose\t210 (70–105 mg/dl)\tCl\t176 mmol/L\t\nBUN\t20 (8–26 mg/dl)\tU. Crea\t66.3 mg/dl\t\nS. Crea\t1.03 (0.72–1.25 mg/dl)\tU.K/U. Crea ratio\t0.18 meq/mmol\t\nMag\t2.1 (1.6–2.6 mg/dl)\t\t\t\nAnion gap\t10 (8–16)\t\t\t\neGFR\t106\t\t\t\nTSH\t0.61 (0.34–5.6 uIU/ml)\t\t\t\nVenous blood gas\t\t\t\t\npH\t7.31 (7.35–7.45)\t\t\t\npCO2\t38 (15–45 mmhg)\t\t\t\nHCO3\t19 (18–26 mmol/L)\t\t\t\nU. K/U. Crea Ratio (<1.5 suggests poor intake, GI loss, transcellular shifts).\n\nTable 2. Factors causing intracellular potassium translocation.\n\nFactors causing intracellular potassium translocation\t\n\nIncreased availability of insulin\n\nElevated β-adrenergic activity – stress or administration of beta agonists\n\nAcidemia\n\nHypokalemic periodic paralysis (HPP)\n\nIncreased blood cell production\n\nHypothermia\n\nIntoxication of barium, cesium, chloroquine, and some antipsychotics\n==== Refs\nReferences:\n1. Tough EA White AR Richards S Campbell J Variability of criteria used to diagnose myofascial trigger point pain syndrome – evidence from a review of the literature Clin J Pain 2007 23 3 278 86 17314589 \n2. Simons DG Travell JG Simons LS Travell & Simons’ myofascial pain and dysfunction: The trigger point manual. v. 1 Upper half of body 2nd ed Baltimore Williams & Wilkins 1999 \n3. Sorrell MR The physical examination of migraine Curr Pain Headache Rep 2006 10 5 350 54 16945251 \n4. Borg-stein J Iaccarino MA Myofascial pain syndrome treatments Phys Med Rehabil Clin N Am 2014 25 2 357 74 24787338 \n5. Scott NA Guo B Barton PM Gerwin RD Trigger point injections for chronic non-malignant musculoskeletal pain: A systematic review Pain Med 2009 10 1 54 69 18992040 \n6. Venâncio Rde A Alencar FG Zamperini C Different substances and dry-needling injections in patients with myofascial pain and headaches Cranio 2008 26 2 96 103 18468269 \n7. Certa H Fedtke N Wiegand HJ Toxicokinetics of p-tert-octylphenol in male Wistar rats Arch Toxicol 1996 71 1–2 112 22 9010593 \n8. Wong CS Wong SH A new look at trigger point injections Anesthesiol Res Pract 2012 2012 492452 21969825 \n9. Payne JM Ultrasound-guided hip procedures Phys Med Rehabil Clin N Am 2016 27 3 607 29 27468669 \n10. Cheng J Abdi S Complications of joint, tendon, and muscle injections Tech Reg Anesth Pain Manag 2007 11 3 141 47 18591992 \n11. Kim D Kim O A case of hypokalemic paralysis provoked after trigger point injection with dexamethasone and lidocaine J Korean Neurol Assoc 2007 25 2 225 28 \n12. Weiner ID Wingo CS Hypokalemia – consequences, causes, and correction J Am Soc Nephrol 1997 8 7 1179 88 9219169 \n13. Gallen IW Rosa RM Esparaz DY On the mechanism of the effects of potassium restriction on blood pressure and renal sodium retention Am J Kidney Dis 1998 31 1 19 27 9428447 \n14. Lin SH Lin YF Halperin ML Hypokalaemia and paralysis QJM 2001 94 3 133 39 11259688 \n15. Lin SH Lin YF Chen DT Laboratory tests to determine the cause of hypokalemia and paralysis Arch Intern Med 2004 164 14 1561 66 15277290 \n16. West ML Marsden PA Richardson RM New clinical approach to evaluate disorders of potassium excretion Miner Electrolyte Metab 1986 12 4 234 38 3762510 \n17. Ethier JH Kamel KS Magner PO The transtubular potassium concentration in patients with hypokalemia and hyperkalemia Am J Kidney Dis 1990 15 4 309 15 2321642 \n18. Choi MJ Ziyadeh FN The utility of the transtubular potassium gradient in the evaluation of hyperkalemia J Am Soc Nephrol 2008 19 3 424 26 18216310 \n19. Kamel KS Halperin ML Intrarenal urea recycling leads to a higher rate of renal excretion of potassium: an hypothesis with clinical implications Curr Opin Nephrol Hypertens 2011 20 5 547 54 21788894 \n20. Beal AL Deuser WE Beilman GJ A role for epinephrine in post-traumatic hypokalemia Shock 2007 27 4 358 63 17414416 \n21. Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 45 7249508 \n22. Tamez-Pérez HE Cisneros-Pérez V Cedillo-Rodríguez JA [Prevalence of hypokalemia in patients with methylprednisolone pulse therapy] Rev Invest Clin 2009 61 3 194 97 [in Spanish] 19736807 \n23. Löfgren A Hahn RG Hypokalemia from intercostal nerve block Reg Anesth 1994 19 4 247 54 7947425 \n24. Schaefer M Link J Hannemann L Rudolph KH Excessive hypokalemia and hyperkalemia following head injury Intensive Care Med 1995 21 3 235 37 7790611 \n25. Hsiao YH Fang YW Leu JG Tsai MH Hypokalemic paralysis complicated by concurrent hyperthyroidism and hyperaldosternoism: A case report Am J Case Rep 2017 18 12 16 28050008\n\n",
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"issn_linking": "1941-5923",
"issue": "18()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000779:Anesthetics, Local; D002045:Bupivacaine; D005938:Glucocorticoids; D006801:Humans; D007008:Hypokalemia; D007273:Injections, Intramuscular; D008297:Male; D008775:Methylprednisolone; D009209:Myofascial Pain Syndromes; D010243:Paralysis; D061028:Trigger Points",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "454-457",
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"references": "21788894;17314589;3762510;7790611;19736807;15277290;21969825;18468269;16945251;17414416;9010593;7249508;18216310;11259688;7947425;27468669;28050008;9219169;24787338;2321642;9428447;18992040;18591992",
"title": "A Case of Trigger-Point Injection-Induced Hypokalemic Paralysis.",
"title_normalized": "a case of trigger point injection induced hypokalemic paralysis"
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"abstract": "Lenticulostriate artery aneurysms are uncommon lesions, usually found in adults post-hemorrhage. Despite their challenging location, mortality rates after initial hemorrhage are favorable. Securing the hemorrhage source is critical but may be complicated by lesional compression or thrombosis on post-hemorrhage vascular imaging. We present key steps in the diagnosis and surgical management of a ruptured lenticulostriate aneurysm. A healthy 18-year-old patient with prior intermittent prescription amphetamine use presented after acute severe headache onset while weight-lifting. On examination, he had trace left upper extremity drift and weakness but was otherwise neurologically intact. A head computed tomography (CT) demonstrated a 2.9×2.6×1.7-cm right basal ganglia intraparenchymal hemorrhage, with trace subarachnoid hemorrhage in the basal cisterns. Secondary imaging including magnetic resonance (MR) imaging, CT angiogram, and digital subtraction angiogram (DSA) was negative for underlying lesions. After an uneventful recovery, a 4-month MR angiogram and subsequent DSA demonstrated a 2.7-mm right lenticulostriate aneurysm in the area of the prior hemorrhage. Treatment was recommended to prevent a rehemorrhage, with the safety of local vessel sacrifice presumed based on prior local tissue damage. Microcatheterization was unsuccessful. A right frontotemporal craniotomy for transsylvian, transinsular microsurgical aneurysm excision was performed, with image guidance used for the insular entry site. The patient was discharged home neurologically intact on postoperative day 2. At one-year follow-up, there were no new or recurrent vascular lesions on imaging. Delayed imaging is critical to identify initially occult cerebrovascular lesions after hemorrhage. The transsylvian, transinsular approach provides safe access to the basal ganglia region in selected patients.",
"affiliations": "Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.;Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.;Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.;Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.;Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.;Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA. Electronic address: neuropub@hsc.utah.edu.",
"authors": "Fredrickson|Vance L|VL|;Makarenko|Serge|S|;Hollon|Todd C|TC|;Rennert|Robert C|RC|;Grandhi|Ramesh|R|;Couldwell|William T|WT|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.wneu.2021.11.076",
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"issn_linking": "1878-8750",
"issue": null,
"journal": "World neurosurgery",
"keywords": "clipping; lenticulostriate aneurysm; microsurgery",
"medline_ta": "World Neurosurg",
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"nlm_unique_id": "101528275",
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"pmid": "34839046",
"pubdate": "2021-11-25",
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"title": "Microsurgical Excision of Ruptured Lenticulostriate Artery Aneurysm.",
"title_normalized": "microsurgical excision of ruptured lenticulostriate artery aneurysm"
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"abstract": "OBJECTIVE\nThe objective of this study is to report a case of Pisa syndrome due to olanzapine use in an autistic adolescent.\n\n\nMETHODS\nThe patient was a 12-year-old adolescent girl who was taking olanzapine for autism-related behavioral problems. Abnormal posture and balance problems appeared in the third month of olanzapine treatment. The patient was diagnosed as having Pisa syndrome after clinical evaluation. Biperiden was started on the patient whose complaints continued despite olanzapine treatment was stopped. Patient's complaints regressed with biperiden treatment.\n\n\nRESULTS\nAccording to our knowledge, there is no an autistic adolescent case of Pisa syndrome previously reported in the literature. Further studies are needed to clarify the etiology and treatment of Pisa syndrome.\n\n\nCONCLUSIONS\nIn patients with balance problems and abnormal posture as a result of olanzapine use, the clinician should keep in mind Pisa syndrome.",
"affiliations": "Department of Child and Adolescent Psychiatry, Faculty of Medicine, Selcuk University, Konya, Turkey.;Department of Child and Adolescent Psychiatry, Faculty of Medicine, Selcuk University, Konya, Turkey.;Department of Child and Adolescent Psychiatry, Faculty of Medicine, Selcuk University, Konya, Turkey.;Department of Child and Adolescent Psychiatry, Faculty of Medicine, Selcuk University, Konya, Turkey.;Department of Child and Adolescent Psychiatry, Bitlis State Hospital, Bitlis, Turkey.",
"authors": "Guler|Hasan Ali|HA|;Turkoglu|Serhat|S|;Cetin|Fatih Hilmi|FH|;Ucar|Halit Necmi|HN|;Erdogan|Yakup|Y|",
"chemical_list": "D014150:Antipsychotic Agents; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000377",
"fulltext": null,
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"issn_linking": "0362-5664",
"issue": "43(2)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D001321:Autistic Disorder; D005260:Female; D006801:Humans; D000077152:Olanzapine; D000071057:Tardive Dyskinesia",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "48-49",
"pmc": null,
"pmid": "32097169",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Olanzapine-Associated Pisa Syndrome in an Autistic Adolescent.",
"title_normalized": "olanzapine associated pisa syndrome in an autistic adolescent"
} | [
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"companynumb": "TR-JUBILANT CADISTA PHARMACEUTICALS-2020JUB00088",
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"abstract": "OBJECTIVE\nDose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT.\nPatients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability.\n\n\nRESULTS\nOf 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%).\n\n\nCONCLUSIONS\nDose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.",
"authors": "Kim|Gun Min|GM|;Kim|Joo Hoon|JH|;Kim|Ji Heung|JH|;Cho|Young Up|YU|;Kim|Seung Il|SI|;Park|Seho|S|;Park|Hyung Seok|HS|;Kim|Ji Ye|JY|;Sohn|Joohyuk|J|",
"chemical_list": "D015415:Biomarkers; D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2018.383",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 3023592110.4143/crt.2018.383crt-2018-383Original ArticleA Phase II Study to Evaluate the Safety and Efficacy of Pegteograstim in Korean Breast Cancer Patients Receiving Dose-Dense Doxorubicin/Cyclophosphamide Kim Gun Min MD1Kim Joo Hoon MD1Kim Ji Heung MD1Cho Young Up MDPhD2Kim Seung Il MDPhD2Park Seho MDPhD2Park Hyung Seok MD2Kim Ji Ye MD2Sohn Joohyuk MDPhD1\n1 Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea\n2 Department of Surgery, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Joohyuk Sohn, MD, PhD Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: 82-2-2228-8135 Fax: 82-2-393-3652 E-mail: oncosohn@yuhs.ac4 2019 19 9 2018 51 2 812 818 30 6 2018 18 9 2018 Copyright © 2019 by the Korean Cancer Association2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nDose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT.\n\nMaterials and Methods\nPatients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability.\n\nResults\nOf 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%).\n\nConclusion\nDose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.\n\nBreast neoplasmsDose-dense chemotherapyPegfilgrastim\n==== Body\nIntroduction\nAnthracycline followed by taxane chemotherapy regimens are considered the standard of care as neoadjuvant or adjuvant chemotherapy for early breast cancer [1]. The introduction of granulocyte colony stimulating factor (G-CSF) enabled dose-dense chemotherapy (DD-CT), defined as the administration of the standard dose chemotherapy over shorter intervals per cycle. The National Comprehensive Cancer Network guidelines recommend a DD regimen as the preferred treatment based on the results of several randomized trials that showed the superiority of DD-CT [2-4]. A recent meta-analysis also reported that DD-CT with G-CSF support lowers the risk of recurrence and breast cancer death by approximately 15% in cases of early breast cancer [5].\n\nHowever, along with the increase in efficacy, DD-CT has the potential to increase toxicity. Several prospective DD-CT trials reported that DD-CT was associated with an increased rate of non-hematologic and hematologic toxicities [2,3,6-9]. Waks et al. [10] reported that the DD-CT regimen was a risk factor for Pneumocystis jirovecii pneumonia (PJP) in a retrospective review of a large population (n=3,322). In addition, limited safety data of DD-CT in Asian breast cancer patients are available, and several studies have shown that the incidence of chemotherapy-related toxicities differs between ethnic groups [11-15]. An investigation of the safety profiles of DD-CT with long-acting G-CSF in Asian breast cancer patients is needed.\n\nPegteograstim, a novel long-acting recombinant human G-CSF, has higher biological activity based on its higher affinity to the G-CSF receptor than pegfilgrastim [16-18]. Here, we evaluated the safety and efficacy of pegteograstim in Korean early breast cancer patients receiving DD-AC (doxorubicin/cyclophosphamide) regimen.\n\nMaterials and Methods\n1. Study design and patients\nThis was a single arm, phase II trial conducted at Yonsei Cancer Center in Korea.\n\nEligible patients were women with histologically confirmed, operable primary breast cancer without distant metastases. The planned regimen was AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) chemotherapy as neoadjuvant or adjuvant therapy for breast cancer. Patients had to have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 and no major cardiovascular morbidity or other serious medical conditions. The main exclusion criteria were previous adjuvant or neoadjuvant treatment, ongoing pregnancy or lactation, abnormal laboratory values precluding the possibility to safely deliver the cytotoxic agents used in the study, and previous or concurrent malignant neoplasms at the other sites.\n\n2. Procedures\nPatients received four cycles of DD-AC (60 mg/m2 doxorubicin and 600 mg/m2 cyclophosphamide administered intravenously on day 1 every 2 weeks). A fixed dose of 6.0 mg pegteograstim was administered subcutaneously on day 2 of each chemotherapy cycle (between 22 and 26 hours after the completion of chemotherapy). Patients with lymph node metastases were treated with taxane chemotherapy (weekly paclitaxel or docetaxel every 3 weeks). Taxane regimen was decided by investigator’s discretion.\n\nBlood sampling for hematological and biochemical assessments was done on day 1 of each cycle and 4 weeks after the last chemotherapy (end of treatment visit). Chemotherapy was administered only if absolute neutrophil count was ≥ 1.0×103 cells/L and platelet counts were ≥ 100×103/L. Supportive care was provided as per the local policy. A dose delay of up to 14 days was allowed to achieve these hematologic parameters. Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE ver. 4.03).\n\n3. Outcomes\nThe primary endpoint was the incidence of febrile neutropenia (FN) in DD-AC with pegteograstim. FN was defined as neutropenia (< 500 neutrophils/μL) with a febrile event (a single oral temperature of ≥ 38.3°C or a temperature of ≥ 38.0°C sustained over a 1-hour period). Secondary endpoints were the incidences of FN in the first cycle of DD-AC, hospitalization for FN, grade 3 or 4 neutropenia in the first cycle of DD-AC, and the dose delay or reduction of chemotherapy. Safety was also a secondary endpoint and was assessed throughout the study treatment according to the NCI-CTCAE ver. 4.03.\n\n4. Statistical considerations\nIn previous DD-CT trials, the incidence of FN in DD-AC ranged widely from 1% to 10% and several guidelines categorize the AC regimen into the intermediate risk group (risk of FN ranges from 10%-25%). Based on those results, we hypothesized that threshold and expected values of the incidences of FN were 5% and 20%, respectively. To meet the threshold and expected values of the incidence of FN with a type I error level of 0.05 and type II error level of 0.20, at least 56 patients were required. As a dropout rate of 10% is expected, we aimed to recruit 63 patients. Statistical analyses were performed using SPSS ver. 22.0 for Window (IBM Corp., Armonk, NY). Descriptive statistics were used for baseline characteristics. Binomial two-sided 95% confidence intervals (CIs) for the change of hematology profile were calculated.\n\n5. Ethical statement\nAll patients provided written informed consent before enrollment. The study protocol was approved by the institutional review board (IRB No. 4-2015-0813). The study was conducted according to the Declaration of Helsinki and the principles of good clinical practice. The trial was registered at ClinicalTrials.gov (NCT03575520).\n\nResults\n1. Patient characteristics\nBetween June 2016 and March 2017, a total of 63 patients were enrolled at Yonsei Cancer Center. The characteristics of the patients included in this study are shown in Table 1. The median (range) age was 50 years (range, 29 to 69 years), and all patients had an ECOG performance status score of 0. Of the 63 patients, 42 (66.7%) were premenopausal women, and 37 (58.7%) were node positive, 22 (24.9%) had grade 3 disease, 18 (28.6%) received neoadjuvant therapy, 37 (58.7%) had estrogen receptor– or progesterone receptor–positive tumors, and 20 (31.7%) had human epidermal growth factor receptor 2–positive tumors.\n\n2. The incidence of FN and dose intensity\nOnly one of 63 patients (1.6%) developed FN during DD-AC chemotherapy. All patients, except one who withdrew from the study after the first cycle of chemotherapy, completed the planned four cycles of DD-AC chemotherapy. Dose delay was observed in four of 63 patients (6.3%) during DD-AC. The duration of dose delay was seven days for all four patients. The reasons for the dose delay were AEs in two patients (liver enzyme elevation grade 3 and mucositis grade 2). The other two patients visited 1 week later due to a mistaken appointment without any reason for the dose delay. Dose reduction was observed in two of 63 patients (3.2%) during DD-AC. The reasons for the dose reductions were recurrent grade 3 FN and grade 3 mucositis in each patient.\n\n3. Safety\nThe most frequently reported AEs are presented in Table 2. All but one of the 63 patients (98.4%) reported at least one AE during DD-AC chemotherapy with pegteograstim subcutaneous injection. Grade 3 to 4 AEs were reported in five of 63 patients (7.9%). All grade 3 or 4 AEs were linked to chemotherapy (grade 3 FN, grade 3 anemia, grade 3 pneumonia, grade 3 mucositis, grade 3 wound infection, and grade 4 neutropenia). One patient withdrew from the study after the first cycle of chemotherapy due to toxicity (pneumonia). She refused further adjuvant chemotherapy. The most frequent AEs were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, diarrhea, and most AEs were due to the chemotherapy. Adverse drug reactions (ADRs) that might be linked to pegteograstim included abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%). Ten patients experience infectious AEs. Regarding to the type of infections, cystitis is most common with six cases (60%) and the remainder were pneumonia, febrile neutropenia, enteritis, esophageal candidiasis, respectively.\n\n4. Change of hematology profile\nThe change in hematology profiles (neutrophil, lymphocyte, platelet counts, and hemoglobin level) at day 1 of each cycle and follow-up is shown in Fig. 1. Mean absolute lymphocyte counts and hemoglobin level decreased gradually during DD-AC chemotherapy and at the follow-up visit. Mean platelet counts decreased gradually during DD-AC chemotherapy but recovered to baseline levels at follow-up. In contrast, mean neutrophil counts were increased during DD-AC but subsequently returned to baseline level at follow-up.\n\nDiscussion\nTo the best of our knowledge, this study is the first to evaluate the efficacy and safety of long acting G-CSF, pegteograstim during DD-AC chemotherapy in Korean early breast cancer patients. We found that FN occurred in only 1.6% of patients receiving DD-AC chemotherapy with pegteograstim support. Grade 3 to 4 AEs were reported in five of 63 patients (7.9%). All but one patient completed the planned four cycles of DD-AC chemotherapy. Dose delay and dose reduction linked to AEs were observed in two of 63 patients (3.2%). The most common ADRs possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache.\n\nCALGB 9741 trial was the first large phase III study to demonstrate that DD-CT improved clinical outcomes regarding both disease-free survival (DFS) and overall survival (OS) in node-positive breast cancer [3]. Similarly, the GIM-II trial showed that DD-CT improved DFS and OS compared to a conventional chemotherapy schedule. In contrast, several trials exploring the role of DD-CT have reported negative results [6-8]. The most recent meta-analysis by the Early Breast Cancer Trialists' Collaborative Group found that DDCT lowers the risk of recurrence and breast cancer death by approximately 15% in early breast cancer [5]. In Korea, longacting G-CSF is now available, but DD-CT is not commonly used as is the case in Western settings. The reasons for this are a lack of safety data for DD-CT in Korean patients and non-reimbursement of long-acting G-CSF for DD-CT.\n\nDD-CT may increase most chemotherapy-related toxicities. In individual trials, non-hematologic and hematologic AEs, except neutropenia, were higher for DD-CT than for conventional schedule chemotherapy [2,6-9]. Petrelli et al. [19] reported that grade 3 to 4 neutropenia and FN rates were not different between DD-CT and conventional chemotherapy, but rates of anemia and thrombocytopenia were significantly higher (relative risk [RR], 3.48; 95% CI, 2.89 to 4.2, p < 0.001 and RR, 2.85; 95% CI, 1.93 to 4.2, p < 0.001) during DD-CT than during conventional chemotherapy [19]. In this study, the incidence of grade 3 or 4 AEs, including FN (1.6%), was within an acceptable range and there were no toxicityrelated deaths. At least in terms of frequency of FN, DD-AC with G-CSF support was safer than conventional AC chemotherapy without G-CSF use.\n\nPegteograstim is a novel monoPEGylated recombinant human G-CSF. It displays higher biological activity based on an improved binding affinity to the G-CSF receptor [16-18]. Lee et al. [18] showed that pegteograstim was as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in breast cancer patients; the incidence of ADRs was 5.3%, and most common ADRs were leukocytosis, blurred vision, injection site pain, headache, and dizziness [16,17]. In this study, the rate of ADRs for pegteograstim was 7.9% with AE profiles similar to the previous study.\n\nWe investigated the change in neutrophil, lymphocyte, platelet, and hemoglobin level at every visit during DD-AC chemotherapy (Fig. 1). Interestingly, lymphocyte count and hemoglobin levels were not recovered one month after the completion of chemotherapy. Although there was no case of PJP in this study, the DD-AC regimen was one of the risk factors for PJP in the retrospective study by Waks et al. [10] They suggested that a high-dose steroid used as an antiemetic over 8 weeks may increase the PJP risk in DD-AC. In this study, we found that most patients had lymphopenia after completion of DD-AC. Prolonged lymphopenia can contribute to infectious vulnerability for PJP.\n\nThis study has several limitations. First, this was a smallsized single-center study. Second, this study did not collect patient-reported outcome (PRO) data. PRO data are increasingly being implemented in oncology clinical trials to evaluate disease-related symptoms, treatment-related AEs, and health-related impacts on quality of life. We collected AE information from patients at regular visits and therefore AE information may not be collected thoroughly. Third, 28.6% of patients received DD-AC as neoadjuvant therapy in this study. There is a possibility of different toxicity profiles between neoadjuvant therapy and adjuvant therapy, despite the regimens being identical.\n\nIn conclusion, DD-AC chemotherapy with pegteograstim support is an efficacious and safe regimen in Korean patients with early breast cancer. Reimbursement by the Korean government of long-acting G-CSF used for DD-CT is warranted in early breast cancer patients.\n\nPegteograstim was supplied by the GC Pharma.\n\nThis research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1324).\n\nFig. 1. Change in hematology profiles on day 1 of each cycle (cycle 1 to 4) and end of treatment (4 weeks after the last chemotherapy). (A) Absolute lymphocyte count (ALC). (B) Hemoglobin level. (C) Platelet count. (D) Absolute neutrophil count (ANC).\n\nTable 1. Baseline characteristics\n\n\tNo. (%) (n=63)\t\nAge, median (range, yr)\t50 (29-69)\t\nMenopausal status\t\t\n Premenopausal\t42 (66.7)\t\n Postmenopausal\t21 (33.3)\t\nType of surgery\t\t\n Mastectomy\t23 (36.5)\t\n Breast-conserving surgery\t40 (63.5)\t\nT category\t\t\n T1\t26 (41.3)\t\n T2\t28 (44.4)\t\n T3\t9 (14.3)\t\nN category\t\t\n 0\t26 (41.3)\t\n 1\t28 (44.4)\t\n 2\t4 (6.3)\t\n 3\t5 (7.9)\t\nTumor grade\t\t\n 1\t3 (4.8)\t\n 2\t35 (55.6)\t\n 3\t22 (34.9)\t\n Missing\t3 (4.8)\t\nTNM stage\t\t\n 1\t29 (46.0)\t\n 2\t28 (44.4)\t\n 3\t6 (9.5)\t\nSubtype\t\t\n HR+/HER2–\t32 (50.8)\t\n HR+/HER2+\t5 (7.9)\t\n HR–/HER2+\t15 (23.8)\t\n HR–/HER2–\t11 (17.5)\t\nTreatment setting\t\t\n Neoadjuvant\t18 (28.6)\t\n Adjuvant\t45 (71.4)\t\nTNM, tumor node metastasis; HR, hormone receptor; HER2, human epidermal growth factor receptor 2.\n\nTable 2. Adverse events\n\nAdverse event\tAll grades (n=63)\tGrade 1-2 (n=63)\tGrade 3-4 (n=63)\t\nHematologic\t\t\t\t\n Neutropenia\t12 (19)\t10 (16)\t2 (3)\t\n Anemia\t56 (89)\t54 (86)\t2 (3)\t\n Thrombocytopenia\t8 (13)\t8 (13)\t0 (\t\n Lymphopenia\t50 (79)\t41 (65)\t9 (14)\t\n Febrile neutropenia\t1 (2)\t-\t1 (2)\t\nNon-hematologic\t\t\t\t\n Infection\t10 (16)\t8 (13)\t2 (3)\t\n Alopecia\t27 (43)\t27 (43)\t0\t\n Asthenia\t25 (40)\t25 (40)\t0\t\n Anorexia\t15 (24)\t15 (24)\t0\t\n Nausea\t37 (59)\t37 (59)\t0\t\n Vomiting\t2 (3)\t2 (3)\t0\t\n Stomatitis\t24 (38)\t23 (37)\t1 (2)\t\n Diarrhea\t10 (16)\t10 (16)\t0\t\n Constipation\t11 (17)\t11 (17)\t0\t\n Bone pain\t8 (13)\t8 (13)\t0\t\n Myalgia\t22 (35)\t22 (35)\t0\t\n Pain, others\t34 (54)\t34 (54)\t0\t\n Cough\t17 (27)\t17 (27)\t0\t\n Dizziness\t21 (33)\t21 (33)\t0\t\n Dyspepsia\t25 (40)\t25 (40)\t0\t\n Insomnia\t15 (24)\t15 (24)\t0\t\n Transaminase elevation\t28 (44)\t28 (44)\t0\t\n Others\t38 (60)\t38 (60)\t0\t\nValues are presented as number (%).\n==== Refs\nReferences\n1 Early Breast Cancer Trialists' Collaborative Group Peto R Davies C Godwin J Gray R Pan HC Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials Lancet 2012 379 432 44 22152853 \n2 Del Mastro L De Placido S Bruzzi P De Laurentiis M Boni C Cavazzini G Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial Lancet 2015 385 1863 72 25740286 \n3 Citron ML Berry DA Cirrincione C Hudis C Winer EP Gradishar WJ Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741 J Clin Oncol 2003 21 1431 9 12668651 \n4 National Comprehensive Cancer Network NCCN clinical practice guidelines in oncology: breast cancer Plymouth Meeting, PA National Comprehensive Cancer Network 2018 \n5 Gray R Bradley R Braybrooke J Davies C Pan H Peto R Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: an EBCTCG meta-analysis of 21,000 women in 16 randomised trials San Antonio Breast Cancer Symposium 2017 Dec 5-9 San Antonio, TX, USA Philadelphia, PA American Association for Cancer Research 2018 \n6 Venturini M Del Mastro L Aitini E Baldini E Caroti C Contu A Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial J Natl Cancer Inst 2005 97 1724 33 16333028 \n7 Foukakis T von Minckwitz G Bengtsson NO Brandberg Y Wallberg B Fornander T Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer: a randomized clinical trial JAMA 2016 316 1888 96 27825007 \n8 Cameron D Morden JP Canney P Velikova G Coleman R Bartlett J Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial Lancet Oncol 2017 18 929 45 28600210 \n9 Mobus V Jackisch C Luck HJ du Bois A Thomssen C Kuhn W Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial Ann Oncol 2018 29 178 85 29069370 \n10 Waks AG Tolaney SM Galar A Arnaout A Porter JB Marty FM Pneumocystis jiroveci pneumonia (PCP) in patients receiving neoadjuvant and adjuvant anthracycline-based chemotherapy for breast cancer: incidence and risk factors Breast Cancer Res Treat 2015 154 359 67 26420402 \n11 Gandara DR Kawaguchi T Crowley J Moon J Furuse K Kawahara M Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics J Clin Oncol 2009 27 3540 6 19470925 \n12 Hasegawa Y Kawaguchi T Kubo A Ando M Shiraishi J Isa S Ethnic difference in hematological toxicity in patients with non-small cell lung cancer treated with chemotherapy: a pooled analysis on Asian versus non-Asian in phase II and III clinical trials J Thorac Oncol 2011 6 1881 8 21841503 \n13 Wang Y Choueiri TK Lee JL Tan MH Rha SY North SA Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients Br J Cancer 2014 110 1433 7 24548864 \n14 Huang RS Kistner EO Bleibel WK Shukla SJ Dolan ME Effect of population and gender on chemotherapeutic agentinduced cytotoxicity Mol Cancer Ther 2007 6 31 6 17237264 \n15 Kim CG Sohn J Chon H Kim JH Heo SJ Cho H Incidence of febrile neutropenia in Korean female breast cancer patients receiving preoperative or postoperative doxorubicin/cyclophosphamide followed by docetaxel chemotherapy J Breast Cancer 2016 19 76 82 27064666 \n16 Hong J Lee B Kang K Lee SH Ryu J Jung G Characterisation of the site-specific monoPEGylated rhG-CSF analogue pegteograstim Biologicals 2018 51 54 61 29107446 \n17 Shin KH Lim KS Lee H Jang IJ Yu KS An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects Invest New Drugs 2014 32 636 43 24468886 \n18 Lee KH Kim JY Lee MH Han HS Lim JH Park KU A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy-induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10-09 Support Care Cancer 2016 24 1709 17 26423618 \n19 Petrelli F Cabiddu M Coinu A Borgonovo K Ghilardi M Lonati V Adjuvant dose-dense chemotherapy in breast cancer: a systematic review and meta-analysis of randomized trials Breast Cancer Res Treat 2015 151 251 9 25917869\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "51(2)",
"journal": "Cancer research and treatment",
"keywords": "Breast neoplasms; Dose-dense chemotherapy; Pegfilgrastim",
"medline_ta": "Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D056910:Republic of Korea; D016896:Treatment Outcome",
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "812-818",
"pmc": null,
"pmid": "30235921",
"pubdate": "2019-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "12668651;16333028;17237264;19470925;21841503;22152853;24468886;24548864;25740286;25917869;26420402;26423618;27064666;27825007;28600210;29069370;29107446",
"title": "A Phase II Study to Evaluate the Safety and Efficacy of Pegteograstim in Korean Breast Cancer Patients Receiving Dose-Dense Doxorubicin/Cyclophosphamide.",
"title_normalized": "a phase ii study to evaluate the safety and efficacy of pegteograstim in korean breast cancer patients receiving dose dense doxorubicin cyclophosphamide"
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"companynumb": "KR-JNJFOC-20190425063",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
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"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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{
"abstract": "BACKGROUND\nCutaneous composite lymphomas are very rare. Their treatment depends upon the different contributing lymphoma entities. Peripheral T-cell lymphoma, not otherwise specified, (PTCL-NOS) represents an aggressive lymphoma subtype. Follicular cutaneous B-cell lymphoma (FCBCL) runs an indolent course. Treatment with pegylated liposomal encapsulated doxorubicin (PLE-DOXO) has yet not been reported in this entity.\n\n\nMETHODS\nA 73-year-old male patient presented with 3 rapidly growing, painful nodules on his left leg. He was diagnosed as composite cutaneous lymphoma consisting of PTCL-NOS and FCBCL. All lesions had been surgically removed. Staging was unremarkable. After 4 months a relapse occurred with involvement of inguinal lymph nodes and systemic treatment with PEL-DOXO 20 mg/ m every 3 weeks was initiated. After 6 cycles PLE-DOXO, which were well tolerated without grade 3 or 4 toxicities, a mixed response was obtained with complete remission of cutaneous lesions.Lymph nodes were treated by radiotherapy. A second relapse occurred after 8 months and various polychemotherapy regimens were applied without remission. The overall survival was 28 months.\n\n\nCONCLUSIONS\nPEL-DOXO is a possible initial systemic treatment in case of PCTL-NOS. Whether polychemotherapy offers an advantage for survival remains questionable but further investigations are needed.",
"affiliations": "Department of Dermatology and Allergology, Insitute of Pathology \"Georg Schmorl\", Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany.",
"authors": "Wollina|Uwe|U|;Langner|Dana|D|;Hansel|Gesina|G|;Haroske|Gunter|G|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "United States",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2778735610.1097/MD.0000000000004796047964000Research ArticleClinical Case ReportPegylated liposomal-encapsulated doxorubicin in cutaneous composite lymphoma A case reportWollina Uwe MD\n∗Langner Dana FacharztHansel Gesina MDHaroske Gunter MDAlaibac. Mauro Department of Dermatology and Allergology, Insitute of Pathology “Georg Schmorl”, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany.∗ Correspondence: Uwe Wollina, Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany (e-mail: wollina-uw@khdf.de).10 2016 28 10 2016 95 43 e47967 4 2016 2 8 2016 15 8 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-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0\nAbstract\nBackground:\nCutaneous composite lymphomas are very rare. Their treatment depends upon the different contributing lymphoma entities. Peripheral T-cell lymphoma, not otherwise specified, (PTCL-NOS) represents an aggressive lymphoma subtype. Follicular cutaneous B-cell lymphoma (FCBCL) runs an indolent course. Treatment with pegylated liposomal encapsulated doxorubicin (PLE-DOXO) has yet not been reported in this entity.\n\nCase presentation:\nA 73-year-old male patient presented with 3 rapidly growing, painful nodules on his left leg. He was diagnosed as composite cutaneous lymphoma consisting of PTCL-NOS and FCBCL. All lesions had been surgically removed. Staging was unremarkable. After 4 months a relapse occurred with involvement of inguinal lymph nodes and systemic treatment with PEL-DOXO 20 mg/ m2 every 3 weeks was initiated. After 6 cycles PLE-DOXO, which were well tolerated without grade 3 or 4 toxicities, a mixed response was obtained with complete remission of cutaneous lesions.\n\nLymph nodes were treated by radiotherapy. A second relapse occurred after 8 months and various polychemotherapy regimens were applied without remission. The overall survival was 28 months.\n\nConclusion:\nPEL-DOXO is a possible initial systemic treatment in case of PCTL-NOS. Whether polychemotherapy offers an advantage for survival remains questionable but further investigations are needed.\n\nKeywords\ncombined cutaneous lymphomafollicular cutaneous B-Cell lymphomapegylated liposomal-encapsulated doxorubicinperipheral T-Cell lymphoma – not otherwise specifiedpolychemotherapyOPEN-ACCESSTRUE\n==== Body\n1 Background\nMajor groups of cutaneous lymphomas are T-cell (CTCL) and B-cell (CBCL) lymphomas. CTCL belongs to the heterogeneous group of non-Hodgkin lymphomas and is primarily indolent. The most important subtypes of CTCL are mycosis fungoides (MF) and Sézary syndrome. CTCL arises in skin but may spread to lymph nodes, peripheral blood, and visceral organs with significantly worsening of prognosis. Staging of CTCL is based on the involvement of the different tissue compartments.[1]\n\n\nCBCL are less frequent than CTCL and constitute about 25 % of all cutaneous lymphomas. CBCL are more indolent than their nodal counterparts and usually have a good prognosis. Follicular CBCL (FCBCL) is the most common subtype. Treatment may be surgically for solitary lesions.[2] Cutaneous composite lymphomas (CCL) are very rare. Because of this, no randomized controlled clinical trials have yet been performed for CCL.[3]\n\n\nDoxorubicin is an active chemotherapeutic agent for CTCL but has the potential of severe cardiotoxicity. Pegylated liposomal encapsulated doxorubicin (PLE-DOXO) increases the concentration of the active compound in skin while reducing cardiac toxicity.[4] Reported overall response rates, that is, complete response (CR) plus partial response (PR), range from 20 % to 44 % in CTCL of MF or Sezary type.[5–9] Interestingly, PLE-DOXO has shown activity in a phase II trial for primary cutaneous B cell lymphoma as well.[10]\n\n\nNo data are available for PLE-DOXO in patients with CCL. Here we report on PLE-DOXO in a patient with CCL.\n\n2 Case presentation\nFor this case report, an ethical committee approval was not necessary. Patient's informed consent was given.\n\nA 73-year old male patient presented in April 2014 with 3 painful nodules on the left upper leg (knee and near the groin) that developed with the last 6 weeks (knee) and the last 3 days (groin). He denied night sweat, fever, weight loss, or loss of appetite. He suffered from several co-morbidities such as arterial hypertension, presbyakusis, cataract of the left eye, embolism of his left ocular artery, and relapsing vertigo due to spine problems. His medication consisted of amino salicylic acid, naftidrofuryl oxalate, and metoprolol succinate.\n\nOn clinical examination, we observed 3 flat nodules, well circumscribed, with a size between 1.5 × 1.1. cm to 2.8 × 1.8 cm. Their color was pink-brownish around the knee and flesh-like near the groin. The tumor near the groin was the largest and the fastest growing (Fig. 1). Our primary working diagnoses were dermatofibroma or cutaneous metastases of CUP syndrome.\n\nFigure 1 Initial clinical presentation of the patient with composite lymphoma of skin. (A) Nodules in the popliteal fossa of the left leg. (B) Tumor growth in the right groin.\n\nWe performed several skin biopsies. Histological examination revealed a dense inflammatory infiltrate composed of lymphoid and blastic cells intermingled with histiocytes, mast cells, plasma cells, and mature lymphocytes. We observed atypical mitoses. There was minimal epidermotropism. The epidermis was papillomatous, with alternating hypo- and hypertrophic sections (Fig. 2 A and B). Immunohistochemistry identified a mixed T- and B-cell population. Medium-sized and large atypical T-lymphocytes expressed CD2, CD3, CD4, CD5, Programmed Cell Death 1 (PD1) protein, and beta-F1 (anti-T-cell receptor beta chain antibody) (Fig. 3 A and B). They were negative for T-cell receptor gamma and mostly negative for ICOS (CD278). There was a mixed reaction to B-cell lymphoma (Bcl) 6 protein, chemokine ligand 13 (CXCL13), and CD30. B lymphocytes were arranged in irregular follicular networks and expressed CD20, CD21, CD79a, paired box-5 (PAX-5), and partially Bcl6. In situ hybridization for Epstein–Barr virus remained negative. Monoclonality was proved for B cells but not for T-cells (Dermatopathology Reference Center, Medical University of Graz, Austria—Prof. Lorenzo Cerroni, MD).\n\nFigure 2 Histopathology of composite lymphoma of skin demonstrating a dense inflammatory dermal infiltrate composed mainly of lymphoid and blastic cells without significant epidermotropism. (A) Overview (HE ×2). (B) Giemsa stain (×4). HE = hematoxylin-eosin.\n\nFigure 3 Characterization of the inflammatory dermal infiltrate by immunohistology with monoclonal antibodies against CD3, CD20, and CD5 (Immunoperoxidase stain, ×4).\n\nBone marrow histology and immunohistology provided no evidence for specific infiltrates of a lymphoma. X-ray of the thorax, abdominal, and lymph node sonography were unremarkable.\n\nLaboratory investigations revealed lymphopenia of 13% (normal range 20–45%), increased lactate dehydrogenase of 5.37 μkat/L (2.25–3.75 μkat/L), elevated thymidine kinase of 6.5 U/L (0–6.1 U/L), an increased CD3/CD4 ration of 5.25 (1.0–2.3), and slightly elevated percentages of CD7+ cells of 82% (49–75%), CD20+ cells of 14.0% (2–12%), and HLA-DR+ cells with 19.0% (0–12%).\n\nThe diagnosis of CCL, composed of peripheral T-cell lymphoma, not otherwise specified (NOS) and follicular B cell lymphoma, pT2N1M0B0, stage IIA was confirmed.\n\nThe patient was classified for prognosis by Prognostic Index for PCTL-NOS (PIT).[11] The patient was older than 60 years of life and laboratory analysis demonstrated increased LDH. Performance status was 0; bone marrow involvement had been excluded. This resulted in PIT group 3 with an estimated 5-year survival rate of 32.9%.\n\nTreatment and course: After complete surgical excision of the 3 tumor nodes, a relapse occurred after 3 months with nodules on the left malleolus medialis, scrotum, and mons pubis. These lesions were biopsied. Histopathologic examination proved the primary diagnosis. As he had enlarged lymph nodes in the left groin, 2 lymph nodes had been taken for restaging. In both nodes, T-cell infiltrates of the NOS lymphoma could be identified with polymorphous T lymphocytes that strongly expressed CD3 and CD4 but were negative for CD10 with multiple CD8+ cells intermingled with some plasma cells and PAX5+ B lymphocytes. The proliferation rate as measured by Ki67-labeling was high (> 70%).\n\nComputerized tomography (CT) disclosed enlarged lymph nodes in the groins of both sides.\n\nThe case was discussed in the interdisciplinary tumor board. Because of the dominant T-cell component in the composite lymphoma systemic and due to the pre-existent cardiovascular risk factors and co-morbidities, PLE-DOXO was recommended due to lower cardiotoxicity and higher drug concentrations in skin.\n\nThe treatment with PLE-DOXO 20 mg/m2 was initiated in September 2014 and performed every 3 weeks.[5] The patient received premedication with ondansetron 8 mg per session. A total of 6 treatment cycles was performed. After the 3rd PLE-DOXO therapy, skin lesions became regressive. No signs of lymph node involvement were observed except for both groins with enlarged nodes of 2.3 × 3.3 cm and 2.5 × 2.2 cm, respectively. After 6 cycles of PLE-DOXO, the cutaneous lymphoma lesions completely disappeared. Inguinal lymph node involvement was stable and no further progression of disease had been observed.\n\nThe patient was discussed in the interdisciplinary tumor board again. Radiotherapy for the inguinal lymph nodes was recommended. Radiotherapy was performed with a linear accelerator and a total dose of 36 Gy in January and February 2015. At the end of this treatment, a new perianal tumor mass had developed. That was followed by cutaneous lesions in groins, gluteal, and on his left foot with tumors and plaques (Fig. 4). He received a combined chemotherapy in the oncology outpatient clinic with gemcitabine, oxaliplatin, and bendamustine. After 2 chemotherapy cycles, he developed a severe leukopenia. Chemotherapy had to be interrupted and recombinant granulocyte growth factor (Filgrastim®) was given s.c. with a daily dosage of 48 mio U for 5 days. On the last day, he was sent to the emergency department because of fever, general malaise, and an acute generalized pruriginous erythema. We treated the patient with systemic (starting dose 100 mg/d) and topical corticosteroids and desloratidin 3 × 5 mg/d. With 1 week, a complete remission of the acute rash was achieved. Our working diagnosis was Filgrastim®-induced exanthema with fever. A DRESS-syndrome was not confirmed, as eosinophils were not increased. In April and May, chemotherapy was intensified to CHOEP q 14 (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone – 14 days cycle). Due to further progress, the protocol was changed in June 2015 to bendamustine, etoposide, and pixantrone until July 2015. He developed fever. The pneumonia was diagnosed and treated by systemic antibiosis. The lymph node involvement was progressive with enlargement of axillary, mediastinal, iliacal, and retroperitoneal involvement.\n\nFigure 4 Relapse of composite lymphoma of skin after radiotherapy. (A) Maculo-papular rash on the trunk. (B) Tumor-like mass with surrounding erythema in the anal fold. (C) Hyperpigmented patch and ulceration on the left foot. (D) Ill-defined hyperpigmented scaly plaque on the left lower leg.\n\nSafety: During PLE-DOXO therapy the patient was monitored by regular laboratory investigations and electrocardiography (ECG). Treatment was well tolerated. The performance status was 0–1 during the whole time of PLE-DOXO. No major toxicities were observed neither in the laboratory nor by ECG. The treatment had been given continuously without any interruption. The wounds in the left groin and on the left foot needed a revision due to delayed wound healing in October 2014. The patient developed a papular rash in November 2014 treated by topical corticosteroids. We observed palmo-plantar hyperkeratosis on erythematous skin diagnosed as hand–foot syndrome (palmo-plantar dysesthesia) that was treated by topical ointment containing urea 10%. After the 6th PLE-DOXO treatment, he developed a papulo-macular rash treated with topical prednicarbate ointment.\n\nDuring polychemotherapy toxicities, grade 3 and 4 were observed. Bone marrow toxicity needed intensified application of GMCSF. Skin toxicity needed hospitalization. Severe infection (pneumonia) occurred. Performance status deteriorated from 0–1 to 3 and temporary to 4. Although an initial response of cutaneous lesions was noted in February 2015, the disease progressed to stage T3N3B0M0 (Stage IVB). He died in August 2015 due to pneumonia and aggressive lymphoma.\n\nOverall survival was 28 months. Progression-free survival after PLE-DOXO initiation was 5 months. There was no progression-free survival thereafter.\n\n3 Discussion\nCCL are very rare cutaneous malignancies. In a series of 1200 cutaneous lymphoproliferative diseases, only 15 cases of CCL could be identified.[3] Our patient suffered from a combination of PTCL-NOS and FBCCL. PTCL-NOS is the most common subtype of PTCL that runs an aggressive course.[12] FBCCL is an indolent lymphoma with good prognosis.[13\n14]\n\n\nNegative prognostic factors for PCTL-NOS include peripheral neutropenia and thrombocytopenia, high tumor proliferative index (Ki67), age > 60 years of life, poor performance status, bone marrow involvement, and increased LDH.[15] Increased thymidine kinase serum levels are a marker of aggressive lymphomas.[16] Our patient had a high proliferative index, increased LDH, and was > 60 years of life. Serum thymidine kinase was only slightly increased. Lymphopenia was present from the beginning. For such patients, a median overall survival of 7.6 months has been calculated.[17] Lymphopenia, on the other side, will have a negative impact on the response to classical DOXO-based chemotherapies.[17]\n\n\nTreatment of PCTL-NOS is not well standardized due to the rareness of this disease. Indeed PCTL-NOS is the rarest type of CTCL.[18] CHOP regimen consisting of cyclophosphamide, DOXO, vincristine, and prednisolone has been used in cutaneous T-cell lymphomas including PTCL-NOS. In a retrospective trial including 56 patients with PTCL-NOS, DOXO has been compared to pirarubicin, a less cardiotoxic DOXO-derivate, as part of CHOP. Complete remission rates in both groups were identical with 52%. The 3-year overall survival was in favor of pirarubicin-CHOP, that is, 67% versus 52% for DOXO-CHOP. The 3-year progression-free survival for pirarubicin-CHOP was 75% versus 33% with DOXO-CHOP.[19] The 5-year survival rate with CHOP is only 19% in PCTL-NOS.[20] Adjuvant radiation therapy to DOXO-based chemotherapy in early stage PCTL-NOS may improve the 3-year survival significantly, that is, 49.7% versus 23.1% (DOXO-based chemotherapy alone).[21]\n\n\nGemcitabine, cisplatin, dexamethasone regimen as salvage therapy of relapsed or refractory PTCL (n = 25) resulted in a complete response in 48% and in partial response in 24%. Progression-free media survival was 9.3 months.[23] Patients with relapse or progression have a poor outcome despite chemotherapy or radiotherapy.[22]\n\n\nCHOP and other polychemotherapy regimens such as DOXO, cyclophosphamide, vincristine, prednisolone or gemcitabine, oxaliplatin, bendamustine, and so on, may result in significant toxicities without improvement of overall survival.[12\n22]\n\n\nIn contrast, PLE-DOXO has a favorable safety profile with proven efficacy in CTCL in particular at a dosage of 20 mg/m2.[5–9] This is the first case report on PLE-DOXO as initial chemotherapy in PCTL-NOS. In a patient with PIT risk group 3, a stable disease with complete response of cutaneous lesions could be achieved. No grade 3 or 4 toxicities were observed. The treatment was well tolerated. Palmo-plantar dysesthesia, however, is a common adverse effects observed in about 50% of patients. Overall survival was about 4 times of the median survival of grade 3 PTCL-NOS with 28 months.[11] Despite escalating polychemotherapy, no remission or further progression-free survival could be achieved. Would the patient have been benefited from a second PLE-DOXO course alike MF patients? We do not know. Further investigations for an optimal treatment algorithm are needed.\n\n4 Conclusions\nWe report a case of a 73-year-old male patient who presented with painful cutaneous nodules identified by histology and immunohistology as CCL composed of PTCL-NOS and FCBCL. We obtained a stable disease with complete remission of cutaneous lesions during 6 cycles of low-dose PEL-DOXO every 3 weeks. The use of PEG-DOXO has yet not been described for this entity although controlled and uncontrolled trials documented clinical efficacy for MF and Sézary syndrome and even in CBCL. Whether escalating polychemotherapy provides benefits for such patients in sense of quality of life, relapse-free, and overall survival has yet not been proven. Further studies are needed to substantiate the positive impression of this well-tolerated treatment in CCL with PTCL-NOS and FCBCL.\n\nAcknowledgments\nThe authors would like to thank Prof. Lorenzo Cerroni (Graz, Austria) for second opinion on the pathologic specimen. Photography Department (Mrs. Ramona Herz) is acknowledged for assistance in preparing the images for the manuscript.\n\nAbbreviations: CBCL = cutaneous B-cell lymphoma, CCL = combined cutaneous lymphoma, CHOP = acronym for non-Hodgkin lymphoma chemotherapy with cyclophosphamide, hydroxydaunorubicin (or doxorubicin or adriamycin), oncovin (vincristine), and prednisolone, CR = complete response, CTCL = cutaneous T-cell lymphoma, DOXO = doxorubicin, FBCL = follicular cutaneous B-cell lymphoma, MF = mycosis fungoides, OR = overall response rate, PLE-DOXO = pegylated liposomal encapsulated doxorubicin, PR = partial response, PTCL-NOS = peripheral T-cell lymphoma, not otherwise specified.\n\nAuthorship: UW reviewed the data and drafted the manuscript. GH was the pathologist on the case and reviewed and reported the morphology and immunohistochemistry. DL and GH were the treating physicians, drafted and reviewed the manuscript. All authors read and approved the final manuscript.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n1 \nOlsen EA Whittaker S Kim YH \nClinical end points and response criteria in Mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer . J Clin Oncol \n2011 ; 29 :2598 –2607 .21576639 \n2 \nWanczinsnki MI Pinto CA Trevisan F \nPrimary cutaneous follicle center lymphoma simulating basal-cell carcinoma on the nasal ala . An Bras Dermatol \n2015 ; 90 \nsuppl 1 :111 –114 .\n3 \nKazakov DV Kutzner H Palmedo G \nPrimary cutaneous lymphoproliferative disorders with dual lineage rearrangement . Am J Dermatopathol \n2006 ; 28 :399 –409 .17012914 \n4 \nWollina U \nLiposomal cancer chemotherapy in dermatology: current status and future prospects . Indian J Dermatol \n2004 ; 49 :109 –116 .\n5 \nWollina U Dummer R Brockmeyer NH \nMulticenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma . Cancer \n2003 ; 98 :993 –1001 .12942567 \n6 \nDi Lorenzo G Di Trolio R Delfino M \nPegylated liposomal doxorubicin in stage IVB mycosis fungoides . Br J Dermatol \n2005 ; 153 :183 –185 .16029347 \n7 \nPulini S Rupoli S Goteri G \nPegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas . Haematologica \n2007 ; 92 :686 –689 .17488695 \n8 \nQuereux G Marques S Nguyen JM \nProspective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sezary syndrome . Arch Dermatol \n2008 ; 144 :727 –733 .18559761 \n9 \nStraus DJ Duvic M Horwitz SM \nFinal results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma . Ann Oncol \n2014 ; 25 :206 –210 .24285015 \n10 \nPulini S Rupoli S Goteri G \nEfficacy and safety of pegylated liposomal doxorubicin in primary cutaneous B-cell lymphomas and comparison with the commonly used therapies . Eur J Haematol \n2009 ; 82 :184 –193 .19215609 \n11 \nGallamini A Stelitano C Calvi R \nPeripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study . Blood \n2004 ; 103 :2474 –2479 .14645001 \n12 \nAderhold K Carpenter L Brown K \nPrimary cutaneous peripheral T-cell lymphoma not otherwise specified: a rapidly progressive variant of cutaneous T-cell lymphoma . Case Rep Oncol Med \n2015 ; 2015 :429068 .26380134 \n13 \nSuárez AL Pulitzer M Horwitz S \nPrimary cutaneous B cell lymphomas. Part I. Clinical features, diagnosis and classification . J Am Acad Dermatol \n2013 ; 69 :329.e1 –329.e13 .23957984 \n14 \nSuárez AL Querfeld C Horwitz S \nPrimary cutaneous B cell lymphomas. Part II. Therapy and future directions . J Am Acad Dermatol \n2013 ; 69 :343.e1 –343.e11 .23957985 \n15 \nXu P Yu D Wang L \nAnalysis of prognostic factors and comparison of prognostic scores in peripheral T cell lymphoma, not otherwise specified: a single-institution study of 105 Chinese patients . Ann Hematol \n2015 ; 94 :239 –247 .25193354 \n16 \nGatt ME Goldschmidt N Kalichman I \nThymidine kinase levels correlate with prognosis in aggressive lymphoma and can discriminate patients with a clinical suspicion of indolent to aggressive transformation . Anticancer Res \n2015 ; 35 :3019 –3026 .25964590 \n17 \nKim YR Kim JS Kim SJ \nLymphopenia is an important prognostic factor in peripheral T-cell lymphoma (NOS) treated with anthracycline-containing chemotherapy . J Hematol Oncol \n2011 ; 4 :34 .21843362 \n18 \nKempf W Rozati S Kerl K \nCutaneous peripheral T-cell lymphomas, unspecified/NOS and rare subtypes: a heterogeneous group of challenging cutaneous lymphomas . G Ital Dermatol Venereol \n2012 ; 147 :553 –562 .23149701 \n19 \nShibata Y Hara T Kasahara S \nCHOP or THP-COP regimens in the treatment of newly diagnosed peripheral T-cell lymphoma, not otherwise specified: a comparison of doxorubicin and pirarubicin . Hematol Oncol \n2015 ; Oct 9. doi: 10.1002/hon.2262. [Epub ahead of print] .\n20 \nLage LA Cabral TC Costa Rde O \nPrimary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations . Rev Bras Hematol Hemoter \n2015 ; 37 :277 –284 .26190436 \n21 \nZhang XM Li YX Wang WH \nSurvival advantage with the addition of radiation therapy to chemotherapy in early stage peripheral T-cell lymphoma, not otherwise specified . Int J Radiat Oncol Biol Phys \n2013 ; 85 :1051 –1056 .23021436 \n22 \nPark BB Kim WS Suh C \nSalvage chemotherapy of gemcitabine, dexamethasone, and cisplatin (GDP) for patients with relapsed or refractory peripheral T-cell lymphomas: a consortium for improving survival of lymphoma (CISL) trial . Ann Hematol \n2015 ; 94 :1845 –1851 .26251158 \n23 \nMak V Hamm J Chhanabhai M \nSurvival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors . J Clin Oncol \n2013 ; 31 :1970 –1976 .23610113\n\n",
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"mesh_terms": "D000368:Aged; D000903:Antibiotics, Antineoplastic; D001706:Biopsy; D058617:Composite Lymphoma; D004317:Doxorubicin; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D011092:Polyethylene Glycols; D012074:Remission Induction; D012878:Skin Neoplasms; D014057:Tomography, X-Ray Computed",
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"title": "Pegylated liposomal-encapsulated doxorubicin in cutaneous composite lymphoma: A case report.",
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"abstract": "BACKGROUND\nWe present a case of a suspected tranexamic acid-related bilateral pulmonary embolism in a healthy and active middle-aged woman who was receiving tranexamic acid for menorrhagia with no other known significant risk factors for thromboembolism.\n\n\nMETHODS\nA 46-year-old Asian woman who was usually fit and well with no remarkable past medical history except for menorrhagia of 1-year duration for which she was receiving tranexamic acid presented to our accident and emergency department with a 2-week history of intermittent pleuritic central chest pain. She was reviewed and discharged to home with a diagnosis of musculoskeletal pain on two hospital visits because she had no significant risk factors for thromboembolism and her workup investigation results for pulmonary embolism and other differential diagnoses were largely unremarkable. On her third visit to the emergency ambulatory clinic with recurring symptoms of pleuritic chest pain, a pulmonary computed tomographic angiogram confirmed bilateral subsegmental pulmonary embolism.\n\n\nCONCLUSIONS\nThis case report reinforces the possible increased risk of thromboembolism in patients receiving tranexamic acid.",
"affiliations": "East Kent Hospitals University NHS Foundation Trust, William Harvey Hospital, Ashford, Kent, UK. eijaopo@yahoo.com.;University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK.;East Kent Hospitals University NHS Foundation Trust, William Harvey Hospital, Ashford, Kent, UK.",
"authors": "Ijaopo|Ezekiel Oluwasayo|EO|;Ijaopo|Ruth Oluwasolape|RO|;Adjei|Sampson|S|",
"chemical_list": "D014148:Tranexamic Acid",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2545\n10.1186/s13256-020-02545-z\nCase Report\nBilateral pulmonary embolism while receiving tranexamic acid: a case report\nIjaopo Ezekiel Oluwasayo eijaopo@yahoo.comezekiel.ijaopo@nhs.net 1 Ijaopo Ruth Oluwasolape r.ijaopo@nhs.net 2 Adjei Sampson sampson.adjei@nhs.net 1 1 grid.417122.30000 0004 0398 7998East Kent Hospitals University NHS Foundation Trust, William Harvey Hospital, Ashford, Kent UK \n2 grid.415490.d0000 0001 2177 007XUniversity Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH UK \n6 11 2020 \n6 11 2020 \n2020 \n14 2125 5 2020 2 10 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nWe present a case of a suspected tranexamic acid–related bilateral pulmonary embolism in a healthy and active middle-aged woman who was receiving tranexamic acid for menorrhagia with no other known significant risk factors for thromboembolism.\n\nCase presentation\nA 46-year-old Asian woman who was usually fit and well with no remarkable past medical history except for menorrhagia of 1-year duration for which she was receiving tranexamic acid presented to our accident and emergency department with a 2-week history of intermittent pleuritic central chest pain. She was reviewed and discharged to home with a diagnosis of musculoskeletal pain on two hospital visits because she had no significant risk factors for thromboembolism and her workup investigation results for pulmonary embolism and other differential diagnoses were largely unremarkable. On her third visit to the emergency ambulatory clinic with recurring symptoms of pleuritic chest pain, a pulmonary computed tomographic angiogram confirmed bilateral subsegmental pulmonary embolism.\n\nConclusion\nThis case report reinforces the possible increased risk of thromboembolism in patients receiving tranexamic acid.\n\nKeywords\nPulmonary embolismVenous thromboembolismTranexamic acidAntifibrinolytic therapyCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nPulmonary embolism (PE) is a common medical condition and remains life-threatening despite advances in its diagnosis and treatment past few decades. The incidence of PE is estimated to be approximately 60 to 70 per 100,000 in the general population [1]. However, the true incidence is far more than what is reported, because PE remains one of the most commonly underdiagnosed medical problems. It is believed to be responsible for 100,000 deaths per year in the United States [2]. In Europe, cases of PE affect 6 to 20 per 10,000 people per year, and 7–11% of people with PE do not survive [3]. If untreated, mortality of acute PE is as high as 30%, whereas the death rate of diagnosed and treated PE is 8% [1]. The confirmation of acute PE diagnosis via lung imaging relies on the history, physical examination, and a high index of clinical suspicion [4]. Prompt diagnosis and treatment are therefore imperative to reduce the morbidity and mortality of PE. This case report provides increased awareness for clinicians on how a commonly prescribed tranexamic acid (TXA) can be a potential cause of PE, particularly in patients considered to have very low risk factors for venous thromboembolism (VTE).\n\nCase presentation\nBackground\nWe present a case of a 46-year-old Asian woman who was usually fit and well except for a 1-year history of menorrhagia prior to her initial presentation in our emergency department (ED). Her menorrhagia was due to multiple fibroids diagnosed via transvaginal ultrasound of the pelvis in 2018, which showed a multifibroid uterus with normal-appearing ovaries and no obvious adnexal cysts/masses. She was then started on TXA (1 g three times daily as required) and mefenamic acid (500 mg three times daily as required) to be taken during her menstrual period to reduce excessive bleeding and pain, respectively. She claimed she did not have to take the TXA (and mefenamic acid) during all her menstrual periods, because she believed the TXA was not required on many occasions. She was physically healthy, of normal weight (body mass index of 22 kg/m2), never smoked cigarettes or drank alcohol, and had no previous history of DVT or PE. She also denied using any form of contraception and had no significant family history of clotting disorders or cancer, but she claimed her mother had type 2 diabetes mellitus and had died of myocardial infarction.\n\nFirst hospital visit (autumn 2019)\nOur patient presented to our ED with a 2-week history of noncardiac-type central chest pain that was nonradiating, pleuritic, and intermittent with occasional shortness of breath on exertion. She had no history of diaphoresis, nausea, vomiting, cough, fever, or any infective symptoms. She had no history of recent long-distance journey or any other significant risk factors suggestive of VTE.\n\nExcept for a fast heart rate (119 beats/minute), her vital signs, including blood pressure and physical examination, were within normal limits. Her chest x-ray was normal, and her Electrocardiogram (ECG) showed no dynamic changes except for sinus tachycardia. Her D-dimer was marginally raised at 0.66 μg/ml (normal range, 0.05 to 0.50 μg/ml), whereas her cardiac troponin I finding was negative. Other routine blood test results, including electrolytes, complete blood count, inflammatory markers, and clotting screen, were within normal limits. She was diagnosed with possible anxiety/musculoskeletal pain and sent home with analgesics and a planned follow-up review of her symptoms in the emergency ambulatory clinic (EAC) after 1 week.\n\nFollow-up review\nAbout 2 weeks after her initial presentation, the patient came back for follow-up review in the EAC as planned. She claimed she still experienced pleuritic chest pain on and off in addition to a new intermittent interscapular pain. A repeat D-dimer test result came back negative (0.35 μg/ml; normal range, 0.05 to 0.50 μg/ml). Likewise, results of her physical examination and recheck of her routine blood tests, including troponin I, clotting screen, and inflammatory markers, were all within normal limits. She was reassured and discharged to home after a (repeat) normal chest x-ray finding. She was informed that a computed tomographic (CT) pulmonary angiogram (CTPA) or ventilation/perfusion measurement was not required.\n\nThird visit\nAbout 2 months after the follow-up review, our patient re-presented to our ED with symptoms of pleuritic central chest pain and intermittent shortness of breath on moderate exertion. She claimed her symptoms were similar to her previous presentations. Further history was taken to exclude infection, cardiac-related problems, and common risk factors for PE, among other illnesses, but the findings were unremarkable. The patient said she last took her TXA for 2 days before the index presentation. Her physical examination results, including respiratory and cardiovascular examinations, were as usual within normal limits. Her vital signs were normal except for tachycardia (pulse rate of 113 beats/minute). Her blood workup showed slightly raised D-dimer (0.93 μg/ml), but other routine blood results for infection, thyroid function, electrolytes, clotting screen, complete blood count, and cardiac biomarkers were again all within normal limits. Her ECG showed sinus tachycardia, but her chest x-ray finding again was normal. Wells Score for PE was 4.5. We had a high suspicion to exclude PE in view of her symptoms and TXA use. So, a therapeutic dose of enoxaparin was started, and we placed an order for CTPA. The CTPA report 2 days later demonstrated filling defects in the distal subsegmental branches of the left lower and right upper segments that confirmed bilateral subsegmental PE (see Figs. 1 and 2).\nFig. 1 Left lower lobe subsegmental PE\n\nFig. 2 Right upper lobe subsegmental PE\n\n\n\nTreatment\nFollowing the confirmation of PE diagnosis on the basis of imaging, our patient’s treatment dose of enoxaparin was changed to apixaban. The planned duration of treatment with apixaban was 3 months; however, this is usually subject to evaluation during patient follow-up in the anticoagulation clinic. Our patient was then advised to stop TXA and informed to use other painkillers, such as paracetamol and/or codeine phosphate, for pain control instead of mefenamic acid due to increased risk of bleeding caused by drug–drug interactions with apixaban.\n\nFollow-up and referrals\nAn outpatient CT scan of the patient’s abdomen and pelvis (CT-AP) was arranged and obtained within 2 weeks after PE diagnosis to rule out any occult malignancy. The CT-AP scan report finding was normal. The patient was subsequently referred for routine follow-up in the anticoagulation clinic within the hematology unit (as per our hospital policy). In the anticoagulation clinic, a patient with acute VTE would usually undergo further evaluation as may be necessary including workup for thrombophilia screen and a decision on duration of anticoagulation treatment is made.\n\nAfter 1-month follow-up of the patient over the telephone, she claimed her pleuritic chest pain has improved significantly and her menorrhagia and menstrual pain remained stable. However, about 11 weeks into the treatment with apixaban, while the patient was under follow-up in the anticoagulation clinic, she was sent for a repeat CTPA due to new-onset cough and breathlessness on exertion together with a raised D-dimer of 0.76. The repeat CTPA scan report showed that the PE noted seen on the previous scan had resolved, and no evidence of a new PE was seen, but there was new consolidation in the right lung. She was treated accordingly with appropriate antibiotics with a good clinical response. Following the resolution of symptoms, the decision was then made in the anticoagulation clinic that thrombophilia screening was no longer indicated in the patient at that time.\n\nDiscussion\nTXA is a generally well tolerated, safe, and effective drug commonly used in the prevention and treatment of excessive bleeding caused by medical, surgical, and postsurgical conditions for which antifibrinolytic therapy is appropriate [5]. It works by directly blocking plasmin formation, displaces plasminogen from the fibrin surface, and has an anti-inflammatory action that occurs through the inhibition of plasmin-mediated activation of complement, monocytes, and neutrophils [6].\n\nAlthough it has been reported that TXA is linked to the development of thromboembolic events, some studies have claimed it does not increase the risk of venous or arterial thrombotic complications [7–10]. In contrast, several other studies have presented concerns about the possible association of TXA with development of VTE [11–14]. A newly published TXA risk evaluation in combat casualties study in trauma patients with severe injuries who were prescribed TXA reported a 3% increased chance of VTE and 9.4% higher odds of PE [15].\n\nIn our patient, TXA appeared to be the likely cause of the PE because no other significant risk factor for PE was identified. The empirical association between PE and TXA in our patient was further buttressed by the negative finding of PE on repeat CTPA as well as the resolution of clinical symptoms after TXA was stopped. This latter statement probably explained why the Hematology team in anticoagulation clinic concluded that thrombophilia screen was no longer indicated in the patient.\n\nIt is important to state that thrombophilia screening is not part of routine workup investigations for diagnosing VTE. However, following an acute diagnosis of bilateral PE in our patient, thrombophilia screening was not done immediately, because research evidence shows that thrombophilia screening results are unreliable in the acute phase of an illness such as thrombosis and also during treatment with an oral anticoagulant. Hence, this explains our local hospital policy to refer all patients with newly diagnosed VTE to the anticoagulation clinic for further workup as required by the hematology team.\n\nFurthermore, the absence of significant risk factors for PE and negative D-dimer probably explained why our patient was reassured and discharged to home during her first and second visits, to the ED and EAC, respectively. It is important to know that TXA can alter D-dimer test results, causing false-negative results [14, 16], and this was probably the case during the second hospital visit of our patient, when her D-dimer test result came back negative. A negative D-dimer finding does not completely exclude VTE diagnosis, particularly when there are suggestive clinical histories and signs of VTE [17, 18]. This case report reiterates the need for healthcare practitioners to have a high index of clinical suspicion for PE when patients taking TXA present with pleuritic chest pain and shortness of breath on exertion, particularly in those considered to have low risk for VTE.\n\nSimilarly, the available information about the side effects of TXA in the British National Formulary (BNF) describes the risk of embolism or thrombosis as rare or very rare [19]. It is possible the potential risk for developing thromboembolic event while receiving TXA is understated. Recent evidence derived from a retrospective study that investigated the association between TXA and VTE in trauma patients showed that TXA was associated with a greater than threefold increased risk for VTE [20]. Although the odds of developing VTE when taking TXA may be uncommon, it may probably not be as rare or very rare as claimed in the BNF. Some studies that report no differences in thrombotic outcomes in patients taking TXA are probably underpowered to identify thrombotic complications or have short duration of follow-up [21].\n\nOur patient experienced some functional limitations and decreased quality of life with delayed PE diagnosis. She would have continued taking TXA without caution and could have been at risk of developing more serious PE complications, such as chronic thromboembolic pulmonary hypertension, life-threatening acute right (heart) ventricular failure, pulmonary infarction, and cardiac arrest, among other problems [22–24]. Worse still, this woman could have been sent home after the third hospital visit with a false reassurance that her symptoms were likely musculoskeletal pain following the absence of significant risk factors for PE. One can only wonder how many people like our patient might have had a delayed or missed diagnosis of thromboembolic event.\n\nConclusion\nThis case report buttresses previous studies and reinforces the possible association of VTE risk in patients receiving TXA. Although the effectiveness of TXA in treating various medical and surgical conditions cannot be overemphasized, it is imperative that every patient started on TXA be informed of the risk of thromboembolism and be made aware of symptoms suggestive of VTE to enable reporting of symptoms. Also, due to TXA thromboembolic adverse effects, TXA should not be prescribed for patients with significant risk factors for thromboembolic disease, except when the benefit is deemed to outweigh its risk [25]. Further large prospective studies are required to clarify the true risk of VTEs while receiving TXA.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors extend very special thanks to John Hodson of Bell Library, Royal Wolverhampton NHS Trust, Wolverhampton, UK, for his assistance with the sorting out of the references.\n\nAuthors’ contributions\nEOI prepared the Case presentation section and wrote the Discussion and Conclusion sections. ROI wrote the Introduction section and contributed to the discussion. SA was involved in patient management and participated in preparing the Case presentation. All authors proofread and agreed to the final version of the manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nThis study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Bĕlohlávek J Dytrych V Linhart A Pulmonary embolism, part I: epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism Exp Clin Cardiol 2013 18 129 138 23940438 \n2. Turetz M Sideris AT Friedman OA Triphathi N Horowitz JM Epidemiology, pathophysiology, and natural history of pulmonary embolism Semin Intervent Radiol 2018 35 92 98 10.1055/s-0038-1642036 29872243 \n3. Pulmonary vascular disease. In European lung white book. Sheffield: European Respiratory Society; European Lung Foundation; 2013–2020. https://www.erswhitebook.org/chapters/pulmonary-vascular-disease/. Accessed 7 Apr 2020.\n4. Ishaaya E Tapson VF Advances in the diagnosis of acute pulmonary embolism F1000Res 2020 9 F1000 Faculty Rev-44 10.12688/f1000research.21347.1 \n5. Pabinger I Fries D Schochl H Streif W Toller W Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis Wien Klin Wochenschr 2017 129 303 316 10.1007/s00508-017-1194-y 28432428 \n6. Reed MR Woolley LT Uses of tranexamic acid Cont Educ Anaesth Crit Care Pain 2015 15 32 37 10.1093/bjaceaccp/mku009 \n7. Sundstrom A Seaman H Kieler H Alfredsson L The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case-control study using the General Practice Research Database BJOG 2009 116 91 97 10.1111/j.1471-0528.2008.01926.x 19016686 \n8. Klaassen RA Selles CA van den Berg JW Poelman MM van der Harst E Tranexamic acid therapy for postoperative bleeding after bariatric surgery BMC Obes 2018 5 36 10.1186/s40608-018-0213-5 30524741 \n9. Roberts I Shakur H Coats T Hunt B Balogun E Barnetson L Cook L Kawahara T Perel P Prieto-Merino D The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients Health Technol Assess 2013 17 10 1 79 10.3310/hta17100 \n10. Chornenki NLJ Um KJ Mendoza PA Samienezhad A Swarup V Chai-Adisaksopha C Siegal DM Risk of venous and arterial thrombosis in non-surgical patients receiving systemic tranexamic acid: A systematic review and meta-analysis Thromb Res 2019 179 81 86 10.1016/j.thromres.2019.05.003 31100632 \n11. Woo KS Tse LK Woo JL Vallance-Owen J Massive pulmonary thromboembolism after tranexamic acid antifibrinolytic therapy Br J Clin Pract 1989 43 465 466 2611113 \n12. Taparia M Cordingley FT Leahy MF Pulmonary embolism associated with tranexamic acid in severe acquired haemophilia Eur J Haematol 2002 68 307 309 10.1034/j.1600-0609.2002.01607.x 12144537 \n13. Krivokuca I Lammers JW Recurrent pulmonary embolism associated with a hemostatic drug: tranexamic acid Clin Appl Thromb Hemost 2011 17 106 107 10.1177/1076029609340902 19833620 \n14. Salam A King C Orhan O Mak V The great deception: tranexamic acid and extensive pulmonary emboli BMJ Case Rep 2013 2013 bcr2012007808 10.1136/bcr-2012-007808 \n15. Adair KE Patrick JD Kliber EJ Peterson MN Holland SR TXA (tranexamic acid) risk evaluation in combat casualties (TRECC) Trauma Surg Acute Care Open 2020 5 e000353 10.1136/tsaco-2019-000353 32072015 \n16. Pong RP Leveque JA Edwards A Yanamadala V Wright AK Herodes M Sethi RK Effect of tranexamic acid on blood loss, D-dimer, and fibrinogen kinetics in adult spinal deformity surgery J Bone Joint Surg Am 2018 100 758 764 10.2106/JBJS.17.00860 29715224 \n17. Nordenholz KE Zieske M Dyer DS Hanson JA Heard K Radiologic diagnoses of patients who received imaging for venous thromboembolism despite negative D-dimer tests Am J Emerg Med 2007 25 1040 1046 10.1016/j.ajem.2007.03.011 18022499 \n18. Stein CE Keijsers CJ Bootsma JE Schouten HJ Missed diagnosis of pulmonary embolism with age-adjusted D-dimer cut-off value Age Ageing 2016 45 910 911 10.1093/ageing/afw132 27496940 \n19. National Institute for Health and Care Excellence (NICE) British National Formulary (BNF): tranexamic acid: side-effects 2020 London BNF/NICE \n20. Myers SP Kutcher ME Rosengart MR Sperry JL Peitzman AB Brown JB Neal MD Tranexamic acid administration is associated with an increased risk of posttraumatic venous thromboembolism J Trauma Acute Care Surg 2019 86 20 27 10.1097/TA.0000000000002061 30239375 \n21. Houston BL Uminski K Mutter T Rimmer E Houston DS Menard CE Garland A Ariano R Tinmouth A Abou-Setta AM Efficacy and safety of tranexamic acid in major non-cardiac surgeries at high risk for transfusion: a systematic review and meta-analysis Transfus Med Rev 2020 34 51 62 10.1016/j.tmrv.2019.10.001 31982293 \n22. Pengo V Lensing AW Prins MH Marchiori A Davidson BL Tiozzo F Albanese P Biasiolo A Pegoraro C Iliceto S Prandoni P Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism N Engl J Med 2004 350 2257 2264 10.1056/NEJMoa032274 15163775 \n23. Klok FA van der Hulle T den Exter PL Lankeit M Huisman MV Konstantinides S The post-PE syndrome: a new concept for chronic complications of pulmonary embolism Blood Rev 2014 28 221 226 10.1016/j.blre.2014.07.003 25168205 \n24. Keller K Tesche C Gerhold-Ay A Nickels S Klok FA Rappold L Hasenfuss G Dellas C Konstantinides SV Lankeit M Quality of life and functional limitations after pulmonary embolism and its prognostic relevance J Thromb Haemost 2019 17 1923 1934 10.1111/jth.14589 31344319 \n25. Savage R Thrombosis with tranexamic acid for menorrhagia Prescriber Update 2003 24 26 27\n\n",
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"keywords": "Antifibrinolytic therapy; Case report; Pulmonary embolism; Tranexamic acid; Venous thromboembolism",
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"title": "Bilateral pulmonary embolism while receiving tranexamic acid: a case report.",
"title_normalized": "bilateral pulmonary embolism while receiving tranexamic acid a case report"
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"abstract": "Multiple myeloma (MM) and primary systemic light chain amyloidosis (AL) are both chronic plasma cell dyscrasias with different clinical expression but limited treatment options for relapsed refractory disease. We report the effect of the addition of clarithromycin on 31 MM and 17 AL with relapsed or refractory disease who had an insufficient response or disease progression while on an IMiD based therapy. In this high risk population, hematological response was reported in 48% of MM patients and 94% of AL patients. Responses were reported early in both groups (median 35 days) and were more sustained in AL patients. Adverse events were common and included mostly grade 1-2 fatigue, infections and abdominal discomfort. Cytopenias were common and cardiac complications were rare in both MM and AL patients. Clarithromycin-IMiD combination therapy appears to be both effective and safe in progressive MM and primarily in AL patients, although a prospective clinical trial is warranted to validate these results. Am. J. Hematol. 92:131-135, 2017. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Shaare-Zedek Medical Center, Jerusalem, Israel.;Department of Hematology, Rambam Medical Center, Haifa, Israel.;Barzilai Medical Center, Ashkelon, Israel.;Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.",
"authors": "Shaulov|Adir|A|;Ganzel|Chezi|C|;Benyamini|Noam|N|;Barshay|Yossef|Y|;Goldschmidt|Neta|N|;Lavie|David|D|;Libster|Diana|D|;Gural|Alex|A|;Avni|Batia|B|;Gatt|Moshe E|ME|",
"chemical_list": "D007147:Immunoglobulin Light Chains; D011500:Protein Synthesis Inhibitors; D017291:Clarithromycin",
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"issue": "92(2)",
"journal": "American journal of hematology",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000686:Amyloidosis; D000971:Antineoplastic Combined Chemotherapy Protocols; D017291:Clarithromycin; D018450:Disease Progression; D005221:Fatigue; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains; D000075363:Immunoglobulin Light-chain Amyloidosis; D007239:Infections; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011500:Protein Synthesis Inhibitors; D012008:Recurrence; D016879:Salvage Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "7610369",
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"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
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"title": "Progressive refractory light chain amyloidosis and multiple myeloma patients are responsive to the addition of clarithromycin to IMiD based therapy.",
"title_normalized": "progressive refractory light chain amyloidosis and multiple myeloma patients are responsive to the addition of clarithromycin to imid based therapy"
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"abstract": "BACKGROUND\nDiabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.\n\n\nMETHODS\nThe study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.\n\n\nRESULTS\nBody mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).\n\n\nCONCLUSIONS\nDespite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.",
"affiliations": "Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.;Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Beijing Innovation Alliance of TB Diagnosis and Treatment, Beijing, 101149, China.;Beijing Innovation Alliance of TB Diagnosis and Treatment, Beijing, 101149, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China.;Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.;Department of Tuberculosis, Wuhan Pulmonary Hospital, Wuhan, 430030, China.;Department of Tuberculosis, Wuhan Pulmonary Hospital, Wuhan, 430030, China.;Department of Tuberculosis, Shenzhen Third People's Hospital, Shenzhen, 518000, China.;The Fifth People's Hospital of Suzhou, Suzhou, 215000, China.;Tianjin Haihe Hospital, Tianjin, 300000, China.;Anhui Chest Hospital, Hefei, 230000, China.;Anhui Chest Hospital, Hefei, 230000, China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.;Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007, China. 1113284116@qq.com.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China. liuyuhong0516@126.com.",
"authors": "Shi|Li|L|;Gao|Jingtao|J|;Gao|Mengqiu|M|;Deng|Ping|P|;Chen|Shu|S|;He|Minfu|M|;Feng|Wenjun|W|;Yang|Xiaoyun|X|;Huang|Yunhui|Y|;He|Fang|F|;Hu|Yumeng|Y|;Lei|Liping|L|;Li|Xuelian|X|;Du|Juan|J|;Hu|Xiaomeng|X|;Liu|Zhi|Z|;Tang|Peijun|P|;Han|Junfeng|J|;Wang|Hua|H|;Han|Yi|Y|;Shu|Wei|W|;Sun|Yuxian|Y|;Pei|Yi|Y|;Liu|Yuhong|Y|",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.1007/s40121-021-00396-9",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n33515206\n396\n10.1007/s40121-021-00396-9\nOriginal Research\nInterim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study\nShi Li 1\nGao Jingtao 2\nGao Mengqiu 3\nDeng Ping 1\nChen Shu 4\nHe Minfu 4\nFeng Wenjun 1\nYang Xiaoyun 1\nHuang Yunhui 1\nHe Fang 1\nHu Yumeng 1\nLei Liping 1\nLi Xuelian 3\nDu Juan 5\nHu Xiaomeng 5\nLiu Zhi 6\nTang Peijun 7\nHan Junfeng 8\nWang Hua 9\nHan Yi 9\nShu Wei 2\nSun Yuxian 2\nPei Yi 1113284116@qq.com\n\n1\nLiu Yuhong liuyuhong0516@126.com\n\n2\n1 grid.412017.1 0000 0001 0266 8918 Department of Tuberculosis, Changsha Central Hospital, University of South China, Changsha, 410007 China\n2 grid.24696.3f 0000 0004 0369 153X Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149 China\n3 grid.24696.3f 0000 0004 0369 153X Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149 China\n4 Beijing Innovation Alliance of TB Diagnosis and Treatment, Beijing, 101149 China\n5 grid.508271.9 Department of Tuberculosis, Wuhan Pulmonary Hospital, Wuhan, 430030 China\n6 grid.410741.7 Department of Tuberculosis, Shenzhen Third People’s Hospital, Shenzhen, 518000 China\n7 grid.490559.4 The Fifth People’s Hospital of Suzhou, Suzhou, 215000 China\n8 grid.417026.6 Tianjin Haihe Hospital, Tianjin, 300000 China\n9 Anhui Chest Hospital, Hefei, 230000 China\n30 1 2021\n30 1 2021\n3 2021\n10 1 457470\n13 10 2020\n5 1 2021\n© The Author(s) 2021\nOpen Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.\nIntroduction\n\nDiabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.\n\nMethods\n\nThe study of patients with MDR/XDR-TB with or without DM (enrolled February 2018–September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.\n\nResults\n\nBody mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28–63) vs. 56 days (IQR 28–84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).\n\nConclusion\n\nDespite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s40121-021-00396-9.\n\nKeywords\n\nAdverse event\nBedaquiline\nDiabetes\nMultidrug resistant\nTuberculosis\nScience and technology bureau Project of Changsha2018-kq1801145 Shi Li Hunan Administration of Traditional Chinese Medicine201890 Shi Li Scientific research project of Hunan provincial health commission20201439 Shi Li issue-copyright-statement© The Author(s) 2021\n==== Body\nKey Summary Points\n\nPatients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.\t\nPatients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.\t\nAll patients had acceptable safety and drug tolerability after 24 weeks of treatment.\t\n\nDigital Features\n\nThis article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.\n\nIntroduction\n\nIn 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].\n\nBedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.\n\nA cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.\n\nMethods\n\nStudy Participants\n\nThis retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.\n\nPatients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.\n\nTreatment Regimen\n\nAccording to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.\n\nBackground regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.\n\nProlongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.\n\nTreatment Evaluation\n\nPatients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].\n\nPatient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.\n\nStatistical Analysis\n\nQualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.\n\nPatients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.\n\nCompliance with Ethics Guidelines\n\nThe study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.\n\nResults\n\nBaseline Characteristics of Patients with MDR/XDR-TB with and Without DM\n\nOf 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline\n\nCharacteristics\tDM group (n = 107)\tNon-DM group (n = 107)\tP value\t\nMean age, years (SD)\t49.8 ± 10.5\t49.3 ± 9.7\t0.736\t\nMale, no. (%)\t98 (91.6)\t98 (91.6)\t> 0.999\t\nMean BMI, kg/m2 (SD)\t23.29 ± 3.9\t20.5 ± 3.6\t< 0.001\t\nPatients with previous anti-TB treatment history, no. (%)\t90 (84.1)\t96 (89.7)\t0.224\t\nDST profile, no. (%)\t\t\t> 0.999\t\n MDR-TB\t36 (33.6)\t36 (33.6)\t\t\n Pre-XDR-TB\t39 (36.5)\t39 (36.5)\t\t\n XDR-TB\t32 (29.9)\t32 (29.9)\t\t\nMedian duration of TB, months (IQR)\t30.0 (9.0–72.0)\t44.0 (12.0–110.0)\t0.170\t\nSite of TB focus, no. (%)\t\t\t0.252\t\n Pulmonary only\t103 (96.3)\t98 (91.6)\t\t\n Pulmonary and extrapulmonary\t4 (3.7)\t9 (8.4)\t\t\nLung cavities, no. (%)\t\t\t0.010\t\n Without any cavities\t14 (13.1)\t29 (27.1)\t\t\n With at least 1 cavity\t93 (86.9)\t78 (72.9)\t\t\nComorbidities, no. (%)\t\n Heart disease\t4 (3.7)\t3 (2.8)\t0.701\t\n Hepatitis infection\t17 (15.9)\t31 (29.0)\t0.022\t\nMedian duration of DM, months (IQR)\t72 (20–120)\t–\tN/A\t\nDM medications, no. (%)\t\t–\tN/A\t\n Insulin\t56 (52.3)\t\t\t\n Oral hypoglycemica\t31 (29.0)\t\t\t\n Both\t13 (12.2)\t\t\t\n None\t7 (6.5)\t\t\t\nMedian fasting plasma glucose, mmol/L (IQR)\t7.7 (5.7–9.5)\t–\tN/A\t\nMedian glycosylated hemoglobin (IQR)\t7.3 (6.2–8.7)\t–\tN/A\t\nMean blood albumin, g/L (SD)\t39.7 ± 5.9\t38.7 ± 5.0\t0.164\t\nBMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable\n\naIncluded metformin, acarbose, and thiazolidinediones\n\nRegarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.\n\nOptimal Background Anti-TB Drug Regimen\n\nAs per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM\n\nDrugs, no. (%)\tDM group (n = 107)\tNon-DM group (n = 107)\tP value\t\nMoxifloxacin\t51 (47.7)\t59 (55.1)\t0.274\t\nLevofloxacin\t10 (9.3)\t11 (10.3)\t0.818\t\nLinezolid\t97 (90.7)\t96 (89.7)\t0.818\t\nClofazimine\t77 (72.0)\t69 (64.5)\t0.240\t\nCycloserine\t91 (85.0)\t89 (83.2)\t0.708\t\nEthambutol\t12 (11.2)\t9 (8.4)\t0.491\t\nPyrazinamide\t24 (22.4)\t19 (17.8)\t0.394\t\nProtionamide\t49 (45.8)\t55 (51.4)\t0.412\t\nAmikacin\t31 (29.0)\t42 (39.3)\t0.113\t\nCapreomycin\t22 (20.6)\t25 (23.4)\t0.620\t\np-Aminosalicylic acid\t43 (40.2)\t33 (30.8)\t0.153\t\nPasiniazid\t2 (1.9)\t2 (1.9)\t> 0.999\t\nAmoxicillin/clavulanic acid\t12 (11.2)\t11 (10.3)\t0.825\t\nStreptomycin\t1 (0.9)\t0 (0)\t> 0.999\t\nClarithromycin\t3 (2.8)\t0 (0)\t0.246\t\nHigh-dose isoniazid\t2 (1.9)\t1 (0.93)\t> 0.999\t\nMedian no. of drugs in background regimen, (IQR)\t5 (4–5)\t5 (4–5)\t0.364\t\n\nInterim Sputum Culture Conversion and Treatment Outcomes\n\nComparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups\n\nSputum conversion\tDM group\tNon-DM group\tP value\t\nCulture conversion at 8th week, n/N (%)\t60/75 (80.0)\t48/59 (81.4)\t0.844\t\nCulture conversion at 24th week, n/N (%)\t66/69 (95.6)\t54/55 (98.2)\t0.629a\t\nTime to culture conversion, days\t56.0 (28–63)\t56.0 (28–84)\t0.876\t\naFisher’s exact test is used\n\nAmong the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).\n\nAccording to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks\n\nOn the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups\n\nInterim treatment outcome, no. (%)\tDM group (n = 107)\tNon-DM group (n = 107)\tP value\t\nFavorable outcome\t97 (90.7)\t100 (93.5)\t0.448\t\n Sputum culture conversion\t66 (61.7)\t54 (50.5)\t\n Completion\t31 (29.0)\t46 (43.0)\t\nUnfavorable outcome\t10 (9.3)\t7 (6.5)\t0.448\t\n Death\t0 (0.0)\t0 (0.0)\t\n Transfer out\t4 (3.7)\t4 (3.7)\t\n Default\t3 (2.8)\t2 (1.9)\t\n Sputum culture reversion\t3 (2.8)\t1 (0.9)\t\n\nMultivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).\n\nSafety\n\nIn the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).\n\nIn the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups\n\nAdverse event, no. (%)\tDM group (n = 107)\tNon-DM group (n = 107)\tP value\t\nElectrocardiogram abnormality\t48 (44.9)\t49 (45.8)\t0.891\t\n QTcF abnormalities\t42 (39.3)\t43 (40.2)\t\t\n Othersa\t6 (5.6)\t6 (5.6)\t\t\nHepatotoxicity\t41 (38.3)\t18 (16.8)\t< 0.001\t\nRenal injury\t13 (12.1)\t8 (7.5)\t0.251\t\nOptic neuritis\t7 (6.5)\t6 (5.6)\t0.775\t\nOtotoxicity\t4 (3.7)\t6 (5.6)\t0.746\t\nHematological injury\t12 (11.2)\t12 (11.2)\t> 0.999\t\nGastrointestinal symptoms response\t11 (10.3)\t4 (3.7)\t0.108\t\nPeripheral neuropathy\t4 (3.7)\t14 (13.1)\t0.027\t\nDermatologic reaction\t0 (0)\t2 (1.9)\t0.498\t\nArthralgia\t3 (2.8)\t0 (0)\t0.246\t\nHemoptysis\t5 (4.7)\t2 (1.9)\t0.442\t\nPsychiatric symptoms\t6 (5.6)\t3 (2.8)\t0.496\t\nElectrolyte disturbance\t4 (3.7)\t1 (0.9)\t0.369\t\nHeadache and dizziness\t6 (5.6)\t0 (0)\t0.029\t\nFever\t2 (1.9)\t0 (0)\t0.498\t\nOthersb\t4 (3.7)\t1 (0.9)\t0.369\t\naIncluding arrhythmias, T wave changes\n\nbIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction\n\nTable 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups\n\nQTcF, ms\tDM group (n = 107)\tNon-DM group (n = 107)\tP value\t\nMean baseline QTcF (SD)\t412.1 ± 22.4\t404.6 ± 24.7\t0.021\t\nMean QTcF during treatment (SD)\t424.9 ± 28.3\t420.7 ± 28.6\t0.005\t\nPatients with at least one QTcF greater than 450 ms, no. (%)\t42 (39.3)\t43 (40.2)\t0.889\t\nPatients with at least one QTcF increment from baseline greater than 60 ms, no. (%)\t15 (14.0)\t20 (18.7)\t0.355\t\nPatients with at least one QTcF greater than 500 ms, no. (%)\t4 (3.7)\t4 (3.7)\t> 0.999\t\nQTcF QT interval with Fridericia correction\n\nNumbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.\n\nDiscussion\n\nFindings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.\n\nIn this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].\n\nIt is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.\n\nMany AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.\n\nBDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.\n\nIn 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.\n\nRecently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].\n\nThis study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.\n\nConclusion\n\nThis study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)\n\nAcknowledgements\n\nWe expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.\n\nFunding\n\nThis work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthors’ Contributions\n\nLS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.\n\nDisclosures\n\nLi Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nThe study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.\n\nData Availability\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nJingtao Gao and Mengqiu Gao are the co-first authors for this article.\n==== Refs\nReferences\n\n1. International Diabetes Foundation Diabetes atlas 2019 9 Brussels IDF\n2. World Health Organization. Global tuberculosis report, 2019. WHO/CDS/TB/2019.20. Geneva: WHO, 2019.\n3. Lutfiana NC van Boven JFM Masoom Zubair MA Pena MJ Alffenaar JC Diabetes mellitus comorbidity in patients enrolled in tuberculosis drug efficacy trials around the world: a systematic review Br J Clin Pharmacol 2019 85 7 1407 1417 10.1111/bcp.13935 30908689\n4. Huangfu P Ugarte-Gil C Golub J Pearson F Critchley J The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis Int J Tuberc Lung Dis 2019 23 7 783 796 10.5588/ijtld.18.0433 31439109\n5. Liu Q Li W Xue M Diabetes mellitus and the risk of multidrug resistant tuberculosis: a meta-analysis Sci Rep 2017 7 1 1090 10.1038/s41598-017-01213-5 28439071\n6. Kang YA Kim SY Jo KW Impact of diabetes on treatment outcomes and long-term survival in multidrug-resistant tuberculosis Respiration 2013 86 6 472 478 10.1159/000348374 23689646\n7. Perez-Navarro LM Restrepo BI Fuentes-Dominguez FJ The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes Tuberculosis (Edinb) 2017 103 83 91 10.1016/j.tube.2017.01.006 28237037\n8. Munoz-Torrico M Caminero Luna J Migliori GB Comparison of bacteriological conversion and treatment outcomes among MDR-TB patients with and without diabetes in Mexico: preliminary data Rev Port Pneumol (2006) 2017 23 1 27 30 28043788\n9. van Crevel R Dockrell HM TANDEM: understanding diabetes and tuberculosis Lancet Diabetes Endocrinol 2014 2 4 270 272 10.1016/S2213-8587(14)70011-7 24703039\n10. WHO. The use of delamanid in the treatment of multidrug-resistant tuberculosis. Interim policy guidance. 2014. http://apps.who.int/iris/bitstream/10665/137334/1/WHO_HTM_TB_2014.23_eng.pdf. Accessed 16 Aug 2016.\n11. Diacon AH Pym A Grobusch M The diarylquinoline TMC207 for multidrug-resistant tuberculosis N Engl J Med 2009 360 23 2397 2405 10.1056/NEJMoa0808427 19494215\n12. Diacon AH Donald PR Pym A Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance Antimicrob Agents Chemother 2012 56 6 3271 3276 10.1128/AAC.06126-11 22391540\n13. Schnippel K Ndjeka N Maartens G Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study Lancet Respir Med 2018 6 9 699 706 10.1016/S2213-2600(18)30235-2 30001994\n14. DAIDS. Division of AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events, version 2.1. 2017. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed 30 Sept 2020.\n15. Dostalek M Akhlaghi F Puzanovova M Effect of diabetes mellitus on pharmacokinetic and pharmacodynamic properties of drugs Clin Pharmacokinet 2012 51 8 481 499 10.1007/BF03261926 22668340\n16. van Heeswijk RPG Dannemann B Hoetelmans RM Bedaquiline: a review of human pharmacokinetics and drug–drug interactions J Antimicrob Chemother 2014 69 9 2310 2318 10.1093/jac/dku171 24860154\n17. Hu M Zheng C Gao F Use of bedaquiline and delamanid in diabetes patients: clinical and pharmacological considerations Drug Des Devel Ther 2016 10 3983 3994 10.2147/DDDT.S121630\n18. Magee MJ Kempker RR Kipiani M Diabetes mellitus is associated with cavities, smear grade, and multidrug-resistant tuberculosis in Georgia Int J Tuberc Lung Dis 2015 19 6 685 692 10.5588/ijtld.14.0811 25946360\n19. Gao M Gao J Xie L Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study Clin Microbiol Infect 2020 10.1016/j.cmi.2020.06.004 32553880\n20. Salhotra VS Sachdeva KS Kshirsagar N Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: an interim analysis Indian J Tuberc 2020 67 1 29 37 10.1016/j.ijtb.2019.10.002 32192613\n21. Borisov SE, Dheda K, Enwerem M, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J. 2017;49(5):1700387.\n22. Kim JH Kwon OJ Kim YS Park MS Hwang S Shim TS Bedaquiline in multidrug-resistant tuberculosis treatment: safety and efficacy in a Korean subpopulation Respir Investig 2020 58 1 45 51 10.1016/j.resinv.2019.08.004\n23. Mbuagbaw L Guglielmetti L Hewison C Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis Emerg Infect Dis 2019 25 5 936 943 10.3201/eid2505.181823 31002070\n24. Muñoz-Torrico M Caminero-Luna J Migliori GB Diabetes is associated with severe adverse events in multidrug-resistant tuberculosis Arch Bronconeumol 2017 53 5 245 250 10.1016/j.arbres.2016.10.021 28089216\n25. Borisov S Danila E Maryandyshev A Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report Eur Respir J. 2019 54 6 1901522 10.1183/13993003.01522-2019 31601711\n26. Olayanju O Esmail A Limberis J A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis Eur Respir J 2020 55 1 1901181 10.1183/13993003.01181-2019 31619478\n27. Franke MF, Khan P, Hewison C, et al. Culture conversion in patients treated with Bedaquiline and/or Delamanid: a prospective multi-country study. Am J Respir Crit Care Med. 2021;203(1):111–19.\n\n",
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"issue": "10(1)",
"journal": "Infectious diseases and therapy",
"keywords": "Adverse event; Bedaquiline; Diabetes; Multidrug resistant; Tuberculosis",
"medline_ta": "Infect Dis Ther",
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"nlm_unique_id": "101634499",
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"pubdate": "2021-03",
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"title": "Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.",
"title_normalized": "interim effectiveness and safety comparison of bedaquiline containing regimens for treatment of diabetic versus non diabetic mdr xdr tb patients in china a multicenter retrospective cohort study"
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"abstract": "Pediatric Castleman disease (CD) is an uncommon and poorly understood disorder of the lymph nodes. Renal failure has not been described in pediatric multicentric CD (MCD). We report four cases, who presented with polyadenopathy, organomegaly, edema and fluid accumulations, high blood pressure, and acute renal failure. In all cases, renal biopsy confirmed diffuse thrombotic microangiopathy. Definitive diagnosis of MCD was made by a biopsy of an affected lymph node located by computer tomography before initiation of corticosteroid therapy. Treatment of CD with corticosteroid therapy and rituximab was rapidly effective without relapse to date.",
"affiliations": "Department of Pediatrics, Centre Hospitalier Universitaire de Rennes, Rennes, France.;Department of Pediatrics, Centre Hospitalier Universitaire Saint Pierre de la Réunion, Saint Pierre, France.;Department of Pediatric Nephrology, Centre Hospitalier Universitaire Necker-Enfant Malades, APHP, Institut Imagine, Université Paris Descartes, Paris, France.;Department of Pediatric Nephrology, Centre Hospitalier Universitaire Robert Debré, assistance publique des hôpitaux de Paris (APHP), Paris, France.;Department of Pediatrics, Centre Hospitalier Universitaire Saint Pierre de la Réunion, Saint Pierre, France.;Department of Pediatric Nephrology, Centre Hospitalier Universitaire Robert Debré, assistance publique des hôpitaux de Paris (APHP), Paris, France.;Department of Pathology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.;Department of Pediatrics, Centre Hospitalier Universitaire de Rennes, Rennes, France.",
"authors": "Cousin|Elie|E|0000-0001-9967-8599;Flodrops|Hugues|H|;Boyer|Olivia|O|;Hogan|Julien|J|;Ruin|Mahe|M|;Couderc|Anne|A|;Goujon|Jean-Michel|JM|;Taque|Sophie|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27045",
"fulltext": null,
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"issn_linking": "1545-5009",
"issue": "65(7)",
"journal": "Pediatric blood & cancer",
"keywords": "acute renal failure; pediatric Castleman disease; thrombotic microangiopathy",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D005871:Castleman Disease; D005260:Female; D006801:Humans; D008297:Male; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27045",
"pmc": null,
"pmid": "29603588",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal failure in pediatric Castleman disease: Four French cases with thrombotic microangiopathy.",
"title_normalized": "renal failure in pediatric castleman disease four french cases with thrombotic microangiopathy"
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"companynumb": "FR-MYLANLABS-2018M1053166",
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"abstract": "OBJECTIVE\nAdministration of infliximab is associated with a well-recognised risk of infusion reactions. Lack of a mechanism-based rationale for their prevention, and absence of adequate and well-controlled studies, has led to the use of diverse empirical administration protocols. The aim of this study is to perform a systematic review of the evidence behind the strategies for preventing infusion reactions to infliximab, and for controlling the reactions once they occur.\n\n\nMETHODS\nWe conducted extensive search of electronic databases of MEDLINE [PubMed] for reports that communicate various aspects of infusion reactions to infliximab in IBD patients.\n\n\nRESULTS\nWe examined full texts of 105 potentially eligible articles. No randomised controlled trials that pre-defined infusion reaction as a primary outcome were found. Three RCTs evaluated infusion reactions as a secondary outcome; another four RCTs included infusion reactions in the safety evaluation analysis; and 62 additional studies focused on various aspects of mechanism/s, risk, primary and secondary preventive measures, and management algorithms. Seven studies were added by a manual search of reference lists of the relevant articles. A total of 76 original studies were included in quantitative analysis of the existing strategies.\n\n\nCONCLUSIONS\nThere is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.",
"affiliations": "Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel levl@clalit.org.il.;Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel.;Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel.;Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel.;Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel.;Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel.;Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel.;Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel.;Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel; Sackler Faculty of Medicine, University of Tel Aviv, Israel.",
"authors": "Lichtenstein|Lev|L|;Ron|Yulia|Y|;Kivity|Shmuel|S|;Ben-Horin|Shomron|S|;Israeli|Eran|E|;Fraser|Gerald M|GM|;Dotan|Iris|I|;Chowers|Yehuda|Y|;Confino-Cohen|Ronit|R|;Weiss|Batia|B|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjv096",
"fulltext": "\n==== Front\nJ Crohns ColitisJ Crohns ColitiseccojceccojcJournal of Crohn's & Colitis1873-99461876-4479Oxford University Press UK 10.1093/ecco-jcc/jjv096Review ArticleInfliximab-Related Infusion Reactions: Systematic Review Lichtenstein Lev \na\nRon Yulia \nb\nKivity Shmuel \nc\nBen-Horin Shomron \nc\nIsraeli Eran \nd\nFraser Gerald M. \na\nDotan Iris \nb\nChowers Yehuda \ne\nConfino-Cohen Ronit \nf\nWeiss Batia \ng\naRabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, University of Tel Aviv, IsraelbTel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, University of Tel Aviv, IsraelcSheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, University of Tel Aviv, IsraeldHadassah-Hebrew University Medical Center, Jerusalem, IsraeleRambam Health Care Campus, Haifa, Israel; Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, IsraelfMeir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, University of Tel Aviv, IsraelgEdmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel; Sackler Faculty of Medicine, University of Tel Aviv, IsraelCorresponding author: Lev Lichtenstein, MD, Gastroenterology Institute, Rabin Medical Center, 39 Jabotinski St, Petah Tikva 49100, Israel. Tel: 972-3-937-7237; fax: 973-3-937-7206; E-mail: levl@clalit.org.il9 2015 19 6 2015 19 6 2015 9 9 806 815 22 11 2014 11 5 2015 17 5 2015 © European Crohn’s and Colitis Organistion 2015.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comObjective:\nAdministration of infliximab is associated with a well-recognised risk of infusion reactions. Lack of a mechanism-based rationale for their prevention, and absence of adequate and well-controlled studies, has led to the use of diverse empirical administration protocols. The aim of this study is to perform a systematic review of the evidence behind the strategies for preventing infusion reactions to infliximab, and for controlling the reactions once they occur.\n\nMethods:\nWe conducted extensive search of electronic databases of MEDLINE [PubMed] for reports that communicate various aspects of infusion reactions to infliximab in IBD patients.\n\nResults:\nWe examined full texts of 105 potentially eligible articles. No randomised controlled trials that pre-defined infusion reaction as a primary outcome were found. Three RCTs evaluated infusion reactions as a secondary outcome; another four RCTs included infusion reactions in the safety evaluation analysis; and 62 additional studies focused on various aspects of mechanism/s, risk, primary and secondary preventive measures, and management algorithms. Seven studies were added by a manual search of reference lists of the relevant articles. A total of 76 original studies were included in quantitative analysis of the existing strategies.\n\nConclusions:\nThere is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.\n\nKeywords:\nInfliximabinfusion reactionsadverse drug reactiondrug hypersensitivitydrug allergydrug toxicityinflammatory bowel diseaseCrohn’s diseaseulcerative colitis\n==== Body\n1. Introduction\nInfliximab [IFX] is a monoclonal antibody designed to intercept and neutralise tumour necrosis factor alpha [TNFα], a key inflammatory cytokine. Since its introduction in 1998, IFX has revolutionised the treatment of inflammatory bowel disease [IBD]. However, administration of IFX is associated with a well-recognised risk of infusion-related adverse events. The exact aetiology and pathogenesis of those infusion reactions [IR] are often unclear, and findings regarding their allergic/immune nature are inconsistent. The lack of a mechanism-based rationale for their prevention, combined with the absence of adequate, well-controlled studies, has led to the use of diverse empirical administration protocols, each with its own instructions for infusion rates, choice of preventive medications, and reaction-management algorithms.1,2,3 We performed a systematic review of strategies for preventing infusion reactions to infliximab and for their management.\n\n2. Methods\nWe conducted extensive electronic search of English language publications listed in the electronic databases of MEDLINE [source: PubMed database, 1997 through April 2015]. The keywords for the search were arranged in three groups. The first group contained the medical subject headings ‘tumor necrosis factor alpha/antagonists and inhibitors’ and free-text terms ‘infliximab [USAN:INN:BAN]’, ‘Remicade’, ‘Avakine’, ‘HSDB 7850’, and ‘UNII-B72HH48FLU’. We used set operator AND to combine rendered results with studies identified with the search term ‘infusion reactions’ and Medical Library Subject heading [MeSH] terms ‘adverse drug reaction’, ‘drug hypersensitivity’, ‘drug allergy’, and ‘drug toxicity’. Finally, the search was further narrowed using MeSH terms ‘inflammatory bowel disease’, ‘Crohn’s disease’, and ‘colitis, ulcerative'. We then performed a manual selection of studies that satisfied the following inclusion criteria: [1] comparative studies, meta-analyses, multicentre cohorts, observational studies, randomised controlled trials, and systematic reviews; [2] enrolment of IBD patients treated with infliximab; and [3] availability of data regarding infusion reactions. Exclusion criteria were: studies not published in the English language; publications inaccessible to Tel-Aviv University e-resources; those unrelated to inflammatory bowel disease or irrelevant to the topic; letters and case reports/case series. Reference lists of all relevant articles were searched for further studies. We also searched for relevant abstracts and other material from meetings. Studies concerning the use of IFX in other specialties, such as rheumatology and dermatology, were included if they reported information that was not yet available from IBD studies.\n\n3. Results\nThe electronic literature search retrieved 203 citations. After application of eligibility criteria, 69 articles remained and were further assessed. We found no randomised controlled trials that pre-defined infusion reaction as a primary outcome. Three RCTs evaluated infusion reaction as a secondary outcome4,5,6; another four RCTs included infusion reactions into safety evaluation analysis.7,8,9 All other reports ranged in level of evidence between meta-analyses [4], multicentre prospective cohorts [8], single-centre cohorts [15], and retrospective trials [21], to systematic reviews [14]; 22 letters and 53 case reports were excluded. An additional 59 articles were excluded for irrelevance, unavailability, or missing premedication and/or the infusion reaction [IR] data. Manual search yielded seven articles for inclusion. This process resulted in 76 articles for inclusion to quantitative analysis of the existing strategies [Figure 1].\n\nFigure 1. Flow chart of the literature search.\n\n4. Terminology and nomenclature\nThe World Health Organization10 nomenclature classifies IR to immunoglobulins into two major subtypes, immediate and late, according to the time interval between the infusion and the onset of an infusion-related adverse event.\n\n4.1. Immediate infusion reactions to IFX\nReactions that develop during the course of the infusion or within 1–2h of its completion are termed immediate-type reactions. Immediate IR are reported in 5–23% of IBD patients participating in large randomised controlled trials involving the originator IFX—Remicade® [Janssen Biotech, Inc., Malvern, PA].4,5,7,8,9 Comparable rates are reported in unselected patient populations.2,11,12,13,14,15,16,17,18 Since most immediate reactions occur during the initial infusions, the per-infusion incidence tends to be higher in relatively short-term studies, as opposed to long-term registry reports. The most frequent manifestations of immediate infusion reactions—as reported by a large community registry19—are pruritus [22.1% of all reported reactions], flushing [9.9%], dyspnoea [6.2%], chest discomfort [5.9%], hypertension [5.9%], myalgia [5.0%], nausea [4.7%], urticaria [4.7%], headache [4.0%], rash [3.4%], and dizziness [2.8%]. Patients with IBD treated with IFX who develop antibodies toward infliximab [ATI] have a 2-fold risk of acute infusion reactions and a 6-fold risk of serious acute infusion reactions.20\n\n\n4.1.1. Possible aetiologies of immediate infusion reactions to IFX\nPossible aetiologies follow.\n\n4.1.1.1. Cytokine-release syndrome\nCytokine release syndrome [‘cytokine storm’] is a generalised term originally coined to describe the explosive release of multiple pro- and anti-inflammatory cytokines and vasoactive substances from immune cells, induced by treatment with anti-thymocyte globulin and anti-T-cell antibody muromonab-CD3 [OKT3]21; the same effect was later reported with other biological agents [eg rituximab22]. Underlying mechanisms may include immune cell hyperactivation, direct apoptosis, complement-mediated lysis, and antibody-dependent cellular toxicity.23 Similar massive, simultaneous release of cytokines from TNF-expressing immune cells affected by IFX has been suggested.24,25,26 The paradoxical increase in serum TNF observed in the immediate aftermath of initial IFX infusion likely constitutes a reflection of this phenomenon.27,28,29\n\n\n4.1.1.2. True anaphylactic reaction\nIgE-mediated [type I] hypersensitivity reactions to IFX may not be as rare as previously thought.30–32\n\n\n4.1.1.3. IgG anaphylaxis\nThe phenomenon of massive activation of neutrophils by monomeric or aggregated IgG and circulating immune complexes, sometimes referred to as IgG anaphylaxis, has been well described in mice,33,34 and is presently being extensively researched in humans.35,36\n\n\n4.1.1.4. Complement activation\nWhen IFX is administered to patients with pre-existing anti-IFX antibodies [antibodies toward infliximab, ATI], the resulting circulating IFX-ATI complexes may activate complement, leading to an immediate infusion reaction.37 Complement activation by IFX molecule aggregates may occur as well.\n\n4.1.1.5. Degranulation\nDegranulation of mast cells and basophils, either through IFX targeting of membrane-bound TNF, or via anaphylatoxins [C3a and C5a] that increase in blood as a consequence of complement activation, is thought to account for some of the immediate infusion reactions to IFX.38\n\n\nClinical manifestations of the immediate IR caused by the aforementioned mechanisms heavily overlap, making it difficult to determine the exact underlying immune/allergic nature of the reaction, based solely on clinical evidence. Some hints, however, can be instructive: IgE-mediated reactions require pre-sensitisation, and should not occur during the first infusion. Wheezing and frank urticaria suggest a massive release of histamine, pointing toward either IgE-mediated or direct mast cell degranulation.39 Presence of fever, on the other hand, suggests an IR caused by cytokine release.\n\n4.1.2. Severity scale for immediate infusion reactions\nIn 2006, the National Cancer Institute [NCI] at the National Institutes of Health [NIH] in the USA introduced comprehensive, standardised terminology to grade adverse effects caused by medical therapies.40 Initially proposed for toxicity related to anti-cancer therapy, the NCI scale has become a cross-field standard in the drug toxicity communication.14,41 The reactions are divided into five severity grades, ranging from: mild [requires observation only]; through moderate [minimal—usually oral—intervention suffices]; and severe [vital organ involved yet not in life-threatening manner; usually requires parenteral medication]; to life-threatening [multi-system involvement of vital organs, urgent and critical care required]; and death. In terms of immediate infusion reactions, the examples can include: transient flushing or rash [mild reaction]; urticaria/myalgia/drug fever [moderate reaction]; bronchospasm/angioedema/hypotension [severe reaction]; and systemic anaphylactic reaction [life-threatening reaction].\n\n4.2. Late infusion reactions to IFX\nOf IBD patients treated by IFX, 1–3% report late-type reactions that first manifest > 24h post-infusion.13,31,42,43,44,45 These IR are usually of the serum sickness type and comprise a variety of local and systemic inflammatory responses caused by fixation and activation of complement by antigen [IFX]antibody [ATI] immune complexes deposited in blood vessels, skin, and joint tissue. The risk appears to be increased with episodic [‘on demand’] regimens, resumption of IFX infusions after a prolonged drug-free interval, and administration of IFX to patients with high ATI titres.42,46,47,48,49 The term ‘delayed-type hypersensitivity’ should probably be reserved for cell-mediated type [Coombs-Gell type IV] reactions: its application to serum sickness [Coombs-Gell type III reactions] may be inappropriate.10,50\n\n\nThe quantitative [stoichiometric] relationship between IFX and ATI affects the size of the resulting immune complexes, and their propensity to elicit the inflammatory reaction. Small complexes usually circulate within the bloodstream without triggering inflammation, and larger ones are easily cleared by the reticuloendothelial system. However, intermediate-sized complexes, which develop in the presence of slight antigen [IFX] excess, tend to be deposited in blood vessels and tissues, where they can fix and activate complement, resulting in the attraction of granulocytes and subsequent vascular and tissue damage.\n\nIn the absence of pre-existing anti-drug antibodies, serum sickness typically develops 1–3 weeks following administration of the culprit agent.10 In patients who have been repeatedly sensitised through antecedent exposure to IFX, immune complex-mediated reactions can occur as early as within 24–36h post-infusion.51 The most common symptoms of late infusion reactions are pruritic skin eruptions, fever, malaise, and polyarthralgia. Jaw pain is repeatedly mentioned among the features of delayed reaction to biological therapy.13,15,31,52,53 Although patients may feel very ill, serum sickness is self-limiting, and the symptoms usually subside within days or weeks; its evolution into life-threatening respiratory distress syndrome [ARDS] has been reported in a single, rather unusual case.54\n\n\n4.3. Originator vs biosimilar IFX\nCT-P13 [Remsima™/Inflectra™, Celltrion Healthcare Inc., Incheon city, Republic of Korea] is the world’s first biosimilar imitation of the originator IFX [Remicade®, Janssen Biotech, Inc., Malvern, PA] and was recently approved for IBD by the European Medicines Agency [EMA]. Currently, safety [as well as efficacy] data on biosimilar IFX are only available in rheumatology. Infusion-related reactions occurred in 6.6% and 8.3% of rheumatoid arthritis patients for CT-P13 and originator IFX, respectively [6.7% vs 13.3% in the ATI-positive group and 4.2% vs 2.8% in the ATI-negative group].55 A smaller study in ankylosing spondylitis also showed close similarity between the biosimilar and the originator IFX.56 Data on IR in IBD are still largely unavailable for CT-P13.\n\n5. IFX infusion protocols\n5.1. Graded dose challenge protocol\nThe manufacturer of the originator IFX recommends that initial [loading] infusions should be administered in a highly controlled manner, beginning with small test doses of the drug, followed by gradual and stepwise escalation of the infusion rate until the full target rate is reached57 [Table 1].\n\nTable 1. Infliximab [IFX] infusion protocols.\n\n\nInitial [graded challenge] rate schedule*\n\t\nInitial 15min [‘test dose’]\t10ml/h\t\nNext 15 min\t20ml/h\t\nNext 15 min\t40ml/h\t\nNext 15 min\t80ml/h\t\nNext, until infusion is complete\t150ml/h\t\n\nStandard [2-] rate protocol*\n\t\n\t\nInitial 15 min\t40ml/h\t\nThen, until infusion is complete\t150ml/h\t\n\nAccelerated [1-h] rate protocol*\t\n\t\nInitial 15 min\t100ml/h\t\nThen, until infusion is complete\t300ml/h\t\n*5mg/kg dose diluted in 250ml of NaCl 0.9%.\n\n5.2. Standard [2-h] rate protocol\nFor patients who tolerate initial [loading] infusions without complications, a simplified single-test dose protocol may be applied57 [Table 1].\n\n5.3. Accelerated [1-h] rate protocol\nIn adult patients who tolerate the standard 5mg/kg maintenance infusions, the infusion time can be further shortened to 60min,58,59 conserving both patient time and healthcare resources60 [Table 1]. Increasing the rate for escalated 10mg/kg doses over 60min,61 and administration of 5mg/kg infusions over 30min,60,62 also appear to be safe.\n\n6. Primary preventive measures\nPrimary prevention strategies for infusion reactions have been assessed in three target populations63: in unselected population [universal prevention]; in populations that were deemed to be particularly predisposed to IR [selective prevention]; and in individuals with warning signs—indicators—of a pending reaction [indicator-based prevention].\n\n6.1. Primary prevention of immediate infusion reactions in unselected population\n6.1.1. Gradual increase of infusion rate\nThe efficacy of an incremental infusion rate schedule to prevent immediate infusion reactions has never been validated in controlled studies. Nevertheless, given the cytokine-release mechanism underlying the majority of such reactions, it would seem to be a prudent approach.\n\n6.1.2. Co-administration of immunomodulators\nCo-administration of thiopurine immunomodulators seems to reduce the risk of early infusion reactions during both episodic64,65 [no longer recommended] and continuous4,7,66 IFX therapy [Table 2]. Such combination therapy has also been shown to improve the efficacy and reduce the immunogenicity of IFX.4 Methotrexate has been similarly efficacious in preventing IR in patients that received an episodic single-dose regimen of IFX.64 Although formally supported as a preventive measure for immediate infusion reactions,67 the use of immunomodulators should be cautiously weighed against the associated safety concerns, especially risk of infections and lymphomas.68,69\n\n\nTable 2. Effect of concomitant treatment with thiopurines on the incidence of infusion reactions [IR] to infliximab [IFX] [SONIC trial].\n\nIncidence\tIFX\tIFX + thiopurines\t\nIR per patient\t16.6%\t5.0%\t\nIR per infusion\t4.6%\t1.0%\t\n6.1.3. Premedication with corticosteroids, antihistamines, and antipyretics\nThe need for routine premedication with corticosteroids, antihistamines, and/or antipyretics in instances of scheduled maintenance therapy with IFX is controversial,70 and evidence regarding its efficacy in patients with IBD is relatively limited. Premedication with intravenous corticosteroids may reduce the immunogenicity of IFX but was not directly shown to reduce the risk of IR.6 Findings for oral corticosteroids71 or oral antihistamines72 in patients with arthritis, or the combination of corticosteroids and antihistamines in paediatric patients with IBD/arthritis,73 were disappointing with respect to IR prevention. Furthermore, robust data prospectively gathered from a large Canadian community registry19 and from another retrospective study2 implied that pre-administration of antihistamines, alone or in combination with corticosteroids and/or antipyretics, was paradoxically associated with higher rates of immediate infusion reactions. However, these findings should be interpreted with caution, due to possible selection bias [patients with a perceived higher risk of infusion reactions may have typically received treatment, prior to IFX infusions]. Some intriguing but uncontrolled preventive experience with oral acetylsalicylic acid has been reported in paediatric patients.74\n\n\n6.2. Primary prevention of immediate infusion reactions in selected populations\nEpisodic [‘on demand'] IFX treatment is associated with the formation of neutralising antibodies against infliximab, and is therefore not recommended.42 However, elective, temporary [eg pregnancy- or surgery-related] interruption of IFX therapy is not unusual. Late immune-related adverse events such as serum sickness were repeatedly reported when infusions were resumed following a prolonged [more than 12-week] drug-free interval.15,48,65 Data on the occurrence of immediate infusion reactions are inconsistent. A significant increase in the frequency of serious immune-related adverse events was observed in some series,65 but not in others.75 Targeted prophylactic premedication with corticosteroids, antihistamines, and antipyretics has become common practice in such instances,70,76 but its efficacy was recently called into question by findings from a large retrospective study,65 though never validated in controlled studies. According to this study, co-administration of immunomodulators was the only preventive measure associated with a reduction of IR frequency [from 34% to 12%].\n\nPatients with atopy constitute another selected population theoretically at risk for IR. Treatments that tend to activate complement result in rise of anaphylatoxins C3a and C5a, triggering degranulation of mast cells and basophils. This phenomenon may be exaggerated in atopic patients; asthma and atopic dermatitis are often regarded as indications for premedication prior to administration of intravenous iron77 and iodine contrast.78 Activation of complement by circulating immune complexes and aggregates of IFX molecules may theoretically occur during some IFX infusions. However, available data suggest that patients with severe atopic dermatitis79 or patients with variety of atopic conditions80 are not at risk for an increased rate of infusion reactions to IFX.\n\n6.3. Indicator-based primary prevention of immediate infusion reactions\nThe presence of ATI is associated with an increased risk of an immediate infusion reaction during both episodic and scheduled administration of IFX.20 One out of six ATI-positive patients will display an infusion reaction when treated with IFX20; the underlying mechanism is unclear. ATI are frequently associated with inadequate trough levels of IFX, and the re-emergence of circulating cells bearing the target antigen [TNF]. Administration of IFX in this setting might trigger cytokine release from these cells, thereby provoking an infusion reaction.65,81,82 Activation of the immune system by circulating IFX-ATI immune complexes constitutes another proposed mechanism.37\n\n\nIt is unclear if rising titres of ATI [or the resulting progressive loss of response] can serve as an indicator of a pending infusion reaction. Assessment of ATI titres has been proposed as a risk stratification strategy for infusion reactions,65,83 but its positive predictive value has thus far been insufficient to draw operative conclusions.20,42 Furthermore, the absence of ATI does not preclude infusion reaction.84,85 Studies of patients with rheumatological diseases32,83 suggested that the assessment of anti-IFX IgE levels could serve as a means to determine the risk of severe infusion reactions to IFX. However, this approach failed to show preventive benefit in patients with IBD.85\n\n\nCoupled with the questionable efficacy of prophylactic premedication, its routine use in patients with ATI may therefore not be justified.\n\n6.4. Primary prevention of late reactions\nIt would appear that late infusion reactions are triggered by the binding of IFX by ATI, followed by deposition of the resulting ATI-IFX immune complexes and fixation of complement. The reintroduction of IFX after a drug holiday,42,46,47,48,49 and the presence of ATI,8,86 have been suggested as risk factors for serum sickness-like reactions, but the relationship is not always consistent.42,47,81 The exact stoichiometric conditions that result in the production of intermediate-sized immune complexes are difficult to predict, as only one out of every 22 ATI-positive patients will develop a late reaction to IFX treatment.20 No operative conclusions regarding the necessity for preventive measures can be drawn from either the presence or the exact titre of ATI.42\n\n\n7. Management of ongoing infusion reactions\n7.1. Management of ongoing immediate infusion reactions to IFX\nThere are no controlled trials to guide the management of IR to IFX. Therapeutic recommendations are based mainly on case reports and expert opinion.31,51,87,88,89,90,91,92 The majority of IFX-related infusion reactions are thought to result from rapid, infusion rate-related cytokine release from the affected immune cells. In these cases, temporary attenuation of the infusion rate is regarded as the most effective, and often the only, required intervention.31,91 However, the appearance of hives, bronchospasm, and vascular compromise should raise suspicions of an IgE-mediated anaphylactic reaction,39 which warrants prompt interruption of the infusion, intramuscular administration of epinephrine, and a further immunological work-up.91 In general, intervention is dictated by severity of the reaction.40 Temporary attenuation of the infusion rate is often the only intervention required in cases of mild and transient immediate infusion reactions. In cases of moderate infusion reactions, temporary interruption of the infusion is necessary in most instances, together with [usually oral] administration of medications to control the symptoms.31,51,87,88,89,90,91,92 The simultaneous involvement of multiple vital organ systems, especially if complicated by respiratory compromise or/and vascular collapse, is a true medical emergency. Regardless of the exact aetiology, prompt initial treatment is crucial. In these extreme, albeit relatively infrequent, scenarios, the importance of the infusion team’s familiarity with the simple and stepwise management algorithm cannot be overemphasised. The recently published guidelines of the World Allergy Organization [WAO]93,94 stress the role of epinephrine as a principal, potentially life-saving intervention. A suggested algorithm for the management of ongoing immediate infusion reactions is depicted in Figure 2.\n\nFigure 2. Suggested management algorithm for infusion reactions.\n\n7.2. Management of late infusion reactions to IFX\nThe relatively rare occurrence of late infusion reactions precludes randomised clinical trials as to how they should be managed. Antihistamines are often suggested for symptomatic relief of pruritus; acetaminophen serves for symptomatic relief of low-grade fever and arthralgias. Patients with higher fever, severe arthralgias/arthritis, or extensive rash/pruritus often require a short course of oral corticosteroids; intravenous corticosteroids can be considered in acutely ill patients.89\n\n\n8. Secondary preventive measures\nAcute infusion reactions tend to recur in about a third of subsequent IFX infusions.19,95 Even when not severe, infusion reactions are important immunological events as they often represent warning signs for emergence of ATI and consequent decline of drug levels and loss of clinical response.20,96,97 In this regard, IR, and especially recurrent IR, should prompt ATI and IFX trough level determination.\n\n8.1. Secondary prevention of immediate infusion reactions to IFX\nA suggested secondary prevention protocol is outlined in Figure 3 and may include the following measures.\n\nFigure 3. Suggested premedication protocol in patients with prior infusion reactions.\n\n8.1.1. Co-administration of immunomodulators\nAlthough a small retrospective study98 showed the addition of immunomodulators to ongoing monotherapy with IFX was able to eliminate pre-formed neutralising ATI and restore clinical response to IFX, it is still unknown whether this approach is effective in preventing recurrent IR. As noted above, the possible benefits of this combination therapy have to be carefully weighed against associated long-term safety concerns.\n\n8.1.2. Graded dose challenge\nExperts suggest the use of graded drug challenge during resumption of IFX infusions, in patients with prior infusion reactions.31,87,88,91 This precautionary measure, originally derived from infusion practices for 5-fluorouracil and vancomycin,31,99,100 consists of incremental administration of small test doses of IFX, followed by gradual, stepwise escalation of the infusion rate until the full target rate [or maximum tolerated rate] is reached [Table 1]. Clinicians assume that if cytokine release underlies the majority of cases of immediate infusion reaction, then any infusion reactions provoked by the smaller test doses would be milder, and easier to manage. Although this assumption has never been formally subjected to controlled validation, in practice, graded dose challenge is widely accepted by most infusion centres.\n\n8.1.3. Premedication with corticosteroids, antihistamines, and/or antipyretics\nNumerous premedication protocols, most of them adapted from administration practices for iodine contrast media,51,90 have been empirically employed in IFX infusion centres to prevent recurrence of moderate infusion reactions. None of these has ever been subjected to controlled validation. In a small retrospective study of paediatric patients,101 the re-treatment of children who had suffered from infusion reactions without prophylactic administration of anti-allergic medications was associated with a significant [50%] likelihood of recurrent infusion reactions. The probability of recurrent infusion reactions tended to be lower in patients premedicated with antihistamines, antipyretics, or corticosteroids. In contrast, others found that in the adult population, premedication was not associated with a reduced risk of recurrent infusion reactions.13 Nevertheless, the prophylactic pre-administration of antihistamines, antipyretics, and/or corticosteroids is frequently suggested,88,89,91 albeit with no widespread agreement on the exact criteria and indications, choice of specific medications, dose, or administration route.31,87,88,89,91 The main argument in favour of premedication is that it may be justified in patients with a history of moderate infusion reactions, even if a large number of patients may need to be treated for even one to benefit. Severe and potentially life-threatening acute generalised infusion reactions usually warrant discontinuation of treatment. If no reasonable therapeutic alternative exists, pretreatment with corticosteroids and antihistamines, and rapid desensitisation by an experienced clinical immunologist/allergist, could be considered.\n\n8.1.4. Desensitisation\nDesensitisation to a specific medication was originally described for IgE-mediated anaphylactic reactions, and involves graded administration of the offending drug, starting with extremely low doses [1:1000 and 1:100 dilutions], followed by slow, stepwise dose escalations, until the target dose is clinically tolerated. Consecutive low-level, subthreshold antigen stimulation seems to render tissue mast cells and probably circulating basophils specifically unresponsive to the offending drug, but not to other stimuli. Internalisation and down-regulation of the high-affinity receptor on the Fc fragment of IgE [FcεRI] are among the mechanisms believed to underlie this effect. Slow depletion of mast cell granules may also take place. Desensitisation protocols are in routine use in antibiotic, anticancer, and biological treatments [including the monoclonal agents rituximab and trastuzumab]. They make possible the administration of life-saving therapies to patients with a history of severe immediate infusion reactions.102 Experience with desensitisation to IFX is limited to case reports and small series studies.38,103,104,105 The reported rate of breakthrough reactions in these series reached 29%,103 remarkably similar to the reaction recrudescence rate observed without desensitisation.19 However, these reactions tended to be significantly milder and, in most cases, allowed for successful continuation of the infusion.\n\n8.2. Secondary prevention of late infusion reactions to IFX\nLate infusion reactions depend on unique stoichiometric conditions, resulting in the production of intermediate-size immune complexes. Such conditions may not recur after subsequent infusions.31,106 Genuine preventive interventions that preclude the formation of immune complexes of reactogenic size must focus on moderation of post-infusion IFX levels [eg by dose escalation, or by split administration of the unchanged dose,51,90] or on elimination of neutralising ATI [eg. through addition of immune modulators to ongoing IFX monotherapy98]. Neither technique has ever been properly evaluated in this setting, and all therefore are still considered theoretical. Premedication with anti-inflammatory/antihistamine medications is not a truly preventive measure. Rather, it is intended to overcome associated signs and symptoms of the anticipated [recurrent] infusion reaction.107 As such, premedication has already been covered in the management chapter.\n\n9. Conclusions\nThere is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.\n\nFunding\nThe Open Access fee for this article was covered by Janssen Israel. Lev Lichtenstein, Yulia Ron, and Batia Weiss received consulting fees from Janssen during the conduct of the study.\n\nConflict of Interest\nLev Lichtenstein reports lecturer and consulting fees from AbbVie, research support from Janssen, a non-financial support from Takeda, all outside the submitted work, and consulting fees from Janssen during the conduct of the study. Yulia Ron reports consulting fees from Janssen during the conduct of the study. Shmuel Kivity has nothing to disclose. Shomron Ben-Horin reports consulting and advisory board fees and/or research support from AbbVie, MSD, Janssen, Takeda, and Celltrion, all outside the submitted work. Eran Israeli has nothing to disclose. Gerald M Fraser has nothing to disclose. Iris Dotan reports advisory board fees from AbbVie, Janssen, Takeda, Genentech, and Pfizer, and lecturer fees from AbbVie, Janssen, Ferring, Falk Pharma, Given Imaging-Covidien, and MSD, all outside the submitted work. Yehuda Chowers reports consulting fees from Abbvie, Janssen, Takeda, and Pharmacosmos, and research support from Abbvie, and Janssen, all outside the submitted work. Ronit Confino-Cohen has nothing to disclose. Batia Weiss reports lecturer fees from Janssen, outside the submitted work, and consulting fees from Janssen during the conduct of the study.\n\nAuthor Contributions\nLev Lichtenstein, Yulia Ron, Shmuel Kivity, Ronit Confino-Cohen, and Batia Weiss conducted the literature search, and contributed to study design, data collection, data analysis, data interpretation, writing, and revision of the manuscript, and figure creation. Shomron Ben-Horin, Eran Israeli, Gerald M Fraser, Iris Dotan, and Yehuda Chowers contributed to study design, data analysis, data interpretation, writing and revision of the manuscript and figure creation. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.\n==== Refs\nReferences\n1. \nAdler J Sandberg KC Shpeen BH \nVariation in infliximab administration practices in the treatment of pediatric inflammatory bowel disease .\nJ Pediatr Gastroenterol Nutr \n2013 ;57 :35 –8 .\n2. \nKeshavarzian A Mayer L Salzberg B \nA multicenter retrospective experience of infliximab in Crohn’s disease patients: infusion reaction rates and treatment persistency .\nGastroenterol Hepatol \n2007 ;3 :381 –90 .\n3. \nDonovan M Lunney K Carter-Pokras O Cross RK \nPrescribing patterns and awareness of adverse effects of infliximab: a health survey of gastroenterologists .\nDig Dis Sci \n2007 ;52 :1798 –805 .17417731 \n4. \nHanauer SB Feagan BG Lichtenstein GR \nMaintenance infliximab for Crohn’s disease: the ACCENT I randomised trial .\nLancet \n2002 ;359 :1541 –9 .12047962 \n5. \nSands BE Anderson FH Bernstein CN \nInfliximab maintenance therapy for fistulizing Crohn’s disease .\nN Engl J Med .\n2004 ;350 :876 –85 .14985485 \n6. \nFarrell RJ Alsahli M Jeen YT Falchuk KR Peppercorn MA Michetti P \nIntravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomised controlled trial .\nGastroenterology \n2003 ;124 :917 –24 .12671888 \n7. \nColombel JF Sandborn WJ Reinisch W \nInfliximab, azathioprine, or combination therapy for Crohn’s disease .\nN Engl J Med \n2010 ;362 :1383 –95 .20393175 \n8. \nRutgeerts P Sandborn WJ Feagan BG \nInfliximab for induction and maintenance therapy for ulcerative colitis .\nN Engl J Med \n2005 ;353 :2462 –76 .16339095 \n9. \nHyams J Crandall W Kugathasan S \nInduction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children .\nGastroenterology \n2007 ;132 :863 –73 ; 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"fulltext_license": "CC BY-NC",
"issn_linking": "1873-9946",
"issue": "9(9)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Crohn’s disease; Infliximab; adverse drug reaction; drug allergy; drug hypersensitivity; drug toxicity; inflammatory bowel disease; infusion reactions; ulcerative colitis",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D004342:Drug Hypersensitivity; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D007262:Infusions, Intravenous",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "806-15",
"pmc": null,
"pmid": "26092578",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": "22819590;21122522;16227416;15468353;12492177;12047962;12671888;23815183;19951375;16084773;23711128;24251990;16021319;24359522;24008815;20848473;16120138;23687260;21122513;12584368;19417683;20002026;19392858;17229796;23651723;16867042;21726254;11233658;21535447;18485127;16793840;15297773;23994253;23102649;15301561;10498591;19473578;12818276;20393175;23459317;19558997;19628314;17324398;12544210;16339095;17417731;23103905;6856733;25110258;11979139;21407184;21162650;17307639;12492735;2523100;19132970;21602689;20535789;15097438;12094858;16092162;6691643;17129817;22766212;24878856;19910036;15761436;21971373;23032984;14699483;19026030;23293080;23829336;19258190;15224278;21960854;20145610;22231796;24486408;24280879;24583135;16918890;23268454;22647738;16434333;21746933;15867583;24565764;14985485;23687259;21544533;19740450;21460715;23252369",
"title": "Infliximab-Related Infusion Reactions: Systematic Review.",
"title_normalized": "infliximab related infusion reactions systematic review"
} | [
{
"companynumb": "NO-CELLTRION INC.-2019NO020541",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DESOGESTREL\\ETHINYL ESTRADIOL"
},
"dru... |
{
"abstract": "A 53-year-old man with ulcerative colitis (UC) suffered fatal acute interstitial pneumonitis (AIP) post completing an accelerated infliximab induction course. This is the first case reported in this setting. A literature review found four similar cases of infliximab-induced interstitial lung disease in the setting of treating patients with UC using standard infliximab regimens had successful treatment of the subjects post infliximab discontinuation. Unfortunately, the patient we are presenting, who had an accelerated infliximab induction course, did not survive. Although a prior small trial along more recent new small studies continue to show a benefit in reducing the need for early colectomy with the accelerated infliximab induction regimen as salvage therapy, it should be used cautiously until more safety data are available. Further larger trials are required to investigate rare side effects that may be associated with this regimen such as rapidly progressive lung toxicity as seen in this patient.",
"affiliations": "Medicine, Western University, London, Canada.;Critical care, Oakville-Trafalgar Memorial Hospital, Oakville, Ontario, Canada.;Internal Medicine, London Health Sciences Centre Victoria Hospital, London, Ontario, Canada.;Medicine, Western University, London, Canada.",
"authors": "Rofaiel|Rymon|R|;Kohli|Sonny|S|;Mura|Marco|M|;Hosseini-Moghaddam|Seyed M|SM|",
"chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219956",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Interstitial lung disease; Mechanical ventilation; Respiratory system; Ulcerative colitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003093:Colitis, Ulcerative; D003937:Diagnosis, Differential; D004334:Drug Administration Schedule; D004417:Dyspnea; D017809:Fatal Outcome; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D012131:Respiratory Insufficiency",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28500116",
"pubdate": "2017-05-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10979281;15564019;15987960;17129817;17495281;18598993;18942740;18946068;19201589;19398919;19561910;21857821;22019799;22347941;22688498;22948700;23001613;23969008;23983443;25086187;25309080;25473247;9001328",
"title": "A 53-year-old man with dyspnoea, respiratory failure, consistent with infliximab-induced acute interstitial pneumonitis after an accelerated induction dosing schedule.",
"title_normalized": "a 53 year old man with dyspnoea respiratory failure consistent with infliximab induced acute interstitial pneumonitis after an accelerated induction dosing schedule"
} | [
{
"companynumb": "CA-CELLTRION HEALTHCARE JAPAN K.K.-2017CA007813",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nWe describe a case of severe hypoglycemia in a 14-month-old child as a suspected adverse drug reaction (ADR) to nadolol, and we performed an analysis of the FDA Adverse Event Reporting System (FAERS) database. Although previous reports have identified the risk of severe hypoglycemia in children during treatment with β-blockers, little is known about hypoglycemia as an ADR in infants treated with nadolol. Moreover, the pharmacodynamic and pharmacokinetic profiles of nadolol in children aged less than 1 year old are still not fully known.\n\n\nMETHODS\nWe extracted all ADR reports involving nadolol from the FAERS database; in order to reduce the risk of bias, we only considered cases that exclusively reported nadolol as the suspect drug. We then selected cases of hypoglycemia in the pediatric population and conducted a manual deduplication.\n\n\nRESULTS\nUpon FAERS database analysis, a total of 2,674 suspected ADR reports to nadolol were found. Of these, 1,950 (73%) were solely attributed to nadolol, and 63 of them were hypoglycemic events. A total of 47 reports included the relevant pediatric age (74.6%). After deduplication, we identified 25 cases (mean age: 3.65 years old); all of these reports were categorized as serious, and hospitalization was required in 15 cases.\n\n\nCONCLUSIONS\nHypoglycemia is a reported life-threatening ADR associated with nadolol, especially in infants, in whom this drug should be used with caution.",
"affiliations": null,
"authors": "Bergamaschi|Francesco|F|;Fumagalli|Mara|M|;Mannarino|Savina|S|;Carlucci|Patrizia|P|;Radice|Sonia|S|;Gringeri|Michele|M|;Mosini|Giulia|G|;Carnovale|Carla|C|;Battini|Vera|V|;Fabiano|Valentina|V|",
"chemical_list": "D009248:Nadolol",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "59(4)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007003:Hypoglycemia; D007223:Infant; D009248:Nadolol; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "333-340",
"pmc": null,
"pmid": "33300862",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe hypoglycemia in children treated with nadolol: A case report and FDA adverse event reporting system (FAERS) database analysis.",
"title_normalized": "severe hypoglycemia in children treated with nadolol a case report and fda adverse event reporting system faers database analysis"
} | [
{
"companynumb": "IT-USWM, LLC-UWM202012-000067",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NADOLOL"
},
"drugadditional": "1",
... |
{
"abstract": "We report the case of a 15-month-old boy with retinoblastoma who developed exotropia secondary to a right medial rectus infarct after intra-arterial chemotherapy. He had unilateral sporadic group C tumor (International Classification of Retinoblastoma) and was treated with intra-arterial melphalan. One week after the first session of intra-ophthalmic arterial melphalan chemotherapy, he was noted to have orbital congestion, exotropia, and right adduction limitation. Magnetic resonance imaging was suggestive of a right medial rectus infarct. The tumor showed a good response to intra-arterial chemotherapy but the exotropia persisted.",
"affiliations": "Department of Radiology, University of Utah, Salt Lake City, Utah.;Department of Radiology, University of Utah, Salt Lake City, Utah.;Department of Radiology, University of Utah, Salt Lake City, Utah.;Department of Ophthalmology, University of Louisville, Louisivlle, KY. Electronic address: aparna.ramasubramanian@louisville.edu.",
"authors": "Lambert|Nathan G|NG|;Winegar|Blair A|BA|;Feola|G Peter|GP|;Ramasubramanian|Aparna|A|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1091-8531",
"issue": "19(6)",
"journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus",
"keywords": null,
"medline_ta": "J AAPOS",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D004487:Edema; D005099:Exotropia; D005451:Fluorescein Angiography; D006801:Humans; D007223:Infant; D007238:Infarction; D007261:Infusions, Intra-Arterial; D007511:Ischemia; D008279:Magnetic Resonance Imaging; D008297:Male; D008558:Melphalan; D009135:Muscular Diseases; D009801:Oculomotor Muscles; D009880:Ophthalmic Artery; D010211:Papilledema; D011859:Radiography; D019572:Retinal Neoplasms; D012175:Retinoblastoma",
"nlm_unique_id": "9710011",
"other_id": null,
"pages": "574-7",
"pmc": null,
"pmid": "26691048",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ocular dysmotility after intra-arterial chemotherapy for retinoblastoma.",
"title_normalized": "ocular dysmotility after intra arterial chemotherapy for retinoblastoma"
} | [
{
"companynumb": "US-MYLANLABS-2016M1001512",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCongenital chloride diarrhea (CCD) is a rare inherited disorder of intestinal electrolyte transport that results in a large wastage of electrolytes and water. Advances in substitution therapy using sodium chloride (NaCl) and potassium chloride (KCl) have dramatically improved survival for patients with CCD. Slow-release KCl is widely prescribed as a potassium supplement; however, it has also occasionally been used in suicide attempts, as potassium poisoning can generate life-threatening hyperkalemia.\n\n\nMETHODS\nA 26-year-old female presented to the emergency department (ED) with self-poisoning, having taken 30 tablets of slow-release KCl (total: 240 mmol potassium) following an auditory hallucination. The patient had been undergoing substitution therapy with NaCl and KCl for CCD and been followed up in the pediatric department. One month prior, she developed insomnia and anxiety and had consulted a psychiatrist. At the ED, although her general condition was good, she appeared agitated. Her serum potassium level was 7.0 mmol/L, indicating hyperkalemia, and electrocardiographic changes showed tenting of the T-waves. She responded to the administration of calcium gluconate, sodium bicarbonate, and insulin with glucose, and the serum potassium level improved. Finally, she was diagnosed with schizophrenia.\n\n\nCONCLUSIONS\nIn CCD management, physicians should pay careful attention to patients' extraintestinal issues, including psychological disorders that may emerge in adulthood.",
"affiliations": "Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 4313192, Japan. sige_pd@yahoo.co.jp.",
"authors": "Iijima|Shigeo|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v8.i8.1463",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960 Baishideng Publishing Group Inc \n\njWJCC.v8.i8.pg1463\n10.12998/wjcc.v8.i8.1463\nCase Report\nSuicide attempt using potassium tablets for congenital chloride diarrhea: A case report\nIijima Shigeo Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 4313192, Japan. sige_pd@yahoo.co.jp\n Author contributions: Iijima S performed the disease consultation, acquired the clinical data, reviewed the literature, and drafted the manuscript.\n\nCorresponding author: Shigeo Iijima, MD, PhD, Associate Professor, Department of Regional Neonatal-Perinatal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 4313192, Shizuoka, Japan. sige_pd@yahoo.co.jp\n\n\n26 4 2020 \n26 4 2020 \n8 8 1463 1470\n17 12 2019 2 3 2020 10 4 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nCongenital chloride diarrhea (CCD) is a rare inherited disorder of intestinal electrolyte transport that results in a large wastage of electrolytes and water. Advances in substitution therapy using sodium chloride (NaCl) and potassium chloride (KCl) have dramatically improved survival for patients with CCD. Slow-release KCl is widely prescribed as a potassium supplement; however, it has also occasionally been used in suicide attempts, as potassium poisoning can generate life-threatening hyperkalemia.\n\nCASE SUMMARY\nA 26-year-old female presented to the emergency department (ED) with self-poisoning, having taken 30 tablets of slow-release KCl (total: 240 mmol potassium) following an auditory hallucination. The patient had been undergoing substitution therapy with NaCl and KCl for CCD and been followed up in the pediatric department. One month prior, she developed insomnia and anxiety and had consulted a psychiatrist. At the ED, although her general condition was good, she appeared agitated. Her serum potassium level was 7.0 mmol/L, indicating hyperkalemia, and electrocardiographic changes showed tenting of the T-waves. She responded to the administration of calcium gluconate, sodium bicarbonate, and insulin with glucose, and the serum potassium level improved. Finally, she was diagnosed with schizophrenia.\n\nCONCLUSION\nIn CCD management, physicians should pay careful attention to patients’ extraintestinal issues, including psychological disorders that may emerge in adulthood.\n\nCongenital chloride diarrheaSubstitution therapySuicidePotassium overdoseSchizophreniaCase report\n==== Body\nCore tip: The main treatment for congenital chloride diarrhea (CCD) is life-long substitution therapy using sodium chloride and potassium chloride. An oral potassium supplement overdose is rare but can cause life-threatening hyperkalemia in cases of intentional high-dosage ingestion. We encountered an adult patient with CCD who developed hyperkalemia due to self-poisoning of prescribed potassium chloride tablets. In patients with CCD, physicians need to consider extraintestinal issues that patients can encounter as they get older, along with the challenges they face concerning life-long diarrhea. It is especially important to be aware of any potential psychiatric disorders that may cause life-threatening sequelae.\n\nINTRODUCTION\nCongenital chloride diarrhea (CCD, OMIM 214700) is a rare autosomal recessive disease of impairment in intestinal Cl−/HCO3− exchange, due to mutations in the solute carrier family 26 member 3 (SLC26A3, OMIM 126650) gene, and is characterized by persistent, life-long, watery diarrhea with a high fecal chloride concentration (> 90 mmol/L)[1]. Worldwide, more than 250 cases of CCD have been reported[2]. Without treatment, most children die in infancy or survive with severely delayed psychomotor development. Advances in substitution therapy with sodium chloride (NaCl) and potassium chloride (KCl) have dramatically improved the survival of these patients, and the long-term prognosis of appropriately managed CCD has been reported to be favorable[3].\n\nAlthough KCl is extensively used to supplement potassium as a therapeutic modality, potassium administration is also known to be a means in suicide/homicide attempts or in lethal procedures for state-sanctioned capital punishment. Potassium poisoning can cause life-threatening hyperkalemia, as harmful effects on the electric activity of the heart are the most important consequences of hyperkalemia. When serum potassium levels exceed 7 mmol/L, remarkable arrhythmic changes can be observed using electrocardiography. With serum potassium levels ≥ 8 mmol/L, sudden cardiac arrest can occur[4].\n\nWe encountered an adult patient with CCD who had attempted suicide through ingesting a large number of KCl tablets that had been prescribed for substitution therapy. No previous studies have focused on mental or psychiatric disorders involving patients with CCD, and no studies have reported the challenges facing patients with CCD related to life-long substitution therapy.\n\nCASE PRESENTATION\nChief complaints\nA 26-year-old female presented to the emergency department (ED) complaining of epigastric discomfort and nausea.\n\nHistory of present illness\nOne month prior, the patient had developed insomnia and anxiety due to domestic difficulties. She consulted a psychiatrist and was prescribed anti-anxiety and hypnotic medications relevant to a diagnosis of adjustment disorders. On the day of the ED visit, she had experienced an auditory hallucination and had ingested 30 tablets of slow-release KCl (each tablet containing 8mmol potassium) in a suicide attempt. She then called her father because of the epigastric discomfort and nausea and he transported her to the ED four hours after ingestion.\n\nHistory of past illness\nAt 16 months old, this patient was diagnosed with CCD based on hypochloremic alkalosis, hyponatremia, hypokalemia with increased plasma renin and aldosterone levels, and high fecal Cl−. In this case, because repeated sweat testing showed normal Cl− concentration and because pulmonary illness did not develop during her clinical course, we are sure that the patient did not have cystic fibrosis. She has undergone substitution therapy with NaCl and KCl. On follow-up, watery diarrhea persisted, but she developed normally. In adulthood, she married and produced a healthy child after an uneventful pregnancy at the age of 24 years. Subsequently, the patient continued to visit the pediatric outpatient clinic four times a year. Her usual serum electrolyte concentrations were as follows: Na+: 140-143 mmol/L; K+: 2.8-3.4 mmol/L, and Cl−: 96-100 mmol/L, with a daily substitution of 48 mmol slow-release KCl. In this case, genetic diagnosis was considered; however, the patient did not approve of this diagnostic method and therefore, it was not performed.\n\nPersonal and family history\nThis patient was born with polyhydramnios at 36 wk gestation and weighing 2550 g. Both her parents are healthy but consanguineous. Her grandmother's brother died immediately after birth; however, the cause of death was unclear.\n\nPhysical examination\nThe patient was agitated, but her general condition was good. Her pulse rate was 105 beats/min and her blood pressure was 101/77 mmHg.\n\nLaboratory examinations\nInitial laboratory blood test results were as follows: pH: 7.419; partial pressure of carbon dioxide (CO2): 30.8 mmHg; bicarbonate (HCO3−): 20.0 mmol/L; base excess (BE): -5.0; Na+: 139 mmol/L; K+: 7.0 mmol/L; Cl−: 105 mmol/L; urea nitrogen: 7.3 mg/dL, and creatinine: 0.52 mg/dL.\n\nImaging examinations\nElectrocardiographic changes of hyperkalemia were observed, with tenting of T-waves and smaller P-waves.\n\nFINAL DIAGNOSIS\nHyperkalemia due to self-poisoning with slow-release KCl tablets in a suicide attempt.\n\nTREATMENT\nThe hyperkalemia was treated with an intravenous injection of 8.5% calcium gluconate (20 mL) and 8.4% sodium bicarbonate (40 mL), and insulin with glucose infusion therapy (5 units of regular insulin (Humulin-R) and 20 g of glucose/hour) was started. The patient responded to treatment and, at six hours post-initiation of treatment, the serum potassium level had corrected to 4.0 mmol/L.\n\nOUTCOME AND FOLLOW-UP\nThe patient was referred to the psychiatry department and was diagnosed with schizophrenia. She was subsequently admitted to an inpatient unit for treatment of her acute presentation with atypical antipsychotics (aripiprazole and risperidone), and she showed significant improvement. Concerning her present CCD management, the substitution therapy with slow-release KCl has been continued with very careful monitoring of this patient because of the lack of an alternative.\n\nDISCUSSION\nThis is the first report focusing on mental or psychiatric disorders involving patients with CCD and the challenges facing these patients related to life-long substitution therapy. Despite persistent diarrhea, it has been reported that most patients with CCD appear to adjust to their condition and experience only minimal social disadvantage[5]. Moreover, ≥ 90% of patients with CCD are reported to consider their general health as excellent or good[3]. The patient presented in this report had acceptable growth, normal development, an uneventful pregnancy, and the delivery of a healthy child. Nevertheless, she had attempted suicide and was diagnosed with schizophrenia. The relationship between CCD and mental or psychiatric disorders remains unclear. Episodes of dehydration can result in mental and psychomotor impairment. In fact, this patient had often been hospitalized with dehydration due to acute gastroenteritis. In a clinical analysis of 21 Finnish patients with CCD published in 1977[6], one patient was reported to have had severe psychological difficulties, the details of which are not known, and the authors in that report indicated that those psychological issues were apparently unrelated to CCD. A recently published nationwide study in Japan reported that 23% of children with CCD had a neurodevelopmental or neuropsychiatric disorder in terms of their long-term outcomes[7]; however, the prevalence of various psychiatric disorders such as depression and schizophrenia in adult patients has not been reported. It is likely that long-term clinical outcomes have neither been captured nor recorded consistently in a standardized manner. Some patients with CCD have been reported to have developed inflammatory bowel disease (IBD)[2,8]. In IBD, psychiatric comorbidity is well recognized[9], and one recent study found a higher incidence of schizophrenia in an IBD cohort compared to controls[10]. Furthermore, an increased risk of a suicide attempt or ideation has been noted as a concern in patients with IBD[11]. Schizophrenia is a very common form of mental illness and its onset is significantly influenced through environmental factors or stressors[12]. One study showed that 30% of patients with schizophrenia had attempted suicide at least once during their lifetime[13]. A systematic review exploring suicide risk in patients with schizophrenia suggested that the risk factors leading to suicide appeared mainly related to stress[14]. In CCD, soiling remains common at all ages and, in adulthood, minor soiling has been reported to occur at night when sleeping or during physical exertion[3]. In addition to stress from persistent diarrhea, patients with CCD who appear socially adjusted may come under considerable physical or social stress after gaining independence from their parents and taking responsibility for their own lives. Following the critical childhood period, most patients with CCD visit the outpatient clinic only once or twice a year for routine examinations and prescriptions[3]. Moreover, most patients with CCD have previously only been followed by a pediatrician[4], who may not be able to recognize or address psychological problems unique to adulthood. Challenges facing adult patients with CCD, including mental health issues, should be investigated in detail, and psychological counseling may be required to improve a patient’s quality of life.\n\nRegarding the therapeutic management of CCD, substitution using NaCl and KCl involves physiological changes and normally has no side-effects[5]. However, an overdose of KCl can generate severe hyperkalemia, leading to serious sequelae. Although poisoning events using drugs and chemicals are common, reports of potassium poisoning, especially in regard to oral self-poisoning, are rare. There are no large case series concerning potassium overdoses in the medical literature. An extensive medical literature search revealed only 13 case reports involving a total of 19 patients having had slow-release potassium poisoning (Table 1)[4,15-26]. Cases involving fatalities and survivors have both been reported. According to those case reports, even in previously healthy patients, ingestion of more than 20 tablets of slow-release potassium at once can cause severe hyperkalemia to develop over several hours, requiring intensive care. However, it takes a much smaller dose of ingested potassium to produce lethal toxicity in patients with compromised renal function than in those with normal renal function[19]. Although our patient had normal renal function, a relatively high incidence (28%) of chronic kidney disease was reported in a Finnish study of patients with CCD[2].\n\nTable 1 Cases of suicidal poisonings associated with an oral intake of slow-release potassium chloride\n\nRef.\tAge/Sex\tUnderlying disease\tPsychiatric disorder\tAmount of K ingested\tTime (h) from ingestion to arrival at ED\tPeak serum K level (mmol/L)\tSymptoms\tECG findings\tTreatment\tOutcome\t\nIllingworth et al[15], 1980\t36/M\tHypertension treated with thiazide diuretic\tNR\tUnknown\t5\t8.9\tVomoting\tWide QRS complex, hyperacute T-waves, short runs of ventricular tachycardia\tCalcium gluconate, sodium bicarbonate, insulin/glucose, frusemide, ion exchange resin\tSurvived\t\nIllingworth et al[15], 1980\t58/F\tHypertension treated with thiazide diuretic\tNR\t20 T/168 mmol\t5\t9.1\tVomiting, sweating, breathlessness, cyanosis\tHyperacute T-waves, left bundle-branch block\tInsulin/glucose, frusemide, gastric lavage, ion exchange resin\tSurvived\t\nIllingworth et al[15], 1980\t59/F\tNR\tNR\t40 T/320 mmol\t3.5\t9.3\tVomit, cardiac arrest\tAsystole\tGastric lavage\tDied\t\nSaxena[4], 1988\t46/F\tNR\tDepression\t100 T/800 mmol\t1\t9.6\tCardiac arrest\tNR\tCalcium gluconate, sodium bicarbonate, insulin/glucose, gastric lavage, activated charcoal, cathartic\tDied\t\nSteedma[16], 1988\t27/F\tHypokalemia due to anorexia\tAnorexia nervosa\t60 T/480 mmol\t12\t9.1\tCyanosis, cold extremities, poor peripheral pulse\t1st degree heart block, wide QRS complex, hyperacute T-waves\tCalcium gluconate, sodium bicarbonate, insulin/glucose, ion exchange resin\tSurvived\t\nColledge et al[17], 1988\t24/M\tNR\tNR\t100 T/800 mmol\t2\t7.9\tVomiting\tHyperacute T-waves, sinus tachycardia, ventricular tachycardia\tCalcium gluconate, sodium bicarbonate, insulin/glucose, gastric lavage, ion exchange resin\tSurvived\t\nPeeters et al[18], 1998\t62/F\tNR\tDepression\t300 T/2400 mmol\tNR\tNR\tAbdominal distention\tNR\tEndoscopic removal\tSurvived\t\nSu et al[19], 2001\t50/F\tHypertension\tAnxiety disorder, depression\t100 T/1000 mmol\t1\t9.7\tCramping abdominal pain, tachycardia\tHyperacute T-waves\tCalcium chloride, sodium bicarbonate, insulin/glucose, gastric lavage, whole bowel irrigation, hemodialysis\tSurvived\t\n\t17/F\tNone\tNone\t30 T/300 mmol\t10\t6.1\tNausea, vomiting, diarrhea\tTachycardia\tWhole bowel irrigation\tSurvived\t\nWan et al[20], 2007\t86/M\tHypertension treated with thiazide diuretic\tDementia\t70 T/560 mmol\tNR\t6.8\tUnknown\tNo feature of hyperkalemia\tCalcium gluconate, sodium bicarbonate, insulin/glucose\tSurvived\t\nHöjer et al[21], 2008\t28/F1\tUnknown disease with pacemaker in situ\tBorderline personality disorder\t100 C/1000 mmol\t3\t9.2\tCardiac arrest\tPacemaker capture\tCalcium gluconate, sodium bicarbonate, insulin/glucose, gastric lavage, activated charcoal, ion exchange resin, hemodialysis\tSurvived\t\n\t28/F1\tUnknown disease with pacemaker in situ\tBorderline personality disorder\t100 C/1000 mmol\t1\t6.9\tCardiac arrest\tPacemaker rhythm\tCalcium gluconate, sodium bicarbonate, insulin/glucose, gastric lavage, activated charcoal, ion exchange resin\tSurvived\t\n\t28/F1\tUnknown disease with pacemaker in situ\tBorderline personality disorder\t70 C/700 mmol\t2.5\t7.1\tNR\tHyperacute T-waves\tSodium bicarbonate, insulin/glucose, ion exchange resin\tSurvived\t\nBosse et al[22], 2011\t56/F\tNR\tDepression\t60 T/480 mmol\t5\t11\tLethargy\tComplex sine-wave rhythm\tCalcium gluconate, sodium bicarbonate, insulin/glucose\tSurvived\t\nGunja[23], 2011\t42/F2\tNR\tBipolar disorder\t40 T/320 mmol\t1.5\t5.5\tNR\tSinus tachycardia, tall T-waves\tInsulin, whole bowel irrigation\tSurvived\t\n\t42/F2\tNR\tBipolar disorder\t100 T/800 mmol\t5\t8.5\tTachycardia\tSinus tachycardia, tall T-waves\tCalcium chloride, sodium bicarbonate, insulin, hemodialysis\tSurvived\t\nNilsson et al[24], 2012\t30/F\tNR\tDepression\t300 T/3000 mmol\t5\t10.3\tDrowsiness, daze\tSine-wave tachycardia\tCalcium gluconate, sodium bicarbonate, insulin/glucose, gastric lavage, ion exchange resin, hemodialysis, surgical removal\tSurvived\t\nGuillermo et al[25], 2014\t42/F\tNR\tBorderline personality disorder\t100 T/800 mmol\t2\t3.9\tSomnolence\tSinus tachycardia\tGastric lavage, activated charcoal, endoscopic removal\tSurvived\t\nBriggs et al[26], 2014\t44/F\tHypokalemia\tAnxiety disorder\t30 T/600 mmol\t1.25\t7.3\tNR\tMildly peaked T-waves\tCalcium gluconate, sodium bicarbonate, insulin/glucose, whole bowel irrigation, ion exchange resin, endoscopic removal\tSurvived\t\n1,2 : Same patient, respectively; C: Capsule; ECG: Electrocardiogram; ED: Emergency department; F: Female; K: Potassium; M: Male; NR: Not reported; T: Tablet.\n\nTherefore, when a patient with CCD develops a psychiatric disorder that may risk an attempt at suicide, other medication should be considered. However, therapeutic attempts to manage diarrhea using cholestyramine, omeprazole, and butyrate have not been as successful as hoped, suggesting that NaCl and KCl supplementation will continue to be more important than antidiarrheal therapy[1-3,7].\n\nCONCLUSION\nIn patients with CCD, diarrhea is life-long and various extraintestinal issues may also emerge as patients become older unless an optimal radical therapy is established. Therefore, physicians need to pay careful attention not only to patients’ physical conditions but also to their mental health throughout their long-term follow-up, to ensure that any subsequent psychiatric disorders do not adversely affect CCD outcomes.\n\nInformed consent statement: Informed written consent was obtained from the patient for publication of this report.\n\nConflict-of-interest statement: The author declares no conflicts of interest.\n\nCARE Checklist (2016) statement: The author has read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: December 17, 2019\n\nFirst decision: February 26, 2020\n\nArticle in press: April 10, 2020\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: Japan\n\nPeer-review report's scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Cui CY S-Editor: Wang J L-Editor: A E-Editor: Liu JH\n==== Refs\n1 Höglund P Holmberg C Sherman P Kere J Distinct outcomes of chloride diarrhoea in two siblings with identical genetic background of the disease: implications for early diagnosis and treatment Gut 2001 48 724 727 11302976 \n2 Wedenoja S Höglund P Holmberg C Review article: the clinical management of congenital chloride diarrhoea Aliment Pharmacol Ther 2010 31 477 485 19912155 \n3 Hihnala S Höglund P Lammi L Kokkonen J Ormälä T Holmberg C Long-term clinical outcome in patients with congenital chloride diarrhea J Pediatr Gastroenterol Nutr 2006 42 369 375 16641574 \n4 Saxena K Death from potassium chloride overdose Postgrad Med 1988 84 97 98, 101-102 3387363 \n5 Holmberg C Congenital chloride diarrhoea Clin Gastroenterol 1986 15 583 602 3527496 \n6 Holmberg C Perheentupa J Launiala K Hallman N Congenital chloride diarrhoea. Clinical analysis of 21 Finnish patients Arch Dis Child 1977 52 255 267 324405 \n7 Konishi KI Mizuochi T Yanagi T Watanabe Y Ohkubo K Ohga S Maruyama H Takeuchi I Sekine Y Masuda K Kikuchi N Yotsumoto Y Ohtsuka Y Tanaka H Kudo T Noguchi A Fuwa K Mushiake S Ida S Fujishiro J Yamashita Y Taguchi T Yamamoto K Clinical Features, Molecular Genetics, and Long-Term Outcome in Congenital Chloride Diarrhea: A Nationwide Study in Japan J Pediatr 2019 214 151 157.e6 31477378 \n8 Asano K Matsushita T Umeno J Hosono N Takahashi A Kawaguchi T Matsumoto T Matsui T Kakuta Y Kinouchi Y Shimosegawa T Hosokawa M Arimura Y Shinomura Y Kiyohara Y Tsunoda T Kamatani N Iida M Nakamura Y Kubo M A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population Nat Genet 2009 41 1325 1329 19915573 \n9 Engelmann G Erhard D Petersen M Parzer P Schlarb AA Resch F Brunner R Hoffmann GF Lenhartz H Richterich A Health-related quality of life in adolescents with inflammatory bowel disease depends on disease activity and psychiatric comorbidity Child Psychiatry Hum Dev 2015 46 300 307 24838299 \n10 Bernstein CN Hitchon CA Walld R Bolton JM Sareen J Walker JR Graff LA Patten SB Singer A Lix LM El-Gabalawy R Katz A Fisk JD Marrie RA CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease Increased Burden of Psychiatric Disorders in Inflammatory Bowel Disease Inflamm Bowel Dis 2019 25 360 368 29986021 \n11 Butwicka A Olén O Larsson H Halfvarson J Almqvist C Lichtenstein P Serlachius E Frisén L Ludvigsson JF Association of Childhood-Onset Inflammatory Bowel Disease With Risk of Psychiatric Disorders and Suicide Attempt JAMA Pediatr 2019 173 969 978 \n12 Day R Nielsen JA Korten A Ernberg G Dube KC Gebhart J Jablensky A Leon C Marsella A Olatawura M Stressful life events preceding the acute onset of schizophrenia: a cross-national study from the World Health Organization Cult Med Psychiatry 1987 11 123 205 3595169 \n13 Radomsky ED Haas GL Mann JJ Sweeney JA Suicidal behavior in patients with schizophrenia and other psychotic disorders Am J Psychiatry 1999 156 1590 1595 10518171 \n14 Hettige NC Bani-Fatemi A Sakinofsky I De Luca V A biopsychosocial evaluation of the risk for suicide in schizophrenia CNS Spectr 2018 23 253 263 28535835 \n15 Illingworth RN Proudfoot AT Rapid poisoning with slow-release potassium Br Med J 1980 281 485 486 7427333 \n16 Steedman DJ Poisoning with sustained release potassium Arch Emerg Med 1988 5 206 211 3233133 \n17 Colledge NR Northridge B Fraser DM Survival after massive overdose of slow-release potassium Scott Med J 1988 33 279 3175610 \n18 Peeters JW van der Werf SD Gastric stenosis after potassium chloride ingestion Endoscopy 1998 30 S110 9932776 \n19 Su M Stork C Ravuri S Lavoie T Anguish D Nelson LS Hoffman RS Sustained-release potassium chloride overdose J Toxicol Clin Toxicol 2001 39 641 648 11762675 \n20 Wan CK Tong HK A case of slow release potassium chloride overdose Hong Kong J Emerg Med 2007 14 169 173 \n21 Höjer J Forsberg S Successful whole bowel irrigation in self-poisoning with potassium capsules Clin Toxicol (Phila) 2008 46 1102 1103 18951269 \n22 Bosse GM Platt MA Anderson SD Presley MW Acute oral potassium overdose: the role of hemodialysis J Med Toxicol 2011 7 52 56 20721655 \n23 Gunja N Decontamination and enhanced elimination in sustained-release potassium chloride poisoning Emerg Med Australas 2011 23 769 772 22151677 \n24 Nilsson TS Malmgren J Knudsen K Parallel haemodialysis and surgery saves a life after massive overdose of potassium pills BMJ Case Rep 2012 2012 \n25 Guillermo PTJ Carlos PHJ Ivonne BAM Herminio TF Rubén RP Extended release potassium salts overdose and endoscopic removal of a pharmacobezoar: A case report Toxicol Rep 2014 1 209 213 28962240 \n26 Briggs AL Deal LL Endoscopic removal of pharmacobezoar in case of intentional potassium overdose J Emerg Med 2014 46 351 354 24113476\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "8(8)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Congenital chloride diarrhea; Potassium overdose; Schizophrenia; Substitution therapy; Suicide",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "1463-1470",
"pmc": null,
"pmid": "32368538",
"pubdate": "2020-04-26",
"publication_types": "D002363:Case Reports",
"references": "16641574;3387363;3233133;11762675;19915573;18951269;28962240;29986021;20721655;11302976;28535835;9932776;24113476;3527496;31424531;7427333;22151677;3595169;31477378;22778452;324405;3175610;24838299;10518171;19912155",
"title": "Suicide attempt using potassium tablets for congenital chloride diarrhea: A case report.",
"title_normalized": "suicide attempt using potassium tablets for congenital chloride diarrhea a case report"
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"companynumb": "JP-PRINSTON PHARMACEUTICAL INC.-2020PRN00235",
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"abstract": "Providing medical care for participants in clinical trials in resource-limited settings can be challenging and costly. Evaluation and treatment of a young man who developed cervical lymphadenopathy during a malaria vaccine trial in Equatorial Guinea required concerted efforts of a multinational, multidisciplinary team. Once a diagnosis of diffuse large B-cell lymphoma was made, the patient was taken to India to receive immunochemotherapy. This case demonstrates how high-quality medical care was provided for a serious illness that occurred during a trial that was conducted in a setting in which positron emission tomography for diagnostic staging, an oncologist for supervision of treatment, and an optimal therapeutic intervention were not available. Clinical researchers should anticipate the occurrence of medical conditions among study subjects, clearly delineate the extent to which health care will be provided, and set aside funds commensurate with those commitments.",
"affiliations": "Sanaria, Inc., Rockville, Maryland.;Ifakara Health Institute, Bagamoyo, Tanzania.;Ministry of Health and Social Welfare, Malabo, Equatorial Guinea.;KEMRI Wellcome Trust Research Programme, Kilifi, Kenya.;Ifakara Health Institute, Bagamoyo, Tanzania.;Medical Care Development International, Malabo, Equatorial Guinea.;Medical Care Development International, Malabo, Equatorial Guinea.;Medical Care Development International, Silver Spring, Maryland.;Medical Care Development International, Malabo, Equatorial Guinea.;Medical Care Development International, Silver Spring, Maryland.;La Paz Medical Center, Malabo, Equatorial Guinea.;La Paz Medical Center, Malabo, Equatorial Guinea.;La Paz Medical Center, Malabo, Equatorial Guinea.;Policlínico Dr. Loeri Comba, Instituto de Seguridad Social, Malabo, Equatorial Guinea.;University of Maryland Medical Center, Baltimore, Maryland.;University of Maryland Medical Center, Baltimore, Maryland.;Cytecare Cancer Hospital, Bengaluru, Karnataka, India.;Sanaria, Inc., Rockville, Maryland.;Ministry of Health and Social Welfare, Malabo, Equatorial Guinea.;Sanaria, Inc., Rockville, Maryland.;Ifakara Health Institute, Bagamoyo, Tanzania.;Sanaria, Inc., Rockville, Maryland.;Sanaria, Inc., Rockville, Maryland.",
"authors": "Manock|Stephen R|SR|;Mtoro|Ali|A|;Urbano Nsue Ndong|Vicente|V|;Olotu|Ally|A|;Chemba|Mwajuma|M|;Sama Roca|Antonio E|AE|;Eburi|Esther|E|;García|Guillermo A|GA|;Cortes Falla|Carlos|C|;Niemczura de Carvalho|Julie|J|;Contreras|Jaime|J|;Saturno|Baltasar|B|;Riocalo|Juan de Dios|JD|;Nze Mba|José Luis|JL|;Koka|Rima|R|;Lee|Seung Tae|ST|;Menon|Hari|H|;Church|L W Preston|LWP|;Ayekaba|Mitoha Ondo'o|MO|;Billingsley|Peter F|PF|;Abdulla|Salim|S|;Richie|Thomas L|TL|;Hoffman|Stephen L|SL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.20-1178",
"fulltext": "\n==== Front\nAm J Trop Med Hyg\nAm J Trop Med Hyg\ntpmd\ntropmed\nThe American Journal of Tropical Medicine and Hygiene\n0002-9637 1476-1645 The American Society of Tropical Medicine and Hygiene \n\n33236704\ntpmd201178\n10.4269/ajtmh.20-1178\nArticles\nProviding Ancillary Care in Clinical Research: A Case of Diffuse Large B-Cell Lymphoma during a Malaria Vaccine Trial in Equatorial Guinea\nManock Stephen R. 12* Mtoro Ali 3 Urbano Nsue Ndong Vicente 4 Olotu Ally 35 Chemba Mwajuma 3 Sama Roca Antonio E. 6 Eburi Esther 6 García Guillermo A. 7 Cortes Falla Carlos 6 Niemczura de Carvalho Julie 7 Contreras Jaime 8 Saturno Baltasar 8 Riocalo Juan de Dios 8 Nze Mba José Luis 9 Koka Rima 10 Lee Seung Tae 10 Menon Hari 11 Church L. W. Preston 1 Ayekaba Mitoha Ondo’o 4 Billingsley Peter F. 1 Abdulla Salim 3 Richie Thomas L. 1 Hoffman Stephen L. 1 1 Sanaria, Inc., Rockville, Maryland;\n2 Department of Family Medicine, John Peter Smith Hospital, Fort Worth, Texas;\n3 Ifakara Health Institute, Bagamoyo, Tanzania;\n4 Ministry of Health and Social Welfare, Malabo, Equatorial Guinea;\n5 KEMRI Wellcome Trust Research Programme, Kilifi, Kenya;\n6 Medical Care Development International, Malabo, Equatorial Guinea;\n7 Medical Care Development International, Silver Spring, Maryland;\n8 La Paz Medical Center, Malabo, Equatorial Guinea;\n9 Policlínico Dr. Loeri Comba, Instituto de Seguridad Social, Malabo, Equatorial Guinea;\n10 University of Maryland Medical Center, Baltimore, Maryland;\n11 Cytecare Cancer Hospital, Bengaluru, Karnataka, India\n* Address correspondence to Stephen R. Manock, Department of Family Medicine, John Peter Smith Hospital, 1500 S. Main St., OPC Bldg., 4th floor, Fort Worth, TX 76104. E-mail: smanock@jpshealth.orgDisclosure: S. L. H., T. L. R., P. F. B., and L. W. P. C. are employed by Sanaria, Inc., which developed PfSPZ Vaccine and PfSPZ-CVac. S. R. M. was employed by Sanaria, Inc. at the time of the clinical trial, but was not at the time the manuscript was prepared and submitted. A. O. was the recipient of a U.K. Medical Research Council African Research Leader award for work unrelated to this manuscript.\n\nDisclaimer: Funders did not contribute to study design, or to the collection, analysis, or interpretation of data, the writing of the manuscript, or the decision to submit it for publication.\n\nFinancial support: The government of Equatorial Guinea, Marathon E.G. Production Limited, Noble Energy Equatorial Guinea, and Atlantic Methanol Production Company LLC provided funding for the clinical trial and treatment of this patient.\n\nAuthors’ addresses: Stephen R. Manock, Department of Family Medicine, John Peter Smith Hospital, Fort Worth, TX and Sanaria, Inc., Rockville, MD, E-mail: smanock@jpshealth.org. Ali Mtoro, Mwajuma Chemba, and Salim Abdulla, Ifakara Health Institute, Bagamoyo, Tanzania, E-mails: amtoro@ihi.or.tz, mchemba@ihi.or.tz, and sabdulla@ihi.or.tz. Vicente Urbano Nsue Ndong and Mitoha Ondo’o Ayekaba, Ministry of Health and Social Welfare, Malabo, Equatorial Guinea, E-mails: viceurb2013@gmail.com and mitoha_ondo@yahoo.com. Ally Olotu, Ifakara Health Institute, Bagamoyo, Tanzania and KEMRI Wellcome Trust Research Programme, Kilifi, Kenya. E-mails: ndaskoiolotu@gmail.com or aolotu@ihi.or.tz. Antonio E. Sama Roca, Esther Eburi, and Carlos Cortes Falla, Medical Care Development International, Malabo, Equatorial Guinea, E-mails: rocantony@gmail.com, eeburi@mcd.org, and ccortes@mcd.org. Guillermo A. García and Julie Niemczura de Carvalho, Medical Care Development International, Silver Spring, MD, E-mails: ggarcia@mcd.org and jniemczura@mcd.org. Jaime Contreras, Baltasar Saturno, and Juan de Dios Riocalo, La Paz Medical Center, Malabo, Equatorial Guinea, E-mails: jaimecdoc@gmail.com, baltasarsaturno@gmail.com, and doctorriocalo@gmail.com. José Luis Nze Mba, Policlínico Dr. Loeri Comba, Instituto de Seguridad Social, Malabo, Equatorial Guinea, E-mail: joseluisnzemba@gmail.com. Rima Koka and Seung Tae Lee, University of Maryland Medical Center, Baltimore, MD, E-mails: mkoka@umm.edu and seunglee@umm.edu. Hari Menon, Cytecare Cancer Hospital, Bengaluru, Karnataka, India, E-mail: hari.menon@cytecare.com. L. W. Preston Church, Peter F. Billingsley, Thomas L. Richie, and Stephen L. Hoffman, Sanaria, Inc., Rockville, MD, E-mails: lwpchurch@sanaria.com, pbillingsley@sanaria.com, trichie@sanaria.com, and slhoffman@sanaria.com.\n\n\n2 2021 \n23 11 2020 \n23 11 2020 \n104 2 695 699\n10 9 2020 25 9 2020 © The American Society of Tropical Medicine and Hygiene2021This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Abstract.\nProviding medical care for participants in clinical trials in resource-limited settings can be challenging and costly. Evaluation and treatment of a young man who developed cervical lymphadenopathy during a malaria vaccine trial in Equatorial Guinea required concerted efforts of a multinational, multidisciplinary team. Once a diagnosis of diffuse large B-cell lymphoma was made, the patient was taken to India to receive immunochemotherapy. This case demonstrates how high-quality medical care was provided for a serious illness that occurred during a trial that was conducted in a setting in which positron emission tomography for diagnostic staging, an oncologist for supervision of treatment, and an optimal therapeutic intervention were not available. Clinical researchers should anticipate the occurrence of medical conditions among study subjects, clearly delineate the extent to which health care will be provided, and set aside funds commensurate with those commitments.\n==== Body\nINTRODUCTION\nAddressing health conditions that arise during clinical trials in places with less than comprehensive medical systems can be difficult. Debate exists about whether and to what extent researchers have obligations to provide ancillary care to study participants, that is, medical care that is needed but not necessary to prevent or mitigate harm caused by participation in research, or answer questions that are the focus of the study.1–4 The evaluation and treatment of serious illnesses can incur a substantial burden in terms of researchers’ time and funds.2\n\nWe report a case of diffuse large B-cell lymphoma that was diagnosed during a double-blind, placebo-controlled trial of whole sporozoite candidate malaria vaccines PfSPZ Vaccine5–10 and PfSPZ-CVac11 in Equatorial Guinea (ClinicalTrials.gov number NCT02859350). The study was approved by the Comité Ético Nacional de Guinea Equatorial, additionally reviewed by the MaGil Institutional Review Board (IRB) in Rockville, MD, the Ifakara Health Institute IRB in Tanzania, and the Ethics Committee of Northwestern and Central Switzerland (EKNZ), and was conducted under a U.S. Food and Drug Administration Investigational New Drug application. All study participants underwent an informed consent process, had a thorough medical history, physical examination and laboratory screening, and were deemed healthy before being enrolled. The study protocol specified that participants would receive general outpatient healthcare services from Equatoguinean study physicians at the research center during the course of the trial. In case of medical conditions that required more specialized or inpatient care, a referral would be made to a tertiary care hospital near the research center (La Paz Medical Center). If the cost of treatment for an illness unrelated to study participation exceeded the amount budgeted for medical care by the trial, the participant would be responsible for obtaining this care through the Ministry of Health and Social Welfare of Equatorial Guinea. Provision of health care beyond the scope of services provided in the country was not anticipated in the study protocol or the informed consent form, and the ethics committees did not provide specific guidelines on the topic.\n\nCASE REPORT\nA previously healthy young adult male subject developed tender left posterior cervical lymph nodes 3 weeks after administration of his first dose of investigational product (later determined to be normal saline placebo). The initial diagnosis was acute bacterial lymphadenitis, and treatment with oral amoxicillin and ibuprofen was given by a study physician. When the lymphadenopathy slowly progressed over the next 2 months, a referral was made to an internist at La Paz Medical Center. There the patient was found to have eosinophilia, a positive toxoplasmosis IgG titer, and mild cervical, supraclavicular, axillary, mesenteric and mediastinal lymphadenopathy by computerized tomography (CT). The patient was referred to the national tuberculosis (TB) program for empiric treatment of suspected TB lymphadenitis. Oral isoniazid, rifampin, pyrazinamide, and ethambutol were given for 4 weeks, during which time the cervical lymph nodes increased in size. Oral trimethoprim–sulfamethoxazole and clindamycin were then given for 10 days for possible toxoplasmosis, but following treatment, the left cervical lymph nodes had enlarged to 10 cm in diameter (see Figure 1), and cervical lymph nodes were now also palpable on the right. The patient complained of left-sided neck pain that radiated down the left arm, throat discomfort with swallowing, and feeling feverish at night. There had been a weight loss of 3 kg over the preceding 2 months, but no sweats or impairment of breathing. A lymph node biopsy was performed at La Paz Medical Center and sent to Policlínico Dr. Loeri Comba in Malabo, Equatorial Guinea, where the pathologist diagnosed a non-Hodgkin lymphoma. Biopsy material was hand-carried to the University of Maryland Medical Center where further testing narrowed the diagnosis to diffuse large B-cell lymphoma. The study team had determined that there were no oncologists and no options for immunochemotherapy in Equatorial Guinea and were concerned that the patient would likely die without treatment. After a search for potential treatment centers, it was established that the Cytecare Cancer Hospital in Bangalore, India, was well-equipped to provide high-quality care for the patient. Oncologists at the University of Maryland and Cytecare agreed that the best treatment would be six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Eleven days after his diagnosis was made, the patient arrived in Bangalore accompanied by his cousin and the research study’s head nurse. The nurse remained with the patient during his first 10 days of evaluation and treatment. Full-body positron emission tomography (PET) showed diffuse hypermetabolic activity and lymphadenopathy. Lactate dehydrogenase was elevated, but there was no anemia and no evidence of extranodal involvement. The patient was determined to have stage IIIBx disease with a Revised International Prognostic Index of 2, predictive of a 4-year overall survival rate of 79% with treatment.12 For the next 4 months, the patient lived in Bangalore with his cousin. He received six cycles of R-CHOP as an outpatient with only mild side effects, and there was a rapid reduction in the size of his cervical lymph nodes. A posttreatment PET scan showed resolution or regression of all previously observed lymphadenopathy and a complete metabolic response to immunochemotherapy, but some new right hilar lymphadenopathy and a small right pleural effusion were seen. Thoracentesis was performed. The pleural fluid was exudative and showed numerous leukocytes (primarily lymphocytes), with no bacteria seen on Gram stain, a negative smear for acid-fast bacilli (AFB), and a negative bacterial culture. Cytopathology carried out on the pleural fluid showed predominantly lymphoid cells which expressed CD3, but not CD20 or CD79a, markers, which was felt to be inconsistent with malignancy. Five days later, the right pleural effusion had increased in size, prompting repeat thoracentesis. Pleural fluid adenosine deaminase activity was elevated, but GeneXpert and a repeat AFB smear were negative. The presumptive diagnosis was pleural TB, possibly secondary to reactivation of previously unrecognized latent TB post-immunochemotherapy. Treatment was begun with oral isoniazid, rifampin, pyrazinamide, and ethambutol. A follow-up ultrasound performed after 2 weeks of therapy showed near resolution of the pleural effusion, supporting the diagnosis of TB. The patient traveled home to Equatorial Guinea 2 days later, where he was promptly referred to the national TB program to complete 6 months of standard directly observed therapy. Physical examination by a physician was advised every 3 months for surveillance, with ultrasound or CT evaluation of any clinical recurrence of cervical lymphadenopathy, or symptoms suggesting intra-abdominal lymphadenopathy. Given his excellent clinical and radiological response to therapy, he was estimated to have a 50–60% likelihood of complete cure.13 The total cost of evaluation and treatment of this patient at Cytecare was 10,521 U.S. dollars, plus an additional 36,128 U.S. dollars for airfare, travel documents, housing, and living expenses in India for the patient, his cousin, and the study head nurse. It was agreed, in writing, that the cost of any future medical care would be the responsibility of the patient and his family. As of 32 months after his final dose of immunochemotherapy, the patient was free of clinical signs and symptoms of lymphoma.\n\nFigure 1. Subject with prominent, progressive cervical lymphadenopathy following treatment for suspected bacterial lymphadenitis, tuberculous lymphadenitis, and toxoplasmosis. This figure appears in color at www.ajtmh.org.\n\nDISCUSSION\nAddressing medical needs that arise during the course of clinical research can be challenging, particularly in resource-limited settings which lack state-of-the-art healthcare services for serious conditions that arise during the course of the trial but are not related to trial participation. There has been considerable debate about whether researchers have an ethical duty to provide care to study subjects, particularly for conditions that are unrelated to their participation in research.1,4,14–16 Some have argued that providing ancillary medical care has the potential to compromise and overwhelm research studies,1,4,15 and that requiring such care could potentially discourage researchers from working in underserved populations.4 Merritt et al.17 propose that nonclinical, public health researchers may be less obliged to address health needs if they do not have the needed expertise to address the problem, particularly if the costs of doing so are inordinate, or other organizations are available to meet the need. Others debate whether incidental medical findings must even be reported to study participants, or referrals be made for further evaluation and treatment.18 Garrett15 optimistically suggests that research protocols be designed to minimize or eliminate the possibility of incidental findings.\n\nEthical arguments in support of an obligation to provide ancillary care tend to be based on the duty of rescue, which holds that everyone has a responsibility to render life-saving assistance to others in need if it is within their power to do so,1,14,16,19,20 provided that this does not incur “serious sacrifice or risk”1 or “conflict with some weighty moral aim.”16 Beyond that general duty, it has been suggested that by granting permission to study their body and its functions, subjects “effectively entrust the researchers with special responsibilities to look after the needs they discover.”21 Ancillary medical care has been called “morally obligatory,”22 and “an integral and necessary part of ethical research with human beings,” particularly if conditions are severe, acute, and/or would have serious consequences if left unmet.3 It has been proposed that an increased responsibility to provide care exists in situations where researchers have a long-term, professional relationship with study participants,3,4 where doing so is within the expertise of the team,4 or when researchers are “in a unique position to help participants.”2 Some have suggested that the duty to address health needs must be anticipated during the planning of research studies, and funds specifically budgeted to provide ancillary care.1,2 In the case of the current study, 166,373 U.S. dollars was allotted as self-insurance for healthcare expenditure for all 135 trial participants, although this did not include a provision for sending patients and staff overseas. Obtaining commercial medical insurance for each research subject would have been another option, although in most cases, this would be prohibitively expensive. In the end, a total of 120,308 U.S. dollars was spent on medical care for all subjects in this study, notwithstanding the unexpected costs of treatment abroad for this patient with lymphoma.\n\nThere is disagreement among those who hold the position that researchers have an obligation to address the health needs of study participants as to the extent of ancillary care that is required. Dickert and Wendler4 propose potential levels of ancillary care: providing diagnostic information, making referrals for care, providing treatment, or paying for treatment. They note that obligations to provide care may be limited by the researchers’ level of expertise or if the care is prohibitively expensive. It has been argued that researchers do not necessarily have a responsibility to provide fully comprehensive medical care to study participants.2 Furthermore, debate exists as to whether researchers from high-income countries should be required to provide the same level of care that is available in their home countries, or whether “it is ethically acceptable to provide treatments based on what is routinely available in the host country.”23 Benatar and Singer have argued that although providing the same standard of care in resource-limited countries as in the industrialized world may not be realistic, the goal should be to provide the highest achievable level of care.24 They propose that this should include providing subjects with treatment that would not ordinarily be available to them in the country where the trial is being carried out. Establishing strict rules as to what level of ancillary care is universally required of researchers working in resource-limited settings has proven to be exceedingly difficult.4,16\n\nIn the current case, the provision of in-country ancillary care for study participants was anticipated and budgeted. The study protocol established that comprehensive primary care would be provided free of charge by physicians at the research center. Healthcare needs that could not be addressed by study physicians were to be referred for appropriate specialty care, and this care was also to be paid for by the trial. Treatment for conditions unrelated to trial participation that exceeded the medical care budget of the study was to have been sought through the Ministry of Health and Social Welfare. However, after months of professional interaction with this participant, study physicians were faced with the challenge of securing potentially life-saving treatment for his lymphoma in a country without PET scanning for diagnostic staging, an oncologist, or the availability of immunochemotherapy. The need for medical care outside the country had not been specifically foreseen, but there were funds set aside for medical emergencies as stated previously. The mean cost of the initial 5 months of treatment for patients with diffuse large B-cell lymphoma in the United States was estimated to be 72,010 U.S. dollars,25 plus an estimated 56,500 U.S. dollars for airfare, travel documents, lodging, and living expenses in the Washington, D.C. area.26 This is nearly three times the total expense of being treated in Bangalore and would have been cost-prohibitive. Thus, being able to obtain reasonably priced, high-quality care in India was critical in this case. India is a well-known destination for medical care and has an established infrastructure to receive large numbers of foreign patients,27–29 with a sizable proportion traveling there from Africa.30 Although the cost of care, travel, and an extended stay in India was not anticipated, they could be accommodated within the budget of a properly funded research program.\n\nBeyond financial costs, it should be recognized that the successful evaluation and treatment of this study participant required a large investment of time and effort by a multinational, multidisciplinary team. Local medical resources were used to the fullest extent possible and included primary care, evaluation at a tertiary care hospital, surgical referral for biopsy, pathology consultation, and TB care. Remote consultations with oncology, pathology, and infectious disease specialists in the United States occurred during his clinical course. Considerable administrative support was required to secure passports and visas, and arrange for overseas travel, lodging in India, provision of per diems, and payment of hospital bills. Our head nurse’s presence in India during the initial days of treatment was instrumental in transitioning care to the oncologist there. Several study team members—administrators, community outreach workers, nurses, and physicians—maintained ongoing communication with the patient during his stay in India, to encourage him and ensure that his needs were being met. Finally, staff at Cytecare Cancer Hospital in Bangalore provided excellent oncology care and a thorough diagnostic workup for the pleural effusion that developed late in the patient’s course, all the while fielding inquiries from the study sponsor in the United States and the research team in Equatorial Guinea.\n\nIn addition to ethical and humanitarian considerations, securing definitive medical care for this lymphoma patient had pragmatic benefits for the malaria vaccine research program. This study was part of a series of clinical trials financed by the government of Equatorial Guinea and international oil and gas companies working in the country. Providing high-quality medical care beyond what was required by the study protocol and consent form was viewed positively by all stakeholders. So rather than detracting from research, this relatively large expenditure on the health of one study participant may serve to further the goals of the overall research program. Others have noted that providing ancillary care is a wise investment when researchers intend to conduct a series of studies with the same population.3\n\nThere are potential pitfalls to providing the sort of comprehensive, specialized care that this lymphoma patient received. Offering free medical care could serve as an inducement to participate in a clinical trial, particularly in settings where health care is difficult to access.3,23 Such an inducement could tempt potential subjects to conceal significant medical conditions at the time of study enrollment to improve their access to otherwise costly care. Also, the provision of comprehensive health care to study participants, and not to others in the community who may have limited access, might run counter to the ethical principal of justice. Perhaps, more equitable approaches that would improve care for the larger population, and not just study subjects, should be sought.15 Finally, there is a concern that providing this level of health care to some individuals in a clinical trial could distract the attention of researchers, thereby compromising the quality of data collection or the safety of other study participants.\n\nIn summary, this is an example of excellent medical care being provided for a study participant who developed a life-threatening illness during a clinical trial in a setting that lacked the healthcare services required for provision of optimal medical treatment for his condition. This case highlights the importance of clinical investigators anticipating such occurrences and deciding before initiation of the trial what their responses to such illnesses will be. Regardless of what the final decision is, the plan should be clearly communicated in the informed consent form, the protocol, and clinical trial agreements. If the decision is made to provide ancillary care, funds must be set aside in advance for its support.\n\nAcknowledgments:\nWe thank the entire Equatorial Guinea Malaria Vaccine Initiative team for their work on the clinical trial, as well as Matilde Riloha Rivas, director of the national malaria control program of the Equatorial Guinea Ministry of Health and Social Welfare, and the Comité Ético Nacional de Guinea Equatorial (CENGE) for their oversight. We are grateful to members of the Data and Safety Monitoring Board for the clinical trial: James Campbell (chair), Feliciano Panades Shumad (local safety monitor), Alberto L. Garcia-Basteiro, Brian Greenwood, and Mark Riddle. The University of Maryland Medical Center staff donated their services and expertise at no charge. We also thank the study subject’s cousin for his moral support during a protracted stay in India. Kellie Boyd and Timothy Kenney of the John S. Marietta Memorial Medical Library at JPS Health Network provided assistance with a literature search. Finally, we are grateful to bioethicist Seema K. Shah for her very helpful review of this manuscript.\n==== Refs\nREFERENCES\n1. Merritt MW , 2011 \nHealth researchers’ ancillary care obligations in low-resource settings: how can we tell what is morally required?\n\nKennedy Inst Ethics J \n21 : 311 –347\n.22187929 \n2. Belsky L Richardson HS , 2004 \nMedical researchers’ ancillary clinical care responsibilities\n. BMJ \n328 : 1494 –1496\n.15205296 \n3. Participants in 2006 Georgetown University Workshop on Ancillary-Care Obligations of Medical Researchers Working in Developing Countries , 2008 \nThe ancillary-care obligations of medical researchers working in developing countries\n. PLoS Med \n5 : e90 .18494553 \n4. Dickert N Wendler D , 2009 \nAncillary care obligations of medical researchers\n. JAMA \n22 : 424 –428\n.\n5. Seder RA \n2013 \nProtection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine\n. Science \n341 : 1359 –1365\n.23929949 \n6. Ishizuka AS \n2016 \nProtection against malaria at 1 year and immune correlates following PfSPZ vaccination\n\nNat Med \n22 : 614 –623\n.27158907 \n7. Epstein JE \n2017 \nProtection against Plasmodium falciparum malaria by PfSPZ vaccine\n. JCI Insight \n2 : e89154 .28097230 \n8. Lyke KE \n2017 \nAttenuated PfSPZ vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection\n. Proc Natl Acad Sci U S A \n114 : 2711 –2716\n.28223498 \n9. Sissoko MS \n2017 \nSafety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial\n. Lancet Infect Dis \n17 : 498 –509\n.28216244 \n10. Jongo SA \n2019 \nSafety and differential antibody and T-cell responses to the Plasmodium falciparum sporozoite malaria vaccine, PfSPZ vaccine, by age in Tanzanian adults, adolescents, children, and infants\n. Am J Trop Med Hyg \n100 : 1433 –1444\n.30994090 \n11. Mordmüller B \n2017 \nSterile protection against human malaria by chemoattenuated PfSPZ vaccine\n. Nature \n542 : 445 –449\n.28199305 \n12. Sehn LH \n2007 \nThe revised international prognostic index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP\n. Blood \n109 : 1857 –1861\n.17105812 \n13. Ziepert M Hasenclever D Kuhnt E Glass B Schmitz N Pfreundschuh M Loeffler M , 2010 \nStandard international prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era\n. J Clin Oncol \n28 : 2373 –2380\n.20385988 \n14. Rulli T Millum J , 2016 \nRescuing the duty to rescue\n. J Med Ethics \n42 : 260 –264\n.24790055 \n15. Garrett JR , 2015 \nCollectivizing rescue obligations in bioethics\n. Am J Bioeth \n15 : 3 –11\n.\n16. MacKay D Rulli T , 2017 \nThe duty to rescue and investigators’ obligations\n. Kennedy Inst Ethics J \n27 : 71 –105\n.28366904 \n17. Merritt MW Taylor HA Mullany LC , 2010 \nAncillary care in community-based public health intervention research\n. Am J Public Health \n100 : 211 –216\n.20019298 \n18. Miller FG Mello MM Joffe S , 2008 \nIncidental findings in human subjects research: what do investigators owe research participants?\n\nJ L Med Ethics \n36 : 271 –279\n.\n19. Scanlon TM , 1998 \nWhat We Owe to Each Other . Cambridge, MA : Harvard University Press , 224 .\n20. Richardson HS Belsky L , 2004 \nThe ancillary-care responsibilities of medical researchers. An ethical framework for thinking about the clinical care that researchers owe their subjects\n. Hastings Cent Rep \n34 : 25 –33\n.15098404 \n21. Richardson HS , 2012 \nMoral Entanglements: the Ancillary-Care Obligations of Medical Researchers . New York, NY : Oxford University Press , 35 .\n22. Richardson HS , 2012 \nMoral Entanglements: the Ancillary-Care Obligations of Medical Researchers . New York, NY : Oxford University Press .\n23. Nuffield Council on Bioethics , 1999 \nThe Ethics of Clinical Research in Developing Countries: A Discussion Paper . Available at: http://nuffieldbioethics.org/wp-content/uploads/Clinical-research-in-developing-countries-Discussion-Paper.pdf. Accessed April 4, 2019 .\n24. Benatar SR Singer PA , 2000 \nA new look at international research ethics\n. BMJ \n321 : 824 –826\n.11009528 \n25. Morrison VA Bell JA Hamilton L Ogbonnaya A Shih HC Hennenfent K Eaddy M Shou Y Galaznik A , 2018 \nEconomic burden of patients with diffuse large B-cell and follicular lymphoma treated in the USA\n. Future Oncol \n14 : 2627 –2642\n.29911900 \n26. GSA.gov , 2019 \nLodging and Per Diem Costs in the Washington, D.C. Area . Available at https://www.gsa.gov/travel/plan-book/per-diem-rates/per-diem-rates-lookup/?action=perdiems_report&state=DC&fiscal_year=2018&zip=&city=. Accessed August 21, 2019 .\n27. Runnels V Turner L , 2011 \nBioethics and transnational medical travel: India, “medical tourism,” and the globalisation of healthcare\n. Indian J Med Ethics \n8 : 42 –44\n.22106599 \n28. Mudur G , 2004 \nHospitals in India woo foreign patients\n. BMJ \n328 : 1338 .\n29. Chinai R Goswami R , 2007 \nMedical visas mark growth of Indian medical tourism\n. Bull World Health Organ \n85 : 164 –165\n.17486202 \n30. Gupta V Das P , 2012 \nMedical tourism in India\n. Clin Lab Med \n32 : 321 –325\n.22727009\n\n",
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"title": "Providing Ancillary Care in Clinical Research: A Case of Diffuse Large B-Cell Lymphoma during a Malaria Vaccine Trial in Equatorial Guinea.",
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"abstract": "The first cases of COVID-19 infection were reported in December, 2019, in Wuhan, China. Italy (in particular Lombardy) and France (in particular Northeast) have been gravely hit. Both physicians and inflammatory bowel disease (IBD) patients are deeply concerned that immunosuppressants or biologics may increase the risk of COVID-19 infection. IOIBD has put in place an international registry, SECURE-IBD, for tracking all the cases with IBDs infected by COVID-19 (SECURE-IBD registry: http://www.covidibd.org). It will describe the outcomes of infected patients and the association between IBD-related medications and these outcomes.",
"affiliations": "Humanitas Clinical and Research Center, Istituto di ricovero e cura a carattere scientifico, Rozzano, Milan, Italy; Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy. Electronic address: mariangela.allocca@humanitas.it.;Humanitas Clinical and Research Center, Istituto di ricovero e cura a carattere scientifico, Rozzano, Milan, Italy; Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy.;Department of Gastroenterology, Inserm U1256 Nutrition - génétique et exposition aux risques environnementaux, Nancy University Hospital, Lorraine University, Vandoeuvre-les-Nancy, France.;Humanitas Clinical and Research Center, Istituto di ricovero e cura a carattere scientifico, Rozzano, Milan, Italy.;Humanitas Clinical and Research Center, Istituto di ricovero e cura a carattere scientifico, Rozzano, Milan, Italy.;Humanitas Clinical and Research Center, Istituto di ricovero e cura a carattere scientifico, Rozzano, Milan, Italy.;Humanitas Clinical and Research Center, Istituto di ricovero e cura a carattere scientifico, Rozzano, Milan, Italy; Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy.;Department of Gastroenterology, Inserm U1256 Nutrition - génétique et exposition aux risques environnementaux, Nancy University Hospital, Lorraine University, Vandoeuvre-les-Nancy, France.",
"authors": "Allocca|Mariangela|M|;Fiorino|Gionata|G|;Zallot|Camille|C|;Furfaro|Federica|F|;Gilardi|Daniela|D|;Radice|Simona|S|;Danese|Silvio|S|;Peyrin-Biroulet|Laurent|L|",
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"title": "Incidence and Patterns of COVID-19 Among Inflammatory Bowel Disease Patients From the Nancy and Milan Cohorts.",
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"abstract": "Lutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.\nWe tracked adverse effects and patient experience in our first year of therapy experience with this new agent.\nIn our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.\nFlare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.",
"affiliations": "Department of Radiation Oncology, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut.;Department of Radiation Oncology, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut.;Department of Oncology Nursing, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut.;Department of Oncology Pharmacy, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut.;Department of Radiation Oncology, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut.",
"authors": "Salner|Andrew L|AL|;Blankenship|Bette|B|;Dunnack|Hayley|H|;Niemann|Christopher|C|;Bertsch|Helaine|H|",
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"fulltext": "\n==== Front\nAdv Radiat Oncol\nAdv Radiat Oncol\nAdvances in Radiation Oncology\n2452-1094 Elsevier \n\nS2452-1094(20)30353-5\n10.1016/j.adro.2020.11.008\n100623\nBrief Opinion\nLutetium Lu-177 Dotatate Flare Reaction\nSalner Andrew L. MDandrew.salner@hhchealth.orga∗ Blankenship Bette MSa Dunnack Hayley BSN, RN, OCNb Niemann Christopher PharmDc Bertsch Helaine MDa a Department of Radiation Oncology, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut\nb Department of Oncology Nursing, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut\nc Department of Oncology Pharmacy, Hartford HealthCare Cancer Institute at Hartford Hospital, Hartford, Connecticut\n∗ Corresponding author: Andrew L. Salner, MD andrew.salner@hhchealth.org\n26 11 2020 \nJan-Feb 2021 \n26 11 2020 \n6 1 1006236 5 2020 11 11 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nLutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.\n\nMethods and Materials\nWe tracked adverse effects and patient experience in our first year of therapy experience with this new agent.\n\nResults\nIn our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.\n\nConclusions\nFlare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.\n==== Body\nIntroduction\nThe advent of peptide receptor radionuclide therapy (PRRT) has provided clinicians with new therapeutic strategies to treat patients with neoplasms for which treatment is less effective and where fewer options remain.1 These therapies offer a molecularly targeted means of delivering precise radiation therapy to the tumors, which are frequently metastatic and resistant to other conventional therapies. Gastroenteropancreatic neuroendocrine tumors (GEP NETs) exemplify a group of tumors that are challenging due to a high likelihood of recurrence and metastasis, and relatively few active therapies that can cause meaningful progression free survival.2 The first of these therapies approved by the US Food and Drug Administration is Lutetium Lu-177 Dotatate (TM Lutathera), an agent that includes a dotatate moiety, which binds tightly to somatostatin receptors on NET cells, and the beta-emitting radionuclide Lutetium-177, with a half-life of 6.7 days and a maximum beta range of 2 mm in tissue. This agent has been used in Europe for many years, and landmark studies have demonstrated substantial improvements in response rates and progression free survival in the GEP NET patient population.3,4 There have also been demonstrable improvements in quality of life.5 Several adverse reactions to this therapy have been reported, including renal, hepatic, and hematologic injury, and increased risk of late organ injury and secondary neoplasms.3,6, 7, 8, 9, 10 In this report, we document a flare reaction in 5 of our initial 12 patients treated and suggest therapeutic strategies to help mitigate this reaction. Although various toxicities including renal, hematologic and gastrointestional have been reported in the literature, flare reaction and suggested mitigation strategies have not been widely reported. Palliative external radiation therapy has been frequently associated with pain flare in patients with bony metastasis.11, 12, 13 The temporary use of corticosteroids has been successfully used to diminish this acute effect.14,15\n\nMethods and Materials\nAs the flagship teaching hospital of one of the largest hospital systems in our state with a high volume of patients with cancer, we have closely followed the research related to PRRTs. We have also been excited about a potential therapeutic strategy to manage patients with progressive NETs. Upon lutetium Lu-177 dotatate approval by the US Food and Drug Administration, our clinical team expressed interest in initiating a program to serve patients with GEP NETs in our system, and as well as those from other hospitals and oncology programs in the state. Delivery of this agent is complex, due in particular to the need for the infusion of amino acid solution as a renal protectant. This solution is highly emetogenic, requiring pretreatment with a group of antiemetic therapies which include ondansetron, aprepitant, and dexamethasone (12-mg single dose). All patients received their monthly somatostatin analog (SSA) dose after completion of their 7-hour amino acid solution infusion. We initiated this program in 2018 through a collaborative effort of radiation oncology, radiation safety, nuclear medicine, oncology nursing, and pharmacy. We developed standard protocols, procedures, and consent; staff and patient educational materials, and documentation standards for lutetium Lu-177 receipt, administration, and patient release. These include monitoring of hematologic, renal, and hepatic function as well as patient adverse effects. By protocol, a total of 4 doses are delivered at 8-week intervals and each dose is followed by the administration of SSA to avoid competition for tumor binding sites.\n\nResults\nAs seen in Table 1, we have treated 12 patients between December 2018 and April 2020. Eight were female and 4 are male. The age range at the time of treatment initiation was 45 to 77 years with a median of 66 years. All patients have GEP NETs with the exception of one patient with a NET arising from a dysplastic kidney, for whom we were able to gain authorization for treatment. All patients had documented progression of disease on SSAs. Some patients also had progression on chemotherapy or mTor inhibitors, palliative external beam irradiation, as well as prior therapy with bland, chemotherapy, or radioembolization of hepatic metastases. All patients had hepatic metastases, and most had metastasis to retroperitoneal or mesenteric nodes as well. Several patients also had bony metastases, pulmonary metastases, and other areas of metastatic disease, including subcutaneous metastases. Most patients had some symptoms of carcinoid syndrome. Some had symptoms emanating from areas of metastases, including bone pain, liver pain, small bowel dysfunction, early satiety, and neuropathic pain related to nerve compression. All patients had documentation of avidity on gallium dotatate positron emission tomography scanning before treatment initiation.Table 1 Patient characeeristics and flare reactions\n\nPatient no./age/sex\tPrimary site\tPrior therapy\tFlare type (CTCAE score)\tMitigation success\t\n1/69/f\tSm bowel\tSSA, temozolomide\tCranial nerve dysfunction (2)\tFair\t\n2/46/f\tSm bowel\tSSA, pall RT\tBone pain (2)\tGood\t\n3/68/m\tPancreas\tSSA, everolimus, Y90 and chemo emb\t\t\t\n4/57/f\tSm bowel\tSSA\t\t\t\n5/68/f\tSm bowel\tSSA, bland and Y90 emb\tEpigastric pain (2)\tFair\t\n6/56/m\tSm bowel\tSSA, TACE\tSmall bowel dysfunction (2)\tFair\t\n7/47/f\tSm bowel\tSSA\tpSBO (3)\tGood\t\n8/65/f\tKidney\tSSA\t\t\t\n9/68/m\tSm bowel\tSSA, Y90\t\t\t\n10/77/f\tSm bowel\tSSA, TACE, ablation. Liver resection\t\t\t\n11/73/f\tSm bowel\tSSA, TACE, everolimus, Y90\t\t\t\n12/45/m\tPancreas\tSSA, everolimus\t\t\t\nAbbreviations: CTCAE = Common Terminology Criteria for Adverse Events; emb = embolization; pall = palliative; pSBO = partial small bowel obstruction; RT = radiation therapy; sm = small; SSA = somatostatin analog therapy; TACE = transarterial chemoembolization.\n\n\n\nFive patients exhibited flare reactions of symptoms during the first week after lutetium Lu-177 dotatate therapy. Two of these were related to bone metastases. In one patient with base of skull metastases, seventh cranial nerve dysfunction was noted. In another with spine metastasis, increased spine pain occurred. In a patient with extremely bulky left liver metastasis, increased epigastric pain and early satiety occurred. In 2 patients with extensive mesenteric metastases, increased bowel dysfunction and partial small bowel obstruction occurred. All of the flare reactions were quantified by Common Terminology Criteria for Adverse Events grades 2 (4 patients) or 3 (1 patient). Mitigation with a short course of oral corticosteroids was generally successful, as well as use of symptomatic medications. Steroid courses either included a methylprednisolone dose pack or a week of prednisone 40 mg daily. In patients who developed a flare reaction after the first of 4 lutetium Lu-177 dotatate administrations, we recommended a steroid course for subsequent courses, and also elected to arrange a phone or physical visit with their radiation oncologist or medical oncologist within the first week after administration to monitor and appropriately manage flare symptoms.\n\nDiscussion\nLutetium Lu-177 dotatate has become an additional effective therapy in the management of patients with GEP NETs.3,4 It is an excellent example of a targeted molecular therapy, as it binds avidly to the somatostatin receptors on NET cells, and delivers a high radiation dose via the beta emitting isotope Lutetium-177. Its use has been associated with a high likelihood of improving progression free survival. It is therefore not unexpected that flare reactions might occur similar to those which occur through the use of external radiation therapy. Flare reactions certainly occur on occasion in patients with symptomatic bony metastases who undergo palliative radiation therapy.11,12 This reaction might be treated with a temporary course of corticosteroids, or analgesics as appropriate.14,15\n\nIn our patients with GEP NETs receiving Lutetium Lu-177 dotatate, we have observed flare reactions associated with bony metastasis and soft tissue deposits of disease, in the liver and small bowel mesentery. These flare reactions are presumably mediated by transient local edema or inflammation secondary to initial tumor cell injury. Therefore, one might conjecture that such a process could occur either in bone or soft tissue if the local environment is subject to swelling causing nerve pressure or other organ dysfunction. Given the risk of such side effects recurring with subsequent doses of the Lutetium Lu-177 dotatate, we discovered that either a short prophylactic course of corticosteroids in subsequent courses was useful, or that close monitoring in the first week after therapy was warranted to manage adverse effects as needed. The single dose of 12 mg of dexamethasone administered on the day of treatment as an antiemetic was clearly not enough to prevent the flare reaction in these patients, likely owing to concomitant timing and lack of steroid presence on subsequent days when radiation was still present.\n\nMitigation of flare related symptoms with steroids or symptomatic medications as judged by patient report and MD assessment was fair to good. It is likely that a patient already focally symptomatic from a GEP-NET lesion, such as in bone or soft tissue, may be at increased risk for experiencing a flare reaction. Radiation oncologists are particularly adept at managing these symptoms owing to the fact that that they may commonly occur during courses of external beam irradiation. One potential benefit of having a radiation oncologist involved in radionuclide therapy for cancer is their expertise in dealing with adverse effects which are in some ways analogous to external radiation therapy.\n\nConclusions\nTumor flare reactions are common with the use of Lutetium Lu-177 dotatate in the management of GEP NETs. In our series of 12 patients, 2 had flare reactions characterized by bony metastasis causing spine pain and cranial nerve dysfunction due to skull base metastasis. An additional 3 patients had flare reactions due to soft tissue metastasis causing pain due to liver metastasis in one and bowel dysfunction in 2. All flare reactions were manifested in the first of 4 administrations. Management with a short course of corticosteroids and appropriate analgesics was generally successful. Use of such strategy for the 3 subsequent courses was helpful, as was close monitoring of the patient in the week after therapy to determine what interventions might be helpful.\n\nSources of support: This work had no specific funding.\n\nDisclosures: none.\n\nData sharing statement: All data generated and analyzed during this study are included in this published article.\n==== Refs\nReferences\n1 Bushnell D.L. Bodeker K.L. Overview and current status of peptide receptor radionuclide therapy Surg Oncol Clin N Am 29 2020 317 326 32151363 \n2 Kulke M.H. Mayer R.J. Carcinoid tumors N Engl J Med 340 1999 858 868 10080850 \n3 Strosberg J. El-Haddad G. Wolin E. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors N Engl J Med 376 2017 125 28076709 \n4 Brabander T. Van der Zwan W.A. Teunissen J.J. Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors Clin Cancer Res 23 2017 4617 4624 28428192 \n5 Strosberg J. Wolin E. Chasen B. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with 177Lu-dotatate in the phase III NETTER-1 Trial J Clin Oncol 36 2018 2578 29878866 \n6 Bergsma H. van Lom K. Raaijmakers M.H.G.P. Persistent hematologic dysfunction after peptide receptor radionuclide therapy with 177Lu-DOTATATE: Incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors J Nucl Med 59 2018 452 28775205 \n7 Bodei L. Kidd M. Paganelli G. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: The value and limitations of clinical factors Eur J Nucl Med Mol Imaging 42 2015 5 25273832 \n8 Bergsma H. Konijnenberg M.W. van der Zwan W.A. Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate Eur J Nucl Med Mol Imaging 43 2016 1802 27160225 \n9 Karfis I. Marin G. Machiels G. Hendlisz A. Flamen P. Acute pancreatitis following peptide receptor radionuclide therapy: An unusual adverse event Clin Nucl Med 43 2018 e232 e233 29762236 \n10 Sabet A. Ezziddin K. Pape U.F. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with (177)Lu-octreotate Eur J Nucl Med Mol Imaging 41 2014 505 24196919 \n11 Chow E. Ling A. Davis L. Pain flare following external beam radiotherapy and meaningful change in pain scores in the treatment of bone metastases Radiother Oncol 75 2005 64 69 15878102 \n12 Hird A. Chow E. Zhang L. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: Results from three Canadian cancer centers Int J Radiat Oncol Biol Phys 75 2009 193 197 19167840 \n13 Taleb A. Tumour flare reaction in cancer treatments: A comprehensive literature review Anticancer Drugs 30 2019 953 958 31348010 \n14 Hird A. Zhang L. Holt T. Dexamethasone for the prophylaxis of radiation-induced pain flare after palliative radiotherapy for symptomatic bone metastases: A phase II study Clin Oncol (R Coll Radiol) 21 2009 329 335 19232483 \n15 Chow E. Loblaw A. Harris K. Dexamethasone for the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: A pilot study Support Care Cancer 15 2007 643 647 17242910\n\n",
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"abstract": "A 26-year-old woman with recurrent unexplained syncope in the postpartum period was diagnosed with long QT syndrome type 2. Traditional implantation of defibrillator using fluoroscopy became contraindicated after she again became pregnant prior to device implantation. A subcutaneous defibrillator was successfully implanted in the second trimester, after a multidisciplinary evaluation. (Level of Difficulty: Intermediate.).",
"affiliations": "University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.;University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.",
"authors": "Myadam|Rahul|R|;Gupta|Sanjaya K|SK|",
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"doi": "10.1016/j.jaccas.2020.12.038",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00026-7\n10.1016/j.jaccas.2020.12.038\nMini-Focus Issue: Electrophysiology\nCase Report: Clinical Case\nSuccessful Subcutaneous Defibrillator Implantation in a Pregnant Patient With Long QT Syndrome\nMyadam Rahul MD a\nGupta Sanjaya K. MD sgupta@saint-lukes.org\n@SanjayaKGupta1\nab∗\na University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA\nb Saint Luke’s Mid-America Heart Institute, Kansas City, Missouri, USA\n∗ Address for correspondence: Dr. Sanjaya K. Gupta, Saint Luke’s Mid-America Heart Institute, 9th Floor, Cardiovascular Research, 4401 Wornall Road, Kansas City, Missouri 64111, USA. sgupta@saint-lukes.org@SanjayaKGupta1\n03 3 2021\n3 2021\n03 3 2021\n3 3 504507\n14 10 2020\n4 12 2020\n24 12 2020\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nA 26-year-old woman with recurrent unexplained syncope in the postpartum period was diagnosed with long QT syndrome type 2. Traditional implantation of defibrillator using fluoroscopy became contraindicated after she again became pregnant prior to device implantation. A subcutaneous defibrillator was successfully implanted in the second trimester, after a multidisciplinary evaluation. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nKey Words\n\npregnancy\nventricular tachycardia\nx-ray fluoroscopy\nAbbreviations and Acronyms\n\nDT, defibrillation threshold\nICD, implantable cardioverter-defibrillator\nLQTS, long QT syndrome\nSCA, sudden cardiac arrest\nS-ICD, subcutaneous implantable cardioverter-defibrillator\nTV-ICD, transvenous implantable cardioverter-defibrillator\n==== Body\nHistory of presentation\n\nA 26-year-old woman was referred to the cardiac electrophysiology service to evaluate 3 syncopal episodes over 3 months. Her first event occurred at rest when she had a sudden loss of consciousness associated with urinary incontinence. The second episode happened at night while attending to a crying baby. She had a brief prodrome of light-headedness, followed by loss of consciousness and urinary incontinence. She did not take any medications and had no family history of sudden cardiac arrest (SCA). A complete cardiac and neurological examination did not reveal any abnormalities.Learning Objectives\n\n• To understand the importance of considering congenital LQTS when evaluating syncope in a postpartum woman, and that genetic testing should be ordered after excluding other causes of syncope.\n\n• To describe the indication for ICD therapy in congenital LQTS patients on beta-blockers who survive sudden cardiac death, and that for patients that do not require pacing, a subcutaneous defibrillator is a comparable option to a transvenous defibrillator and is preferred when fluoroscopy is contraindicated.\n\n• To explain the importance of a multidisciplinary team in caring for pregnant patients with high-risk cardiac conditions, such as LQTS.\n\nDifferential Diagnosis\n\nCardiac arrhythmia, valvular heart disease, neurogenic or vasovagal syncope, or seizures.\n\nInvestigations\n\nAn initial electrocardiogram showed sinus rhythm with a prolonged QT/QTc interval of 484/511 ms (Figure 1). She had mild hypokalemia, 3.0 mEq/dl (normal 3.5 to 5.2 mEq/dl), that was felt to cause a prolonged QT interval. Neurological workup revealed normal magnetic resonance imaging of the brain and electroencephalogram. After electrolyte replacement, she was discharged with plans for an ambulatory cardiac monitor. However, she had another syncopal episode 3 days later and returned to the hospital. An electrocardiogram showed persistent long QTc interval (486 ms) even though her potassium normalized (3.9 mEq/dl). An echocardiogram demonstrated an ejection fraction of 50% to 55% without valvular abnormalities. Genetic testing for congenital long QT syndrome (LQTS) was ordered due to the typical presentation of syncopal episodes in a postpartum woman with auditory triggers and the absence of other causes of QT prolongation. The genetic analysis showed a mutation in KCNH2, consistent with hereditary LQTS type 2.Figure 1 Electrocardiogram\n\nElectrocardiogram on presentation after second syncopal episode showing a corrected QT interval of 511 ms.\n\nManagement\n\nThe patient was started on metoprolol tartrate 25 mg twice daily. It was recommended that she undergo implantable cardioverter-defibrillator (ICD) implantation for secondary prevention of polymorphic ventricular tachycardia. However, she unexpectedly had a positive pre-procedural urine pregnancy test. A multidisciplinary team was constituted, including cardiology, anesthesia, and maternal-fetal medicine, given the high risk of SCA during pregnancy and the postpartum period in LQTS type 2. The implantation of the ICD was delayed to the second trimester, given the danger of general anesthesia and narcotics to the fetus in the first trimester (1). She was prescribed a wearable cardiac defibrillator (Life Vest, Zoll Inc., Pittsburgh, Pennsylvania) in the interim, due to the known increased risk of SCA in pregnant LQTS type 2 patients.\n\nAt 20 weeks gestation, the patient presented for ICD implantation. She was sedated using propofol and fentanyl and received only a limited amount (15 ml) of lidocaine due to low body weight (45.4 kg) and concern for transplacental transmission. A subcutaneous implantable cardioverter-defibrillator (S-ICD) (EMBLEM S-ICD A209 generator, Boston Scientific, Natick Massachusetts) was implanted via a 2-incision technique, sparing the suprasternal incision (2). The generator was placed between the serratus anterior and latissimus muscles via an intermuscular method. Defibrillation threshold (DT) testing was withheld at the time of implantation. The patient was not exposed to any radiation during the procedure. The peri-procedural fetal monitoring was unremarkable. The patient was discharged post-procedure and took metoprolol throughout her pregnancy.\n\nDiscussion\n\nIn patients with congenital LQTS, the measures recommended for the prevention of SCA include beta-blockers, ICD implantation, and left cervicothoracic sympathectomy (3). Rarely, an ICD implantation becomes necessary during pregnancy. The 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines recommend considering an ICD implantation when necessary in all pregnant women (3). However, novel defibrillator implantation methods need to be considered in pregnancy to prevent fetal radiation exposure. Abello et al. (4) described a pregnant patient with mitral valve prolapse who underwent ICD placement under transesophageal echocardiogram guidance. A few cases of successful device implantation using electroanatomic mapping were reported (5). However, these nonconventional transvenous implantable cardioverter-defibrillator (TV-ICD) implantation methods have limited reproducibility in other settings due to the financial costs and the lack of data on safety outcomes. In this setting, an S-ICD is an alternative with established safety outcomes in nonpregnant women. To date, 1 other reported case of S-ICD implantation in pregnancy was described by Viani et al. (6). Some studies have shown that atrial pacing may be beneficial in preventing polymorphic ventricular tachycardia in LQTS (7). However, in our patient, permanent cardiac pacing was felt to be unnecessary as the arrhythmias were only provoked by pregnancy.\n\nThe use of an S-ICD may have an advantage over TV-ICD, especially in younger patients without a pacing indication. A PRospective, rAndomizEd Comparison of subcuTaneOous and tRansvenous ImplANtable Cardioverter Defibrillator Therapy (PRAETORIAN) was a multicenter, prospective, randomized trial that compared S-ICD with TV-ICD and concluded that S-ICD was noninferior to TV-ICD. Lead-related complications occurred more often in TV-ICD (6.6%) versus S-ICD patients (1.4%) (hazard ratio: 0.24; p = 0.001) (8). Moreover, studies have shown that about 20% of transvenous leads fail by 10 years, which increases both the financial costs and the procedural complications associated with TV-ICD (9). Care must be taken when programming an S-ICD to reduce inappropriate therapy.\n\nThe role of DT testing during S-ICD implantation is uncertain. Although guidelines recommend routine DT for all patients receiving an S-ICD, this is controversial (10). However, in our patient, DT was withheld at the time of device implantation due to potential risk to the fetus.\n\nFollow-Up\n\nThe patient delivered a healthy, full-term infant without complications. However, 7 weeks after the delivery, she experienced another syncopal episode at home. She presented to the emergency room and was noted to have a QTc of 499 ms. Interrogation of her S-ICD revealed appropriate detection and successful defibrillation of torsade de pointes at a cycle length of 198 ms (Figure 2). She subsequently underwent an elective tubal ligation procedure. She is currently working and raising her 3 children without any further reported syncopal episodes or ICD shocks.Figure 2 Implantable Cardioverter-Defibrillator Shock\n\nThe patient had an episode of torsade de pointes at a rate >250 beats/min and received appropriate therapy for polymorphic ventricular tachycardia.\n\nConclusions\n\nOur case describes a woman who was at exceptionally high risk for SCA, given 3 previous syncopal events associated with congenital LQTS, who subsequently became pregnant. Our case provides evidence that an S-ICD can be safely implanted during pregnancy without the risk of radiation exposure and should be considered in patients who are at high risk for SCA during the peripartum period. This case also highlights the importance of a multidisciplinary team approach when caring for pregnant cardiac patients.\n\nFunding Support and Author Disclosures\n\nDr. Gupta has received modest research grants from Medtronic; and has served as a consultant for Medtronic, Boston Scientific, and Respicardia; none of these are relevant to this paper. Dr. Myadam has reported that he has no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n==== Refs\nReferences\n\n1 Rosen M.A. Management of anesthesia for the pregnant surgical patient Anesthesiology 91 1999 1159 1163 10519516\n2 Brouwer T.F. Miller M.A. Quast A.F.B.E. Implantation of subcutaneous implantable cardioverter defibrillator: an evaluation of 4 implantable techniques Circ Arrhythm Electrophysiol 10 2017 e004663\n3 Al-Khatib S.M. Stevenson W.G. Ackerman M.J. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society J Am Coll Cardiol 72 2018 e91 e220 29097296\n4 Abello M. Peinado R. Merino J.L. Cardioverter defibrillator implantation in a pregnant woman guided with transesophageal echocardiography Pacing Clin Electrophysiol 26 2003 1913 1914 12930513\n5 Payne J. Lo M. Paydak H. Maskoun W. Near-zero fluoroscopy implantation of dual-chamber pacemaker in pregnancy using electroanatomic mapping Heart Rhythm Case Rep 3 2017 205 209\n6 Viani S. Zucchelli G. Paperini L. Subcutaneous implantable defibrillator in an acromegalic pregnant woman for secondary prevention of sudden cardiac death: when (2) technologies save (2) lives Int J Cardiol 223 2016 313 315 27543699\n7 Eldar M. Griffin J.C. Van Hare G.F. Combined use of beta-adrenergic blocking agents and long-term cardiac pacing for patients with the long QT syndrome J Am Coll Cardiol 20 1992 830 837 1356115\n8 Knops R.E. Olde Nordkamp L.R.A. Delnoy P.H.M. Subcutaneous or transvenous defibrillator therapy N Engl J Med 383 2020 526 536 32757521\n9 Kleemann T. Becker T. Doenges K. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of >10 years Circulation 115 2007 2474 2480 17470696\n10 Wilkoff B.L. Fauchier L. Stiles M.K. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing Heart Rhythm 13 2016 e50 e86 26607062\n\n",
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"keywords": "DT, defibrillation threshold; ICD, implantable cardioverter-defibrillator; LQTS, long QT syndrome; S-ICD, subcutaneous implantable cardioverter-defibrillator; SCA, sudden cardiac arrest; TV-ICD, transvenous implantable cardioverter-defibrillator; pregnancy; ventricular tachycardia; x-ray fluoroscopy",
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"title": "Successful Subcutaneous Defibrillator Implantation in a Pregnant Patient With Long QT Syndrome.",
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"abstract": "BACKGROUND\nThe optimal sequence of chemotherapeutic agents is not firmly established for the treatment of metastatic colorectal cancer (mCRC). This phase II multi-centre study investigated the efficacy and tolerability of a standard capecitabine plus irinotecan (XELIRI) regimen with bevacizumab in previously untreated patients with mCRC.\n\n\nMETHODS\nPatients received intravenous irinotecan 175 mg/m(2) on day 1 and oral capecitabine 1000 mg/m(2) (800 mg/m(2) for patients >65 years of age) twice daily on days 2-8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks.\n\n\nRESULTS\nSeventy-seven patients were included in the intention-to-treat and safety populations. Progression-free survival at 9 months was 61%. The overall response and disease control rates were 51% and 84%, respectively. Median progression-free and overall survival times were 11.9 and 24.8 months, respectively. 48 patients (62%) had at least one grade 3/4 adverse event, the most common being asthenia, diarrhoea and neutropenia. Quality of life varied little over the study period with mean visual analogue scale general health scores ranging from 71 to 76 over cycles 1-11.\n\n\nCONCLUSIONS\nOur study found irinotecan and capecitabine administered fortnightly with bevacizumab in patients with mCRC to be an effective and tolerable regimen.\n\n\nBACKGROUND\nclinicaltrials.gov identifier NCT00875771. Trial registration date: 04/02/2009.",
"affiliations": "Servicio de Oncología, Hospital Universitario Gregorio Marañón, C/Maiquez 7, 2nd floor, 28007, Madrid, Spain. pgarcaalfonso@gmail.com.;Servicio de Oncología, Hospital Virgen del Rocío, 41004, Sevilla, Spain. manuelchavesconde@gmail.com.;Servicio de Oncología, Hospital Universitario Gregorio Marañón, C/Maiquez 7, 2nd floor, 28007, Madrid, Spain. andresmunmar@hotmail.com.;Servicio de Oncología, Hospital Lleida Arnau de Vilanova, 25198, Barcelona, Spain. asaluds@hotmail.com.;Servicio de Oncología, Hospital Universitario de Burgos, 09005, Burgos, Spain. meuris2903@gmail.com.;Servicio de Oncología, Hospital 12 Octubre, 28041, Madrid, Spain. cgravalos@telefonica.net.;Servicio de Oncología, Hospital General Universitario, 03011, Alicante, Spain. bmassutis@seom.org.;Servicio de Oncología, Hospital Virgen de las Nieves, 18014, Granada, Spain. encarna.gonzalez@hotmail.es.;Servicio de Oncología, ICO. Hospital. Josep Trueta, 17007, Gerona, Spain. bqueralt@iconcologia.net.;Servicio de Oncología, Hospital Nuestra Señora de Valme, 41014, Sevilla, Spain. alopezladron@yahoo.es.;Servicio de Oncología, Hospital General de L'Hospitalet, 08906, Barcelona, Spain. ferran.losa@sanitatintegral.org.;Servicio de Oncología, Hospital Puerta del Mar, 11009, Cádiz, Spain. mariajose.gomezreina@gmail.com.;Servicio de Oncología, Hospital Virgen de los Lirios, 03804, Alicante, Spain. oltra_amp@gva.es.;Reina Sofía Hospital, University of Córdoba, Maimonides Institute of Biomedical Research (IMIBIC). Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain. earandaa@seom.org.",
"authors": "Garcia-Alfonso|Pilar|P|;Chaves|Manuel|M|;Muñoz|Andrés|A|;Salud|Antonieta|A|;García-Gonzalez|Maria|M|;Grávalos|Cristina|C|;Massuti|Bartomeu|B|;González-Flores|Encarna|E|;Queralt|Bernardo|B|;López-Ladrón|Amelia|A|;Losa|Ferran|F|;Gómez|Maria Jose|MJ|;Oltra|Amparo|A|;Aranda|Enrique|E|;|||",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 25925749129310.1186/s12885-015-1293-yResearch ArticleCapecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study Garcia-Alfonso Pilar pgarcaalfonso@gmail.com 1Chaves Manuel manuelchavesconde@gmail.com 2Muñoz Andrés andresmunmar@hotmail.com 1Salud Antonieta asaluds@hotmail.com 3García-Gonzalez Maria meuris2903@gmail.com 4Grávalos Cristina cgravalos@telefonica.net 5Massuti Bartomeu bmassutis@seom.org 6González-Flores Encarna encarna.gonzalez@hotmail.es 7Queralt Bernardo bqueralt@iconcologia.net 8López-Ladrón Amelia alopezladron@yahoo.es 9Losa Ferran ferran.losa@sanitatintegral.org 10Gómez Maria Jose mariajose.gomezreina@gmail.com 11Oltra Amparo oltra_amp@gva.es 12Aranda Enrique earandaa@seom.org 13on behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) 1 Servicio de Oncología, Hospital Universitario Gregorio Marañón, C/Maiquez 7, 2nd floor, 28007 Madrid, Spain 2 Servicio de Oncología, Hospital Virgen del Rocío, 41004 Sevilla, Spain 3 Servicio de Oncología, Hospital Lleida Arnau de Vilanova, 25198 Barcelona, Spain 4 Servicio de Oncología, Hospital Universitario de Burgos, 09005 Burgos, Spain 5 Servicio de Oncología, Hospital 12 Octubre, 28041 Madrid, Spain 6 Servicio de Oncología, Hospital General Universitario, 03011 Alicante, Spain 7 Servicio de Oncología, Hospital Virgen de las Nieves, 18014 Granada, Spain 8 Servicio de Oncología, ICO. Hospital. Josep Trueta, 17007 Gerona, Spain 9 Servicio de Oncología, Hospital Nuestra Señora de Valme, 41014 Sevilla, Spain 10 Servicio de Oncología, Hospital General de L’Hospitalet, 08906 Barcelona, Spain 11 Servicio de Oncología, Hospital Puerta del Mar, 11009 Cádiz, Spain 12 Servicio de Oncología, Hospital Virgen de los Lirios, 03804 Alicante, Spain 13 Reina Sofía Hospital, University of Córdoba, Maimonides Institute of Biomedical Research (IMIBIC). Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain 29 4 2015 29 4 2015 2015 15 32724 10 2014 31 3 2015 © Garcia-Alfonso et al.; licensee BioMed Central. 2015This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe optimal sequence of chemotherapeutic agents is not firmly established for the treatment of metastatic colorectal cancer (mCRC). This phase II multi-centre study investigated the efficacy and tolerability of a standard capecitabine plus irinotecan (XELIRI) regimen with bevacizumab in previously untreated patients with mCRC.\n\nMethods\nPatients received intravenous irinotecan 175 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 (800 mg/m2 for patients >65 years of age) twice daily on days 2–8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks.\n\nResults\nSeventy-seven patients were included in the intention-to-treat and safety populations. Progression-free survival at 9 months was 61%. The overall response and disease control rates were 51% and 84%, respectively. Median progression-free and overall survival times were 11.9 and 24.8 months, respectively. 48 patients (62%) had at least one grade 3/4 adverse event, the most common being asthenia, diarrhoea and neutropenia. Quality of life varied little over the study period with mean visual analogue scale general health scores ranging from 71 to 76 over cycles 1–11.\n\nConclusion\nOur study found irinotecan and capecitabine administered fortnightly with bevacizumab in patients with mCRC to be an effective and tolerable regimen.\n\nTrial registration\nclinicaltrials.gov identifier NCT00875771. Trial registration date: 04/02/2009.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12885-015-1293-y) contains supplementary material, which is available to authorized users.\n\nKeywords\nIrinotecanCapecitabineBevacizumabMetastatic colorectal cancerChemotherapyissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nAccording to the World Health Organisation’s most current statistics there are just over 12.6 million cases of cancer diagnosed each year. Colorectal cancer is the 5th most common and accounts for 9.7% of all cancers [1]. Standard treatments for patients with metastatic colorectal cancer (mCRC) usually consist of combination chemotherapy based on fluorouracil or capecitabine plus either oxaliplatin or irinotecan, and a targeted agent such as bevacizumab, cetuximab or panitumumab [2,3]. The most commonly used chemotherapy regimens are fluorouracil with folinic acid plus oxaliplatin (FOLFOX), fluorouracil with folinic acid plus irinotecan (FOLFIRI), capecitabine plus oxaliplatin (XELOX), and capecitabine plus irinotecan (XELIRI). However, the optimal sequence of chemotherapeutic agents is not firmly established, and most patients will receive a fluoropyrimidine, irinotecan and oxaliplatin over the course of their treatment.\n\nRandomised phase III studies have shown that the addition of bevacizumab to first- or second-line chemotherapy regimens extends overall survival and/or progression-free survival in patients with mCRC compared with chemotherapy alone [4-7]. Consequently, bevacizumab is indicated for the first- and second-line treatment of patients with mCRC [2,3].\n\nSome uncertainty surrounds the most effective and tolerable schedule for administering irinotecan-based regimens such as XELIRI. The BICC-C and EORTC 40015 studies suggested that 3-weekly administration of irinotecan plus capecitabine can be associated with unacceptable gastrointestinal side effects [8,9], although both studies were confounded by the concomitant use of celecoxib, which is known to be associated with gastrointestinal toxicity. Consequently, different drug doses and administration regimens have been investigated with the aim of improving the tolerability of the combination of irinotecan and capecitabine [10-12].\n\nWe have previously shown that 2-weekly irinotecan plus capecitabine (irinotecan on day 1 every 2 weeks; plus capecitabine on days 1–7, followed by a week of rest) was effective and well tolerated in patients with mCRC [13]. Preclinical studies had shown this 2-weekly schedule, which is similar to the FOLFIRI schedule, to be more effective than the standard 3-weekly regimen and to allow the administration of higher capecitabine doses [14]. In our study, the adverse-event profile of XELIRI was acceptable, with asthenia, nausea, vomiting and diarrhoea being the most commonly observed grade 3/4 adverse events (occurring in 7–9% of patients). Dose delays and reductions occurred in <12% of patients for irinotecan and <5% of patients for capecitabine [13]. We subsequently incorporated bevacizumab into this regimen and demonstrated that this combination of a targeted agent with chemotherapy was effective and well tolerated in patients with mCRC [15].\n\nThe present phase II multicentre study was undertaken on behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) to assess the efficacy and tolerability of 2-weekly regimen of irinotecan in combination with capecitabine plus bevacizumab in a larger population of previously untreated patients with mCRC.\n\nMethods\nPatients and study design\nPatients ≥18 years of age with histologically proven, measurable mCRC that was not initially totally resected were included in this phase II open-label study. To be included, patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and could have had prior surgical treatment of their disease. No prior chemotherapy was allowed, other than adjuvant or neoadjuvant therapy completed at least 6 months before inclusion in the study; patients who received adjuvant therapy must not have progressed during or within 6 months of completing treatment. Additionally each patient was discussed by a multi-disciplinary team within each cancer centre to confirm their suitability for inclusion in the study.\n\nPatients were not eligible for inclusion in the study if they had a history of central nervous system disease, psychiatric disability, clinically significant cardiac disease, lack of integrity of the upper gastrointestinal tract, malabsorption syndrome or inability to take oral medication. Exclusion criteria included any surgical procedures in the 28 days before the start of the study or if any surgery was scheduled to take place during the study. The use of oral anticoagulants or full-dose parenteral thrombolytic agents was not permitted, although low-dose warfarin was allowed. Chronic treatment with high-dose aspirin or antiplatelet agents was not permitted.\n\nPatients with creatinine clearance <30 mL/minute or serum creatinine >1.5 times the upper limit of normal (ULN) were excluded from the study, as were those with: an absolute neutrophil count <1.5 × 109/L; platelet count <100 × 109/L; haemoglobin <9 g/dL; International Normalised Ratio >1.5; total bilirubin >1.5 × ULN; alanine aminotransferase and/or aspartate aminotransferase >2.5 x ULN (or >5 × ULN in case of liver metastases); or alkaline phosphatase >2.5 × ULN (or >5 × ULN in case of liver metastases or >10 × ULN in case of bone metastases).\n\nThe study protocol (Study TTD-08-03; EudraCT: 2008-004688-20; clinicaltrials.gov identifier NCT00875771) was approved by the Spanish Medicine Agency as well as the Institutional Review Board and Ethics Committee of each participating site (for details please refer to the Additional file 1). Reference Ethic Committee: “Comité Ético de Investigación Clínica” of the Hospital Universitario de Burgos, Avda. del Cid, 96,09005 Burgos on January 2009. Study procedures were carried out in accordance with the Declaration of Helsinki and its subsequent amendments, and Good Clinical Practice guidelines. Written, informed consent was obtained from all patients before enrolment.\n\nTreatment\nTreatment consisted of irinotecan 175 mg/m2 as an intravenous infusion on day 1 every 2 weeks, capecitabine 1000 mg/m2 (800 mg/m2 for patients >65 years of age) twice daily on days 2–8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks. Treatment was continued until disease progression, unacceptable toxicity or patient withdrawal.\n\nThe doses of the chemotherapeutic agents were modified appropriately in each cycle according to the occurrence of toxicities. Once a dose was reduced, doses were not increased in subsequent cycles. If two dose reductions were sanctioned as a result of toxicity, patients experiencing the same complications were withdrawn from the study unless they had achieved an objective response to treatment, in which case the decision to continue treatment was left to the judgment of the investigator. If chemotherapy was delayed, administration of bevacizumab was also delayed. If the administration of chemotherapy was delayed for more than 2 cycles, the patient was withdrawn from the study. If irinotecan was discontinued, capecitabine and bevacizumab were to be continued unless unacceptable toxicity was observed. Similarly, if either capecitabine or bevacizumab were interrupted, treatment with the remaining agents could be continued at the investigator’s discretion.\n\nAssessments\nThe response to treatment was assessed using the radiological RECIST criteria [16] at 6-cycle intervals until the disease progressed or the patient died. No independent radiological review committee was established.\n\nAdverse events were assessed at study visits and reported by patients. Adverse events were classified according to the National Cancer Institute Common Toxicity Criteria (CTC) version 3.0 [17]). All adverse events, regardless of their relation to the study treatment, were followed until resolution even if patients had withdrawn from the study.\n\nQuality of life was measured using the EuroQoL 5-Dimensions (3-level) questionnaire (EQ-5D-3 L), a generic instrument used for measuring health status [18]. Quality of life assessments were performed at baseline, before each odd-numbered cycle (3, 5, 7, etc.) and in the 30 days following discontinuation of study therapy. A minimum of three assessments was required for the patient’s data to be included in the quality of life analysis. The EQ-5D-3 L assesses five different aspects of health (mobility, personal care, daily activities, pain/discomfort and anxiety/depression), each with three response categories. In addition, self-assessed general health was recorded using a 20 cm visual analogue scale (VAS) ranging from 0 (“worst imaginable health state”) to 100 (“best imaginable health state”).\n\nStatistical analyses\nThe primary endpoint of this phase II study was progression-free survival at 9 months. The secondary endpoints were: progression-free survival, overall survival, response rate, safety, resection rate and quality of life. Efficacy analyses were performed on the intention-to-treat population i.e. patients who received at least one dose of study medication. Safety analyses were performed on patients who received at least one dose of study medication (the safety population).\n\nThe sample size was based on a single-stage Fleming design, with p0 = 12% at 2 years (equivalent to a median progression-free survival of 8 months), p1 = 25% (equivalent to a median progression-free survival of 12 months), and an alpha error of 0.05 and a beta error of 0.01, resulting in a requirement for seventy-one evaluable patients. Allowing for a 10% dropout rate, seventy-nine patients were planned to be recruited.\n\nSurvival analyses were performed using Kaplan–Meier methodology; 95% confidence intervals (CIs) were calculated for the primary and secondary outcomes. Qualitative variables were described using absolute and relative frequencies; quantitative variables were described with means, medians and standard deviation (SD). All analyses were performed using SPSS version 17.0 (SPSS Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc.).\n\nResults\nPatients\nA total of eighty-one patients were enrolled in the study at twelve Spanish centres between 14 April 2009 and 20 April 2010. Four patients failed the screening process, with three violating entry criteria; one patient was hospitalised prior to initiation of treatment and could not be treated with the study regimen. The remaining seventy-seven patients received treatment and were included in the intention-to-treat and safety populations.\n\nPatient characteristics are summarised in Table 1. A total of sixty-five patients had relevant comorbidities, the most common being hypertension in 32 patients (42%, twenty-seven of whom were taking antihypertensive agents) and 14 patients (18%) with diabetes mellitus. Twenty-one (27%) patients were ≥70 years of age. Fifty patients (65%) had undergone surgical resection of the primary tumour. Of the remaining twenty-seven patients who did not have surgical resection, four presented with intestinal perforation or occlusion.Table 1 \nPatient characteristics at baseline (N =77)\n\n\n\nSex\n\t\nN\n\t\n%\n\t\nMale\t51\t66.2\t\nFemale\t26\t33.8\t\nMedian age, years (range)\t65 (41–81)\t\n\nECOG performance status\n\t\nN\n\t\n%\n\t\n0\t46\t59.7\t\n1\t28\t36.4\t\n2\t3\t3.9\t\n\nLocation of primary tumour\n\t\nN\n\t\n%\n\t\nRectum\t24\t31.2\t\nColon\t41\t53.2\t\nColon and rectum\t12\t15.6\t\n\nNo. of lesions\n\t\nN\n\t\n%\n\t\n1\t6\t7.8\t\n2\t13\t16.9\t\n≥3\t58\t75.4\t\n\nPrior therapy\n\t\nN\n\t\n%\n\t\nSurgery\t50\t64.9\t\nAdjuvant chemotherapy\t27\t35.1\t\nRadiotherapy\t9\t11.7\t\n\nMetastatic site\n\t\nN\n\t\n%\n\t\nLiver\t48\t62.3\t\nLung\t42\t54.5\t\nLocal\t18\t23.4\t\nOther\t27\t35.1\t\n\nOrgans with metastases\n\t\nN\n\t\n%\n\t\n1\t31\t40.3\t\n2\t32\t41.6\t\n≥3\t14\t18.2\t\nAbbreviation: ECOG Eastern Cooperative Oncology Group.\n\n\n\nTumour KRAS status was determined in seventy-one patients (92%); thirty-six patients (51%) had wild-type KRAS tumours and thirty-five (49%) had mutant KRAS tumours.\n\nTreatment\nPatients underwent treatment for a median of 6.2 months (range 0.4–21.6 months) and received a total of 1009 cycles (876 cycles of bevacizumab, 973 cycles of irinotecan and 982 cycles of capecitabine). A median of 12.0 cycles (range 1.0–43.0 cycles) was administered; the median number of cycles of irinotecan, capecitabine and bevacizumab administered were 12.0 (range 1.0–43.0), 12.0 (range 1.0–43.0) and 11.0 (range 1.0–33.0), respectively.\n\nThe median relative dose intensities were: bevacizumab 89%, irinotecan 85%, and capecitabine 89%. Absolute median dose intensities were: bevacizumab 2.1 mg/kg/week, irinotecan 77.5 mg/m2/week, capecitabine 1439 mg/day.\n\nTreatment was delayed in fifty-seven patients (74%) resulting in delays in 160 of the 1009 cycles (16%). The most common reasons for delayed doses were: neutropenia (25 cycles; 16%), administrative reasons (23 cycles; 14%); diarrhoea (19 cycles; 12%) and patient decision (15 cycles; 9%).\n\nBevacizumab was delayed in 119 cycles (14%) in twenty-four patients (31%), most commonly as a result of thromboembolism (67 cycles; 56%), fistula (9 cycles; 8%), wound-healing complications (8 cycles; 7%), and surgery (9 cycles; 8%). The irinotecan dose was reduced or delayed in 78 cycles (8%) in thirty-seven patients (48%) most commonly as a result of asthenia (12 cycles; 15%), diarrhoea (13 cycles; 17%) and at the discretion of the investigator (22 cycles; 28%). The capecitabine dose was reduced or delayed in 85 cycles (9%) in forty-six patients (60%) primarily as a result of diarrhoea (18 cycles; 21%).\n\nMost patients received more than one line of treatment with sixty-two patients (81%) receiving second-line therapy, twenty-eight of whom had second-line bevacizumab-containing regimens. Thirty-seven patients received third-line and later lines of therapy.\n\nEfficacy\nPatients were followed for a median of 23.3 months (range 0.4–39.6 months). Efficacy outcomes are shown in Table 2 and Figure 1. Progression-free survival at 9 months (the primary endpoint) was 61% (95% CI: 48–73%). The median progression-free survival was 11.9 months (95% CI: 10.8–13.1 months) and median overall survival was 24.8 months (95% CI: 19.9–29.7 months). The overall response rate was 51% (95% CI: 39–62%) and the disease control rate was 84% (95% CI: 74–91%).Table 2 \nEfficacy (\nN\n= 77)\n\n\nOutcome\tMonths\t95% CI\t\nMedian time to progression\t11.9\t10.8–13.1\t\nMedian progression-free survival\t11.8\t10.7–13.0\t\nMedian overall survival\t24.8\t19.9–29.7\t\n\nResponse to treatment\n\t\nN\n\t\n%\n\t\nComplete response\t4\t5.2\t\nPartial response\t35\t45.5\t\nStable disease\t26\t33.8\t\nProgressive disease\t5\t6.5\t\nNot evaluable\t7\t9.1\t\n\nResponse rates\n\t\n%\n\t\n95% CI\n\t\nOverall response rate\t50.6\t39.1–62.0\t\nDisease control rate\t84.4\t74.0–91.3\t\nAbbreviation: CI confidence interval.\n\nFigure 1 Overall survival (A) and progression-free survival (B) in patients treated with bevacizumab, capecitabine and irinotecan every 2 weeks.\n\n\n\nMedian progression-free survival was 12.0 months (95% CI: 6.6–17.5 months) in patients with wild-type KRAS tumours and 11.8 months (95% CI: 10.7–13.0 months) in those with mutant KRAS tumours (P= 0.985) (Figure 2). Overall survival was also similar in patients with wild-type and mutant KRAS tumours: 28.5 months (95% CI: 21.4–35.6 months) versus 27.9 months (95% CI: 21.4–34.3 months), respectively (P= 0.659; Figure 2). Confirmed response rates were 44.4% in patients with wild-type KRAS tumours and 37.1% in those with mutant KRAS tumours (P >0.05).Figure 2 Overall survival (A) and progression-free survival (B) according to tumour KRAS status in patients treated with bevacizumab, capecitabine and irinotecan every 2 weeks.\n\n\n\nSeventeen patients (22%) had surgical resection of metastases during the study (65% liver metastases, 18% lung metastases, 12% peritoneal metastases and other sites). The median time to surgery after treatment initiation was 6.7 months. Twelve patients (71%) underwent R0 resection, three (18%) had an R1 resection and two (12%) were not evaluable. Thirteen of the seventeen patients who underwent surgical resection had further treatment (chemotherapy or immunotherapy). With respect to second-line chemotherapy six patients received post-surgical treatment with bevacizumab plus capecitabine/irinotecan and three patients received other bevacizumab-containing regimens. The remaining patients received a variety of other regimens that included oxaliplatin, cetuximab and panitumumab.\n\nSafety\nTo date, forty-five patients (58%) have died and thirty-two (42%) are still alive. The causes of death were: progressive disease (N = 35), adverse events (N = 7) and unknown (N = 3). Adverse events leading to death included: multi-organ failure (N = 2), gastrointestinal perforation (N = 2), respiratory and cardiac insufficiency due to chronic obstructive pulmonary disease (N = 1), myocardial infarction (N = 1) and respiratory insufficiency (N = 1). One of the gastrointestinal perforation events was considered to be related to treatment with bevacizumab; the two multi-organ failures were considered following discussion and scrutiny by the investigators to be related to capecitabine/irinotecan, rather than to disease progression as these events were reported in the context of toxicities.\n\nA total of seventy-six patients (99%) had at least one adverse event related to treatment; forty-eight patients (62%) had at least one grade 3 or 4 adverse event. The most common grade 3 and 4 related adverse events were asthenia, diarrhoea and neutropenia (Table 3). Adverse events of special interest for bevacizumab are summarised in Table 4. Pulmonary embolism occurred in 10 patients, four of whom were >70 years of age; eight of these events were asymptomatic and two were symptomatic.Table 3 \nGrade 3 and 4 adverse events related to treatment occurring in >2% of patients (N = 77)\n\n\nAdverse event\tGrade 3\tGrade 4\t\n\nN\n\t%\t\nN\n\t%\t\nNeutropenia\t5\t6.5\t3\t3.9\t\nFebrile neutropenia\t3\t3.9\t2\t2.6\t\nAlopecia\t3\t3.9\t0\t0\t\nHand–foot syndrome\t4\t5.2\t0\t0\t\nVomiting\t4\t5.2\t0\t0\t\nNausea\t3\t3.9\t0\t0\t\nDiarrhoea\t13\t16.9\t1\t1.3\t\nAsthenia\t12\t15.6\t1\t1.3\t\nTable 4 \nGrade 3 -5 adverse events of interest with bevacizumab (\nN\n= 77)\n\n\nAdverse event\tGrade 3\tGrade 4\tGrade 5\t\n\nN\n\t%\t\nN\n\t%\t\nN\n\t%\t\nHypertension\t2\t2.6\t0\t0\t0\t0\t\nProteinuria\t1\t1.3\t0\t0\t0\t0\t\nGastrointestinal perforation\t1\t1.3\t1\t1.3\t1\t1.3\t\nArterial thrombosis\t1\t1.3\t0\t0\t0\t0\t\nDeep vein thrombosis\t1\t1.3\t1\t1.3\t0\t0\t\nPulmonary thromboembolism\t2\t2.6\t8\t10.4\t0\t0\t\n\n\nQuality of life\nEQ-5D-3 L questionnaires were completed by 70 patients (91%) at cycle 1, 58 of 70 patients (83%) at cycle 3, 49 of 64 patients (77%) at cycle 5, 38 of 55 patients (69%) at cycle 7, 36 of 47 patients (77%) at cycle 9, and 31 of 45 patients (69%) at cycle 11. After this point, the number of patients who completed questionnaires continued to decline, although some patients completed questionnaires until cycle 43.\n\nPatient quality of life did not vary greatly over the study period (Figure 3). Most patients reported having no problems with mobility, patient care or activities of daily living during the first cycles of treatment. More than 50% of patients experienced pain or discomfort in the early cycles, although this proportion decreased as the study progressed. More than half of all patients reported feeling moderately or very anxious, or depressed throughout the study period. Mean VAS general health scores ranged from 71 to 76 over cycles 1–11 (Figure 3).Figure 3 Changes in quality of life over the first 11 cycles of treatment as measured by the EuroQoL 5-Dimensions (3-level) questionnaire and patients’ VAS assessment of general health. Abbreviation: VAS = visual analogue scale.\n\n\n\nDiscussion\nConsiderable uncertainty surrounds the most effective use of irinotecan in combination with capecitabine for the treatment of patients with mCRC. Some studies have shown that irinotecan can be associated with significant gastrointestinal toxicities and, as a result, several doses and administration regimens have been investigated in order to maximise efficacy and tolerability.\n\nThis study has demonstrated that administering capecitabine–irinotecan plus bevacizumab every 2 weeks is a feasible and tolerable first-line treatment option for patients with mCRC. Cross-study comparisons, which should be made with caution, suggest that median progression-free survival and overall survival in the present study (11.8 months and 24.8 months, respectively) are similar to those reported in other phase II studies of bevacizumab plus XELIRI [19-22] and superior to those in which XELIRI was administered without bevacizumab [8,11,12]. This suggests that the efficacy of treatment was not compromised by the 2-weekly dosing schedule.\n\nThe safety profile of capecitabine–irinotecan plus bevacizumab administered every 2 weeks was comparable with reports from other phase II studies. We observed grade 3/4 diarrhoea in 18% of patients, which is similar to the 10–19% reported by others [19-22]; moreover, only one patient had grade 4 diarrhoea. Grade 3/4 neutropenia appeared to be somewhat less common than in other studies, occurring in 10% of patients in our study compared with 12–18% reported in those other studies.\n\nThromboembolic events have been reported as a complication of treatment with XELIRI–bevacizumab in the French FNCCLC ACCORD 13/0503 study, in which 24% of patients in the XELIRI–bevacizumab arm reported a venous thrombosis or pulmonary embolism [22]. In the present study, thromboembolic events were observed in 17% of patients, most of which were asymptomatic. Four of the eight grade 4 pulmonary emboli occurred in patients who were >70 years of age, amongst whom such events have been reported to be more common [23,24]. Indeed the incidence of thromboembolic events increased with age in bevacizumab-treated patients in the BRiTE registry, although the increase was not statistically significant after adjustment for baseline ECOG performance status, hypertension, the absence of anticoagulant therapy at baseline and prior history of thromboembolic events [25].\n\nMedian dose intensities were 89% for bevacizumab, 85% for irinotecan and 89% for capecitabine, suggesting that the regimen was generally well tolerated. These findings were within the confidence intervals of other studies that have reported on tolerability of the combination [21,22,26].\n\nResponse to treatment was not dependent on tumour KRAS status, as observed in other studies of bevacizumab plus chemotherapy in patients with mCRC [7,27-29]. As with the prognostic value of KRAS genotype study [29], we found that progression-free survival and overall survival were not extended significantly in KRAS wild-type genotypes over the mutant form. When interpreting these findings, it is important to note that the KRAS analysis was conducted retrospectively in a non-comparative trial.\n\nQuality of life, as measured using the EQ-5D-3 L questionnaire, was maintained throughout the study, suggesting that treatment did not have a substantial negative impact on patients’ everyday activities. The evidence supports the validity of the EQ-5D-3 L tool in measuring quality of life in cancer patients [30], although the 5-level classification system, EQ-5D-5 L, has less ceiling effect and greater discriminative power [31] and we would consider using this tool in future studies. It is tricky to compare the VAS scores in Figure 3 with the EQ-5D-3 L scores. The subjective nature of the VAS scores gives some insight into the psychological tolerance of the effect of treatment on patients than the more objective EQ-5D-3 L. This self-perception of wellbeing improves over the course of the study. It would be interesting to investigate this (perhaps ‘placebo-like’) phenomenon more deeply in a separate study.\n\nConclusions\nIn conclusion, this multicentre phase II study supports the use of irinotecan and capecitabine administered every 2 weeks with bevacizumab in patients with mCRC. The study included patients with multiple comorbidities, and elderly patients, and therefore indicates that this is an effective and tolerable regimen.\n\nAdditional file\n\nAdditional file 1: \nInstitutional Review Board and Ethics Committee.\n\n\n\n\n\nAbbreviations\nECOGEastern Cooperative Oncology Group\n\nFOLFIRIFluorouracil with folinic acid plus irinotecán\n\nFOLFOXFolinic acid plus oxaliplatino\n\nmCRCMetastatic colorectal cancer\n\nTTDSpanish cooperative group for the treatment of digestive tumors\n\nXELIRICapecitabine plus irinotecán\n\nXELIRICapecitabine plus irinotecán\n\nXELOXCapecitabine plus oxaliplatin\n\nCompeting interests\n\nP Garcia-Alfonso: Consultant /Advisory Role: Amgen, Bayer, Merck, Roche and Sanofi. E. Aranda: Consultant /Advisory Role: Amgen, Bayer, Celgene, Merck, Roche and Sanofi. All remaining authors have declared no conflict of interests.\n\nAuthors’ contributions\n\nPGA and EA were responsible for conception and design, and data analysis and interpretation. PGA, MC, AM, AS, MGG, CG, BM, EGF, BQ, ALL, FL, MJG, AO and EA were responsible for collection and assembly of data, provision of study materials or patients, manuscript writing and final approval of manuscript.\n\nAuthors’ information\n\nSupported by the TTD, Madrid, Spain.\n\nAcknowledgements\nThe authors wish to thank the patients, and the medical and nursing staff of all the participating institutions; Inma Ruiz de Mena at the TTD Data Center; Dynamic Solution for monitoring, statistics and data management. Support for third-party medical writing assistance was provided by Roche Farma, Spain.\n\nFinancial support for this research trial was provided by Roche Farma, S.A.\n\nThe findings have been presented in part at:\n\n● American Society of Clinical Oncology (ASCO) Annual Meeting Proceedings. J Clin Oncol29: 2011 (suppl; abstr e13018).\n\n● 14th World Congress on Gastrointestinal Cancer (2012) Ann Oncol23 (suppl 4): iv103-iv104.\n\n● American Society of Clinical Oncology (ASCO) (2013) Gastrointestinal Cancers Symposium. J Clin Oncol Vol31, No 4_suppl (February 1 Supplement): 501.\n==== Refs\nReferences\n1. Ferlay J, Shin H, Bray F, Forman D, C Mathers, Parkin D. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10. 2010. Lyon, France: International Agency for Research on Cancer. Available from: http://globocan.iarc.fr. Accessed on 10 November 2013.\n2. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (2013) Colon cancer Version 3. Available at http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed on 6 March 2013.\n3. 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Renouf DJ Welch S Moore MJ Krzyzanowska MK Knox J Feld R A phase II study of capecitabine, irinotecan, and bevacizumab in patients with previously untreated metastatic colorectal cancer Cancer Chemother Pharmacol 2012 69 1339 44 10.1007/s00280-012-1843-9 22349811 \n22. Ducreux M Adenis A Pignon J-P François E Chauffert B Ichanté JL Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomised phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study) Eur J Cancer Oxf Engl 1990 2013 49 1236 45 \n23. White RH The epidemiology of venous thromboembolism Circulation 2003 107 23 suppl 1 I–4–I–8 \n24. Stein PD Hull RD Kayali F Ghali WA Alshab AK Olson RE Venous thromboembolism according to age: the impact of an aging population Arch Intern Med 2004 164 2260 5 10.1001/archinte.164.20.2260 15534164 \n25. Kozloff M Yood MU Berlin J Flynn PJ Kabbinavar FF Purdie DM Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study Oncologist 2009 14 862 70 10.1634/theoncologist.2009-0071 19726453 \n26. Ardavanis A Kountourakis P Mantzaris I Malliou S Doufexis D Sykoutri D Bevacizumab added to the irinotecan and capecitabine combination for advanced colorectal cancer: a well-tolerated, active and convenient regimen Anticancer Res 2008 28 3087 92 19031962 \n27. Hurwitz HI Yi J Ince W Novotny WF Rosen O The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer Oncologist 2009 14 22 8 10.1634/theoncologist.2008-0213 19144677 \n28. Price TJ Hardingham JE Lee CK Weickhardt A Townsend AR Wrin JW Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer J Clin Oncol Off J Am Soc Clin Oncol 2011 29 2675 82 10.1200/JCO.2010.34.5520 \n29. Bruera G Cannita K Di Giacomo D Lamy A Troncone G Dal Mas A Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease BMC Med 2012 10 135 10.1186/1741-7015-10-135 23136868 \n30. Pickard AS De Leon MC Kohlmann T Cella D Rosenbloom S Psychometric comparison of the standard EQ-5D to a 5 level version in cancer patients Med Care 2007 45 259 63 10.1097/01.mlr.0000254515.63841.81 17304084 \n31. Janssen MF Pickard AS Golicki D Gudex C Niewada M Scalone L Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study Qual Life Res Int J Qual Life Asp Treat Care Rehabil 2013 22 1717 27 10.1007/s11136-012-0322-4\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "15()",
"journal": "BMC cancer",
"keywords": null,
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "327",
"pmc": null,
"pmid": "25925749",
"pubdate": "2015-04-29",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18421054;18065406;19031962;19097774;19144677;19331137;19726453;19738605;20978503;21646616;22240792;22349811;23012255;12814979;12954586;14716761;15175435;15534164;15668285;17304084;17442997;17947725;22748098;23136868;23168366;23352604;23184421",
"title": "Capecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study.",
"title_normalized": "capecitabine and irinotecan with bevacizumab 2 weekly for metastatic colorectal cancer the phase ii avaxiri study"
} | [
{
"companynumb": "ES-PFIZER INC-2015163409",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Oxaliplatin immune-induced syndrome (OIIS) is an uncommon, potentially life-threatening, side effect associated with oxaliplatin-based chemotherapy. The present study reports 5 original cases of OIIS and systematically reviewed the available published cases. We retrospectively analyzed the clinical archives of the Niguarda Cancer Center from 2009 to 2015 and conducted a search for OIIS using the PubMed database, followed by deeper investigation of the references of the recorded studies. We pooled our series with other reported cases for systematic review in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement using only English language as the selection criterion. A total of 61 OIIS cases were analyzed, the largest series reported to date. Of the 61 patients, 56 (91.8%) had received oxaliplatin for metastatic colorectal cancer. In 32 of the 61 patients (52.5%), OIIS was associated with grade 4 thrombocytopenia and in 4 (6.6%) with grade 4 anemia. OIIS was fatal in 4 patients. In 49 patients, oxaliplatin-induced immune system activation was tested using the Coombs test or by detection of antiplatelet antibodies and was positive in 87.7% of the patients. The average number of oxaliplatin cycles until the onset of OIIS was 16.7, and the number was significantly lower when oxaliplatin was administered as a rechallenge after a period of vacancy of treatment with this agent (4.6 cycles as rechallenge vs. 13.6 as first-time exposure; P < .00001). OIIS is triggered by cumulative administration of oxaliplatin, characteristically with a threefold earlier onset when the drug is administered as a rechallenge. Prompt identification of OIIS can be expected to reduce the risk of iatrogenic morbidity and mortality.",
"affiliations": "Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Nephrology, Dialysis, and Transplant Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Nephrology, Dialysis, and Transplant Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Immunohematolgy and Transfusion Medicine Department, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Immunohematolgy and Transfusion Medicine Department, Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Electronic address: andrea.sartorebianchi@ospedaleniguarda.it.;Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.",
"authors": "Bencardino|Katia|K|;Mauri|Gianluca|G|;Amatu|Alessio|A|;Tosi|Federica|F|;Bonazzina|Erica|E|;Palmeri|Laura|L|;Querques|Marialuisa|M|;Ravera|Federica|F|;Menegotto|Alberto|A|;Boiani|Elisa|E|;Sartore-Bianchi|Andrea|A|;Siena|Salvatore|S|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-0028",
"issue": "15(3)",
"journal": "Clinical colorectal cancer",
"keywords": "Chemotherapy; Hemolysis; Rechallenge; Thrombocytopenia; Timing",
"medline_ta": "Clin Colorectal Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013577:Syndrome",
"nlm_unique_id": "101120693",
"other_id": null,
"pages": "213-21",
"pmc": null,
"pmid": "26979913",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Oxaliplatin Immune-Induced Syndrome Occurs With Cumulative Administration and Rechallenge: Single Institution Series and Systematic Review Study.",
"title_normalized": "oxaliplatin immune induced syndrome occurs with cumulative administration and rechallenge single institution series and systematic review study"
} | [
{
"companynumb": "IT-HOSPIRA-3253476",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"d... |
{
"abstract": "A 30-year-old woman contracted Plasmodium falciparum malaria in the first trimester of her pregnancy while taking chloroquine for malaria prophylaxis. Her illness was characterized by hemolytic anemia with IgG1 coating of the surface of the erythrocytes and IgG3 in her serum. The hemolysis subsided following treatment of the malaria infection early in the third trimester. She delivered at term an infant who had hypoplasia of the right tibia and fibula and absence of the fifth ray of the right foot. The hemolytic process was attributed to the malaria infection, and the birth defect may have been related to the antimalarial therapy in the first trimester of pregnancy.",
"affiliations": null,
"authors": "Drouin|J|J|;Rock|G|G|;Jolly|E E|EE|",
"chemical_list": "D000962:Antimalarials; D007074:Immunoglobulin G; D003165:Complement System Proteins",
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-4409",
"issue": "132(3)",
"journal": "Canadian Medical Association journal",
"keywords": null,
"medline_ta": "Can Med Assoc J",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000744:Anemia, Hemolytic, Autoimmune; D000962:Antimalarials; D003165:Complement System Proteins; D003298:Coombs Test; D003937:Diagnosis, Differential; D004912:Erythrocytes; D005260:Female; D005360:Fibula; D006801:Humans; D007074:Immunoglobulin G; D007231:Infant, Newborn; D008288:Malaria; D008297:Male; D010963:Plasmodium falciparum; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D013977:Tibia; D014034:Toes",
"nlm_unique_id": "0414110",
"other_id": null,
"pages": "265-7",
"pmc": null,
"pmid": "3881157",
"pubdate": "1985-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6993068;4631762;371880;86777;7000157;4957827;7002393;14198705;14465271;1249707;4229630;795036;14897925;13983000",
"title": "Plasmodium falciparum malaria mimicking autoimmune hemolytic anemia during pregnancy.",
"title_normalized": "plasmodium falciparum malaria mimicking autoimmune hemolytic anemia during pregnancy"
} | [
{
"companynumb": "CA-SA-2018SA116471",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CHLOROQUINE"
},
"drugadditional": null,
"d... |
{
"abstract": "A report of acute azithromycin-induced hepatocellular injury is described.\nAn 83-year-old male was admitted with possible community-acquired pneumonia and received azithromycin and ceftriaxone. After 2 doses of azithromycin, the patient's aspartate aminotransferase and alanine aminotransferase were greater than 3 times the upper limit of normal and continued to rise with subsequent doses. A diagnostic abdominal ultrasound revealed hepatomegaly. Total bilirubin remained within normal limits during the course. Rosuvastatin and fenofibrate were held on admission and were not resumed in the setting of elevated liver enzymes. Rivaroxaban was held in the setting of worsening renal function. Hepatitis serologies were negative. Liver enzymes, international normalized ratio (INR), and activated partial thromboplastin time (aPTT) continued to climb until hospital day 5 when azithromycin was discontinued in response. Liver enzymes, INR, aPTT, and lactate dehydrogenase all decreased from hospital days 6 through 8.\nA potentially serious liver injury occurred with the initiation of azithromycin and began to resolve quickly after its discontinuation. While cholestatic injury with azithromycin is well described, this is only the third reported case of direct hepatocellular injury.",
"affiliations": "Department of Pharmacy Services, 22374Princeton Baptist Medical Center, Birmingham, AL, USA.;Department of Pharmacy Services, 22374Princeton Baptist Medical Center, Birmingham, AL, USA.",
"authors": "Ellison|Carolyn A|CA|https://orcid.org/0000-0003-1870-3647;Blackwell|Sarah B|SB|https://orcid.org/0000-0001-6664-5213",
"chemical_list": "D017963:Azithromycin",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190019894428",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "34(3)",
"journal": "Journal of pharmacy practice",
"keywords": "azithromycin; hepatocellular liver injury",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D017963:Azithromycin; D006528:Carcinoma, Hepatocellular; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D019934:International Normalized Ratio; D008113:Liver Neoplasms; D008297:Male",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "493-496",
"pmc": null,
"pmid": "31928122",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Hepatocellular Injury Associated With Azithromycin.",
"title_normalized": "acute hepatocellular injury associated with azithromycin"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2020GMK046855",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nThe incidence of cutaneous infections by dematiaceous fungi is rising in our environment due to the high number of solid organ transplant recipients (SOTR).\n\n\nOBJECTIVE\nTo review our experience in the management of cutaneous phaeohyphomycoses in a Spanish reference centre for dermatological care of SOTR.\n\n\nMETHODS\nRetrospective clinical, histopathological and microbiological review of all SOTR diagnosed of a phaeohyphomycosis in a 7-year period.\n\n\nRESULTS\nEleven SOTR were identified (8 lung and 3 kidney). The lesions were solitary in six patients and multiple in five, affecting mostly the lower extremities. Early lesions showed epidermal hyperplasia and a diffuse dermal suppurative granulomatous infiltrate that was progressively substituted by fibrosis when the lesions were treated. Septated fungal structures with refractile walls were identified. DNA sequencing confirmed the presence of Alternaria spp (8 cases), Cladosporium cladosporioides, Microsphaeropsis arundinis and Exophiala oligosperma. Three patients with single lesions were treated with surgery, while the other 8 required long-term antifungal therapy, including itraconazole, voriconazole and/or terbinafine, combined with surgery and reduction in tacrolimus doses.\n\n\nCONCLUSIONS\nA clinical, histopathological and microbiological correlation is essential to corroborate this diagnosis. Solitary lesions are easily treated with surgery, but larger or multiple lesions may require long medical treatments combined with surgery and modification of immunosuppressive medication. The list of dematiaceous fungi implicated in cutaneous infections is expanding, in line with the availability of more sophisticated identification methods and the increasing number of immunosuppressed patients.",
"affiliations": "Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Microbiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Nephology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Neumology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.",
"authors": "Ferrándiz-Pulido|Carla|C|http://orcid.org/0000-0003-3688-9596;Martin-Gomez|M Teresa|MT|;Repiso|Trinidad|T|;Juárez-Dobjanschi|Cecilia|C|;Ferrer|Berta|B|;López-Lerma|Ingrid|I|;Aparicio|Gloria|G|;González-Cruz|Carlos|C|http://orcid.org/0000-0003-0117-8858;Moreso|Francesc|F|http://orcid.org/0000-0002-7267-3963;Roman|Antonio|A|;García-Patos|Vicente|V|http://orcid.org/0000-0003-1654-6035",
"chemical_list": "D000935:Antifungal Agents",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12853",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "62(2)",
"journal": "Mycoses",
"keywords": "alternaria; cutaneous infection; dematiaceous fungui; immunosuppression; itraconazole; organ transplant recipients; voriconazole",
"medline_ta": "Mycoses",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D001203:Ascomycota; D003646:Debridement; D019468:Disease Management; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D060446:Phaeohyphomycosis; D012189:Retrospective Studies; D012867:Skin; D013030:Spain; D066027:Transplant Recipients; D019737:Transplants",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "121-127",
"pmc": null,
"pmid": "30230044",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cutaneous infections by dematiaceous opportunistic fungi: Diagnosis and management in 11 solid organ transplant recipients.",
"title_normalized": "cutaneous infections by dematiaceous opportunistic fungi diagnosis and management in 11 solid organ transplant recipients"
} | [
{
"companynumb": "ES-ROCHE-2280221",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHypercalcemia associated with lymphomas can be secondary to increased calcitriol [1,25(OH)2 vitamin D3], PTHrP, or osteolytic metastases.\n\n\nOBJECTIVE\nA case of calcitriol-mediated hypercalcemia secondary to non-Hodgkin lymphoma in a patient with postsurgical hypoparathyroidism is presented.\n\n\nMETHODS\nSingle patient managed at a tertiary health care facility in the United States.\n\n\nMETHODS\nA 55-year-old white woman had a total thyroidectomy and radioiodine ablation for a 3.5-cm follicular carcinoma. Surgery was complicated by permanent hypoparathyroidism treated with calcium, calcitriol, and cholecalciferol. For over 16 years she had no evidence of either residual thyroid tissue in the neck or metastasis. Her corrected serum calcium levels were appropriately maintained in the low-normal range. During a routine clinic visit, she had mild hypercalcemia; calcium and cholecalciferol were reduced by 50%, while calcitriol was continued. Two weeks later, she presented with nausea, abdominal pain, and multiple rapidly enlarging cervical and axillary lymph nodes with elevated calcium and calcitriol. A fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan and lymph node biopsy were diagnostic for non-Hodgkin lymphoma.\n\n\nMETHODS\nCalcium and calcitriol were stopped; hypercalcemia was corrected with iv fluids. Chemotherapy resulted in an excellent response within 7 weeks; calcitriol normalized, and the patient developed recurrent hypocalcemia. Positron emission tomography/computed tomography scans at 7 weeks and 3 months after treatment documented near-complete resolution of the lesions. Outcome and Result: Sixteen months after the treatment of lymphoma, the patient remains free of disease and is on calcium, calcitriol, and cholecalciferol.\n\n\nCONCLUSIONS\nClinicians should have a high index of suspicion for malignancy when patients presents with rapid and high elevations of serum calcium.",
"affiliations": "Department of Medicine, Section of Endocrinology and Metabolism, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103.",
"authors": "Sundaresh|Vishnu|V|;Levine|Steven N|SN|",
"chemical_list": "D002762:Cholecalciferol; D002117:Calcitriol; D002118:Calcium",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2014-3063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "100(1)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D018263:Adenocarcinoma, Follicular; D002117:Calcitriol; D002118:Calcium; D002762:Cholecalciferol; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D006996:Hypocalcemia; D007011:Hypoparathyroidism; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged; D013964:Thyroid Neoplasms; D013965:Thyroidectomy; D016896:Treatment Outcome",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "21-4",
"pmc": null,
"pmid": "25303492",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "From hypocalcemia to hypercalcemia-an unusual clinical presentation of a patient with permanent postsurgical hypoparathyroidism.",
"title_normalized": "from hypocalcemia to hypercalcemia an unusual clinical presentation of a patient with permanent postsurgical hypoparathyroidism"
} | [
{
"companynumb": "US-TEVA-545484USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
},
"drugadditional": null,
... |
{
"abstract": "A 34-year-old female patient presented to our hospital with lower extremity edema and proteinuria during pregnancy. Renal biopsy was performed and the patient was diagnosed with nephrotic syndrome due to lupus-like membranous nephropathy. This diagnosis was reached upon as laboratory findings upon admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed negative, did not fulfill the criteria for systemic lupus erythematosus (SLE) proposed by the American College of Rheumatology (ACR) and the patient did not reveal any typical physical manifestations of SLE. Methylprednisolone pulse therapy was started followed by oral administration of prednisolone. Urinary protein excretion diminished after 1 year of treatment. Eleven years later, the same patient was admitted to our hospital again with relapse of nephrotic syndrome. Laboratory findings upon second admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed positive, fulfilled the ACR criteria. Renal biopsy was performed again, resulting in a diagnosis of lupus nephritis. Steroid therapy combined with administration of mycophenolate mofetil led to an incomplete remission. Immunofluorescence studies confirmed the presence of IgG, IgM, C3, and C1q in renal biopsy specimens both at first and second admissions. Furthermore, immunofluorescence studies confirmed the presence of IgG1-4 in the first biopsy and tubuloreticular inclusions (TRIs) were revealed using electron microscopy. The present case represents the possibility that characteristic pathological findings of lupus nephritis, including TRIs, can reveal themselves before a diagnosis of SLE.",
"affiliations": "Department of Nephrology, Nippon Medical School Chiba Hokusoh Hospital, 1715, Kamagari, Inzai, Chiba, 270-1694, Japan. t-yamada@nms.ac.jp.;Department of Nephrology, Nippon Medical School Chiba Hokusoh Hospital, 1715, Kamagari, Inzai, Chiba, 270-1694, Japan.;Department of Nephrology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Nephrology, Nippon Medical School Chiba Hokusoh Hospital, 1715, Kamagari, Inzai, Chiba, 270-1694, Japan.;Department of Nephrology, Nippon Medical School Chiba Hokusoh Hospital, 1715, Kamagari, Inzai, Chiba, 270-1694, Japan.;Department of Nephrology, Nippon Medical School Musashi Kosugi Hospital, 1-396, Kosugimachi, Nakahara-ku, Kawasaki, Kanagawa, 211-8533, Japan.;Department of Nephrology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Analytic Human Pathology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.;Department of Nephrology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.",
"authors": "Yamada|Takehisa|T|0000-0001-9474-1341;Itagaki|Fumiaki|F|;Aratani|Sae|S|;Kawasaki|Sayuri|S|;Terada|Kousuke|K|;Mugishima|Koji|K|;Kashiwagi|Tetsuya|T|;Shimizu|Akira|A|;Tsuruoka|Shuichi|S|",
"chemical_list": "D000974:Antibodies, Antinuclear; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007074:Immunoglobulin G; D009173:Mycophenolic Acid; D008775:Methylprednisolone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-019-00412-5",
"fulltext": "\n==== Front\nCEN Case RepCEN Case RepCEN Case Reports2192-4449Springer Singapore Singapore 41210.1007/s13730-019-00412-5Case ReportA case of membranous nephropathy diagnosed with lupus nephritis 11 years after onset http://orcid.org/0000-0001-9474-1341Yamada Takehisa 0476-99-1111t-yamada@nms.ac.jp 1Itagaki Fumiaki 1Aratani Sae 3Kawasaki Sayuri 1Terada Kousuke 1Mugishima Koji 2Kashiwagi Tetsuya 3Shimizu Akira 4Tsuruoka Shuichi 31 grid.416273.50000 0004 0596 7077Department of Nephrology, Nippon Medical School Chiba Hokusoh Hospital, 1715, Kamagari, Inzai, Chiba 270-1694 Japan 2 grid.459842.60000 0004 0406 9101Department of Nephrology, Nippon Medical School Musashi Kosugi Hospital, 1-396, Kosugimachi, Nakahara-ku, Kawasaki, Kanagawa 211-8533 Japan 3 grid.410821.e0000 0001 2173 8328Department of Nephrology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603 Japan 4 grid.410821.e0000 0001 2173 8328Department of Analytic Human Pathology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603 Japan 9 8 2019 9 8 2019 11 2019 8 4 301 307 26 11 2018 31 7 2019 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.A 34-year-old female patient presented to our hospital with lower extremity edema and proteinuria during pregnancy. Renal biopsy was performed and the patient was diagnosed with nephrotic syndrome due to lupus-like membranous nephropathy. This diagnosis was reached upon as laboratory findings upon admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed negative, did not fulfill the criteria for systemic lupus erythematosus (SLE) proposed by the American College of Rheumatology (ACR) and the patient did not reveal any typical physical manifestations of SLE. Methylprednisolone pulse therapy was started followed by oral administration of prednisolone. Urinary protein excretion diminished after 1 year of treatment. Eleven years later, the same patient was admitted to our hospital again with relapse of nephrotic syndrome. Laboratory findings upon second admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed positive, fulfilled the ACR criteria. Renal biopsy was performed again, resulting in a diagnosis of lupus nephritis. Steroid therapy combined with administration of mycophenolate mofetil led to an incomplete remission. Immunofluorescence studies confirmed the presence of IgG, IgM, C3, and C1q in renal biopsy specimens both at first and second admissions. Furthermore, immunofluorescence studies confirmed the presence of IgG1–4 in the first biopsy and tubuloreticular inclusions (TRIs) were revealed using electron microscopy. The present case represents the possibility that characteristic pathological findings of lupus nephritis, including TRIs, can reveal themselves before a diagnosis of SLE.\n\nKeywords\nMembranous lupus nephritisLupus-like membranous nephropathyTubuloreticular inclusionIgG subclassissue-copyright-statement© Japanese Society of Nephrology 2019\n==== Body\nIntroduction\nThere has been a growing body of reports regarding membranous nephropathy (MN) cases that present like lupus nephritis [1–7] without fulfilling the classification criteria for systemic lupus erythematosus (SLE) proposed by the American College of Rheumatology (ACR) [8–10]. The importance of pathological findings from renal biopsy specimens has been highlighted by the recently defined classification criteria for SLE, proposed by the Systemic Lupus International Collaborating Clinics (SLICC) group in 2012 [11]. These new classification proposals suggest that a diagnosis for SLE can be reached not only in patients who fulfill at least four criteria, including at least one clinical and one immunological criteria, but also in patients with biopsy-proven lupus nephritis combined with the presence of anti-nuclear antibodies (ANA) or anti-double-stranded DNA (anti-dsDNA) antibodies [11]. Until this new proposal was made, cases which did not satisfy at least four criteria were tended to be excluded from a possibility of SLE, even though they had shown characteristic pathological findings of lupus nephritis.\n\nRecently, we encountered a female patient who had SLE with lupus nephritis. At first, the patient presented to our hospital with nephrotic syndrome. According to the ACR criteria [10], which were formerly conventionally used at first admission, the patient was excluded from a possibility of SLE, despite pathological findings of lupus-like MN, because they tested negative for both ANA and anti-dsDNA antibodies. Eleven years later, the same patient was admitted to our hospital again due to relapse of nephrotic syndrome. Laboratory findings upon second admission, wherein both ANA and anti-dsDNA antibodies revealed positive, fulfilled both ACR and SLICC criteria [10, 11].\n\nCase report\nA 34-year-old woman presented to our hospital with edema of the lower extremities during the eighth. week of pregnancy. She had had neither reproductive nor obstetric history before. She had neither skin rash nor arthralgia. She had neither photosensitivity nor oral ulcers. Laboratory tests conducted upon admission revealed hypoalbuminemia, proteinuria, and hyperlipidemia. Both ANA and anti-dsDNA antibody test yielded negative results. Levels of CH50, C3, and C4 were all normal. The levels of hepatitis B surface-antigen and hepatitis C virus antibodies were also normal (Table 1). There were no symptoms of malignancy. Percutaneous renal biopsy yielded characteristic findings of MN, which were revealed using light microscopy (Fig. 1). Pathological features, including slight subepithelial deposits and the presence of tubuloreticular inclusions in endothelial cells, were revealed using electron microscopy (Fig. 2a, b). Although immunofluorescence studies yielded positive stains for IgG (including all four subclasses, IgG1–4), IgM, C3 and C1q (Figs. 3, 4), the patient was diagnosed with lupus-like MN because laboratory findings upon admission did not fulfill the ACR criteria [10] and there were no typical physical manifestations of SLE. Methylprednisolone pulse therapy followed by oral administration of prednisolone was commenced, resulting in complete remission after 1 year. She delivered normally without any complication at 37th week of her pregnancy. After first remission, the patient was transferred to her primary care doctor. Laboratory findings for the patient were therefore not observed until second admission.Table 1 Laboratory findings at first admission\n\nUrinalysis\tBC\t IgA\t179 mg/dL\t\n Pro.\t\n(3 +)\n\t T.Bil\t0.1 mg/dL\t IgM\t183 mg/dL\t\n Glu.\t(−)\t AST\t13 IU/L\t CH50\t38.0 U/dL\t\n Urobili.\t(±)\t ALT\t10 IU/L\t C3\t130 mg/dL\t\n Bil.\t(−)\t UA\t3.0 mg/dL\t C4\t33.2 mg/dL\t\n Ket.\t(−)\t LDH\t130 IU/L\t Anti-nuclear-Ab\t< × 40\t\n Occult blood\t\n(1 +)\n\t P\t3.4 g/dL\t Anti-dsDNAIgG\t2.4 IU/mL\t\nSed.\t Alb\t1.4 g/dL\t PR3-ANCA\t< 1.3 U/mL\t\n RBC\t\n50–99/HPF\n\t CK\t29 IU/L\t MPO-ANCA\t< 1.3 U/mL\t\n WBC\t5–9/HPF\t BUN\t5.1 mg/dL\t Anti-GBM-Ab\t< 10 EU\t\n Casts\t\n50–99/HPF\n\t Cr\t0.59 mg/dL\t HBs-Ag\t(−)\t\nCBC\t Na\t139 mEq/dL\t HCV-Ab\t(−)\t\n WBC\t7870/mL\t K\t3.8 mEq/dL\t TPHA\t(−)\t\n RBC\t296 × 104/mL\t Cl\t108 mEq/dL\t RPR\t(−)\t\n Hb\t9.3 g/dL\t Glu.\t75 mg/dL\t Anti-SSA\t(−)\t\n Hct\t26.3%\t T.chol\t547 mg/dL\t Anti-SSB\t(−)\t\n MCV\t78.2%\t TG\t172 mg/dL\t Anti-CL-β2GP\t< 1.3 U/mL\t\n MCH\t24.7 pg\tSerology\t Anti-cardio-IgG\t2 U/mL\t\n MCHC\t31.5%\t CRP\t< 0.05 mg/dL\t Urinary protein excretion\t7.5 g/day\t\n PLT\t20.9 × 104/mL\t IgG\t492 mg/dL\t Selectivity index\t0.117\t\nAbnormal data have been underlined\n\nAnti-nuclear-Ab antinuclear antibodies, Anti-dsDNAIgG anti-double stranded deoxyribonucleic acid-immunoglobulin G antibodies, PR3-ANCA proteinase3-antineutrophil cytoplasmic antibodies, MPO-ANCA myeloperoxidase-antineutrophil cytoplasmic antibodies, Anti-GBM-Ab anti-glomerular basement membrane antibodies, Anti-CL-β2GP anti-cardiolipin beta2 glycoprotein 1 antibodies, TPHA treponema pallidum hemagglutination test, RPR rapid plasma regain card agglutination test, SS Sjögren’s syndrome\n\nFig. 1 Pathological findings in renal biopsy during first admission. Light microscopy revealed mild thickening of glomerular basement membrane with stippling and spike formation (PASM staining, × 400)\n\nFig. 2 Electron microscopy revealed slight subepithelial deposits (arrows) (a). Notably, a magnified view of the square demonstrated tubuloreticular inclusion (arrow) in the endothelial cell (b)\n\nFig. 3 Immunofluorescence studies revealed granular deposits of IgG, IgM, C3, and C1q, with only slight deposits of C4 and IgA in the glomeruli\n\nFig. 4 Immunofluorescence studies of IgG subclasses revealed positive stains for all four (IgG1–4)\n\n\n\nEleven years later, the same patient presented to our hospital with edema of lower extremities and self-reported abdominal distension. She had not yet experienced menopause. Tests revealed hypoalbuminemia, proteinuria, and hyperlipidemia. The value of lupus anticoagulant was normal. Serological tests yielded positive results for both ANA and anti-dsDNA antibodies. Laboratory findings at second admission suggested leukocytopenia and hypocomplementemia (Table 2). These clinical findings fulfilled the ACR and the SLICC criteria [10, 11]. In addition to subepithelial spikes and deposits, hypercellularity in mesangial and endocapillary lesions were demonstrated in pathological findings from renal biopsy specimens upon second admission (Figs. 5, 6). These findings suggested membranoproliferative glomerulonephritis with positive stains for IgG, IgM, IgA, C3, and C1q (Fig. 7), which were compatible with class IV + V lupus nephritis. We could not obtain enough samples for an electron microscopic study at second renal biopsy. Methylprednisolone pulse therapy followed by oral administration of prednisolone combined with mycophenolate mofetil achieved incomplete remission after 6 months. The patient is currently under observation at our outpatient clinic.Table 2 Laboratory findings at second admission\n\nUrinalysis\tBC\tSerology\t\n Pro.\t\n(4 +)\n\t T.Bil\t0.2 mg/dL\t CRP\t< 0.05 mg/dL\t\n Glu.\t(−)\t AST\t28 IU/L\t IgG\t649 mg/dL\t\n Urobili.\t(±)\t ALT\t12 IU/L\t IgA\t189 U/dL\t\n Bil.\t(−)\t γ-GTP\t10 IU/L\t IgM\t170 mg/dL\t\n Ket.\t(−)\t ALP\t99 IU/L\t CH50\t5 U/dL\t\n Occult blood\t\n(2 +)\n\t LDH\t247 IU/L\t C3\t3.6 mg/dL\t\nSed.\t TP\t3.5 g/dL\t C4\t34 mg/dL\t\n RBC\t5–9/HPF\t Alb\t1.3 g/dL\t Anti-nuclear-Ab\t\n× 1280 (homogeneous)\n\t\n WBC\t5–9/HPF\t CK\t135 IU/dL\t Anti-dsDNAIgG\t> 380 IU/mL\t\n Casts\t100–999/HPF\t BUN\t7.3 mg/dL\t PR3-ANCA\t< 0.5 U/mL\t\nCBC\t Cr\t0.65 mg/dL\t MPO-ANCA\t< 0.5 U/mL\t\n WBC\t2790/mL\t Na\t144 mEq/dL\t Anti-GBM-Ab\t< 0.5 U/mL\t\n RBC\t406 × 104/mL\t K\t3.0 mEq/dL\t Anti-CL-β2GP\t< 1.3 U/mL\t\n Hb\t9.1 g/dL\t Cl\t108 mEq/dL\t Anti-cardio-IgG\t7 U/mL\t\n Hct\t30.2%\t Ca\t7.2 mg/dL\t HBs-Ag\t(−)\t\n MCV\t74.4%\t P\t4.3 mg/dL\t HCV-Ab\t(−)\t\n MCH\t22.4 pg\t T.chol\t429 mg/dL\t TPHA\t(−)\t\n MCHC\t30.1%\t TG\t80 mg/dL\t RPR\t(−)\t\n PLT\t23.9 × 104/mL\t LDL-chol\t399 mg/dL\t Lupus anticoagulant\t4.5 s\t\nUrinary protein excretion\t16.6 g/day\t\nAbnormal data have been underlined\n\nAnti-nuclear-Ab antinuclear antibodies, Anti-dsDNAIgG anti-double stranded deoxyribonucleic acid-immunoglobulin G antibodies, PR3-ANCA proteinase3-antineutrophil cytoplasmic antibodies, MPO-ANCA myeloperoxidase-antineutrophil cytoplasmic antibodies, Anti-GBM-Ab anti-glomerular basement membrane antibodies, Anti-CL-β2GP anti-cardiolipin beta2 glycoprotein 1 antibodies, TPHA treponema pallidum hemagglutination test, RPR rapid plasma regain card agglutination test\n\nFig. 5 Pathological findings in renal biopsy during second admission. Double contour and hypercellularity in mesangial lesions represent a pattern of membranoproliferative glomerulonephritis (PAS staining, × 400)\n\nFig. 6 PASM staining revealed subepithelial deposits and spike formation (PASM staining, × 400)\n\nFig. 7 Immunofluorescence studies revealed positive mesangial and peripheral stains for IgG, IgM, IgA, C3, C1q, and C4\n\n\n\nDiscussion\nThe clinical criteria for SLE have been evolving ever since the ACR proposed the preliminary criteria [8] in 1971, the revised versions of which were proposed in 1982 and 1997 [9, 10]. Currently, the most widely used classification criteria for SLE are those revised and validated by SLICC [11]. According to their suggestions, at least four criteria,—including at least one clinical criterion and one immunological criteria—are necessary for the diagnosis of SLE. Importantly, however, SLICC criteria also suggest that a diagnosis of SLE can be made based on biopsy-proven lupus nephritis combined with the presence of ANA or anti-dsDNA antibodies [11]. Compared with the ACR criteria, the SLICC criteria highlight the importance of renal pathological findings in the process of diagnosing SLE, resulting in improved sensitivity compared with the ACR criteria [12].\n\nDoi et al. have reported that there are differences in the distribution of IgG subclasses that are deposited in renal tissue between primary MN and lupus nephritis [13]. In their report, IgG4 was the predominant subclass detected in primary MN with granular deposits detected along the capillary walls of glomeruli; neither IgG2 nor IgG3 deposition was identified in patients with primary MN. Conversely, all IgG subclasses were detected in samples from lupus nephritis patients, with the prevalence of IgG1 and IgG3 [13].\n\nThe present case demonstrated characteristic findings of lupus-like MN, in which all IgG subclasses were detected by immunofluorescence studies (Fig. 4), although laboratory tests were negative for both ANA and anti-dsDNA antibodies upon first admission (Table 1). During first admission at which time SLICC criteria [11] had not yet been published, laboratory findings did not satisfy the current ACR criteria [10]. Furthermore, retrospectively, those laboratory findings also failed to satisfy the SLICC criteria [11], despite lupus-like features in the renal biopsy specimens (Figs. 2, 3), because test for both ANA and anti-dsDNA antibodies yielded negative results (Table 1). Eleven years later, serum titers of ANA and anti-dsDNA antibodies had increased, resulting in tests yielding positive results upon second admission (Table 2). Assessment of renal biopsy specimens at second admission demonstrated membranoproliferative glomerulonephritis via light microscopy and positive stains for IgG, IgM, IgA, C3, and C1q in immunofluorescence studies, compatible with class IV + V lupus nephritis (Figs. 5, 6, 7). These laboratory and pathological findings fulfilled SLICC criteria [11]. Although tests for both ANA and anti-dsDNA antibodies yielded negative results, immunofluorescence studies revealed positive stains for IgG, IgM, C3, and C1q combined with all positive stains for IgG subclasses in the first biopsy (Figs. 3, 4). Therefore, there remained the possibility that our patient would progress to SLE later—as suggested by lupus-like immunofluorescence findings.\n\nCases of lupus-like MN without a diagnosis of SLE have been reported [2–7] recently, beginning with Simenhoff and Merrill suggesting that lupus nephritis may present only as a renal manifestation, without any other manifestations of SLE [1]. In fact, some patients who have lupus-like pathological features in renal biopsy specimens, without a diagnosis of SLE, subsequently fulfill the criteria for SLE years later [2–7, 14]. The literature reviews have revealed that the average age of such patients is 24.7 years and that 25% develop SLE after a mean followup period of 5 years [14]; our patient was older and the time to develop SLE was longer, than those reported previously [2–7]. In such cases, it is necessary for physicians to continue to observe autoantibody levels even when the patients were excluded from a possibility of SLE during initial treatment.\n\nIn addition to IgG subclass stains, tubuloreticular inclusion can also play an important role in distinguishing secondary MN from primary [15]. Gianviti et al. have reported delayed onset of SLE in pediatric patients with lupus-like immunofluorescence patterns and cytoplasmic tubuloreticular inclusions in renal biopsies [7]. In the present case, observation of pathological features with an electron microscope revealed tubuloreticular inclusions in the endothelial cells in the first biopsy (Fig. 2b). Taking this together with the immunofluorescence findings (Figs. 3, 4), we conclude that the pathological features of MN in the first biopsy represented an early phase of membranous lupus nephropathy.\n\nWith regard to the effects of her pregnancy on SLE, it is well known that early phase of SLE is likely to be associated with pregnancy. It is also reported that risk of the disease exacerbation and pregnancy complications increase in patients with lupus nephritis [16–18]. We speculated that pregnancy might trigger off not only our patient’s lupus-like MN, but also the seroconversion of ANA and anti-dsDNA antibodies at second admission, while she delivered normally without any complication at 37th week of her pregnancy. It is reported that serum complement levels increase during pregnancy [19], while our patient’s serum complement levels were normal at first admission. The possibility was that the characteristic finding of low serum complement levels in SLE might be masked by her pregnancy. Although immunofluorescence for IgG subclasses revealed all positive stains for IgG1–4 and tubuloreticular inclusions were demonstrated in an electron microscopy, we diagnosed our patient with lupus-like MN, not lupus nephritis at first admission. It was because that the possibility of pregnancy-induced effect on autoimmune system in our patient could not be excluded and that there were no typical physical manifestations of SLE at first admission.\n\nIn conclusion, we have reported on a case of MN diagnosed with lupus nephritis 11 years after onset. Although the patient could not be diagnosed with SLE at first admission, lupus-like pathological findings were already observable in renal biopsy specimens. Immunofluorescence studies and the presence of tubuloreticular inclusions helped to differentiate lupus-like MN from idiopathic MN. In such cases, it is necessary for physicians to carefully observe whether the classification criteria for SLE are fulfilled after the remission of symptoms following initial treatment. The classification criteria proposed by SLICC [11] are therefore helpful for physicians to predict the chance of progression into SLE of patients who are excluded from a possibility of SLE but present with lupus-like nephropathy.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors wish to acknowledge Dr. Hiroshi Kitamura (National Hospital Organization Chiba-East-Hospital) and Dr. Nobuaki Yamanaka (Tokyo Kidney Research Institute) for advice on the clinicopathological meanings of tubuloreticular inclusions.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nEthical approval\nAll procedures performed in this case report were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nInformed consent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n==== Refs\nReferences\n1. Simenhoff ML Merrill JP The spectrum of lupus nephritis Nephron 1964 1 348 374 10.1159/000179349 14312771 \n2. Kallen RJ Lee SK Aronson AJ Spargo BH Idiopathic membranous glomerulonephropathy preceding the emergence of systemic lupus erythematosus in two children J Pediatr 1977 90 72 76 10.1016/S0022-3476(77)80767-1 830897 \n3. Caims SA Corbett CL Lawler W Mallick NP Acheson EJ Dosa S Williams DG The delayed appearance of an antinuclear factor and the diagnosis of systemic lupus erythematosus in glomerulonephritis Postgrad Med J 1979 55 723 727 10.1136/pgmj.55.648.723 317153 \n4. Shearn MA Hopper J Biava CG Membranous lupus nephropathy initially seen as an idiopathic membranous nephropathy Arch Intern Med 1980 140 1521 1523 10.1001/archinte.1980.00330220073026 7436650 \n5. Adu D Williams DG Taube D Vilches AR Turner DR Cameron JS Ogg CS Late onset systemic lupus erythematosus and lupus-like disease in patients with apparent idiopathic glomerulonephritis Q J Med 1983 208 471 487 \n6. Wen YK Chen ML Clinicopathological study of originally non-lupus “full-house” nephropathy Renal Fail 2010 32 1025 1030 10.3109/0886022X.2010.510614 \n7. Gianviti A Barsotti P Barbera V Faraggiana T Rizzoni G Delayed onset of systemic lupus erythematosus in patients with “full-house” nephropathy Pediatr Nephrol 1999 13 683 687 10.1007/s004670050681 10502127 \n8. Cohen AS Reynolds WE Franklin EC Kulka JP Ropes MW Shulman LE Wallace SL Preliminary criteria for the classification of systemic lupus erythematosus Bull Rheum Dis 1971 21 643 648 \n9. Tan EM Cohen AS Fries JF Masi AT McShane DJ Rothfield NF Schaller JG Talal N Winchester RJ The 1982 revised criteria for the classification of systemic lupus erythematosus Arthritis Rhuematol 1982 25 1271 1277 10.1002/art.1780251101 \n10. Hochberg MC Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus Arthritis Rhuematol 1997 40 1725 10.1002/art.1780400928 \n11. Petri M Orbai AM Alarcón GS Gordon C Merrill JT Fortin PR Bruce IN Isenberg D Wallace DJ Nived O Sturfelt G Ramsey-Goldman R Bae SC Hanly JG Sánchez-Guerrero J Clarke A Aranow C Manzi S Urowitz M Gladman D Kalunian K Costner M Werth VP Zoma A Bernatsky S Ruiz-Irastorza G Khamashta MA Jacobsen S Buyon JP Maddison P Dooley MA van Vollenhoven RF Ginzler E Stoll T Peschken C Jorizzo JL Callen JP Lim SS Fessler BJ Inanc M Kamen DL Rahman A Steinsson K Franks AG Jr Sigler L Hameed S Fang H Pham N Brey R Weisman MH McGwin G Jr Magder LS Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis Rheumatol 2012 64 2677 2686 10.1002/art.34473 \n12. Rijnink EC Teng YKO Kraaij T Dekkers OM Bruijn JA Bajema IM Validation of the Systemic Lupus International Collaborating Clinics classification criteria in a cohort of patients with full house glomerular deposits Kidney Int 2018 93 214 220 10.1016/j.kint.2017.07.017 28950993 \n13. Doi T Mayumi M Kanatsu K Suehiro F Hamashima Y Distribution of IgG subclasses in membranous nephropathy Clin Exp Immunol 1984 58 57 62 6383668 \n14. Sam R Joshi A James S Jen KY Amani F Hart P Schwartz MM Lupus-like membranous nephropathy: is it true or not? Clin Exp Nephrol 2015 19 395 402 10.1007/s10157-014-1002-1 24993947 \n15. Jeannette JC Iskandar SS Dalldorf FG Pathological differentiation between lupus and nonlupus membranous glomerulopathy Kidney Int 1983 24 377 385 10.1038/ki.1983.170 6358633 \n16. Le Thi Huong D Wechsler B Piette JC Bletry O Godeau P Pregnancy and its outcome in systemic lupus erythematosus Q J Med 1994 87 721 729 10.1093/oxfordjournals.qjmed.a068889 \n17. Moroni G Quaglini S Banfi G Caloni M Finazzi S Ambroso G Como G Ponticelli C Pregnancy in lupus nephritis Am J Kidney Dis 2002 40 713 720 10.1053/ajkd.2002.35678 12324905 \n18. Smyth A Oliveira GH Lahr BD Bailey KR Norby SM Garovic VD A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis Clin J Am Soc Nephrol 2010 5 2060 2068 10.2215/CJN.00240110 20688887 \n19. Johnson U Gustavii B Complement components in normal pregnancy Acta Pathol Microbiol Immunol Scand 1987 95 97 99\n\n",
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"journal": "CEN case reports",
"keywords": "IgG subclass; Lupus-like membranous nephropathy; Membranous lupus nephritis; Tubuloreticular inclusion",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000328:Adult; D000974:Antibodies, Antinuclear; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors; D005260:Female; D015433:Glomerulonephritis, Membranous; D005938:Glucocorticoids; D006760:Hospitalization; D006801:Humans; D007074:Immunoglobulin G; D007668:Kidney; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008775:Methylprednisolone; D009173:Mycophenolic Acid; D009404:Nephrotic Syndrome; D011507:Proteinuria; D012008:Recurrence; D012074:Remission Induction",
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"pubdate": "2019-11",
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"title": "A case of membranous nephropathy diagnosed with lupus nephritis 11 years after onset.",
"title_normalized": "a case of membranous nephropathy diagnosed with lupus nephritis 11 years after onset"
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"abstract": "OBJECTIVE\nIn preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy.\n\n\nMETHODS\nSixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants.\n\n\nRESULTS\nThere were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P = 0.13). The rate was similar to the 3-4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomide-exposed and non-leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non-leflunomide-exposed RA groups.\n\n\nCONCLUSIONS\nAlthough the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.",
"affiliations": "Rady Children's Hospital, University of California, San Diego, California 92093-0828, USA. chchambers@ucsd.edu",
"authors": "Chambers|Christina D|CD|;Johnson|Diana L|DL|;Robinson|Luther K|LK|;Braddock|Stephen R|SR|;Xu|Ronghui|R|;Lopez-Jimenez|Janina|J|;Mirrasoul|Nicole|N|;Salas|Elizabeth|E|;Luo|Yunjun J|YJ|;Jin|Shelia|S|;Jones|Kenneth Lyons|KL|;|||",
"chemical_list": "D000924:Anticholesteremic Agents; D018501:Antirheumatic Agents; D007555:Isoxazoles; D002792:Cholestyramine Resin; D000077339:Leflunomide",
"country": "United States",
"delete": false,
"doi": "10.1002/art.27358",
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"issn_linking": "0004-3591",
"issue": "62(5)",
"journal": "Arthritis and rheumatism",
"keywords": null,
"medline_ta": "Arthritis Rheum",
"mesh_terms": "D000328:Adult; D000924:Anticholesteremic Agents; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001724:Birth Weight; D049628:Body Size; D002792:Cholestyramine Resin; D000013:Congenital Abnormalities; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007555:Isoxazoles; D000077339:Leflunomide; D016014:Linear Models; D015999:Multivariate Analysis; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors",
"nlm_unique_id": "0370605",
"other_id": null,
"pages": "1494-503",
"pmc": null,
"pmid": "20131283",
"pubdate": "2010-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15958772;9494812;1591483;11841641;11724104;7362664;12563675;17602201;2725616;11241434;14130709;3559800;19006208;17604599;11745831;16649008",
"title": "Birth outcomes in women who have taken leflunomide during pregnancy.",
"title_normalized": "birth outcomes in women who have taken leflunomide during pregnancy"
} | [
{
"companynumb": "US-APOTEX-2019AP021853",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWith increasing use of atypical antipsychotics among pediatric patients, detailed information about safety and tolerability is crucial.\n\n\nMETHODS\nData were pooled from two 8-week, randomized, double-blind, multicenter, parallel-group trials comparing aripiprazole versus placebo in subjects aged 6 to 17 years with irritability associated with DSM-IV-TR-diagnosed autistic disorder: one flexibly dosed (aripiprazole 2-15 mg/d; target of 5, 10, or 15 mg/d), the other fixed-dose (aripiprazole 5, 10, or 15 mg/d). The first was conducted from June 2006-April 2008, and the second, from June 2006-June 2008. Adverse events were characterized with respect to incidence, duration, severity, timing of peak incidence of onset, and dose-response relationship. Extrapyramidal symptoms, drooling, and metabolic parameters were evaluated.\n\n\nRESULTS\nThree hundred thirteen subjects comprised the safety sample (aripiprazole 212, placebo 101). Discontinuations due to adverse events with aripiprazole versus placebo were, overall, 10.4% versus 6.9%; subjects 6-12 years: 10.8% versus 5.1%; and subjects 13-17 years: 8.9% versus 13.6%. Common adverse events with aripiprazole versus placebo included sedation (20.8% vs 4.0%), fatigue (16.5% vs 2.0%), vomiting (13.7% vs 6.9%), increased appetite (12.7% vs 6.9%), somnolence (10.4% vs 4.0%), and tremor (9.9% vs 0.0%). Most adverse events were mild or moderate and occurred early. Only fatigue showed a dose-response relationship (P < .05). Mean body weight change (last observation carried forward, 1.6 vs 0.4 kg) was higher with aripiprazole than placebo (P < .001). There were no between-treatment differences in metabolic changes. The extrapyramidal symptom-related adverse event incidence with aripiprazole versus placebo was, overall, 20.8% vs 9.9%; the incidence of akathisia-related events was 3.3% vs 8.9%.\n\n\nCONCLUSIONS\nAripiprazole was generally safe and well tolerated in subjects (6-17 years) with irritability associated with autistic disorder in these 8-week studies; clinicians should be aware of this clinical profile and strategies to manage adverse events if they occur.\n\n\nBACKGROUND\nclinicaltrials.gov Identifiers NCT00332241 and NCT00337571.",
"affiliations": "Center for Clinical and Community Research, Children's National Medical Center, Washington, DC, USA. arobb@cnmc.org",
"authors": "Robb|Adelaide S|AS|;Andersson|Candace|C|;Bellocchio|Elizabeth E|EE|;Manos|George|G|;Rojas-Fernandez|Carlos|C|;Mathew|Suja|S|;Marcus|Ronald|R|;Owen|Randall|R|;Mankoski|Raymond|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2155-7780",
"issue": "13(1)",
"journal": "The primary care companion for CNS disorders",
"keywords": null,
"medline_ta": "Prim Care Companion CNS Disord",
"mesh_terms": null,
"nlm_unique_id": "101547532",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "21731831",
"pubdate": "2011",
"publication_types": "D016428:Journal Article",
"references": "10596264;15733025;19948625;19861668;4917967;16832314;18533764;18533766;19467582;2574607;7814313;19797985;19368416",
"title": "Safety and tolerability of aripiprazole in the treatment of irritability associated with autistic disorder in pediatric subjects (6-17 years old):results from a pooled analysis of 2 studies.",
"title_normalized": "safety and tolerability of aripiprazole in the treatment of irritability associated with autistic disorder in pediatric subjects 6 17 years old results from a pooled analysis of 2 studies"
} | [
{
"companynumb": "US-OTSUKA-2020_011553",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors.",
"affiliations": "Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA. smythl@mskcc.org.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.;Department of Psychiatry, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.;Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.;Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.;Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.;Oncology Clinical Sciences, Regeneron Pharmaceuticals, Tarrytown, NY, USA.;Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.",
"authors": "Smyth|Lillian M|LM|;Monson|Kelsey R|KR|;Jhaveri|Komal|K|;Drilon|Alexander|A|;Li|Bob T|BT|;Abida|Wassim|W|;Iyer|Gopa|G|;Gerecitano|John F|JF|;Gounder|Mrinal|M|;Harding|James J|JJ|;Voss|Martin H|MH|;Makker|Vicky|V|;Ho|Alan L|AL|;Razavi|Pedram|P|;Iasonos|Alexia|A|;Bialer|Philip|P|;Lacouture|Mario E|ME|;Teitcher|Jerrold B|JB|;Erinjeri|Joseph P|JP|;Katabi|Nora|N|;Fury|Matthew G|MG|;Hyman|David M|DM|",
"chemical_list": "D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016190:Carboplatin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-017-0445-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "35(6)",
"journal": "Investigational new drugs",
"keywords": "Buparlisib; Carboplatin; PTEN; Paclitaxel; Phase ib",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000631:Aminopyridines; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines; D009369:Neoplasms; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D014018:Tissue Distribution",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "742-750",
"pmc": null,
"pmid": "28281183",
"pubdate": "2017-12",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "24663045;11556941;21730275;22473468;20103642;17452630;15324695;21188471;15252137;18216329;18794879;20215542;20713879;12094235;20570890;22588880;19629070;18676830;15254063;18594509;22162589;26552953;16717171;22665543;15016963;22690082;19398573;22188813;18755892;17936563;21594665;24405565;26098748;11861387;21135276;25672916;20813970;22585170;23888040;24470511;24387334;20216404",
"title": "A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel.",
"title_normalized": "a phase 1b dose expansion study of the pan class i pi3k inhibitor buparlisib bkm120 plus carboplatin and paclitaxel in pten deficient tumors and with dose intensified carboplatin and paclitaxel"
} | [
{
"companynumb": "US-CIPLA (EU) LIMITED-2018US17581",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": n... |
{
"abstract": "Bariatric surgery is an effective therapy for obesity but is associated with long-term complications such as dumping syndromes and nutritional deficiencies. We report a case of a 26-year-old caucasian female, with history of morbid obesity and gestational diabetes (GDM), who became pregnant 4 months after Roux-en-Y bypass surgery. She developed GDM during subsequent pregnancy, which was initially managed with metformin and insulin. Nocturnal hypoglycaemia causing sleep disturbance and daytime somnolence occured at 19 weeks of pregnancy (19/40). Treatment with rapid-acting carbohydrates precipitated further hypoglycaemia. Laboratory investigations confirmed hypoglycaemia at 2.2 mmol/L with appropriately low insulin and C-peptide, intact HPA axis and negative IgG insulin antibodies. The patient was seen regularly by the bariatric dietetic team but concerns about compliance persisted. A FreeStyle Libre system was used from 21/40 enabling the patient a real-time feedback of changes in interstitial glucose following high or low GI index food intake. The patient declined a trial of acarbose but consented to an intraveneous dextrose infusion overnight resulting in improvement but not complete abolishment of nocturnal hypoglycaemia. Hypoglycaemias subsided at 34/40 and metformin and insulin had to be re-introduced due to high post-prandial blood glucose readings. An emergency C-section was indicated at 35 + 1/40 and a small-for-gestational-age female was delivered. There have been no further episodes of hypoglycaemia following delivery. This case illustrates challenges in the management of pregnancy following bariatric surgery. To our knowledge, this is the first use of FreeStyle Libre in dumping syndrome in pregnancy following bariatric surgery with troublesome nocturnal hypoglycaemia.\nBariatric surgery represents the most effective treatment modality in cases of severe obesity. With increasing prevalence of obesity, more people are likely to undergo bariatric procedures, many of which are women of childbearing age.Fertility generally improves after bariatric surgery due to weight reduction, but pregnancy is not recommended for at least 12-24 months after surgery. If pregnancy occurs, there are currently little evidence-based guidelines available on how to manage complications such as dumping syndromes or gestational diabetes (GDM) in women with history of bariatric surgery.Diagnosis of GDM relies on the use of a 75 g oral glucose tolerance test (OGTT). The use of this test in pregnant women is not recommended due to its potential to precipitate dumping syndrome. Capillary glucose monitoring profiles or continuous glucose monitoring (CGM) is being currently discussed as alternative testing modalities.As the CGM technology becomes more available, including the recently introduced FreeStyle Libre Flash glucose monitoring system, more pregnant women, including those after bariatric surgery, will have access to this technology. We suggest urgent development of guidelines regarding the use of CGM and flash glucose monitoring tools in these circumstances and in the interim recommend careful consideration of their use on a case-to-case basis.",
"affiliations": "Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Obstetrics, Gynaecology and Neonatology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.",
"authors": "Novodvorsky|Peter|P|;Walkinshaw|Emma|E|;Rahman|Waliur|W|;Gordon|Valerie|V|;Towse|Karen|K|;Mitchell|Sarah|S|;Selvarajah|Dinesh|D|;Madhuvrata|Priya|P|;Munir|Alia|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1530/EDM-17-0128",
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-17-0128EDM170128Novel Diagnostic ProcedureExperience with FreeStyle Libre Flash glucose monitoring system in management of refractory dumping syndrome in pregnancy shortly after bariatric surgery P Novodvorsky and othersFreeStyle Libre in dumping syndrome in pregnancyNovodvorsky Peter 12Walkinshaw Emma 12Rahman Waliur 1Gordon Valerie 1Towse Karen 1Mitchell Sarah 1Selvarajah Dinesh 12Madhuvrata Priya 3Munir Alia 121 Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK\n2 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK\n3 Department of Obstetrics, Gynaecology and Neonatology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK\nCorrespondence should be addressed to P Novodvorsky; Email: p.novodvorsky@sheffield.ac.uk12 12 2017 2017 2017 17-012814 11 2017 23 11 2017 © 2017 The authors2017The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Bariatric surgery is an effective therapy for obesity but is associated with long-term complications such as dumping syndromes and nutritional deficiencies. We report a case of a 26-year-old caucasian female, with history of morbid obesity and gestational diabetes (GDM), who became pregnant 4 months after Roux-en-Y bypass surgery. She developed GDM during subsequent pregnancy, which was initially managed with metformin and insulin. Nocturnal hypoglycaemia causing sleep disturbance and daytime somnolence occured at 19 weeks of pregnancy (19/40). Treatment with rapid-acting carbohydrates precipitated further hypoglycaemia. Laboratory investigations confirmed hypoglycaemia at 2.2 mmol/L with appropriately low insulin and C-peptide, intact HPA axis and negative IgG insulin antibodies. The patient was seen regularly by the bariatric dietetic team but concerns about compliance persisted. A FreeStyle Libre system was used from 21/40 enabling the patient a real-time feedback of changes in interstitial glucose following high or low GI index food intake. The patient declined a trial of acarbose but consented to an intraveneous dextrose infusion overnight resulting in improvement but not complete abolishment of nocturnal hypoglycaemia. Hypoglycaemias subsided at 34/40 and metformin and insulin had to be re-introduced due to high post-prandial blood glucose readings. An emergency C-section was indicated at 35 + 1/40 and a small-for-gestational-age female was delivered. There have been no further episodes of hypoglycaemia following delivery. This case illustrates challenges in the management of pregnancy following bariatric surgery. To our knowledge, this is the first use of FreeStyle Libre in dumping syndrome in pregnancy following bariatric surgery with troublesome nocturnal hypoglycaemia.\n\nLearning points:\nBariatric surgery represents the most effective treatment modality in cases of severe obesity. With increasing prevalence of obesity, more people are likely to undergo bariatric procedures, many of which are women of childbearing age.\n\nFertility generally improves after bariatric surgery due to weight reduction, but pregnancy is not recommended for at least 12–24 months after surgery. If pregnancy occurs, there are currently little evidence-based guidelines available on how to manage complications such as dumping syndromes or gestational diabetes (GDM) in women with history of bariatric surgery.\n\nDiagnosis of GDM relies on the use of a 75 g oral glucose tolerance test (OGTT). The use of this test in pregnant women is not recommended due to its potential to precipitate dumping syndrome. Capillary glucose monitoring profiles or continuous glucose monitoring (CGM) is being currently discussed as alternative testing modalities.\n\nAs the CGM technology becomes more available, including the recently introduced FreeStyle Libre Flash glucose monitoring system, more pregnant women, including those after bariatric surgery, will have access to this technology. We suggest urgent development of guidelines regarding the use of CGM and flash glucose monitoring tools in these circumstances and in the interim recommend careful consideration of their use on a case-to-case basis.\n==== Body\nBackground\nBariatric surgery represents a very effective method in the treatment of morbid obesity and related complications. Bariatric procedures induce major changes in the structure and function of the gastrointestinal tract leading to increased propensity to early and late dumping syndromes (DS) and nutritional deficiencies (1). The latest UK national bariatric surgery registry from 2014 reports that from 12 869 women who had bariatric surgery between 2011 and 2013, nearly 70% were of childbearing age (2), and these numbers are likely to rise since the prevalence of obesity increases. Fertility improves following bariatric surgery due to improved ovulation rates linked with weight loss; however, women are advised to avoid pregnancy for 12–24 months after bariatric intervention to reduce the risk of intrauterine growth retardation caused by the ongoing catabolic state (3). To our knowledge, data on pregnancy numbers after bariatric surgery in the UK are currently not available.\n\nPregnancy constitutes a state of increased insulin resistance. Gestational diabetes mellitus (GDM) is defined as diabetes diagnosed during the second or third trimester of pregnancy that was not clearly overt prior to gestation. It is linked with an increased risk of adverse outcomes for the mother and for the baby (4). A significant proportion of women who had bariatric intervention, despite having lost significant amount of weight, would still have a body mass index (BMI) >30 kg/m2 at the time of booking appointment or would have had previous history of GDM thus fulfilling the current National Institute for Health and Care Excellence (NICE) criteria for GDM screening (5). A standard screening and diagnostic test for GDM, the 75 g 2-h oral glucose tolerance test (OGTT) is considered to be risky in patients after bariatric surgery due to its potential to cause DS as a result of altered glycaemic responses. Alternative approaches such as capillary glucose monitoring or the use of continuous glucose monitoring (CGM) are currently being debated (6). In addition, once diagnosed, GDM in women after bariatric surgery constitutes a challenging clinical condition requiring multidisciplinary management with surgical, medical, obstetric and dietetic input with currently little evidence-based guidelines available (3).\n\nFreeStyle Libre Flash glucose monitoring system (FL) (Abbott Diabetes Care, Maidenhead, UK) represents a variation of CGM that has been recently introduced into clinical practice. It consists of a sensor that measures interstitial glucose (IG) levels at closed spaced intervals with a storage capacity of 8 h of IG data and of a reader with a monitor. In order to get a coherent IG profile, the user is asked to swipe the reader over the sensor at least every 8 h. IG data are displayed on the monitor of the reader together with IG trends. FL thus provides a useful and less costly alternative to standard CGM despite its recognised limitations such as inability to set alarms for high or low IG levels and a recognised tendency to lower-than-expected IG values in lower glucose ranges compared to the reference method (7).\n\nCase presentation\nA 26-year-old Caucasian female with history of morbid obesity (pre-surgery BMI 44.3 kg/m2) and GDM in her two previous pregnancies underwent Roux-en-Y gastric bypass (RYGB) surgery and became pregnant four months later. The patient had a background of polycystic ovarian syndrome, endometriosis, laparoscopic right ovarian cystectomy, appendectomy and vitamin D deficiency. She also developed mild cholestasis of pregnancy and was treated with ursodeoxycholic acid. There was also a history of complex social circumstances and domestic abuse. There was no family history of obesity, diabetes, GDM or any other endocrine condition in her first-degree relatives. Her brother and grandfather from mother’s side had a history of lung emphysema. She has received the standard dietary education and counselling provided by the bariatric dietician team for people undergoing bariatric interventions at Sheffield Teaching Hospitals NHS Foundation Trust before and subsequently after her bariatric surgery. This included provision of detailed verbal and written information regarding necessary dietary modifications, vitamin and micronutrient supplementation together with the recommendation of avoiding pregnancy for 12–24 months after the bariatric surgery. During the course of pregnancy, she has been taking vitamin and micronutrient supplementation (WLS Forte and Calcium Plus, FitForMe, Rotterdam, Netherlands) and in addition, a cholecalciferol 800 IU tablet per day.\n\nAs expected, she continued to lose weight in the months following the bariatric surgery, which continued during the course of pregnancy (Fig. 1).\nFigure 1 Weight chart of the 26-year-old lady with history of Roux-en-Y gastric bypass surgery who became pregnant shortly after. Times of bariatric intervention and approximate time of conception are indicated with arrows.\n\n\n\n\nDue to the previous history of GDM and bariatric surgery, the patient was offered capillary blood glucose monitoring at her booking appointment at 11th week of gestation (11/40), instead of the usual 2-h 75 g OGTT test. The recorded blood glucose (BM) values were diagnostic of GDM (6) (Table 1A) and metformin was started at 15/40. BM values continued to be elevated on metformin (Table 1B), and insulin (Humulin I and Humalog (Eli Lilly)) was added 2 weeks later.\nTable 1 Example of capillary blood glucose profiles on diet alone (A) and on metformin (B).\n\nFasting BM\t1 h post\tPre-lunch\t1 h post\tPre-dinner\t1 h post\t\nA. Diet alone\t\n 6.3*\t8.4\t4.3\t8.3\t6.3\t9.1\t\n 5.4\t8.4\t5.4\t9.5\t6.5\t10.1\t\nB. On metformin\t\n 6.0\t7.2\t7.0\t9.3\t6.3\t8.3\t\n 4.2\t6.3\t5.0\t14.3\t8.0\t10.2\t\nFigures in bold are indicative of gestational diabetes mellitus (GDM).\n\n*All figures are reported in mmol/L.\n\n\n\n\nAt 19/40, this lady was admitted under the care of the Obstetrics and Gynaecology team with persistent vomiting. A week prior to admission (18/40), she began to record BM readings in the hypoglycaemic range that were symptomatic, with a tremor and increased sweating. Metformin and insulin were stopped at 19/40, but the post-prandial and nocturnal hypoglycaemia persisted. She had no history of chronic liver disease, and her liver function tests were normal apart from a mild elevation of bile acids in the range of 20–37 µmol/L (reference range (RR): 0–14 µmol/L) throughout the 3rd trimester of her pregnancy in keeping with the diagnosis of cholestasis of pregnancy. Her renal function was normal.\n\nInvestigation\nLaboratory investigations showed a blood glucose value of 2.2 mmol/L with appropriately low insulin levels (14.8 pmol/L,RR: 17.8–173 pmol/L) and C-peptide levels (113 pmol/L, RR: 298–2350 pmol/L), negative IgG insulin antibodies and 09:00 h cortisol value of 658 nmol/L, indicating an intact hypothalamic–pituitary–adrenal axis.\n\nTreatment\nDiagnosis of late DS, most likely in combination with an early dumping phase, was established, and this lady received appropriate dietary advice from the bariatric dietetic team. She was advised to take frequent small-portioned meals, with the exclusion of high glycaemic index (GI) food and a preference for low GI food. Avoidance of liquid carbohydrates and drinking fluids with meals (1, 3) was recommended. She found it difficult to adhere to dietary recommendations and treated hypoglycaemia with fast-acting carbohydrates resulting in subsequent hypoglycaemia and disturbed sleep with excess daytime tiredness. FL was introduced at 22/40 in order to avoid frequent nocturnal finger prick BM measurements and as an educational tool with the aim to help the patient to identify hypoglycaemic triggers (Fig. 2A).\nFigure 2 Interstitial glucose (IG) profiles uploaded from the FreeStyle Libre Flash glucose monitoring system. (A) IG profiles with dietary interventions. (B) IG profiles with overnight (00:00–07:00 h) i.v. dextrose infusions at variable rates as indicated. (C) IG profiles at the time when the patient has been gradually weaned off the overnight i.v. dextrose infusions. Line in red indicates IG <4 mmol/L. * indicates capillary blood glucose measurement.\n\n\n\n\nDespite these measures, this lady continued to experience ongoing symptomatic hypoglycaemia that she was able to treat independently. Despite very low IG and BM readings (finger prick BM readings marked in Fig. 2 with *), there was no history of collapse, seizure or loss of consciousness. Disturbed sleep continued to have negative impact on her wellbeing. At 25/40, a decision was made to prevent nocturnal hypoglycaemia with continuous intravenous dextrose infusion overnight (00:00–07:00 h) (Fig. 2B). Poor compliance with dietary recommendations persisted despite ongoing support from the diabetes specialist nurses and bariatric dieticians. The patient declined a trial of acarbose due to concerns about potential risks to the unborn baby and was resistant to the suggestion of discharge with community support. This was substantiated by the fear of inability to treat her hypoglycaemia when on her own and not being able to look after her 2 young children. Gradually, intravenous dextrose infusions were discontinued (Fig. 2C), and the patient was discharged home at 29/40.\n\nFollowing discharge, this lady did not attend an appointment with the diabetes team and she returned her FL device shortly after. She was reviewed in the antenatal clinic in later stages of her pregnancy (32/40), and because of elevated post-prandial BM values metformin (32/40) and later insulin (Humalog) were re-introduced (33/40). Hypoglycaemias were less prominent and resolved completely at 34/40. The estimated fetal weight (EFW), which was on the 50th centile during the earlier stages of pregnancy declined at later stages resulting in EFW at 5th centile at 33/40 (Fig. 3). Head circumference (HC) and abdominal circumference (AC) followed a similar trend.\nFigure 3 Antenatal weight chart. Gestational stage in week is on the X axis, fundal height at the left Y axis and estimated weight by scan on the right Y axis.\n\n\n\n\nOutcome and follow-up\nThe patient was readmitted under the care of the Obstetrics and Gynaecology team at 34/40 due to reduced fetal movements and an emergency caesarean section was indicated at 35 + 1/40. She gave birth to a healthy baby girl with a birth weight of 2100 g.\n\nAfter delivery, the patient continued to monitor her BMs with finger prick testing, and her BM readings remained within the normal range with no further occurrence of hypoglycaemia. She was invited for a fasting plasma glucose test at 6 weeks postnatally, but did not attend to this or any further appointments.\n\nDiscussion\nRYGB intervention is reported to result in DS in approximately 40% of patients, and it has previously been suggested that the presence of DS was essential for weight reduction, a hypothesis that has been refuted by further prospective studies (8). DS is characterised by vasomotor and GI symptoms caused by altered gastric emptying and subsequent rapid exposure of the small intestine to nutrients (1). Early DS is triggered by rapid passage of hyperosmolar content into the small bowel causing excessive release of GI hormones and shift of fluids into the GI lumen. It presents with abdominal pain, bloating, diarrhoea and vasomotor symptoms such as palpitations, flushing, sweating or tachycardia. Late DS is characterised by symptoms of hypoglycaemia and occurs typically between 1 and 3 h after meal ingestion (1). Rapid gastric emptying leads to expeditious glucose absorption from the small bowel leading to initial hyperglycaemia. Subsequent peak insulin secretion perpetuated by increased glucagon-like peptide 1 levels eventually causes hypoglycaemia (1, 9).\n\nThe advent of CGM technology enabled observation of abnormal glycaemic profiles in non-pregnant women after RYGB surgery. These are characterised by early, high and short-lasting IG peaks returning back to normal values before the usual time points for BM measurements after the 75 g OGTT (1 or 2 h post glucose challenge) (10). Interestingly, a subsequent study found very similar CGM profiles in pregnant women after RYGB (11). The peak IG value was reached at 54 ± 9 min and the percentage of time spent with IG values above 140 mg/dL (7.8 mmol/L) was similar to that observed in women with GDM (11). These findings indicate that the standard 75 g OGTT test is of poor diagnostic value of GDM in women post bariatric surgery. The other concern about the OGTT in this population is that the rapid absorption of dextrose can precipitate DS as discussed earlier.\n\nDietary modifications represent the mainstay of the management of late DS – patients are advised to avoid refined carbohydrates and increase the intake of high-GI food, which should be taken in multiple small portions throughout the day. Avoidance of drinks taken with food and recumbent position whilst eating are also recommended (1, 3). If dietary measures are not sufficient, use of acarbose, octreotide and diazoxide have been reported (1, 3). However, usage of these agents is limited by the lack of well-controlled studies examining their safety in pregnant women. In refractory cases, more invasive measures have been reported – continuous enteral feeding or a re-do surgery (1, 3). The patient from our report was aware of the paucity of safety data for these agents in pregnancy and refused to take any for this reason.\n\nIn our case, an emergency C-section at 35 + 1/40 was indicated due to reduced fetal movements and a baby girl with a small-for-gestational-age birth weight of 2100 g was delivered. A large observational study from Sweden compared the outcomes of 670 pregnancies in women who had undergone bariatric surgery with control pregnancies matched for the mother’s pre-surgery BMI, age, parity, smoking history, educational level and delivery year (12). Pregnancies after bariatric surgery were associated with higher risk for small-for-gestational-age infants and shorter gestation, but the risk of pre-term birth was not significantly different (12). The outcome of the pregnancy from our case therefore partially reflects these large cohort observations.\n\nWe cannot provide a compelling explanation as to why this patient’s hypoglycaemic episodes started towards the end of the first trimester, neither can we explain why they stopped completely in the 34th week of her pregnancy, and she has remained asymptomatic until the present time. We can presume that pregnancy soon after the bariatric intervention contributed to the way how her symptoms presented. The pathophysiology of DS is not yet fully understood in the non-pregnant individuals either (1). We know from clinical observation that DS are common after pregnancy and can present a real diagnostic and therapeutic challenge (3). Normal pregnancy is a state of insulin resistance (IR) that gradually increases throughout its course with rising plasma insulin concentrations in an attempt to maintain normoglycaemia (13). We can therefore hypothesise that increased IR in later stages of pregnancy can trigger a higher post-prandial insulin secretion leading to subsequent hypoglycaemia (late dumping syndrome) in pregnant women with history of bariatric surgery, but further research will be required to confirm this hypothesis. Very recently, case reports of pregnant women with history of bariatric surgery suffering from dumping syndrome have been reported, and they seem to follow a similar time pattern with the occurrence of hypoglycaemic symptoms in 24th week of pregnancy in both cases (14, 15) and a nearly complete remission of symptoms after the delivery in one of the cases (15). Authors of the other case report do not comment on the presence or absence of symptoms after delivery (14). On the other hand, observational studies in pregnant women with type 1 diabetes show an increased risk of severe hypoglycaemia in 1st trimester and pregnancy-related intrinsic factors are postulated to play a role (16). Our patient did not experience any hypoglycaemic episodes during 1st trimester of her pregnancy, however.\n\nFinally, the indications for the use of FL system in our patient were to avoid frequent nocturnal finger prick BM measurements that interfered with her sleep and as an educational tool with the aim to help her to identify hypoglycaemic triggers. The use FL had undoubtedly positive impact on the above, however, the ability to continuously check real-time IG levels led to a degree of anxiety and stress when IG readings were less than 4 mmol/L despite her being oligosymptomatic or asymptomatic on most occasions. The patient was very keen to receive inpatient care despite reassurances that she could safely be discharged. She had a complex social and psychological background, which caused additional distress during her admission. This led to a perceived dependence on midwifery staff. She used the data from FL as evidence that she was still having episodes of hypoglycaemia and leverage to extend her admission. We would therefore advise caution in CGM usage in individuals where excessive data may cause additional distress.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nThe authors confirm that written informed consent was obtained from the patient for publication of this article.\n\nAuthor contribution statement\nP Novodvorsky attended to the patient and wrote the manuscript. E Walkinshaw, W Rahman, V Gordon, K Towse, S Mitchell, D Selvarajah, P Madhuvratha and A Munir attended to the patient and reviewed the manuscript.\n==== Refs\nReferences\n1 Tack J Deloose E \n2014 \nComplications of bariatric surgery: dumping syndrome, reflux and vitamin deficiencies . Best Practice and Research Clinical Gastroenterology \n28 \n741 –749 . (10.1016/j.bpg.2014.07.010 )25194187 \n2 Welbourn RSP Finlay I Sareela A Somers S Mahawar K Walton P Kinsman R \n2014 \nThe United Kingdom National Bariatric Surgery Registry: Second Registry Report . Dendrite Clinical Systems Published by the British Obesity & Metabolic Society. Accesed from http://nbsr.co.uk/wp-content/uploads/2014/11/Extract_from_the_NBSR_2014_Report.pdf\n3 Narayanan RP Syed AA \n2016 \nPregnancy following bariatric surgery-medical complications and management . Obesity Surgery \n26 \n2523 –2529 . (10.1007/s11695-016-2294-x )27488114 \n4 American Diabetes Association2017 \nStandards of medical care in Diabetes-2017 . Diabetes Care \n40 \n(Supplement 1) \nS4 –S5 . (10.2337/dc17-S003 )27979887 \n5 Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period , 2015 (available at: https://www.nice.org.uk/guidance/ng3)\n6 Adam S Ammori B Soran H Syed AA \n2017 \nPregnancy after bariatric surgery: screening for gestational diabetes . BMJ \n356 \nj533 (10.1136/bmj.j533 )28159743 \n7 Fokkert MJ van Dijk PR Edens MA Abbes S de Jong D Slingerland RJ Bilo HJ \n2017 \nPerformance of the FreeStyle Libre Flash glucose monitoring system in patients with type 1 and 2 diabetes mellitus . BMJ Open Diabetes Research and Care \n5 \ne000320 (10.1136/bmjdrc-2016-000320 )\n8 Banerjee A Ding Y Mikami DJ Needleman BJ \n2013 \nThe role of dumping syndrome in weight loss after gastric bypass surgery . Surgical Endoscopy \n27 \n1573 –1578 . (10.1007/s00464-012-2629-1 )23233009 \n9 Salehi M Gastaldelli A D'Alessio DA \n2014 \nBlockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass . Gastroenterology \n146 \n669.e662 –680.e662 . (10.1053/j.gastro.2013.11.044 )24315990 \n10 Hanaire H Bertrand M Guerci B Anduze Y Guillaume E Ritz P \n2011 \nHigh glycemic variability assessed by continuous glucose monitoring after surgical treatment of obesity by gastric bypass . Diabetes Technology and Therapeutics \n13 \n625 –630 . (10.1089/dia.2010.0203 )21488800 \n11 Bonis C Lorenzini F Bertrand M Parant O Gourdy P Vaurs C Cazals L Ritz P Hanaire H \n2016 \nGlucose profiles in pregnant women after a gastric bypass : findings from continuous glucose monitoring . Obesity Surgery \n26 \n2150 –2155 . (10.1007/s11695-016-2061-z )26757924 \n12 Johansson K Stephansson O Neovius M \n2015 \nOutcomes of pregnancy after bariatric surgery . New England Journal of Medicine \n372 \n2267 (10.1056/NEJMc1503863 )\n13 Sonagra AD Biradar SM Dattatreya K Murthy DSJ \n2014 \nNormal pregnancy – a state of insulin resistance . Journal of Clinical and Diagnostic Research \n8 \nbib1 –bib3 . (10.7860/JCDR/2014/10068.5081 )\n14 Edawati DE Abigail J Mardiana K Ming-Cheng C Harris NS \n2017 \nPregnancy and dumping syndrome post-bariatric surgery: a case report . Medical Journal of Malaysia \n72 \n133 –134 .28473681 \n15 Pacheco LV Gilsanz CDP Redondo LR Navalón CI Espín NVGT Espína MBGT Muñoz MR Avilés AM \n2017 \nLate dumping syndrome in pregnant women after ROUX-EN-Y gastric bypass (RYGB) surgery.\nPresented at the 19th European Congress of Endocrinology , Lisbon, Portugal \nEndocrine Abstracts\n49 EP705. (10.1530/endocabs.49.EP705 )\n16 Evers IM ter Braak EW de Valk HW van Der Schoot B Janssen N Visser GH \n2002 \nRisk indicators predictive for severe hypoglycemia during the first trimester of type 1 diabetic pregnancy . Diabetes Care \n25 \n554 –559 . (10.2337/diacare.25.3.554 )11874946\n\n",
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"abstract": "Somatostatinomas are rare neuroendocrine tumors (NET) that arise in the gastrointestinal (GI) tract. Because of their insidious growth, they are usually asymptomatic until late stages, presenting as malignant disease. We report the case of a 50-year-old woman who presented with epigastric abdominal pain, diarrhea and significant weight loss in the last two years. On clinical examination the patient met the criteria for neurofibromatosis type 1 (NF1). Abdominal CT and MRI revealed an infiltrative duodenal mass, with pancreatic invasion, locoregional enlarged lymph nodes and disseminated hepatic nodules. Microscopy and immunohistochemistry uncovered a neuroendocrine tumor, staining positive for chromogranin A (CgA), synaptophysin and somatostatin, with a Ki67 = 1%. Somatostatin receptors (SSTRs) type 2 were negative and SSTRs type 5 were positive in less than 50% of tumoral cells. Our patient was classified as a T3N1M1 stage IV metastatic duodenal grade 1 somatostatinoma and treatment with somatostatin analogues and chemotherapy with capecitabine and temozolomide was started, with so far abdominal imaging follow-up showing stable disease. When a patient is diagnosed with a rare NET, such as a somatostatinoma, it is of utmost importance to determine if it is a sporadic tumor or just a feature of a genetic disorder.",
"affiliations": "Endocrinology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Endocrinology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Endocrinology Department, Elias Hospital, 011461 Bucharest, Romania.;Dermatology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Gastroenterology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Radiology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Radiology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Radiology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Pathology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Oncology Department, Titu Maiorescu University of Medicine, 040051 Bucharest, Romania.",
"authors": "Martin|Sorina|S|;Fica|Simona|S|;Parfeni|Ovidiu|O|;Popa|Liliana|L|;Manuc|Teodora|T|;Rizea|Oana|O|;Lupescu|Ioana|I|;Gherghe|Mirela|M|;Becheanu|Gabriel|G|;Croitoru|Adina|A|",
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"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418 MDPI \n\n10.3390/diagnostics10090620\ndiagnostics-10-00620\nCase Report\nSomatostatinoma and Neurofibromatosis Type 1-A Case Report and Review of the Literature\nMartin Sorina 12* Fica Simona 12 Parfeni Ovidiu 2 Popa Liliana 34 Manuc Teodora 5 Rizea Oana 67 Lupescu Ioana 67 Gherghe Mirela 68* Becheanu Gabriel 910 Croitoru Adina 1112 1 Endocrinology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; simonafica55@gmail.com\n2 Endocrinology Department, Elias Hospital, 011461 Bucharest, Romania; parfeniovidiu@gmail.com\n3 Dermatology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; lilidiaconu@yahoo.com\n4 Dermatology Department, Elias Hospital, 011461 Bucharest, Romania\n5 Gastroenterology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania; teodora.manuc@gmail.com\n6 Radiology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; rizea.oana@gmail.com (O.R.); ioana.lupescu@umfcd.ro (I.L.)\n7 Radiology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania\n8 Nuclear Medicine Department, Alexandru Trestioreanu Oncological Institute, 022328 Bucharest, Romania\n9 Pathology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; gbecheanu@yahoo.com\n10 Laboratory of Histopathology and Immunohistochemistry, Victor Babes National Institute of Pathology, 050096 Bucharest, Romania\n11 Oncology Department, Titu Maiorescu University of Medicine, 040051 Bucharest, Romania; adina.croitoru09@yahoo.com\n12 Oncology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania\n* Correspondence: sorina.martin@gmail.com (S.M.); mirela_gherghe@yahoo.com (M.G.); Tel.: +0040-722-71-4897 (S.M.); +0040-72-054-4679 (M.G.)\n21 8 2020 \n9 2020 \n10 9 62018 7 2020 17 8 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Somatostatinomas are rare neuroendocrine tumors (NET) that arise in the gastrointestinal (GI) tract. Because of their insidious growth, they are usually asymptomatic until late stages, presenting as malignant disease. We report the case of a 50-year-old woman who presented with epigastric abdominal pain, diarrhea and significant weight loss in the last two years. On clinical examination the patient met the criteria for neurofibromatosis type 1 (NF1). Abdominal CT and MRI revealed an infiltrative duodenal mass, with pancreatic invasion, locoregional enlarged lymph nodes and disseminated hepatic nodules. Microscopy and immunohistochemistry uncovered a neuroendocrine tumor, staining positive for chromogranin A (CgA), synaptophysin and somatostatin, with a Ki67 = 1%. Somatostatin receptors (SSTRs) type 2 were negative and SSTRs type 5 were positive in less than 50% of tumoral cells. Our patient was classified as a T3N1M1 stage IV metastatic duodenal grade 1 somatostatinoma and treatment with somatostatin analogues and chemotherapy with capecitabine and temozolomide was started, with so far abdominal imaging follow-up showing stable disease. When a patient is diagnosed with a rare NET, such as a somatostatinoma, it is of utmost importance to determine if it is a sporadic tumor or just a feature of a genetic disorder.\n\nneuroendocrine tumorsomatostatinomaneurofibromatosis type 1somatostatin analogueschemotherapycapecitabinetemozolomide\n==== Body\n1. Introduction\nSomatostatinomas are neuroendocrine tumors of D-cell origin that contain and sometimes secrete somatostatine [1]. The estimated incidence of this tumor is about one in 40 million [2] and it represents about 4% of gastrointestinal neuroendocrine tumors (GI-NETs) [3]. Approximately 55% of somatostatinomas are in the pancreas and the reminder arise in the ampulla and periampullary region of the duodenum and rarely in the jejunum [4]. Usually, somatostatinomas present as a metastatic disease, 75% of them being malignant tumors [5]. Somatostatinomas can occur in association with multiple endocrine neoplasia (MEN)-1, neurofibromatosis type 1 (NF1), tuberous sclerosis and von-Hipple Lindau syndrome (VHL), and a new syndrome, via hypoxia-inducible factor 2 somatic mutation, which includes somatostatinoma, paraganglioma/pheochromocytoma and polycythemia, found only in females, had been also described [6].\n\nNF1 is the most common hereditary multitumor syndrome with an incidence at birth of approximately 1:3000 and it is caused by mutations in the NF1 gene. NF1 is localized on chromosome band 17q11.2 and it acts as a tumor suppressor gene. Biallelic NF1 inactivation results in complete loss of functional neurofibromin activity. Neurofibromin acts as a negative regulator of the RAS-MAPK pathway, and it has a GTPase activating domain that interacts with RAS and converts active RAS-GTP to its inactive form. Apart from NF1 promotor hypermethylation, other somatic inactivation events occur in tumors associated with NF1, such as intragenic mutations and loss of heterozygosity [7]. Persons with NF1 develop both benign and malignant tumors at increased frequency throughout life, neurofibromas being the most common type of benign tumor. Optic pathway gliomas are the predominant type of intracranial neoplasms and can lead to endocrine disorders, mostly in pediatric population [8]. The frequency of intrabdominal manifestations of NF1 ranges from 5 to 25%, and they appear during midlife, usually later than cutaneous manifestations. NF1 associates multiple gastrointestinal stromal tumors and neuroendocrine tumors of the adrenal, duodenal ampulla, pancreas and other sites [7]. Approximately 10% of the patients with NF1 develop somatostatinomas, which are typically located in the duodenum, are rarely associated with somatostatinoma syndrome and are less likely to metastasize as compared with sporadic somatostatinomas [9]. Patients presenting with this tumor are usually over 50, with a roughly equal gender distribution [2].\n\nSomatostatin is a tetradecapeptide that inhibits numerous endocrine hormones, including insulin; pancreatic polypeptide; cholecystokinin; gastrin; glucagon; gastric inhibitory polypeptide; secretin; motilin; and exocrine functions such as gastrointestinal transit time, intestinal motility and absorption of nutrients from the small intestine. The classic somatostatinoma syndrome is described as an association of weight loss; abdominal pain; and less often diabetes mellitus, cholelithiasis and diarrhea/ steatorrhea. This syndrome occurs more often in tumors that are localized in the pancreas than those in the duodenum [9]. Most tumors appear to be well-differentiated islet cell or carcinoid-type tumors on light microscopy and they have positive somatostatin and chromogranin A (CgA) immunohistochemistry. Sporadic and NF1 related duodenal somatostatinomas frequently present with psammoma bodies [10].\n\nSomatostatinomas are usually found during exploratory laparotomy, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound or gastrointestinal endoscopy studies that are performed due to various symptoms and signs associated with somatostatinoma syndrome. The diagnosis can also be established by the presence of a fasting plasma somatostatin level exceeding 30 pg/ml [9,11]. Imaging can localize the tumor and stage the extent of disease. The evaluation of patients with somatostationoma begins with a helical, multiphasic, contrast-enhanced CT. MRI is performed when CT shows indeterminate lesions that need further characterization. Endoscopic ultrasound (EUS) can also be performed in patients with inconclusive CT or MRI. Somatostatin receptor scintigraphy or Ga-68 DOTATATE positron emission tomography (PET)/CT represent high sensitivity imaging evaluation methods and are performed if the finding of extra-abdominal metastases would change the treatment [12,13].\n\nUsually, at diagnosis, patients present with metastatic disease, but survival rate is high, especially in those with metastatic duodenal somatostatinoma [6]. In cases of nonmetastatic somatostatinoma the surgical removal of the tumor represents the only chance of cure. Surgery can also be used in metastatic or locoregional extensive disease, for debulking, to provide symptomatic relief and prolong survival rate [14,15]. Metastatic liver disease can be treated by radiofrequency ablation, cryoablation, hepatic artery embolization or chemoembolization with doxorubicin, cisplatin and mitomycin C and selective intraarterial irradiation with yttrium labeled microspheres, alone or in combination with surgery [15,16]. Somatostatin analogues (SSAs) inhibit somatostatin secretion, providing relief of symptoms such as diarrhea, diabetes and weight loss and they are used for patients with metastatic or inoperable somatostatinoma [17,18,19]. It had been shown that lanreotide is associated with significantly prolonged progression free survival (PFS) compared to placebo [20]. Molecularly targeted therapy (everolimus, sunitinib) is used for patients with progressive advanced somatostatinomas. Conventional chemotherapy (CHT) combined with SSAs has been used as an initial treatment for highly symptomatic disease due to tumor bulk or for those who have rapidly enlarging metastases, but the experience with systemic chemotherapy in patients with somatostatinomas is limited [9]. Radiotherapy using SSAs coupled with Lutetium-177 represent a promising approach in the treatment of NETs and was associated with best tumor response, especially in patients with a high uptake on Octreoscan, limited hepatic tumor mass and a high Karnofsky performance score [20].\n\nThere are not enough data on somatostatinomas to give accurate estimates of survival, but the prognosis with any therapy is poor in patients with metastatic disease. The follow-up extends to a maximum of 10 years post-resection, and it should consist of history and physical examination, a check of the fasting plasma somatostatin level and imaging studies every 6 to 12 months or more often in the first year [9].\n\n2. Case Presentation\nWe report the case of a 50 years old woman, without any significant personal or family history, who presented with epigastric abdominal pain, diarrhea and 30 kg weight loss in the last 2 years. The patient signed a written informed consent and the ethics committee of Elias Hospital approved the publication of this case report (no 5316/2020). The clinical examination revealed elevated blood pressure (160/100 mmHg) and the presence of a few café au lait spots located on the upper limbs; large, poorly circumscribed areas of hyperpigmentation on the trunk; bilateral axillary freckling (Figure 1 and Figure 2); and multiple asymptomatic, soft, flesh-colored, sessile or dome-shaped cutaneous tumors, 1–2 cm in diameter, nonadherent to the underlying structures, distributed on the trunk and limbs, highly suggestive of neurofibromas (Figure 3). Several painless, violaceous, subcutaneous pseudoatrophic macules, with a rubbery consistency, ranging in size from 5 mm to 2 cm, typically found in NF1, were also present on the abdominal wall (Figure 4).\n\nThe mucous membranes did not show any pathologic changes and Lisch nodules were absent. Based upon the presence of three out of seven characteristic clinical features, our patient met diagnostic criteria developed by the United States National Institutes of Health (NIH) Consensus Conference in 1987 and updated in 1997 and was clinically diagnosed with neurofibromatosis type 1 (NF1) [21]. Biological evaluation was unremarkable except for diabetes mellitus (HbA1c% = 7%, fasting glycemia = 136mg/dl) and vitamin D deficiency (25 hydroxy-vitamin D = 10.53 ng/mL).\n\nUpper digestive endoscopy revealed a gastric mucosa with prepyloric, circumferential linear and round-oval ulcerations, the largest of 6 mm, with the base covered with fibrin debris and an infiltrated area of 7 mm that could be seen between the first and second portion of the duodenum, on the medial wall, with rigidity and exaggerated friability upon biopsy. The normal papilla was visualized distally to the infiltrated area. A multiphasic contrast-enhanced CT diagnosed a 32 × 37 × 47 mm infiltrative duodenal mass, with heterogenous contrast enhancement, which narrowed the duodenal lumen and compressed the pancreatic head, and multiple low-density hepatic nodules strongly suggestive of metastatic disease. On MRI, the tumor displayed irregular borders with high contrast subtraction and heterogenous texture; it was located near the ampulla, in the second segment of the duodenum, with pancreatic invasion, associated locoregional enlarged lymph nodes and multiple disseminated hepatic nodules, with maximum diameters of 12 × 10 mm, suggestive of miliary metastatic disease (Figure 5 and Figure 6).\n\nPathological exam of the duodenal biopsy described in our case a tumor with glandular and cribriform structures in the lamina propria, with an infiltrative aspect, focal foveolar metaplasia of the villous epithelia (Figure 7), cribriform structures with cuboidal or low columnar epithelial cells, with eosinophilic cytoplasm and round, central, monotonous nuclei, without visible nucleoli (Figure 8) and the tumor had a glandular (acinar) growth pattern with calcospherites (psammoma bodies). Immunohistochemistry described a tumor positive for chromogranin A, synaptophysin and somatostatin with a Ki67 of 1% (Figure 9). Somatostatin receptors (SSTR) type 2 were negative and SSTR type 5 were positive in less than 50% of tumoral cells.\n\nOur patient was evaluated using the radiopharmaceutical labelled with 99 mTc, available at the moment of diagnosis; 740 MBq 99mTc-EDDA/HYNIC-Tyr3-Octreotide was injected intravenously, with an acquisition protocol of early (1 h after injection) and late (4 h after injection) whole body scans with a two-headed, large field-of-view gamma camera equipped with low energy high resolution (LEHR) collimator and SPECT-CT acquisition 2 h after injection, on the region of interest (abdomen). On somatostatin receptor scintigraphy (SRS), SPECT-CT acquisition, we noticed the duodenal tumor compressing the pancreatic head and the particular aspect of very small disseminated nodules in both hepatic lobes, but without any uptake of the specific radiopharmaceutical; the aspect correlates with the immunohistochemistry results (Figure 10 and Figure 11).\n\nIn this context we performed an endocrinological screening for MEN1 and pheochromocytoma which were negative. Plasma chromogranin A and 24 h urinary 5-hydroxyindoleacetic acid (5- HIAA) were in normal ranges. Unfortunately, plasma levels of somatostatin could not be measured at diagnosis.\n\nAccording to the American Joint Committee on Cancer TNM staging system for neuroendocrine tumors of the duodenum and ampulla of Vater [22], our patient was classified as a T3, N1, M1 stage IV metastatic duodenal, grade 1, SSTR negative somatostatinoma. The patient was discussed in our multidisciplinary team meeting. NCCN guidelines version 1.2019 recommend for clinically significant tumor burden: lanreotide or octreotide and/or everolimus, peptide receptor radionuclide therapy with radiolabeled somatostatin analogues (PRRT), hepatic-directed therapy or interferon alfa-2b or cytotoxic chemotherapy if no other options feasible [23]. The MRI appearance of miliary liver metastases, with significant tumor burden, led us to decide on the association of SSAs with chemotherapy, as in our country we did not have other available reimbursed therapeutic options. We began the treatment with lanreotide Autogel 120 mg every 28 days and capecitabine 750 mg/m2/BID on days 1–14, and temozolomide 200 mg/m2/ID on days 10–14 every 28 days (CAPTEM). Follow-up at 3 (Figure 12), 6, 9 and 12 months with abdominal MRI and thorax CT showed stable disease. In May 2020, follow-up CT scan at 16 months from diagnosis showed a 14 × 8 mm segment 6 liver lesion, suggestive of a new metastasis, which needed to be monitored (Figure 13).\n\nThere was a very good tolerability of both SSAs and chemotherapy. The patient presented grade 2 thrombocytopenia at cycles 3 and 4 and grade 2 palmar-plantar erythrodysesthesia at cycles 3, 4 and 5. Diarheea disappearead after the first two months of therapy.\n\n3. Discussion\nNF1 is an autosomal dominant disorder with complete penetrance and variable expression, associated with an increased risk of developing benign and malignant tumors of the skin, central and peripheral nervous system, adrenals and gastrointestinal tract, including pancreatic tumors [7,24]. The NF1 gene mutations determine a reduction or a complete loss of function of the cytoplasmatic protein, neurofibromin, which regulates cellular proliferation by inactivating p21 RAS and the MAP kinase [7,25]. The diagnosis of NF1 is based upon the presence of characteristic clinical features. According to NIH criteria, at least two of the following clinical features must be present to make the diagnosis of NF1: six or more café au lait macules (0.5 cm in children or >1.5 cm in adults), two or more cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma, axillary or groin freckling, optic pathway glioma, two or more Lisch nodules (iris hamartomas seen on slit lamp examination) and bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudoarthrosis), first degree relative with NF1 [21]. As in our case, approximately 50% of NF1 patients have no family history of disease because the NF1 gene has high mutation rates in humans [26]. The multidisciplinary team management of this particular case also included genetic counseling. Genetic testing can be considered for a molecular diagnosis and can help direct screening of family members. Often, genetic testing is not required, but can it be a useful tool in confirming the diagnoses of children who do not meet diagnostic criteria or only exhibit café-au-lait macules and axillary freckling. Although of great academic interest, given the unquestionable clinical diagnosis, the fact that our patient did not have any first degree relatives that could benefit from the testing and that a positive NF1 mutation result is not a predictor of the severity or complications of the disorder, with some specific exceptions, we decided not to perform a genetic testing. The disorder is associated with an 8–15-year reduction in average life expectancy in both genders, primarily due to malignant neoplasms and cardiovascular disorders. Malignant peripheral nerve sheath tumor, breast cancer, cutaneous neurofibromas and significant psychiatric and neurologic diagnoses are common problems in patients with NF1 [27]. Patients with NF1 are also prone to developing gastrointestinal and retroperitoneal lesions, such as true neurogenic neoplasms, interstitial cell of Cajal lesions, NETs and adrenal tumors (pheochromocytoma) [7]. In 1982, Cantor et al. first documented the association between duodenal somatostatinoma and NF1 [28]. The association was afterwards described as a common gastrointestinal manifestation in patients with NF1 [11,29]. A case report and review of the literature, published in 1995, described 29 cases of duodenal somatostatinoma unassociated with NF1 and 27 cases of duodenal somatostatinoma associated with NF1, out of which four were also found to have adrenal pheochromocytomas [30]. An analysis of 162 patients with somatostatinomas (81 pancreatic somatostatinomas vs. 81 duodenal somatostatinomas) found a statistically significant difference between these two groups, regarding the incidence of NF1 (20% vs. 43.2%) [4]. In a more recent analysis, Garbrecht et al. confirmed the occurrence of duodenal somatostatinoma in NF1 patients, but with a lower frequency (14%), and found no pancreatic somatostatinoma associated with NF1 [10]. A 2010 review of literature showed that 47% of periampullary tumors in NF1 patients were of neuroendocrine origin with 40% being reported as somatostatinoma, 6% as carcinoid and 1% as malignant endocrine tumor [31].\n\nSomatostatinoma is a rare NET [9] that originates in the enteric endocrine cells [32]. More than half of them are located in the pancreas and the rest in the ampulla or periampullary region of the duodenum or rarely in the jejunum. The tumors can be classified as functioning or non-functioning, depending on the secretion of somatostatin and often can present as metastatic disease upon diagnosis [9]. Duodenal somatostatinomas frequently display obstructive jaundice, abdominal pain, cholelithiasis, vomiting and abdominal bleeding [11] and can be accompanied by a somatostatin syndrome (steatorrhea, diabetes mellitus, cholelithiasis, weight loss), usually only if they are larger than 4 cm in size [33]. In our case, although the tumor was larger than 4 cm, located near the duodenal ampulla, with pancreatic invasion, the patient did not develop obstructive jaundice or cholelithiasis, but, instead, she presented diarrhea, weight loss and secondary diabetes mellitus. Although high plasma somatostatin levels (>30 pg/mL) may be a valuable tool to establish the biological diagnosis of somatostatinoma [9] and our patient associated somatostatin syndrome, we were not able to measure the somatostatin levels before the treatment initiation. Cg A is a neuroendocrine protein located in the secretory vesicles of neurons and endocrine cells, plays an important role in vesicle formation, is the precursor for many functional peptides (vasostatin, pancreastatin, catestatin, parastatin, etc.) and can be measured in order to provide information about diagnosis, prognosis and follow-up in NETs [34,35]. However, Cg A concentration may be normal in some low proliferative index NETs, as was the case for our patient. Pheochromocytomas are associated with VHL disease, MEN and NF1. In patients with NF1 they can occur with a frequency of 0.1–5.7%, higher than in the general population [36]. Moreover, there is also a hypoxia-inducible factor 2 somatic mutation, detected in ampullary somatostatinomas as part of a syndrome of paraganglioma and somatostatinoma, associated with polycythemia and found only in females [6]. Our patient had normal plasma normetanephrines and metanephrines, but further regular screening for other malignancies associated with NF1 is mandatory [27].\n\nDuodenal neuroendocrine tumors account for about 20% of gastrointestinal tract neuroendocrine tumors and may show G-cell differentiation (gastrinomas) or D-cell differentiation expressing somatostatin, termed somatostatinomas, if they are functional. Acinar and psammomatous somatostatinomas are commonly found in the periampullary region in patients with NF1 and represent one third of somatostatin expressing tumors. Sometimes patients with NF1 may present other mesenchymal lesions: neurofibromas and gastrointestinal stromal tumors. Biopsy was performed and light microscopy revealed the presence of psammoma bodies, which had been previously identified in 68% of duodenal somatostatinomas [11]. Immunohistochemistry showed positive staining for Cg A, synaptophysin and somatostatin, Ki67 % = 1%, SSTR5 positive in less than 50% of tumor cells and negative SSTR2. Somatostatin receptor-based imaging can provide useful information on overall tumoral burden and location, and positive imaging can also confirm the presence of SSTRs [37]. SRS is a molecular imaging procedure for NET diagnosis and staging; it is more sensitive and specific at the biological than anatomical level, in contrast to conventional imaging, which it complements; the detection rate was reported to be between 80–100% in different studies [38,39,40]. There are two radiopharmaceuticals available on the market 111In-pentetreotide ([111In-DTPA0]-octreotide) with affinity for SSTR 2 and SSTR 5 and 99 mTc-EDDA/HYNIC-Tyr3-Octreotide, with high affinity for SSTR 2, but with a lesser extent for SSTR 3 and SSTR 5. 68Ga-DOTATATE is superior to other imaging modalities [6], but it was not available; therefore, we performed a 99 mTc-tektrotyde scintigraphy with no tumoral uptake for radiolabeled SSA.\n\nConventional and functional imaging revealed in our case, on diagnosis, a stage IV duodenal somatostatinoma (T3, N1, M1) with pancreatic invasion, locoregional lymph nodes enlargement and multiple disseminated hepatic nodules described as miliary metastases. Although it seems unreasonable to include SSAs in the therapeutic approach of a mostly SSTR negative somatostatinoma, in patients with symptomatic disease, clinically significant tumor burden or progressive disease, there is evidence in favor of SSA therapy (octreotide LAR or lanreotide) that can improve the related symptoms by reducing somatostatin secretion and potentially control tumor growth [20,41]. The correct mechanism by which SSAs inhibit tumoral somatostatin secretion is poorly understood. A possible explanation could be that octreotide has a higher affinity for the somatostatin receptor than for natural somatostatin and the enzymatic degradation of synthetic SSAs is on a slower rate than that of natural somatostatin [19]. High expression of SSTR 2 in NETs was associated with improved PFS and overall survival (OS) in patients treated with SSAs. Yet, there was no clear correlation between high vs. low expression of SSTRs 1–5 and uptake on somatostatin scintigraphy [42]. In one study, three out of ten patients with SSTR 2 negative and SSTR 5 positive NETs were responsive to SSA therapy [43]. Novel strategies such as SSTR 2 receptor gene transfer might prove useful as new therapies for unresectable tumors [44]. Diarrhea and weight loss, presenting signs in our patient and components of the somatostatinoma syndrome, ameliorated in the first couple of months as a result of SSA therapy. Intriguing enough, some studies have shown that patients with metastatic or inoperable NETs and no radiolabeled analogue uptake on Octreoscan or 68Ga-DOTA-peptides PET/CT, may also respond well to SSA therapy [43]. Although SSAs are highly effective at improving the hormone hypersecretion-associated symptoms, there is limited experience and little evidence that SSA therapy inhibits tumor growth, especially in somatostatinomas. Considering the results of randomized controlled studies for metastatic midgut NETs (octreotide) and gastroenteropancreatic NETs (lanreotide) without hormone-mediated symptoms, a reduction in tumor growth is expected. Therefore, due to the miliary aspect of liver metastases that could lead to acute liver failure, we decided to add SSAs to chemotherapy, as first-line therapy.\n\nCytotoxic chemotherapy with 5-fluorouracil, capecitabine, dacarbazine, oxaliplatin, streptozocin and temozolomide can be used, in association with SSAs, in patients with progressive metastatic disease [26]. ESMO guidelines recommend CHT in advanced pancreatic NETs (pNETs) and in neuroendocrine neoplasms (NEN) G3 of any site [45]. A systematic review showed that patients treated with CHT for locally advanced or metastatic well-differentiated G1/G2 GI NETs experienced poor results (OR rate range 5.8–17.2%) [46]. The use of the CAPTEM regimen is associated with objective responses and promising survival outcomes in metastatic, well-differentiated, intermediate and high-grade NETs (two-year OS = 42%, median PFS = 10 months, median PFS = 17 months in patients who received CAPTEM in first line) [47]. More studies reported similar results regarding CAPTEM regimen in NEN, with significantly higher PFS, median OS, objective response rate and disease control rate in pNENs compared with non-pNENs [48,49]. Pancreatic NENs have a lower O (6)-methylguanine-DNA methyltransferase (MGMT) expression than non-pNENs, and this might be the rationale for a superior treatment response to CAPTEM regimen. Yet, the use of MGMT expression or promoter methylation as a sole predictor for response to CAPTEM is not recommended and more biomarkers are needed for clinical decision making [49,50].\n\nCAPTEM regimen is rarely associated with serious toxicities (grade 3 or 4 stratified by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade) and has low discontinuation rates, even in patients who follow the treatment for more than a year [48]. The ENETs guidelines currently recommend this regimen for patients with intermediate and high-grade NETs as a second line therapy [51]. In a retrospective study, patients with metastatic intermediate and high-grade NETs (pancreatic and nonpancreatic included) treated with CAPTEM had median PFS of 15.9 months as compared to a median PFS of 3.1 months when subsequent lines of therapy were used [52]. Similarly, in a series of 30 patients with metastatic well or moderately differentiated pNETs who received CAPTEM in the first-line setting, the objective radiographic response rate was 70% with a median PFS of 18 months, a 2-year OS rate of 92% and a 12% rate of grade 3 and 4 toxicities [53]. This regimen clearly proves its superiority compared to other cytotoxic regimens (triplet combination of streptozocin, doxorubicin and 5-fluorouracil) with a response rate of 39%, a 2-year OS rate of 74% and a 23% rate of grade 3 and 4 toxicities [54].\n\nRADIANT-4, a phase 3 study, found that treatment with everolimus is associated with significant improvement in PFS vs. placebo, in patients with advanced, progressive, well-differentiated, non-functional neuroendocrine tumors of lung or gastrointestinal origin [55]. The appropriate sequencing or combination of various drugs remains unclear and is mostly dependent on patient individual factors, such as comorbidities or side effects.\n\nAblative methods, including radiofrequency ablation and cryoablation, and hepatic artery chemoembolization with doxorubicin, cisplatin and mitomycin C, can result in tumor regression and control of the symptoms. Additionally, surgery is recommended for symptoms palliation [6]. PRRT is recommended for patients with inoperable or metastasized NETs. Lutetium-177 coupled with SSAs is a very promising approach in treatment of NETs [56]. The combined therapy with 177Lu-DOTATE plus octreotide LAR showed better tumor response rate vs. therapy with octreotide LAR alone [57]. Furthermore, combining PRRT with capecitabine and temozolomide (radiosensitizing chemotherapy) may be feasible with minimal incremental toxicity [58]. There are some inclusion criteria for PRRT, such as inoperable/metastatic, well differentiated (G1/G2) NET (well-differentiated G3 NET may be considered), sufficient tumor uptake on the diagnostic somatostatin scintigraphy, sufficient bone marrow reserves, creatinine clearance >50 mL/min, Karnofsky performance status >50, expected survival >3 months and signed informed consent [56]. In our case, due to no somatostatin analogue uptake on the scintigraphy, PRRT could not be considered.\n\n4. Conclusions\nIn conclusion, the lesson to be learned from this case resides in the fact that somatostatinomas are rare NETs, seldom associated with somatostatinoma syndrome, which can sometimes occur in the settings of a genetic syndrome such as NF1. Despite the progress achieved in the management of metastatic, progressive, unresectable NETs, in general, and for somatostatinoma, in particular, prognosis is poor, and the optimal treatment of choice still remains a challenge for the multidisciplinary team involved.\n\nFunding\nThe APC was funded by Carol Davila University of Medicine and Pharmacy, Bucharest based on the law 3132/30.01.2020.\n\nConflicts of Interest\nThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 Bilateral axillary freckling and and café au lait spot on the left arm (scale 1:13).\n\nFigure 2 Large, poorly circumscribed areas of cutaneous hyperpigmentation and freckling on the trunk (scale 1:13/1:6/1:13/1:13).\n\nFigure 3 Multiple cutaneous neurofibromas distributed on the trunk and limbs (scale 1:7/1:13/1:11/1:11).\n\nFigure 4 Asymptomatic, violaceous subcutaneous tumors in the abdominal area-pseudoatrophic macules typically found in NF1 (scale 1:11/1:8).\n\nFigure 5 Axial MRI exam—duodenal tumor. (a) Gadolinium enhanced T1w image showing an hyperintense lesion in the arterial phase suggestive of the neuroendocrine etiology (arrow). (b) Diffusion Weighted Imaging (DWI) showing an hyperintense lesion with intense diffusion restriction (arrow).\n\nFigure 6 Axial MRI exam—multiple hepatic nodular lesions suggesting miliary metastic disease. (a) Gadolinium enhanced T1w showing hypervascular lesions (arrow). (b) T1w image, hepato-biliary phase after gadolinium enhancemet, showing hypointense lesions suggestive of the tumoral etiology (arrows).\n\nFigure 7 Histological findings. (a) HE, 40X. Duodenal biopsy with glandular and cribriform structures in the lamina propria, with the infiltrative aspect. (b) HE, 100X. Detail of the previous picture with cribriform structures and focal foveolar metaplasia of the villous epithelia.\n\nFigure 8 Histological findings. (a) HE, 200X. Cribriform structure with cuboidal or low columnar epithelial cells, with eosinophilic cytoplasm and round, central, monotonous nuclei, without visible nucleoli. Some necrotic cells and calcospherites are visible in the glandular lumina. (b) Glandular (acinar) growth pattern of the tumor with calcospherites (psammoma bodies).\n\nFigure 9 Imnuohistochemistry findings 40X. (a) Chromogranin A (Cell Marque, monoclonal, dilution 1:100): positive reaction of the tumoral cells, cytoplasmic, with internal positive control. (b) Synaptophysin (Immunopath, monoclonal, dilution 1:500): positive reaction of the tumoral cells, cytoplasmic, with internal positive control. (c) Somatostatin (Abcam, monoclonal, dilution 1:200): positive reaction of the tumoral cells, cytoplasmic, with internal positive control. (d) Ki67 (Leika, monoclonal, dilution 1:100): 1% in tumoral cells, with internal positive control in cryptic epithelial cells.\n\nFigure 10 Axial unenhanced CT and fused SPECT-CT images showing duodenal tumor and multiple small hepatic metastasis with no uptake of 99mTc-EDDA/HYNIC-Tyr3-Octreotide (red arrows).\n\nFigure 11 Sagital and coronal CT and SPECT-CT acquisition; duodenal tumor without 99mTc-EDDA/HYNIC-Tyr3-Octreotide uptake, suggesting no expression of SSTR2 or SSTR5 (red arrows).\n\nFigure 12 Follow up MRI at 3 months. (a) Slight regression of the duodenal tumor on T1w image after gadolinium enhancement (arrow). (b) Minimal regression of the metastatic hepatic lesions on the hepato-biliary phase (arrows).\n\nFigure 13 Follow up CT scan at 16 months from diagnosis (a) CECT - arterial phase- stable duodenal tumor. 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Lodish M.B. Stratakis C.A. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes Best Pract. Res. Clin. Endocrinol. Metab. 2010 24 439 449 10.1016/j.beem.2010.02.002 20833335 \n26. Ferner R.E. Neurofibromatosis 1 and neurofibromatosis 2: A twenty first century perspective Lancet Neurol. 2007 6 340 351 10.1016/S1474-4422(07)70075-3 17362838 \n27. Stewart D.R. Korf B.R. Nathanson K.L. Stevenson D.A. Yohay K. Care of adults with neurofibromatosis type 1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG) Genet. Med. 2018 20 671 682 10.1038/gim.2018.28 30006586 \n28. Cantor A.M. Rigby C.C. Beck P.R. Mangion D. Neurofibromatosis, phaeochromocytoma, and somatostatinoma BMJ 1982 285 1618 1619 10.1136/bmj.285.6355.1618 6128052 \n29. Cappelli C. Agosti B. Braga M. Cumetti D. Gandossi E. Rizzoni D. Agabiti Rosei E. Von Recklinghausen’s neurofibromatosis associated with duodenal somatostatinoma. A case report and review of the literature Minerva Endocrinol. 2004 29 19 24 15258554 \n30. Mao C. Shah A. Hanson D.J. Howard J.M. Von Recklinghausen’s disease associated with duodenal somatostatinoma: Contrast of duodenal versus pancreatic somatostatinomas J. Surg. Oncol. 1995 59 67 73 10.1002/jso.2930590116 7745981 \n31. Relles D. Baek J. Witkiewicz A. Yeo C.J. Periampullary and duodenal neoplasms in neurofibromatosis type 1: Two cases and an updated 20-year review of the literature yielding 76 cases J. Gastrointest. Surg. 2010 14 1052 1061 10.1007/s11605-009-1123-0 20300877 \n32. Adams M.S. Bronner-Fraser M. Review: The role of neural crest cells in the endocrine system Endocr. Pathol. 2009 20 92 100 10.1007/s12022-009-9070-6 19377845 \n33. Kim J.A. Choi W.H. Kim C.N. Moon Y.S. Chang S.H. Lee H.R. Duodenal somatostatinoma: A case report and review. [published correction appears in Korean J. Intern. Med. 26 June 2011, 253] Korean J. Intern. Med. 2011 26 103 107 10.3904/kjim.2011.26.1.103 21437171 \n34. Al-Risi E.S. Al-Essry F.S. Mula-Abed W.S. Chromogranin A as a biochemical marker for neuroendocrine tumors: A single center experience at Royal Hospital, Oman Oman Med. J. 2017 32 365 370 10.5001/omj.2017.71 29026467 \n35. Gut P. Czarnywojtek A. Fischbach J. Bączyk M. Ziemnicka K. Wrotkowska E. Gryczyńska M. Ruchała M. Chromogranin A—Unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls Arch. Med. Sci. 2016 12 1 9 10.5114/aoms.2016.57577 26925113 \n36. Dluhy R.G. Pheochromocytoma—Death of an axiom N. Engl. J. Med. 2002 346 1486 1488 10.1056/NEJM200205093461911 12000821 \n37. Srirajaskanthan R. Kayani I. Quigley A.M. Soh J. Caplin M.E. Bomanji J. The role of 68Ga-DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on 111In-DTPA-octreotide scintigraphy J. Nucl. Med. 2010 51 875 882 10.2967/jnumed.109.066134 20484441 \n38. Krenning E.P. Kwekkeboom D.J. Bakker W.H. Breeman W.A. Kooij P.P. Oei H.Y. van Hagen M. Postema P.T. de Jong M. Reubi J.C. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: The Rotterdam experience with more than 1000 patients Eur. J. Nucl. Med. 1993 20 716 731 10.1007/BF00181765 8404961 \n39. Asnacios A. Courbon F. Rochaix P. Bauvin E. Cances-Lauwers V. Susini C. Schulz S. Boneu A. Guimbaud R. Buscail L. Indium-111-pentetreotide scintigraphy and somatostatin receptor subtype 2 expression: New prognostic factors for malignant well-differentiated endocrine tumors J. Clin. Oncol. 2008 26 963 970 10.1200/JCO.2007.12.7431 18281671 \n40. Wong K.K. Cahill J.M. Frey K.A. Avram A.M. Incremental value of 111-in pentetreotide SPECT/CT fusion imaging of neuroendocrine tumors Acad. Radiol. 2010 17 291 297 10.1016/j.acra.2009.08.015 19962915 \n41. Rinke A. Wittenberg M. Schade-Brittinger C. Aminossadati B. Ronicke E. Gress T.M. Müller H.H. Arnold R. PROMID Study Group Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results of long-term survival Neuroendocrinology 2017 104 26 32 10.1159/000443612 26731483 \n42. Qian Z.R. Li T. Ter-Minassian M. Yang J. Chan J.A. Brais L.K. Masugi Y. Thiaglingam A. Brooks N. Nishihara R. Association between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors Pancreas 2016 45 1386 1393 10.1097/MPA.0000000000000700 27622342 \n43. Vezzosi D. Bennet A. Rochaix P. Courbon F. Selves J. Pradere B. Buscail L. Susini C. Caron P. Octreotide in insulinoma patients: Efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies Eur. J. Endocrinol. 2005 152 757 767 10.1530/eje.1.01901 15879362 \n44. Baldelli R. Barnabei A. Rizza L. Isidori A.M. Rota F. Di Giacinto P. Paoloni A. Torino F. Corsello S.M. Lenzi A. Somatostatin analogs therapy in gastroenteropancreatic neuroendocrine tumors: Current aspects and new perspectives Front. Endocrinol. 2014 5 7 10.3389/fendo.2014.00007 \n45. Pavel M. Öberg K. Falconi M. Krenning E.P. Sundin A. Perren A. Berruti A. ESMO Guidelines Committee Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann. Oncol. 2020 31 844 860 10.1016/j.annonc.2020.03.304 32272208 \n46. Lamarca A. Elliott E. Barriuso J. Backen A. McNamara M.G. Hubner R. Valle J.W. Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: A lost cause? Cancer Treat. Rev. 2016 44 26 41 10.1016/j.ctrv.2016.01.005 26855376 \n47. Sahu A. Jefford M. Lai-Kwon J. Thai A. Hicks R.J. Michael M. CAPTEM in Metastatic well-differentiated intermediate to high grade neuroendocrine tumors: A single centre experience J. Oncol. 2019 2019 Article 10.1155/2019/9032753 30915122 \n48. Thomas K. Voros B.A. Meadows-Taylor M. Smeltzer M.P. Griffin R. Boudreaux J.P. Thiagarajan R. Woltering E.A. Ramirez R.A. Outcomes of Capecitabine and Temozolomide (CAPTEM) in advanced Neuroendocrine Neoplasms (NENs) Cancers 2020 12 206 10.3390/cancers12010206 \n49. Owen D.H. Alexander A.J. Konda B. Wei L. Hemminger J.A. Schmidt C.R. Abdel-Misih S. Dillhoff M.E. Sipos J.A. Kirschner L.S. Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O6-methylguanine DNA methyltransferase as a biomarker for response Oncotarget 2017 8 104046 104056 10.18632/oncotarget.22001 29262620 \n50. Walter T. van Brakel B. Vercherat C. Hervieu V. Forestier J. Chayvialle J.A. Molin Y. Lombard-Bohas C. Joly M.O. Scoazec J.Y. O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: Prognostic relevance and association with response to alkylating agents Br. J. Cancer 2015 112 523 531 10.1038/bjc.2014.660 25584486 \n51. Garcia-Carbonero R. Sorbye H. Baudin E. Raymond E. Wiedmann B. Niederle B. Sedlackova E. Toumpanakis C. Anlauf M. Cwifla J.B. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas Neuroendocrinology 2016 103 186 194 10.1159/000443172 26731334 \n52. Peixoto R.D. Noonan K.L. Pavlovich P. Kennecke H.F. Lim H.J. Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs J. Gastrointest. Oncol. 2014 5 247 252 10.1200/jco.2014.32.3_suppl.343 25083296 \n53. Strosberg J.R. Fine R.L. Choi J. Nasir A. Coppola D. Chen D.T. Helm J. Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas C Cancer 2011 117 268 275 10.1002/cncr.25425 \n54. Kouvaraki M.A. Ajani J.A. Hoff P. Wolff R. Evans D.B. Lozano R. Yao J.C. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. [published correction appears in J. Clin. Oncol. 1 January 2005, 23, 248] J. Clin. Oncol. 2004 22 4762 4771 10.1200/JCO.2004.04.024 15570077 \n55. Fazio N. Buzzoni R. Delle Fave G. Tesselaar M.E. Wolin E. Van Cutsem E. Tomassetti P. Strosberg J. Voi M. Bubuteishvili-Pacaud L. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis Cancer Sci. 2018 109 174 181 10.1111/cas.13427 29055056 \n56. Hicks R.J. Kwekkeboom D.J. Krenning E. Bodei L. Grozinsky-Glasberg S. Arnold R. Borbath I. Cwikla J. Toumpanakis C. Kaltsas G. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: Peptide receptor radionuclide therapy with radiolabeled somatostatin analogues Neuroendocrinology 2017 105 295 309 10.1159/000475526 28402980 \n57. Strosberg J. El-Haddad G. Wolin E. Hendifar A. Yao J. Chasen B. Mittra E. Kunz P.L. Kulke M.H. Jacene H. NETTER-1 trial investigators. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors N. Engl. J. Med. 2017 376 125 135 10.1056/NEJMoa1607427 28076709 \n58. Claringbold P.G. Price R.A. Turner J.H. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors Cancer Biother. Radiopharm. 2012 27 561 569 10.1089/cbr.2012.1276 23078020\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "10(9)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "capecitabine; chemotherapy; neuroendocrine tumor; neurofibromatosis type 1; somatostatin analogues; somatostatinoma; temozolomide",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32825782",
"pubdate": "2020-08-21",
"publication_types": "D002363:Case Reports",
"references": "26855376;16253902;10792774;15879362;28076709;23119102;16183524;17122609;10374671;3128965;29055056;20484441;25083296;20833335;6128052;20824724;7745981;26712231;20300877;26731483;26925113;32272208;3291522;3041116;29262620;18281671;9691916;25584486;17362838;12000821;29026467;26769865;32294191;28402980;19962915;31947598;15570077;21437171;2920654;20180029;15258554;24570674;11459269;18310290;3031836;19377845;25014687;30006586;27622342;8404961;18618495;26731334;27510677;23078020;30915122",
"title": "Somatostatinoma and Neurofibromatosis Type 1-A Case Report and Review of the Literature.",
"title_normalized": "somatostatinoma and neurofibromatosis type 1 a case report and review of the literature"
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"abstract": "Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement are a unique category in the WHO classification, and include cases with rearrangement of PDGFRA, PDGFRB, FGFR1, and PCM1-JAK2. We report three patients presented with eosinophilia and FLT3 rearrangement: the first case with chronic eosinophilic leukemia, not otherwise specified and T-lymphoblastic leukemia/lymphoma; the second case with myeloid sarcoma; and the last case with high-grade myelodysplastic syndrome. The first case showed t(13;14)(q12;q32), which encoded FLT3-TRIP11. The patient was treated with intense chemotherapy and subsequently sorafenib with clinical improvement. Unfortunately, the patient showed persistent residual disease and passed away 9 months after the diagnosis from pneumonia. The other two cases both showed ETV6-FLT3. The second patient was treated with local radiation and systemic chemotherapy including sorafenib and was alive. The third patient was treated with chemotherapy but showed transformation to acute myeloid leukemia and died 15 months after diagnosis. These cases are among a growing number of cases with FLT3 rearrangement that all showed similar clinicopathologic features characterized by myeloproliferative neoplasm with eosinophilia and frequent T lymphoblastic leukemia/lymphoma. Therefore, we propose that the myeloid/lymphoid neoplasms with eosinophilia and FLT3 rearrangement be included in the WHO category of myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement.",
"affiliations": "Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, United States.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, United States.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, United States.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Adaptive Biotechnologies, 1551 Eastlake Ave E, Ste 200, Seattle, WA, United States.;Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, United States.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.;Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, United States. Electronic address: Ling.Zhang@moffitt.org.",
"authors": "Shao|Haipeng|H|;Wang|Wei|W|;Song|Jinming|J|;Tang|Guilin|G|;Zhang|Xiaohui|X|;Tang|Zhenya|Z|;Srivastava|Jaya|J|;Shah|Bijal|B|;Medeiros|L Jeffrey|LJ|;Zhang|Ling|L|",
"chemical_list": "C087043:ETS translocation variant 6 protein; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; C497970:FLT3 protein, human; C000624294:TRIP11-FLT3 fusion protein, human; D051941:fms-Like Tyrosine Kinase 3",
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2020.106460",
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"issn_linking": "0145-2126",
"issue": "99()",
"journal": "Leukemia research",
"keywords": "ETV6; Eosinophilia; FLT3; Myeloproliferative neoplasm; T-lymphoblastic leukemia; TRIP11",
"medline_ta": "Leuk Res",
"mesh_terms": "D059786:Abnormal Karyotype; D000368:Aged; D001853:Bone Marrow; D002882:Chromosomes, Human, Pair 13; D002883:Chromosomes, Human, Pair 14; D018450:Disease Progression; D004802:Eosinophilia; D006801:Humans; D017681:Hypereosinophilic Syndrome; D007938:Leukemia; D008198:Lymph Nodes; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D015514:Oncogene Proteins, Fusion; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D023981:Sarcoma, Myeloid; D014178:Translocation, Genetic; D014944:World Health Organization; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "106460",
"pmc": null,
"pmid": "33166908",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Myeloid/lymphoid neoplasms with eosinophilia and FLT3 rearrangement.",
"title_normalized": "myeloid lymphoid neoplasms with eosinophilia and flt3 rearrangement"
} | [
{
"companynumb": "US-BAXTER-2020BAX024719",
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"activesubstancename": "CYCLOPHOSPHAMIDE"
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{
"abstract": "Acquired methaemoglobinaemia is a potentially fatal impairment in oxygen delivery if not recognised early and treated appropriately. Benzocaine used as an anaesthetic for endoscopic procedures is an uncommon but clinically important precipitant of acquired methaemoglobinaemia. We present a case of an elderly woman who developed perioral cyanosis and desaturation 20 min after a transoesophageal echocardiogram. Further evaluation led to the diagnosis of benzocaine-induced methaemoglobinaemia and timely treatment with intravenous methylene blue was initiated.",
"affiliations": "Department of Internal Medicine, Reading Health System, West Reading, Pennsylvania, USA.",
"authors": "Aryal|Madan Raj|MR|;Gupta|Shobhit|S|;Giri|Smith|S|;Fraga|Julian Diaz|JD|",
"chemical_list": "D000779:Anesthetics, Local; D008751:Methylene Blue; D001566:Benzocaine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000779:Anesthetics, Local; D001566:Benzocaine; D017548:Echocardiography, Transesophageal; D005260:Female; D006801:Humans; D008708:Methemoglobinemia; D008751:Methylene Blue",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24042203",
"pubdate": "2013-09-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16640711;19725841;18605250;16986127;22162610;15342970;12574744;16517334;17074536;16166392;16275102;17803228",
"title": "Benzocaine-induced methaemoglobinaemia: a life-threatening complication after a transoesophageal echocardiogram (TEE).",
"title_normalized": "benzocaine induced methaemoglobinaemia a life threatening complication after a transoesophageal echocardiogram tee"
} | [
{
"companynumb": "US-PFIZER INC-2015315471",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "A 45-year-old man suffered compartment syndrome of the hands as a complication of prolonged cardiopulmonary resuscitation. He was admitted following a hypothermic out-of-hospital cardiac arrest due to cold-water submersion. The patient was in cardiac arrest for 4 h with mechanical cardiopulmonary resuscitation delivered using the Lund University Cardiac Arrest System (Jolife AB, Lund, Sweden). Cardiopulmonary resuscitation along with aggressive rewarming achieved return of spontaneous circulation. He developed compartment syndrome in his left hand which was likely exacerbated by having his arm strapped to the Lund University Cardiac Arrest System device throughout the resuscitation. The compartment syndrome was managed conservatively. Despite preservation of neurological function the patient died of complications from the cardiac arrest after an extended intensive care unit stay. We recommend healthcare providers unstrap patient's hands during prolonged mechanical cardiopulmonary resuscitation.",
"affiliations": "Conquest Hospital Hastings UK.;Conquest Hospital Hastings UK.;Resuscitation Department East Sussex NHS Healthcare Trust UK.;Department of Anaesthesia and Intensive Care East Sussex NHS Healthcare Trust UK.;Department of Anaesthesia and Intensive Care East Sussex NHS Healthcare Trust UK.",
"authors": "Lesser|F D|FD|;Yakubi|M|M|;Rochester|S|S|;Evans|J|J|;Highgate|J|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/anr3.12025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2637-3726",
"issue": "8(1)",
"journal": "Anaesthesia reports",
"keywords": "hypothermia; peripheral compartment syndrome: diagnosis",
"medline_ta": "Anaesth Rep",
"mesh_terms": null,
"nlm_unique_id": "101759073",
"other_id": null,
"pages": "10-13",
"pmc": null,
"pmid": "32154512",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25277343;32051937;29124382;17574182;8898137;29088439;10755426;26477701;24176273",
"title": "Compartment syndrome of the hand as a complication of prolonged mechanical cardiopulmonary resuscitation.",
"title_normalized": "compartment syndrome of the hand as a complication of prolonged mechanical cardiopulmonary resuscitation"
} | [
{
"companynumb": "GB-PFIZER INC-2020291686",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": "1",
... |
{
"abstract": "Relapsed/refractory NB carries a bleak outcome, warranting novel treatment options. HaploHSCT induces a graft-versus-NB effect via natural killer cell alloreactivity. Review of patients with relapsed/refractory NB who underwent haploHSCT with ex vivo T-cell depletion in our unit from 2013 through 2018. Ten patients were identified (male=5; median age at haploHSCT=6.45 y, range: 3.49-11.02 y). Indications were relapsed in 7 and refractoriness in 3; disease status at haploHSCT was CR in 2, PR in 6, and PD in 2. All patients received peripheral blood stem cell grafts after ex vivo T-cell depletion (CD3/CD19-depletion=1; TCR-αβ/CD19-depletion=4; CD3/CD45RA-depletion=4; and TCR-αβ/CD45RA-depletion=1). Conditioning regimens were fludarabine-based. Neutrophils engrafted on median D + 10 (range: D + 9 to +13), and platelets engrafted (≥20 × 109 /L) on median D + 8 (range: D + 5 to D + 14). Early T- and NK-cell recovery were evident. Of the 10 patients, acute rejection developed in 1 (who died of PD despite rescue HSCT), and 1 died of sepsis before engraftment; 8 experienced full donor-chimerism post-HSCT. Among the 8, 6 experienced CR, 1 died of PD, and 1 died of pulmonary hypertensive crisis before evaluation. At publication, 4 were in remission (2.8, 7.4, 28.5, and 58.9 months). No significant GvHD occurred. HaploHSCT with selective ex vivo T-cell depletion may be a safe and useful salvage strategy for relapsed/refractory NB.",
"affiliations": "Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.;Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.;Division of Transplantation and Immunogenetics, Department of Pathology, Queen Mary Hospital, Hong Kong SAR, China.;Department of Pathology, Queen Mary Hospital, Hong Kong SAR, China.;Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.;Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.;Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.;Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.",
"authors": "Liu|Anthony P Y|APY|http://orcid.org/0000-0002-8597-9128;Lee|Pamela P W|PPW|;Kwok|Janette S Y|JSY|;Leung|Rock Y Y|RYY|;Chiang|Alan K S|AKS|;Ha|Shau-Yin|SY|;Cheuk|Daniel K L|DKL|;Chan|Godfrey C F|GCF|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": null,
"journal": "Pediatric transplantation",
"keywords": "haploidentical; hematopoietic stem cell transplantation; immunotherapy; neuroblastoma; relapse",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13240",
"pmc": null,
"pmid": "29921011",
"pubdate": "2018-06-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Selective T cell-depleted haploidentical hematopoietic stem cell transplantation for relapsed/refractory neuroblastoma.",
"title_normalized": "selective t cell depleted haploidentical hematopoietic stem cell transplantation for relapsed refractory neuroblastoma"
} | [
{
"companynumb": "CN-ADIENNEP-2019AD000007",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THIOTEPA"
},
"drugadditional": "3",
... |
{
"abstract": "Electroconvulsive therapy (ECT) has been used to treat severe treatment-resistant major depressive disorder. Multiple psychotropic medications are usually prescribed in high doses prior to or concomitantly with ECT. Little is known about the interaction of ECT with psychotropic medications. ECT is known to induce seizures, but its tendency to induce absence seizures is not. We present a case of a 44-year-old female, on multiple psychotropic medications, who had frequent atypical absence seizures for many days after ECT. Electroencephalography (EEG) confirmed atypical absence seizures by the presence of typical 2.5 to 3 Hz generalized sharp and slow waves with disorganized background activity.",
"affiliations": "UMDNJ Cooper University Medical Center Camden, NJ, USA. burakgazi-dalkilic-evren@cooperhealth.edu",
"authors": "Burakgazi|Evren|E|;Dalkilic|Alican|A|;Moghal|Usman|U|;Shah|Umang|U|;Carran|Melissa|M|",
"chemical_list": "D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": "10.1177/1550059412452674",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-0594",
"issue": "44(1)",
"journal": "Clinical EEG and neuroscience",
"keywords": null,
"medline_ta": "Clin EEG Neurosci",
"mesh_terms": "D000328:Adult; D003865:Depressive Disorder, Major; D004351:Drug Resistance; D004565:Electroconvulsive Therapy; D004569:Electroencephalography; D004832:Epilepsy, Absence; D005260:Female; D006801:Humans; D011619:Psychotropic Drugs; D013226:Status Epilepticus",
"nlm_unique_id": "101213033",
"other_id": null,
"pages": "62-9",
"pmc": null,
"pmid": "23248334",
"pubdate": "2013-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of atypical absence seizures after electroconvulsive treatment in a patient with treatment-resistant depression.",
"title_normalized": "a case of atypical absence seizures after electroconvulsive treatment in a patient with treatment resistant depression"
} | [
{
"companynumb": "US-APOTEX-2015AP006322",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
},
"drugadditional": null,... |
{
"abstract": "Methylphenidate-induced hepatic injury was documented by abnormal liver function tests including a markedly elevated serum bilirubin, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase. Liver biopsy confirmed portal inflammation and hepatocellular disarray. Enzyme changes were reproducible with rechallenge of the drug (Ritalin). The drug is capable of producing hepatic injury, particularly when given in nonstandard doses intravenously.",
"affiliations": null,
"authors": "Mehta|H|H|;Murray|B|B|;LoIudice|T A|TA|",
"chemical_list": "D008774:Methylphenidate",
"country": "United States",
"delete": false,
"doi": "10.1097/00004836-198404000-00010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0192-0790",
"issue": "6(2)",
"journal": "Journal of clinical gastroenterology",
"keywords": null,
"medline_ta": "J Clin Gastroenterol",
"mesh_terms": "D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008111:Liver Function Tests; D008774:Methylphenidate; D019966:Substance-Related Disorders",
"nlm_unique_id": "7910017",
"other_id": null,
"pages": "149-51",
"pmc": null,
"pmid": "6715854",
"pubdate": "1984-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride.",
"title_normalized": "hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride"
} | [
{
"companynumb": "US-MYLANLABS-2018M1069948",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugadditional": "1",
... |
{
"abstract": "We present the case of a 70-year-old woman with a history of seronegative arthritis, recurrent pleural effusion and weight loss. A prior lung biopsy had revealed non-caseating epithelioid cell granulomas without evidence for microbial organisms on special stains. Intestinal biopsy findings where suspicious for Whipple's disease, which was confirmed by PCR testing, both on the intestinal and retrospectively on the lung tissue. Treatment with ceftriaxone resulted in clinical deterioration with fever, arthritis and recurrent pleuritis consistent with immune reconstitution inflammatory syndrome. Dose increase of glucocorticoids and therapy rotation to doxycycline and hydroxychloroquine resulted in rapid clinical improvement.",
"affiliations": "Internal Medicine, Hospital Uster, Uster, Switzerland hofmannpatrick@bluewin.ch.;Internal Medicine, Hospital Uster, Uster, Switzerland.;Internal Medicine, Hospital Uster, Uster, Switzerland.;Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.",
"authors": "Hofmann|Patrick|P|http://orcid.org/0000-0002-4586-641X;Durisch|Nina|N|;Buetikofer|Claudia|C|;Helmchen|Birgit Maria|BM|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243633",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "infectious diseases; pleural infection; stomach and duodenum",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008171:Lung Diseases; D012189:Retrospective Studies; D054851:Tropheryma; D008061:Whipple Disease",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34144955",
"pubdate": "2021-06-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Granulomatous lung disease and immune reconstitution inflammatory syndrome in Whipple's disease.",
"title_normalized": "granulomatous lung disease and immune reconstitution inflammatory syndrome in whipple s disease"
} | [
{
"companynumb": "CH-TEVA-2021-CH-1942053",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Sorafenib is an oral multi-kinase inhibitor that targets tumor growth and angiogenesis signal transduction pathways. Two global phase III trials showed that sorafenib prolonged the survival of patients with advanced hepatocellular carcinoma (HCC). Based on the positive results of these trials, Japan approved sorafenib for advanced HCC in May 2009. However, in the SHARP trial and the Asia-Pacific trials, no cases of complete response(CR)were reported. Thereafter, only a relatively small number of CR cases were reported for sorafenib therapy. We herein report the case of a 64-year-old Japanese man infected with hepatitis B virus who developed bone metastasis 9 months after resection of HCC. Sorafenib therapy plus zoledronic acid was initiated. The patient achieved a CR after 15 months of therapy, and there has been no sign of recurrence 12 months following cessation of administration. Regarding toxicity, the patient developed a grade 2 hand foot skin reaction that required a temporary 50% dose reduction of sorafenib. To our knowledge, this is the first case of CR in advanced HCC with bone metastasis treated with sorafenib plus zoledronic acid.",
"affiliations": "Second Dept. of Surgery, Dokkyo Medical University Koshigaya Hospital.",
"authors": "Natori|Takeshi|T|;Yamaguchi|Masahiko|M|",
"chemical_list": "D004164:Diphosphonates; D007093:Imidazoles; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077211:Zoledronic Acid; D000077157:Sorafenib",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "40(5)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D006528:Carcinoma, Hepatocellular; D004164:Diphosphonates; D006801:Humans; D007093:Imidazoles; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009536:Niacinamide; D010671:Phenylurea Compounds; D012074:Remission Induction; D000077157:Sorafenib; D000077211:Zoledronic Acid",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "635-7",
"pmc": null,
"pmid": "23863589",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complete response after sorafenib therapy plus zoledronic acid for advanced hepatocellular carcinoma with bone metastasis - a case report.",
"title_normalized": "complete response after sorafenib therapy plus zoledronic acid for advanced hepatocellular carcinoma with bone metastasis a case report"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201605426",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
... |
{
"abstract": "We describe the case of a 60-year-old man suffering from an advanced thymic neuroendocrine tumor with left supraclavicular lymph node and multiple bone metastases. The patient initially underwent systemic therapy with somatostatin analogues. Thereafter, peptide receptor radionuclide therapy (PRRT) was considered because the lesions had remained stable despite the pharmacological therapy. PRRT was performed 10 months after the initial treatment in a European hospital. Eighteen months after the treatment, cranial nerve palsy arising from skull base metastases and Horner's syndrome induced by left supraclavicular lymph node metastases became exacerbated. Therefore, a course of external radiotherapy was performed with palliative intent in our hospital. During the radiotherapy planning, the biodistribution of 111In-octreotide was examined to determine whether the absorbed dose of the previous PRRT was acceptable. As a result, external radiotherapy was performed, and an acute radiation reaction was observed; the severity of the reaction was typical of reactions to neck radio-therapy. The treatment course of the present case was considered to be instructive because PRRT cannot be performed in Japan at present.",
"affiliations": null,
"authors": "Kawase|Takatsugu|T|;Kubota|Kazuo|K|;Takeda|Yuichiro|Y|;Udagawa|Hibiki|H|;Sugiyama|Haruhito|H|;Sakashita|Baku|B|;Uchino|Minako|M|;Itazawa|Tomoko|T|;Hasuo|Kanehiro|K|",
"chemical_list": "D007205:Indium Radioisotopes; D018000:Receptors, Peptide; C094279:indium-111-octreotide; D015282:Octreotide",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-7854",
"issue": "51(2)",
"journal": "Kaku igaku. The Japanese journal of nuclear medicine",
"keywords": null,
"medline_ta": "Kaku Igaku",
"mesh_terms": "D006801:Humans; D007205:Indium Radioisotopes; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D015282:Octreotide; D018000:Receptors, Peptide; D013953:Thymus Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "2985202R",
"other_id": null,
"pages": "47-53",
"pmc": null,
"pmid": "25011199",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Additional external radiotherapy to multiple metastases originating from thymic neuroendocrine tumor following peptide receptor radionuclide therapy: a case report.",
"title_normalized": "additional external radiotherapy to multiple metastases originating from thymic neuroendocrine tumor following peptide receptor radionuclide therapy a case report"
} | [
{
"companynumb": "PHHY2014JP085438",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nResults of a study of postsurgical opioid-related adverse drug events (ORADEs) within a large health system are reported.\n\n\nMETHODS\nIn a retrospective cohort study, data from the information database of an 11-hospital Texas health system were analyzed to (1) describe postsurgical opioid use among adult patients undergoing elective or emergency surgery over a one-year period, (2) identify ORADE risk factors and associated costs, and (3) compare clinical and economic outcomes in patients who experienced ORADEs and those who did not. Multivariate logistic regression was used to identify ORADE risk factors. Propensity score-matched comparisons of outcomes in patients with and without ORADEs were conducted.\n\n\nRESULTS\nAmong 6,285 patients in the study population, 6,274 (99.8%) received postsurgical opioids; 11.5% of those patients experienced an ORADE. ORADE risk factors included age (≥65 years), male sex, prior opioid use, chronic obstructive pulmonary disease, cardiac dysrhythmias, regional enteritis, diverticulitis, and ulcerative colitis. Patients with multiple risk factors had higher mean hospitalization costs ($21,073) relative to patients with one risk factor ($14,110) or no risk factor ($11,433) and accounted for a disproportionately large share of overall costs; patients who experienced ORADEs were more likely to be cost and length of stay (LOS) outliers.\n\n\nCONCLUSIONS\nAnalysis of information from a large database demonstrated that opioid-treated postsurgical inpatients who had multiple risk factors for ORADEs were more likely to have higher mean costs, greater readmission rates, and longer LOS than patients with fewer risk factors.",
"affiliations": "Harold S. Minkowitz, M.D., is Anesthesiologist, Memorial Hermann Memorial City Medical Center, Houston, TX. Stephen K. Gruschkus, Ph.D., M.P.H., was, when this article was written, Assistant Director, Applied Data Analytics, Xcenda, AmerisourceBergen Consulting Services, Palm Harbor, FL. Manan Shah, Pharm.D., Ph.D., is Director, Health Services and Outcomes Research, Bristol-Myers Squibb, Plainsboro, NJ; when this article was written, he was Director, Applied Data Analytics, Xcenda. Aditya Raju, M.S., is Manager, Global Health Economics and Outcomes Research, Xcenda.;Harold S. Minkowitz, M.D., is Anesthesiologist, Memorial Hermann Memorial City Medical Center, Houston, TX. Stephen K. Gruschkus, Ph.D., M.P.H., was, when this article was written, Assistant Director, Applied Data Analytics, Xcenda, AmerisourceBergen Consulting Services, Palm Harbor, FL. Manan Shah, Pharm.D., Ph.D., is Director, Health Services and Outcomes Research, Bristol-Myers Squibb, Plainsboro, NJ; when this article was written, he was Director, Applied Data Analytics, Xcenda. Aditya Raju, M.S., is Manager, Global Health Economics and Outcomes Research, Xcenda.;Harold S. Minkowitz, M.D., is Anesthesiologist, Memorial Hermann Memorial City Medical Center, Houston, TX. Stephen K. Gruschkus, Ph.D., M.P.H., was, when this article was written, Assistant Director, Applied Data Analytics, Xcenda, AmerisourceBergen Consulting Services, Palm Harbor, FL. Manan Shah, Pharm.D., Ph.D., is Director, Health Services and Outcomes Research, Bristol-Myers Squibb, Plainsboro, NJ; when this article was written, he was Director, Applied Data Analytics, Xcenda. Aditya Raju, M.S., is Manager, Global Health Economics and Outcomes Research, Xcenda.;Harold S. Minkowitz, M.D., is Anesthesiologist, Memorial Hermann Memorial City Medical Center, Houston, TX. Stephen K. Gruschkus, Ph.D., M.P.H., was, when this article was written, Assistant Director, Applied Data Analytics, Xcenda, AmerisourceBergen Consulting Services, Palm Harbor, FL. Manan Shah, Pharm.D., Ph.D., is Director, Health Services and Outcomes Research, Bristol-Myers Squibb, Plainsboro, NJ; when this article was written, he was Director, Applied Data Analytics, Xcenda. Aditya Raju, M.S., is Manager, Global Health Economics and Outcomes Research, Xcenda. aditya.raju@xcenda.com.",
"authors": "Minkowitz|Harold S|HS|;Gruschkus|Stephen K|SK|;Shah|Manan|M|;Raju|Aditya|A|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp130031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "71(18)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D003153:Community Health Services; D062313:Databases, Pharmaceutical; D005260:Female; D017721:Hospital Costs; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010149:Pain, Postoperative; D010359:Patient Readmission; D012189:Retrospective Studies; D012307:Risk Factors; D013781:Texas; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1556-65",
"pmc": null,
"pmid": "25174016",
"pubdate": "2014-09-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Adverse drug events among patients receiving postsurgical opioids in a large health system: risk factors and outcomes.",
"title_normalized": "adverse drug events among patients receiving postsurgical opioids in a large health system risk factors and outcomes"
} | [
{
"companynumb": "US-JNJFOC-20150209298",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROMORPHONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCentral nervous system (CNS) infiltration of Richter's syndrome (RS) is rare and only a few cases were discussed. Of these published cases, either they were accompanied with lymph node involvement or with a history of chronic lymphocytic leukemia (CLL). To our knowledge, this is the first published case of RS of the brain and meninges diagnosed concurrently with CLL in the absence of any evidence of lymphoma outside of the CNS.\nA 67-year-old female presented with slurred speech, headache, and left-sided hemiparesis. Magnetic resonance imaging of the brain revealed an irregular lesion 30 mm in diameter in the right parietal lobe. The mass was totally removed and pathology revealed diffuse large B-cell lymphoma (DLBCL) of non-germinal center type by Hans' classification. The patient's leukocyte count was 12.1 × 109/L (76.9% lymphocytes), and fluorescence-activated cell sorting (FACS) analysis of blood revealed a clonal B-cell population (36.75% leukocytes) corresponding to the immunological CLL profile (Matutes score of 5/5). Bone marrow (BM) aspiration and biopsy also indicated CLL. The analysis of immunoglobulin heavy chain gene (IGH) and kappa chain gene (IGK) in the patient's BM and CNS tissue indicated that the DLBCL of the brain was derived from the CLL clone.\nRS of the CNS diagnosed concurrently with CLL.\n\n\nMETHODS\nThe patient received intravenous chemotherapy (6.0 g methotrexate) and intrathecal chemotherapy (10 mg methotrexate, 50 mg cytarabine, 5 mg dexamethasone).\n\n\nRESULTS\nThe patient returned to our department with left-sided hemiparesis and headache 2 weeks after the chemotherapy. Repeat MRI showed progression of the brain lesion. Her general condition deteriorated significantly with confusion and high fever, and she died within a few days at only 10 weeks after the onset of symptoms.\n\n\nCONCLUSIONS\nThe survival of CNS-RS patients is very poor and and is always complicated with multiple and different genetic alterations. Because of chemotherapy insensitivity, a multidisciplinary treatment including surgery and radiotherapy together with novel agents may be an option to improving patient outcomes.",
"affiliations": "Myeloma and Lymphoma Research Center.;Myeloma and Lymphoma Research Center.;Myeloma and Lymphoma Research Center, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province.;Department of Pathology, Peking University, Third Hospital, Beijing.;Department of Pathology.;Flow Cytometry Center, Second Affiliated Hospital of Dalian Medical University, Dalian, China.",
"authors": "Xu|Liye|L|;Song|Jin Cheng|JC|;Sun|Xiu Hua|XH|;Gao|Zi Fen|ZF|;Lv|Li|L|;Zhu|Jie|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000012701",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30313065MD-D-18-0381310.1097/MD.0000000000012701127014800Research ArticleClinical Case ReportRichter's syndrome of the central nervous system diagnosed concurrently with chronic lymphocytic leukaemia A case report and literature reviewXu Liye MDaSong Jin Cheng MDb∗Sun Xiu Hua MDcGao Zi Fen PhDdLv Li MDeZhu Jie MDfA. N/ a Myeloma and Lymphoma Research Centerb Myeloma and Lymphoma Research Centerc Myeloma and Lymphoma Research Center, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Provinced Department of Pathology, Peking University, Third Hospital, Beijinge Department of Pathologyf Flow Cytometry Center, Second Affiliated Hospital of Dalian Medical University, Dalian, China.∗ Correspondence: Jin Cheng Song, Myeloma and Lymphoma Research Center, Second Affiliated Hospital of Dalian Medical University, Dalian, China, Postal address: Zhongshan Road No. 467, Shahekou District, Dalian 116027, and Liaoning Province, China (e-mail: wwepqwq@163.com).10 2018 12 10 2018 97 41 e127019 6 2018 11 9 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/4.0.Abstract\nRationale:\nCentral nervous system (CNS) infiltration of Richter's syndrome (RS) is rare and only a few cases were discussed. Of these published cases, either they were accompanied with lymph node involvement or with a history of chronic lymphocytic leukemia (CLL). To our knowledge, this is the first published case of RS of the brain and meninges diagnosed concurrently with CLL in the absence of any evidence of lymphoma outside of the CNS.\n\nPatient concerns:\nA 67-year-old female presented with slurred speech, headache, and left-sided hemiparesis. Magnetic resonance imaging of the brain revealed an irregular lesion 30 mm in diameter in the right parietal lobe. The mass was totally removed and pathology revealed diffuse large B-cell lymphoma (DLBCL) of non-germinal center type by Hans’ classification. The patient's leukocyte count was 12.1 × 109/L (76.9% lymphocytes), and fluorescence-activated cell sorting (FACS) analysis of blood revealed a clonal B-cell population (36.75% leukocytes) corresponding to the immunological CLL profile (Matutes score of 5/5). Bone marrow (BM) aspiration and biopsy also indicated CLL. The analysis of immunoglobulin heavy chain gene (IGH) and kappa chain gene (IGK) in the patient's BM and CNS tissue indicated that the DLBCL of the brain was derived from the CLL clone.\n\nDiagnoses:\nRS of the CNS diagnosed concurrently with CLL.\n\nInterventions:\nThe patient received intravenous chemotherapy (6.0 g methotrexate) and intrathecal chemotherapy (10 mg methotrexate, 50 mg cytarabine, 5 mg dexamethasone).\n\nOutcomes:\nThe patient returned to our department with left-sided hemiparesis and headache 2 weeks after the chemotherapy. Repeat MRI showed progression of the brain lesion. Her general condition deteriorated significantly with confusion and high fever, and she died within a few days at only 10 weeks after the onset of symptoms.\n\nLessons:\nThe survival of CNS-RS patients is very poor and and is always complicated with multiple and different genetic alterations. Because of chemotherapy insensitivity, a multidisciplinary treatment including surgery and radiotherapy together with novel agents may be an option to improving patient outcomes.\n\nKeywords\ncentral nervous systemchronic lymphocytic leukemia (CLL)diffuse large B-cell lymphoma (DLBCL)immunoglobulin heavy chain variable region geneRichter's syndromeRichter's transformationOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nIn 1928, Maurice N. Richter first reported the transformation of B cell chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL), which became known as Richter's syndrome (RS), or Richter's transformation (RT). We now know that although DLBCL is the most common type of RS, occurring in approximately 5–10% of CLL patients, other rarer types such as Hodgkin and composite lymphoma also can occur.[1] The reported incidence of RS has varied from 2% to 10% with a median time from CLL diagnosis to RT of 23.0 months.[2] RS is typically characterized by an aggressive presentation, chemotherapy-resistance, and poor survival, with reported median survival times of 8 months and a 5-year survival rate less than 5%.[3,4] The majority of RS cases occur in lymph nodes, but other primary sites such as the gastrointestinal system, eye, nose, skin, bone, bronchus, and even face have been reported.[5] Central nervous system (CNS) infiltration RS is quite rare. Here we report an unusual case of patient who initially presented with the simultaneous occurrence of CLL in the blood and bone marrow (BM) and DLBCL in the brain and meninges. To our knowledge, this is the first published case of RS of the brain and meninges diagnosed concurrently with CLL in the absence of any evidence of lymphoma outside of the CNS.\n\n2 Case presentation\nA 67-year-old female presented with slurred speech, headache, and left-sided hemiparesis in March 2017. Upon admission, she had a white blood cell (WBC) count of 22.2 × 109/L and lymphocyte count of 14.5 × 109/L, with a normal hemoglobin level and platelet count. Magnetic resonance imaging (MRI) of the brain revealed an irregular lesion with a diameter of 30 mm in the right parietal lobe (Fig. 1A). The mass was completely removed via surgical resection and pathological evaluation revealed a diagnosis of DLBCL (Fig. 2), of a non-germinal center type by Hans’ classification. The immune phenotype was CD20 (+), BCL-2(+, 70%), BCL-6(+, 40%), CD10 (–), CD21 (–), CD23 (–), CD3 (–), CD5 (+, a few cells), MUM-1(+), p53(+, 80%), C-myc (+, 30%), Ki-67 index of 80%, and EBER(–). The patient's symptoms disappeared after the surgery.\n\nFigure 1 Magnetic resonance images of the tumoral lesion in the right parietal lobe before surgery (A); recurrence of the tumor mass at 1 month after surgery (B); and progression of the brain lesion after chemotherapy (C).\n\nFigure 2 Brain tumor histology showed infiltration consistent with DLBCL on hematoxylin-eosin (H&E) staining (40 × 10) (A). Immunocytochemical staining for CD20 within the brain mass was positive (20 × 10) (B). DLBCL = diffuse large B-cell lymphoma.\n\nThe patient attended to our department in April 2017 for chemotherapy, without night sweats, fever or body weight loss. Peripheral blood examination revealed a hemoglobin level of 120 g/L, a platelet count of 257 × 109/L, and a leukocyte count of 12.1 × 109/L (76.9% lymphocytes). Fluorescence-activated cell sorting (FACS) analysis of the blood revealed a clonal B-cell population (36.75% leukocytes) co-expressing CD5, CD19, CD23, CD43, CD79b, surface lambda, CD20 (dim), and CD22 corresponding to the immunological profile of CLL (Matutes score of 5/5). Staining results for CD38, CD13, FMC-7, cKappa, and CD10 were negative. BM (BM) aspiration revealed 46.5% mature lymphocytes and 2% prolymphocytes (Fig. 3). FACS analysis of BM also confirmed the diagnosis of CLL. BM biopsy revealed nodular BM infiltration by small lymphocytes, and the immune phenotype was CD20 (+), CD23 (+), CD5 (+), CD3 (–), p53 (+), CyclinD1 (–), and CD10(–), also consistent with CLL. No lymph node enlargement or hepatosplenomegaly was observed on enhanced computed tomography. Testing for human immunodeficiency virus (HIV) was negative, and the lactase dehydrogenase level was 155 IU/L (normal range: 120–250 IU/L). A patchy, locally enhanced lesion was found in the right parietal lobe of brain on MRI (Fig. 1B). No abnormalities were found on ophthalmological examination. The cerebrospinal fluid (CSF) was turbid, with an elevated protein concentration of 804 mg/L and normal glucose level of 2.9 mmol/L. Cytological analysis of the CSF revealed many lymphocytes, and some were lymphoma cells. Specifically, we counted 463 lymphocytes, and 200 were B lymphocytes found to express CD20, CD22 and CD19 but not CD5 or CD23 on FACS analysis of the CSF. These FACS results indicated the cells were DLBCL cells. Simultaneous diagnosis of CLL and DLBCL of the CNS was established (RS). However, the relationship between the CNS lesion and peripheral CLL cells was not definite, and thus, we analyzed the expression of immunoglobulin heavy chain gene (IGH) and kappa chain gene (IGK) in the patient's BM and CNS tissue. The observed amplified segments (monoclonal peaks at 330 bp for IGH and 144 bp for IGK) seemed to be identical and indicated that the DLBCL in the brain was derived from the CLL clone. (Due to copyright issues, we could not present images from the IGH analysis).\n\nFigure 3 Bone marrow aspiration showing mature lymphocytoid cells with a condensed circular nucleus.\n\nThe patient received intravenous chemotherapy (6.0 g methotrexate) and intrathecal chemotherapy (10 mg methotrexate, 50 mg cytarabine, 5 mg dexamethasone). Unfortunately, she returned to our department with left-sided hemiparesis and headache after 2 weeks. Repeat MRI showed progression of brain lesion (Fig. 1C). The patient's condition was too poor for her to receive the planned radiotherapy, and it continued to decline significantly with the development of confusion and high fever. She died within a few days at just 10 weeks after the onset of symptoms.\n\n3 Discussion\nRS within the CNS tissue is very rare, and we could identify only a few published cases (Table 1).[6–17] Of the 16 cases described in the literature, 9 patients received treatment after CLL was found. The median age among the 16 cases was 64 years, and the male to female ratio was 11: 5. None of the cases were classified as Binet stage C. The median transformation time for RS was 38.0 months, with the longest duration being 10 years from the initial diagnosis of CLL. This transformation time was longer than that for RS occurring outside of the brain (mean transformation time for RS outside the CNS, 23.0 months).[2] Survival among these patients ranged from 10 days to more than 2 years, and the median survival time of 6.0 months was shorter than the median survival time of 8.0 months for RS occurring in other sites.[4] All 16 published cases of RS infiltration of the CNS had either lymph node involvement or a history of CLL. Thus, the case described in the present report is unusual and the first published case to be simultaneously diagnosed with CLL and DLBCL in the brain and meninges without evidence of lymphoma outside of the CNS.\n\nTable 1 Reported cases of RS isolated within the CNS.\n\nAmong the reported cases, the clinical presentation of CNS-RS was headache, hemiparesis, vomiting, and confusion and lacking specific symptoms. Whether the use of chemotherapy as treatment for CLL will increase the risk of RS has remained controversial. Traditional chemotherapy was reported to double the risk of RT to a rate of 1% per annum for those treated with chemotherapy from the rate of 0.5% per annum among those not treated with chemotherapy.[18] However, others have concluded that the evidence for an increased risk of Richter's transformation in CLL patients treated with chemotherapy in combination with rituximab is inadequate.[19,20] Multiple factors have been linked to an increased risk of RS in CLL patients, including Rai stages III–IV, lymph node size >3 cm, deletion of the p53/Rb/p27genes, mutations of the SAMHD1/XPO1/MED12/NOTCH1/MYC genes, loss of cell cycle inhibitors CDKN1A/CDKN2A/CDKN1B, CD38 expression (CD38 ≥30%), stereotyped B-cell receptor, telomere length <5000 base pairs, absence of del13q14/11q23, overexpression of ZAP70/BCL2/LRP4 genes, decreased expression of MYBL1, immunoglobulin heavy chain variable region (IGHV) homology >98%, and IGHV gene usage (B-cell receptor subset 8 using IGHV4–39/IGHD6–13/IGHJ5), trisomy 12, and chromosome 11 abnormalities.[4,5,21] Notably, 95% of DLBCL cases resulting from Richter's transformation display an ABC phenotype, in which staining for CD20 expression is generally positive and that for CD5 and CD23 expression may be dim to negative as in the present case, which is similar to the phenotype of de novo DLBCL. However, molecular profiles including genetic alterations and immunoglobulin gene mutations are found more frequently among patients with RS than those with de novo DLBCL,[22] and these abnormalities may increase the proliferation of CLL cells. In other words, the genetic abnormalities resulting from combinations of multiple, different genetic lesions may promote the development of RS in CLL patients. Importantly, positron emission tomography (PET) can be helpful for identifying RS in CLL patients at high risk. With a maximum standardized uptake value (SUVmax) cut-off of 5.0, PET was shown to detect RT of CLL to DLBCL with a high sensitivity (91%) and high negative predictive value (97%).[23] Papajik et al reported a median SUVmax for suspected or confirmed RT of 16.5.[24] Unfortunately, our patient did not undergo PET-CT scanning for economic reasons. Without the results from such examination, she underwent surgical resection first, which could significantly impact her performance status and which also delayed the administration of chemotherapy and radiotherapy to possibly negative influence her survival.\n\nIt is believed that RS cells will express the same surface light chain restriction as its derived CLL clones.[4] In order to definitively determine the clonal relationship of the CNS lesion with the CLL cells in the present case, we examined the sequences of IGH and IGK with the patient's BM and CNS tissue. Monoclonal peaks at 330 bp for IGH and 144 bp for IGK were observed for both the brain DLBCL and BM samples, indicating the gene sequences were identical in the 2 tissue types and that the CLL and DLBCL cells originated from the same B-cell clone. Mao et al found in a study of 23 patients, that RS cells were clonally related to the original CLL (as in our case) in 78% of cases, while the RS cells were clonally unrelated in 22% of cases.[25] The clonally related cells show a higher prevalence of tumor p53 disruption (60.0% versus 23.1% for clonally unrelated cells),[26] which will lead to expression of p53. The expression of p53 by 80% of cells in the brain lesion in the present case indicated that the cancer was aggressive and would be difficult to treat. Hence, it is important to detect p53 expression within lesions as a potential risk factor for poor prognosis among CLL patients. An additional study reported that the clonally related type of RS is characterized by rapid deterioration of performance status, chemotherapy-resistance, immunosuppression, and a poor survival with a median overall survival of 14.2 months versus 62.5 months for the cohort with clonally unrelated RS.[27]\n\nAlthough rare, RS within the CNS has consistently presented with rapid development, and the optimal treatments remain unknown. Therapeutic regimens established for primary CNS lymphoma have been applied, with chemotherapy combined with rituximab often being used to treat RS. Unfortunately, the results have been generally disappointing due to the chemotherapy-resistance and poor performance status of the patients.[28] Allogeneic stem cell transplantation has been found to improve survival in select patients.[29] Multidisciplinary treatment including surgery and radiotherapy together with stem cell transplantation and novel agents may be an option for chemoresistant RS in patients whose physical condition permits such treatments.\n\n4 Conclusions\nTo our knowledge, this is the first published case of RS of the brain and meninges that lacked evidence of lymphoma outside of the CNS and was diagnosed concurrent with CLL. Thus, the clinical and pathological descriptions of this case expand the literature related to RS of the CNS. Based on our review of the available but limited literature on RS of the CNS, recognition of risk factors is important for early diagnosis. So far, survival has remained very poor, with RS being insensitive to chemotherapy due to multiple different genetic alterations. Further research is needed to explore the pathogenic mechanism of RS in the CNS and to develop the optimal treatment strategy.\n\nAcknowledgments\nWe thank Professor Simon for editing and proofreading this manuscript.\n\nAuthor contributions\nLYX and JCS were involved in patient care and data collection and were major contributors in writing the manuscript. XHS and JCS were involved in the study concept and design of the study. JZ performed flow cytometry. ZFG and LL performed the pathological analysis and IGHV analysis. JCS was involved in manuscript editing. All authors read and approved the final manuscript.\n\nConceptualization: Jin-Cheng Song.\n\nData curation: Liye Xu, Jin-Cheng Song, Li Lv, Jie Zhu.\n\nFormal analysis: Jin-Cheng Song, Zifen Gao, Jie Zhu.\n\nInvestigation: Xiuhua Sun.\n\nMethodology: Liye Xu, Xiuhua Sun, Zifen Gao, Li Lv, Jie Zhu.\n\nProject administration: Jin-Cheng Song.\n\nResources: Xiuhua Sun.\n\nSoftware: Zifen Gao, Li Lv.\n\nWriting – original draft: Liye Xu.\n\nWriting – review & editing: Jin-Cheng Song.\n\njin-cheng song orcid: 0000-0001-9263-4614\n\nAbbreviations: BM = bone marrow, CLL = chronic lymphocytic leukemia, CNS = central nervous system, CSF = cerebrospinal fluid, DLBCL = diffuse large B-cell lymphoma, FACS = fluorescence-activated cell sorting, IGHV = immunoglobulin heavy chain variable region, MRI = magnetic resonance imaging, PET = positron emission tomography, RS = Richter's syndrome, RT = Richter's transformation, SUVmax = maximum standardized uptake value.\n\nThe datasets supporting the conclusions of this article are included within the article.\n\nThe institutional review board of Second Affiliated Hospital of Dalian Medical University approved this report.\n\nWritten informed consent for publication of this case report and any accompanying images was obtained from the patient. A copy of this written consent is available for review by the Editor-in-Chief of this journal.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Molica S \nA systematic review on Richter syndrome: what is the published evidence . Leuk Lymphoma \n2010 ;51 :415–21 .20078326 \n[2] Rossi D Cerri M Capello D \nBiological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome . Br J Haematol \n2008 ;142 :202–15 .18492108 \n[3] O’Neill BP Habermann TM Banks PM \nPrimary central nervous system lymphoma as a variant of Richter's syndrome in two patients with chronic lymphocytic leukemia . Cancer \n1989 ;64 :1296–300 .2766225 \n[4] Eyre TA Schuh A \nAn update for Richter syndrome - new directions and developments . Br J Haematol \n2017 ;178 :508–20 .28439883 \n[5] Omoti CE Omoti AE \nRichter syndrome: a review of clinical, ocular, neurological and other manifestations . Br J Haematol \n2008 ;142 :709–16 .18492119 \n[6] Mahe B Moreau P Bonnemain B \nIsolated Richter's syndrome of the brain: two recent cases . Nouv Rev Fr Hematol \n1994 ;36 :383–5 .7892133 \n[7] Resende LS Bacchi CE Resende LA \nIsolated Richter's syndrome in central nervous system: case report . Arq Neuropsiquiatr \n2005 ;63 :530–1 .16059612 \n[8] Bayliss KM Kueck BD Hanson CA \nRichter's syndrome presenting as primary central nervous system lymphoma. Transformation of an identical clone . Am J Clin Pathol \n1990 ;93 :117–23 .2294692 \n[9] Agard G Hamidou M Leautez S \nNeuro-meningeal location of Richter syndrome . Rev Med Interne \n1999 ;20 :64–7 .10220822 \n[10] Bagic A Lupu VD Kessler CM \nIsolated Richter's transformation of the brain . J Neurooncol \n2007 ;83 :325–8 .17570037 \n[11] Robak T Gora-Tybor J Tybor K \nRichter's syndrome in the brain first manifested as an ischaemic stroke . Leuk Lymphoma \n2004 ;45 :1261–7 .15360010 \n[12] Floisand Y Delabie J Fossa A \nRichter syndrome presenting as a solitary cerebellar tumor during first-line treatment for chronic lymphocytic leukemia . Leuk Lymphoma \n2011 ;52 :2007–9 .21663503 \n[13] Stuplich M Mayer K Kim Y \nRichter syndrome and brain involvement: low-grade lymphoma relapsing as cerebral high-grade lymphoma . Acta Haematol \n2012 ;127 :93–5 .22156510 \n[14] Ishida F Nakazawa H Takezawa Y \nRichter transformation in the brain from chronic lymphocytic leukemia . J Clin Exp Hematop \n2013 ;53 :157–60 .23995113 \n[15] Jain P Benjamini O Pei L \nCentral nervous system Richter's transformation and parvovirus B19 infection . Leuk Lymphoma \n2013 ;54 :2070–2 .23320889 \n[16] Schmid C Diem H Herrmann K \nUnusual sites of malignancies: CASE 2. Central neurogenic hyperventilation as a complication of Richter's syndrome . J Clin Oncol \n2005 ;23 :2096–8 .15774798 \n[17] Ghofrani M Tantiwongkosi B Smith AS \nRichter transformation of chronic lymphocytic leukemia presenting as a dural-based non-hodgkin lymphoma mass . AJNR Am J Neuroradiol \n2007 ;28 :318–20 .17297005 \n[18] Parikh SA Rabe KG Call TG \nDiffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukemia (CLL): a cohort study of newly diagnosed patients . Br J Haematol \n2013 ;162 :774–82 .23841899 \n[19] Catovsky D Richards S Matutes E \nAssessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial . Lancet \n2007 ;370 :230–9 .17658394 \n[20] Solh M Rai KR Peterson BL \nThe impact of initial fludarabine therapy on transformation to Richter syndrome or prolymphocytic leukemia in patients with chronic lymphocytic leukemia: analysis of an intergroup trial (CALGB 9011) . Leuk Lymphoma \n2013 ;54 :252–4 .22897733 \n[21] Rossi D \nRichter's syndrome: novel and promising therapeutic alternatives . Best Pract Res Clin Haematol \n2016 ;29 :30–9 .27742070 \n[22] Condoluci A Rossi D \nTreatment of Richter's syndrome . Curr Treat Options Oncol \n2017 ;18 :1–4 .28110381 \n[23] Bruzzi JF Macapinlac H Tsimberidou AM \nDetection of Richter's transformation of chronic lymphocytic leukemia by PET/CT . J Nucl Med \n2006 ;47 :1267–73 .16883004 \n[24] Papajik T Myslivecek M Urbanova R \n2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography examination in patients with chronic lymphocytic leukemia may reveal Richter transformation . Leuk Lymphoma \n2014 ;55 :314–9 .23656196 \n[25] Mao Z Quintanilla-Martinez L Raffeld M \nIgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution . Am J Surg Pathol \n2007 ;31 :1605–14 .17895764 \n[26] Rossi D Spina V Deambrogi C \nThe genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation . Blood \n2011 ;117 :3391–401 .21266718 \n[27] Tsimberidou AM O’Brien S Khouri I \nClinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation . J Clin Oncol \n2006 ;24 :2343–51 .16710033 \n[28] Tsimberidou AM Keating MJ \nRichter's transformation in chronic lymphocytic leukemia . Semin Oncol \n2006 ;33 :250–6 .16616072 \n[29] Cwynarski K van Biezen A de Wreede L \nAutologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia (Richter's syndrome): a retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European Group for Blood and Marrow Transplantation . J Clin Oncol \n2012 ;30 :2211–7 .22547610\n\n",
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"title": "Richter's syndrome of the central nervous system diagnosed concurrently with chronic lymphocytic leukaemia: A case report and literature review.",
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"abstract": "Quantify the effect of prenatal polysubstance exposure on neonatal outcomes compared to methadone exposure alone.\n\n\n\nThis retrospective cohort study compared infants with methadone-only exposure to methadone with additional psychoactive substances. Outcomes included time to maximum Finnegan scores, proportion requiring scheduled morphine, and length of stay (LOS).\n\n\n\nWe identified 323 subjects. The median time to maximum Finnegan score was 38.0 h with 94% peaking within 96 h. Forty-five percent of methadone-only infants were started on scheduled morphine compared to 54% of polysubstance infants (p = 0.10). LOS for polysubstance-exposed infants was 1.30 times longer than infants with methadone-only exposure (95% confidence interval: 1.05, 1.60).\n\n\n\nExposure to methadone with additional psychoactive substances is associated with longer LOS, but not postnatal morphine use or peak withdrawal symptoms. Most infants experience peak withdrawal symptoms within 4 days and may not benefit from longer observation.",
"affiliations": "Department of Pediatrics, University of Washington, Seattle, WA, USA. corrie.mcdaniel@seattlechildrens.org.;Department of Pediatrics, University of Washington, Seattle, WA, USA.;Department of Pediatrics, University of Washington, Seattle, WA, USA.;Department of Pediatrics, University of Washington, Seattle, WA, USA.;Department of Internal Medicine, Providence St. Vincent Hospital, Portland, OR, USA.;Seattle Children's Research Institute, Seattle, WA, USA.",
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"abstract": "BACKGROUND\nCrohn's disease is a chronic inflammatory bowel disease of unknown etiology which may affect any part of the bowel. Fistulas are a common and often serious complication of Crohn's disease. The treatment for fistulizing Crohn's disease can be medical, surgical or a combination of the two. Recently, adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, has been suggested as a safe and effective treatment for the induction and maintenance of remission in adult patients with moderate to severe Crohn's disease, who are refractory to conventional therapy or intolerant to infliximab. However, large studies focusing on evaluating the efficacy of adalimumab in fistulizing Crohn's disease have not yet been published.\n\n\nMETHODS\nWe report the cases of three patients, of European Caucasian ethnicity and Greek nationality, with active luminal and fistulizing Crohn's disease. All of the cases were treated successfully with adalimumab. Patient 1 (a 44-year-old man) and patient 2 (an 18-year-old woman) developed early post-surgical enterocutaneous fistulas, while patient 3 (a 20-year-old woman) had peri-anal fistulizing Crohn's disease. Adalimumab treatment (160 mg subcutaneously at week zero, 80 mg at week two, and 40 mg every other week) was used for three different indications: (1) after the failure of other conservative medical treatments for Crohn's disease (patient 1); (2) as a monotherapy in treating a naive patient (patient 2); (3) after an intolerance to infliximab (patient 3). A remission of the active luminal and fistulizing disease was achieved soon after the initiation of adalimumab and sustained thereafter with maintenance doses. No further surgical intervention was required and no adverse effects were observed in any of the cases.\n\n\nCONCLUSIONS\nFistulizing Crohn's disease remains a challenge in clinical practice. Adalimumab seems to be an effective, well-tolerated and safe treatment option for the induction and maintenance of remission in patients with moderate to severe peri-anal fistulizing Crohn's disease. Furthermore, adalimumab seems to be a promising treatment option for patients with moderate to severe fistulizing Crohn's disease with enterocutaneous fistulas. However, this clinical observation needs to be investigated in further clinical trials.",
"affiliations": "1st Surgical Department, Medical School, Democritus University of Thrace, University Hospital of Alexandroupolis, University Campus, Dragana 681 00, Alexandroupolis, Greece. eeffraem@med.duth.gr.",
"authors": "Kouklakis|George|G|;Efremidou|Eleni I|EI|;Zezos|Peter|P|;Liratzopoulos|Nikolaos|N|;Souftas|Vassilios D|VD|;Gatopoulou|Anthia|A|;Simopoulos|Konstantinos|K|;Manolas|Konstantinos J|KJ|",
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"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-5-1092141858810.1186/1752-1947-5-109Case ReportAdalimumab - an effective and promising treatment for patients with fistulizing Crohn's disease: a case series Kouklakis George 1gkouklak@med.duth.grEfremidou Eleni I 2eeffraem@med.duth.grZezos Peter 1zezosp@hol.grLiratzopoulos Nikolaos 2nliratzop@med.duth.grSouftas Vassilios D 3vsouftas@med.duth.grGatopoulou Anthia 1gatop@otenet.grSimopoulos Konstantinos 4simop@med.duth.grManolas Konstantinos J 2kmanolas@med.duth.gr1 Endoscopy Unit, 1st Surgical Department, Medical School, Democritus University of Thrace, University Hospital of Alexandroupolis, University Campus, Dragana 681 00 Alexandroupolis, Greece2 1st Surgical Department, Medical School, Democritus University of Thrace, University Hospital of Alexandroupolis, University Campus, Dragana 681 00, Alexandroupolis, Greece3 Department of Radiology, Medical School, Democritus University of Thrace, University Hospital of Alexandroupolis, University Campus, Dragana 681 00, Alexandroupolis, Greece4 2nd Surgical Department, Medical School, Democritus University of Thrace, University Hospital of Alexandroupolis, University Campus, Dragana 681 00, Alexandroupolis, Greece2011 19 3 2011 5 109 109 21 10 2009 19 3 2011 Copyright ©2011 Kouklakis et al; licensee BioMed Central Ltd.2011Kouklakis 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.Introduction\nCrohn's disease is a chronic inflammatory bowel disease of unknown etiology which may affect any part of the bowel. Fistulas are a common and often serious complication of Crohn's disease. The treatment for fistulizing Crohn's disease can be medical, surgical or a combination of the two. Recently, adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, has been suggested as a safe and effective treatment for the induction and maintenance of remission in adult patients with moderate to severe Crohn's disease, who are refractory to conventional therapy or intolerant to infliximab. However, large studies focusing on evaluating the efficacy of adalimumab in fistulizing Crohn's disease have not yet been published.\n\nCase presentation\nWe report the cases of three patients, of European Caucasian ethnicity and Greek nationality, with active luminal and fistulizing Crohn's disease. All of the cases were treated successfully with adalimumab. Patient 1 (a 44-year-old man) and patient 2 (an 18-year-old woman) developed early post-surgical enterocutaneous fistulas, while patient 3 (a 20-year-old woman) had peri-anal fistulizing Crohn's disease. Adalimumab treatment (160 mg subcutaneously at week zero, 80 mg at week two, and 40 mg every other week) was used for three different indications: (1) after the failure of other conservative medical treatments for Crohn's disease (patient 1); (2) as a monotherapy in treating a naive patient (patient 2); (3) after an intolerance to infliximab (patient 3). A remission of the active luminal and fistulizing disease was achieved soon after the initiation of adalimumab and sustained thereafter with maintenance doses. No further surgical intervention was required and no adverse effects were observed in any of the cases.\n\nConclusions\nFistulizing Crohn's disease remains a challenge in clinical practice. Adalimumab seems to be an effective, well-tolerated and safe treatment option for the induction and maintenance of remission in patients with moderate to severe peri-anal fistulizing Crohn's disease. Furthermore, adalimumab seems to be a promising treatment option for patients with moderate to severe fistulizing Crohn's disease with enterocutaneous fistulas. However, this clinical observation needs to be investigated in further clinical trials.\n==== Body\nIntroduction\nCrohn's disease (CD) is a granulomatous, segmental, transmural inflammation of unknown etiology, affecting the bowel and predisposing the formation of strictures, perforation, abscesses and fistulas. Fistulas occur in 30 to 50 percent of CD patients during the course of disease. Peri-anal fistulas are the most common type (50 percent), followed by internal enteroenteric fistulas (25 percent) [1].\n\nThe treatment for fistulizing Crohn's disease (FCD) can be medical, surgical or a combination of the two. Various medical therapies, including antibiotics, immunomodulators (azathioprine, 6-mercaptopurine, cyclosporine) and total parenteral nutrition (TPN), have been used to treat FCD and have been effective to some degree. It is well-known that inflammation in CD is associated with high levels of tissue tumor necrosis factor-a (TNF-a) expression, and therapies directed against this cytokine have recently become the focus of interest. Infliximab, a chimeric (75 percent human and 25 percent murine) immunoglobulin G1(IgG1) monoclonal antibody against TNF-a, is the prototype anti-TNF-a agent shown to be efficacious in both the induction and maintenance of fistula closure in approximately two-thirds of patients and has now become the cornerstone of medical therapy for FCD [2]. However, some patients with FCD are refractory or intolerant to this agent. Recently, adalimumab (D2E7/Humira®, Abbott Laboratories), a fully humanized, subcutaneously-delivered immunoglobulin G1(IgG1) monoclonal antibody, which binds with high affinity and specificity to TNF but not to lymphotoxin, has been proven to be a safe and effective treatment for the induction and maintenance of remission in adult patients with moderate to severe CD (luminal and/or fistulizing), who are refractory to conventional therapy or intolerant to infliximab [3-5].\n\nIn the ACCENT II trial, Sands et al. evaluated and proved the efficacy of infliximab as a maintenance therapy for CD patients with fistulas [2]. Although previous studies which evaluated adalimumab included patients with FCD [3-5], there is one study published by Hinojosa et al. that clearly demonstrates the efficacy of adalimumab treatment in patients with luminal and/or FCD [6]. There is also published data about the efficacy of anti-TNF therapy, including adalimumab, in the sub-group of patients with peri-anal FCD [7,8].\n\nIn this case series, we describe our experience with adalimumab in the treatment of three adult patients with FCD that resulted in rapid fistula closure and sustained luminal disease remission.\n\nCase presentation\nWe report the cases of three patients, of European Caucasian ethnicity and Greek nationality, with active luminal and FCD.\n\nPatient 1\nA 44-year-old man with a small bowel obstruction (SBO) underwent a laparotomy which revealed a stenosing, edematous small bowel segment near a former anastomosis. A total of 50 cm of his small bowel was resected. He had previously undergone an extensive surgical resection of the ileum for SBO. Both histologic examinations were suggestive of ischemic enteritis.\n\nOne week later, post-operative enterocutaneous fistulas (ECF) developed next to the drainage catheters originating from the anastomosis site. We administered TPN and antibiotics (ciprofloxacin 1000 mg/day and metronidazole 1500 mg/day for two weeks). One month later, the fistulas were still active, with draining of fecal-mucopurulent discharge as a byproduct of the fistulas daily upon oral feeding. An endoscopic examination revealed linear, deep ulcers with edematous margins in his ascending colon, cecum, ileocecal valve and terminal ileum. A histologic examination revealed a mild derangement of the enteric crypts architecture, moderate inflammatory focal cryptitis, neutrophilic and eosinophilic infiltration, and glandular abscesses without mucus. The findings were consistent with the diagnosis of CD and treatment with adalimumab subcutaneous injections was initiated (160 mg at week zero, 80 mg at week two, and 40 mg every other week). Drainage from all fistulas was stopped one week after the first dose, while a complete closure of the fistulas was achieved at week six and complete remission of the mucosal lesions was observed in an endoscopy after 14 weeks of treatment. He is currently in remission. This is maintained with adalimumab monotherapy at 40 mg subcutaneously every other week, without any adverse effects.\n\nPatient 2\nAn 18-year-old woman presenting with fever (38.2°C) and localized right lower quadrant pain underwent surgery for acute appendicitis. During a laparotomy, severe inflammation of her cecum and terminal ileum was observed, but only an appendicectomy was performed. Ten days later, a post-operative fistula developed at the surgical wound with a fecal-purulent discharge. A colonoscopy revealed linear ulcers in her ileum and ascending colon. A histologic examination revealed focal ulceration of the surface epithelium, derangement of the architecture of enteric crypts, severe cryptitis, and a moderate inflammatory infiltration of the lamina propria with neutrophil leucocytes, lymphocytes, plasma cells and eosinophils and epithelioid granulomas. She was treated with adalimumab monotherapy at a dosage of 160 mg at week zero, 80 mg at week two, and 40 mg every other week. Two weeks after the third injection, (in the sixth week of treatment) the fistula was completely healed, while an endoscopy showed healing of the gastrointestinal ulcers and luminal disease remission. She is currently undergoing maintenance treatment with adalimumab at 40 mg every other week.\n\nPatient 3\nA 20-year-old woman was referred to our endoscopy unit with five peri-anal fistulizing ducts which had developed during a two-year course of fever and bloody diarrhea. A colonoscopy revealed linear ulcers in her terminal ileum, cecum and ascending colon. A histologic examination of the biopsy samples showed mucosal surface erosions and dense inflammatory cellular infiltrations of lymphocytes, plasma cells, eosinophils and neutrophil leucocytes in the lamina propria extending to the muscularis mucosa and crypt abscesses. A diagnosis of CD was confirmed with a Crohn's Disease Activity Index (CDAI) score of 320 and a Peri-anal Disease Activity Index (PDAI) score of 14. An examination under anesthesia revealed complex peri-anal disease and non-cutting drainage setons were inserted in the fistula tracks. Consequently, she was treated with mesalamine (3.2 g/d), oral prednisolone (1 mg/kg) with a tapering schedule, metronidazole (1500 mg/d for 10 days) and ciprofloxacin (1000 mg/d for one month). Three months later, there had been no significant improvement and she continued to require high doses of prednisolone (20 mg/d). A steroid-sparing treatment with azathioprine (100 mg/day) and later with methotrexate (15 mg/wk) failed because of serious drug-induced adverse effects; she developed pancreatitis after six weeks of azathioprine and hepatitis after three weeks of methotrexate. Finally, infliximab (5 mg/kg at weeks zero, two, and six, and then every eight weeks) was administered and resulted in the closure of two of five draining fistula ducts (PDAI score: 7). Unfortunately, during the sixth injection (in the 30th week of treatment), she developed severe acute laryngismus with hoarseness, dyspnea, cyanosis and tachycardia. The infliximab treatment was discontinued. Four weeks later, an endoscopic evaluation showed a recurrence of active luminal CD, while the peri-anal disease had not deteriorated (PDAI score: 7). Treatment with per-oral prednisolone (1 mg/kg) was administered in combination with adalimumab subcutaneous injections at a dosage of 160 mg at week zero, 80 mg at week two and 40 mg every other week. This combination of treatment resulted in a complete closure of the fistulas after seven weeks (PDAI score: 0) and complete remission of luminal CD (CDAI score: 132). Subsequently, the corticosteroids were discontinued while adalimumab was continued as a maintenance treatment at a dose of 40 mg every other week. She has experienced complete fistula closure for the last 18 months without any adverse effects.\n\nDiscussion\nOur case report describes the cases of three patients with both active luminal and FCD who were treated successfully with adalimumab (Table 1). Patient 3, had severe peri-anal FCD, while patients 1 and 2 developed post-operative ECF. In the latter two cases, the development of fistulas was the reason for further endoscopic investigation and the final diagnosis of CD.\n\nTable 1 Demographic and clinical details of patients treated with adalimumab\n\nNumber\tCase\tLuminal + FCD\tFistula type\tPrevious failed and/or intolerant therapies\tCurrent treatment\tAdverse effects\tTreatment outcome\t\n1\t44, M ileo-colonic CD\tYes\tEnterocutaneous, post-operative\tParenteral nutrition Antibiotics - ciprofloxacine and metronidazole\tAdalimumab monotherapy [160-80-40]\tno\tLuminal disease remission Fistula healing\t\n3\t20, F ileo-colonic CD peri-anal disease\tYes\tPeri-anal\tCorticosteroid resistant Antibiotics - ciprofloxacine and metronidazole Azathioprine (fever and pancreatitis) Methotrexate (hepatitis) Reaction to infliximab (laryngismus)\tCorticosteroids (tapered off) plus Adalimumab [160-80-40] Seton drainage\tno\tLuminal disease remission Fistula healing\t\n2\t18, F ileo-colonic CD\tYes\tEnterocutaneous, post-operative\tNo\tAdalimumab monotherapy [160-80-40]\tno\tLuminal disease remission Fistula healing\t\nCD: Crohn's disease; M: male; F: female\n\nIn patients 1 and 2, adalimumab treatment was used for three different indications: (1) the failure of other conservative medical treatments for CD (patient 1); as monotherapy in treating a naive patient (patient 2); following an intolerance to infliximab (patient 3). Treatment with adalimumab was proven to be efficacious and safe in all of the three cases.\n\nRemission of active luminal and fistulizing disease was achieved soon after the initiation of adalimumab and sustained thereafter with maintenance doses of adalimumab. No further surgical intervention was necessary and no adverse effects were observed in any of the cases.\n\nThe treatment of fistulas, which complicate CD in up to 40 percent of cases, has greatly evolved in the last 15 years, mainly because of improvements in medical therapy including immunomodulators (azathioprine, methotrexate) and biologics (infliximab, adalimumab) [7,8]. The advent of immunomodulators and, later, anti-TNF-a agents has positioned conservative medical therapy as the first-line treatment for CD fistulas, with surgery reserved for refractory or complicated cases. Several published studies show that TNF-a antagonists (anti-TNF-a) are effective in inducing and maintaining disease remission in patients with CD. Infliximab has been shown to be effective for the treatment of FCD in adult patients with peri-anal fistulas. Infliximab has even been shown to sustain a response in patients who had an initial clinical response with fistulas closure to induction therapy [7,8].\n\nThe ACCENT II trial assessed the efficacy of infliximab maintenance therapy in adult patients with CD who had at least one draining abdominal or peri-anal fistula over a period of at least three months [2]. All patients received an induction dose of 5 mg/kg in weeks zero, two, and six and afterwards they were randomized to either a placebo or infliximab maintenance therapy (5 mg/kg every eight weeks) for a total of 54 weeks. The data indicated that a maintenance treatment with infliximab was superior to the placebo in patients who responded to infliximab induction therapy at weeks zero, two and six. At week 54, 19 percent of patients receiving the placebo had complete fistula closure compared with 36 percent of patients in the infliximab maintenance group (p = 0.009). More recently, adalimumab, another TNF-a antagonist, has been approved in the US and EU for the treatment of CD. Clinical trials have demonstrated that adalimumab is both effective for the induction and maintenance of remission in patients with moderate to severe CD, and safe and efficacious in regaining a medical response in patients intolerant or non-responsive to infliximab [3-5,7,8].\n\nIn the CHARM trial, the primary objective was to assess the benefit of two adalimumab dosing regimens - 40 mg every other week and weekly - in maintaining clinical remission at 26 and 56 weeks in patients with moderate to severe CD. Overall efficacy in fistula closure was also assessed, with significant effects of adalimumab on fistula closure observed at 26 and 56 weeks. Complete fistula closure was observed more frequently among patients treated with adalimumab than those who were receiving a placebo: 30 percent and 13 percent, respectively, at week 26 (p = 0.043) and 33 percent and 13 percent, respectively, at week 56 (p = 0.016). At week 56, fistula closure was maintained in 100 percent of patients who had complete fistula closure at week 26 [4,8].\n\nHinojosa et al. also evaluated adalimumab in a sub-set of 22 patients with FCD who lost response to or could not tolerate infliximab. After adalimumab induction therapy with 160 mg at week zero and 80 mg at week two, 23 percent of patients experienced fistula remission and 41 percent experienced fistula improvement at week four [6]. In addition, adalimumab has been reported as an effective and safe treatment in a pediatric CD patient with severe refractory luminal and fistulizing disease [9].\n\nRecently-reported data from an extension of the CHARM trial includes a description and analysis of the demographics, disease characteristics and outcome in the sub-group of patients with fistulas treated with adalimumab, along with an evaluation of the two-year maintenance of fistula closure during treatment with adalimumab (ADHERE trial) [7]. This analysis has shown that adalimumab therapy was associated with progressive increases in fistula closure over time, with statistically significant differences between the placebo and adalimumab groups (p < 0,05) which were first observed at 16 weeks (15 percent in the placebo group versus 36 percent in the adalimumab group) [7]. For all randomly-assigned patients, there was a significant decrease in the mean number of draining fistulas per day among patients treated with adalimumab by comparison with patients treated with a placebo during the double-blind treatment period (0,88 for the adalimumab group versus 1,34 for the placebo group; p = 0,002). Approximately 60 percent of the patients with FCD who were treated with adalimumab had healed fistulas after two years of therapy, while 90 percent of patients with healed fistulas at the end of the CHARM trial maintained closure following one additional year of treatment in the ADHERE trial [7]. The effect of adalimumab on the number of draining fistulas in each sub-group (based on immunosuppressants, antibiotics or previous TNF antagonists experience) was similar to that observed for the placebo and adalimumab groups [7]. This recent data shows that adalimumab therapy for FCD resulted in a significant and complete healing of draining fistulas, with a safety profile consistent with previous studies on patients with active CD [8].\n\nAdalimumab is also a well-tolerated treatment for CD in patients who are infliximab naive and for those who do not respond to or are intolerant of infliximab [4,5,7]. In patients treated with adalimumab, reactions at the injection site are the most common adverse effects, while large series show low rates of serious adverse effects similar to a placebo [4,5,7,8]. Adalimumab also offers the benefits of decreased immunogenicity and the ease of subcutaneous administration. Data from the CLASSIC II trial demonstrated that the percentage of patients developing antibodies to adalimumab was low (2.6 percent) [5].\n\nIn the case of patient 3, adalimumab therapy resulted in complete disease remission and the closure of peri-anal fistulas. This fistula healing was maintained for 18 months without adverse effects.\n\nAlthough adalimumab has been evaluated for its efficacy in the healing of peri-anal fistulas in active CD, there is, as yet, no published data on the use of adalimumab in patients with ECF. In general, patients with inflammatory bowel disease represent a high-risk group for the formation of ECF, as a result of both the process of their disease and the need for multiple surgeries [10-12].\n\nECF are one of the most complex and challenging complications encountered in surgical practice. The majority of them (75 to 85 percent) are post-operative in origin, while spontaneous fistulas account for 15 to 25 percent of all ECF [12-14]. Due to several advances in medical treatment, the rates of spontaneous fistula closure have improved significantly, while mortality remains high, ranging between 5 and 25 percent [15].\n\nThe current management of ECF includes controlling sepsis, optimization of the nutritional state, wound care, assessment of the fistula anatomy, and the timing of surgery and surgical strategy (the SOWATS guideline), with priority given to sepsis treatment and restoration of the nutritional state [12-15]. Independent variables examined in reported studies, which are essential in promoting the spontaneous closure of ECF, include control of malnutrition, hydroelectrolytic imbalance, serum albumin and elimination of sepsis [14]. In addition, it is generally recommended that patients do not undergo restorative surgery in the three to six month period after the development of ECF [12-15]. Earlier studies also report that the spontaneous closure of ECF is less common in fistulas caused by malignancy or CD and is predominantly seen in colonic ECF, in low-output ECF and in patients with a closed abdomen [13,14]. Moreover, the probability and timing of a spontaneous closure of post-operative ECF is related to the location of the fistula, the site of origin, the output during 24 hours, the type of post-operative ECF and the fistulous tract. Overall, small bowel post-operative ECF have a lower chance of spontaneous closure (~30 percent) compared to colonic fistulas (~85 percent), while jejunal fistulas have a higher rate (~40 percent) compared to ileal fistulas (~25 percent). Multiple post-operative ECF, and those with a complex fistulous tract and high output (>500 ml/24 hours), have a low rate of spontaneous closure (3 and 2,5 times higher versus single and low-output post-operative ECF, respectively). Due to these multiple variables, the rates of spontaneous closure of post-operative ECF vary (17 to 71 percent) (Table 2) [12-14].\n\nTable 2 Treatment management of ECF and outcomes\n\nTreatment\tECF outcome\t\nSOWATS treatment guideline (medical + surgical treatment)\tMortality: 10-30%\nFistula closure: ~87,4%\t\n\t\nMedical treatment\nAlimentary tract rest\nRestoration of circulating volume\nRestoration of hydroelectrolytic balance\nNutritional support (optimal TPN)\n(fistula closure rate: 89-92,3%)\nControlling sepsis\nWound care\tMortality: 5-25%\nSpontaneous closure: 17-71%\t\n\t\nRestorative surgery\nMinimal period: >6 weeks\tMortality: 9,6%-10,8%\n(sepsis-related death: ~15,1%)\nSurgical closure: 52-90,7%\nPersisting fistula: 3-50%\t\nDefinitive surgery\nMinimal period: >6 months\n(median period: 8 months)\t\t\n\t\nSmall bowel ECF\tMortality: ~35%\nSpontaneous closure: ~30%\t\n\t\nColonic ECF\tMortality: ~22%\nSpontaneous closure: ~85%\t\nReferences: [12-15]\n\nIn our case report, we describe the cases of two patients who developed post-operative ECF refractory to classical management with TPN, antibiotics, octreotide and wound care. The sites of origin were the small bowel (patient 1) and the cecum (patient 2) and there were simple fistulous tracts in both cases. Further investigation led to a diagnosis of active CD and treatment with a TNF-a antagonist was initiated. Both patients received adalimumab. We achieved a remission of the disease and a complete spontaneous closure of the post-operative ECF in both cases.\n\nConclusions\nThe results from a meta-analysis by Peyrin-Biroulet et al. demonstrate that anti-TNF therapy is safe and effective for both luminal and FCD, in patients who are refractory to standard medical therapy. Due to the small sample size of these drugs, it was not possible to perform a sub-group analysis or a direct comparison between anti-TNF agents, however, in an overall analysis, anti-TNF therapy was more effective than a placebo for fistula healing in FCD. The above, more detailed, analysis elevated the results from the ACCENT II study on the safety and efficacy of infliximab in inducing and maintaining fistula closure [8]. The CHARM trial, and more recently the study by Colombel et al. regarding the ADHERE study, showed that adalimumab therapy results in the significant and complete healing of draining fistulas in active FCD. Furthermore, the long-term healing of draining fistulas was maintained over two years from the baseline of the CHARM study, while in the fistula cohort there were no differences in the rate of adverse effects in patients who received adalimumab compared to those who received a placebo [7].\n\nThe presence of active inflammation as a result of CD, following on from or without surgery, predisposes to fistulation. An early diagnosis of ECF, the resuscitation of the patient, the provision of nutritional support and the control of sepsis have decreased morbidity and mortality rates and often result in a spontaneous closure of fistulas. Definitive surgical management should be performed only after the restitution of normal physiology and nutritional improvement; usually after at least six months, but often over a longer period [12-15].\n\nOur goal in this case report was to audit the results of adalimumab therapy in patients with moderate to severe FCD. Although our case series cannot safely propose a treatment approach, our secondary aim was to report on both the spontaneous closure of post-operative ECF with adalimumab therapy in patients with severe active CD, and adalimumab as a monotherapy treatment for the long-term maintenance of both a remission of CD and the healing of fistulas. Our main message is that the combination of adalimumab therapy and a standardized management protocol for ECF can result in a good patient outcome in cases of FCD. Nevertheless, larger studies focusing on the evaluation of adalimumab treatment in patients with FCD, especially patients who develop spontaneous or post-operative ECF, are needed to expand on the present experience of treatment in this sub-population of CD.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nGK conceived of the study and participated in its design and coordination. EIE participated in the design of the study, the acquisition and interpretation of the data and the drafting of the manuscript. PZ participated in the sequence alignment and the drafting of the manuscript. NL participated in the design of the study and the coordination and helped to revise the manuscript. VDS participated in the coordination and acquisition of data. AG participated in the sequence alignment and interpretation of data. KS revised the manuscript for the intellectual content and gave final approval of the version to be published. KJM participated in the conception of the study, revised the manuscript for the intellectual content and gave final approval of the version to be published. All authors read and approved the final manuscript.\n==== Refs\nSchwartz DA Loftus EV JrTremaine WJ Panaccione R Harmsen WS Zinsmeister AR Sandborn WJ The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota Gastroenterology 2002 122 4 875 880 10.1053/gast.2002.32362 11910338 \nSands BE Anderson FH Bernstein CN Chey WY Feagan BG Fedorak RN Kamm MA Korzenik JR Lashner BA Onken JE Rachmilewitz D Rutgeerts P Wild G Wolf DC Marsters PA Travers SB Blank MA van Deventer SJ Infliximab maintenance therapy for fistulizing Crohn's disease N Engl J Med 2004 350 876 885 10.1056/NEJMoa030815 14985485 \nHanauer SB Sandborn WJ Rutgeerts P Fedorak RN Lukas M MacIntosh D Panaccione R Wolf D Pollack P Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial Gastroenterology 2006 130 323 333 10.1053/j.gastro.2005.11.030 16472588 \nColombel JF Sandborn WJ Rutgeerts P Enns R Hanauer SB Panaccione R Schreiber S Byczkowski D Li J Kent JD Pollack PF Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial Gastroenterology 2007 132 52 65 10.1053/j.gastro.2006.11.041 17241859 \nSandborn WJ Hanauer SB Rutgeerts P Fedorak RN Lukas M MacIntosh DG Panaccione R Wolf D Kent JD Bittle B Li J Pollack PF Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial Gut 2007 56 1232 1239 10.1136/gut.2006.106781 17299059 \nHinojosa J Gomollón F García S Bastida G Cabriada JL Saro C Ceballos D Peñate M Gassull MA Spanish Scientific Group on Crohn's Disease and Ulcerative Colitis Efficacy and safety of short-term adalimumab treatment in patients with active Crohn's disease who lost response or showed intolerance to infliximab: a prospective, open-label, multicentre trial Aliment Pharmacol Ther 2007 25 409 418 10.1111/j.1365-2036.2006.03232.x 17269996 \nColombel JF Schwartz DA Sandborn WJ Kamm MA D'Haens G Rutgeerts P Enns R Panaccione R Schreiber S Li J Kent JD Lomax KG Pollack PF Adalimumab for the treatment of fistulas in patients with Crohn's disease Gut 2009 58 940 948 10.1136/gut.2008.159251 19201775 \nPeyrin-Biroulet L Deltenre P de Suray N Branche J Sandborn WJ Colombel JF Efficacy and safety of tumor necrosis factor antagonists in crohn's disease: meta-analysis of placebo-controlled trials Clin Gastroenterol Hepatol 2008 6 644 653 10.1016/j.cgh.2008.03.014 18550004 \nHadziselimovic F Adalimumab induces and maintains remission in severe, resistant paediatric Crohn disease J Pediatr Gastroenterol Nutr 2008 46 208 211 10.1097/MPG.0b013e318124504b 18223382 \nTaner T Cima RR Larson DW Dozois EJ Pemberton JH Wolff BG Surgical treatment of complex enterocutaneous fistulas in IBD patients using human acellular dermal matrix Inflamm Bowel Dis 2009 15 8 1208 1212 10.1002/ibd.20882 19170192 \nGarcia-Olmo D Herreros D Pascual M Pascual I De-La-Quintana P Trebol J Garcia-Arranz M Treatment of enterocutaneous fistula in Crohn's Disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion Int J Colorectal Dis 2009 24 1 27 30 10.1007/s00384-008-0559-0 18696086 \nEvenson AR Fischer JE Current management of enterocutaneous fistula J Gastrointest Surg 2006 10 3 455 464 10.1016/j.gassur.2005.08.001 16504896 \nMartinez JL Luque-Leon E Mier J Blanco-Benavides R Robledo F Systematic management of postoperative enterocutaneous fistulas: factors related to outcomes World J Surg 2008 32 436 443 10.1007/s00268-007-9304-z 18057983 \nVisschers RG Olde Damink SW Winkens B Soeters PB Van Gemert WG Treatment strategies in 135 consecutive patients with enterocutaneous fistulas World J Surg 2008 32 445 453 10.1007/s00268-007-9371-1 18175171 \nHollington P Mawdsley J Lim W Gabe SM Forbes A Windsor AJ An 11-year experience of enterocutaneous fistula Br J Surg 2004 91 1646 1651 10.1002/bjs.4788 15505866\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "5()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "109",
"pmc": null,
"pmid": "21418588",
"pubdate": "2011-03-19",
"publication_types": "D016428:Journal Article",
"references": "11910338;16504896;17269996;18696086;19201775;16472588;18223382;17299059;18175171;14985485;18550004;18057983;17241859;19170192;15505866",
"title": "Adalimumab - an effective and promising treatment for patients with fistulizing Crohn's disease: a case series.",
"title_normalized": "adalimumab an effective and promising treatment for patients with fistulizing crohn s disease a case series"
} | [
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"companynumb": "GR-JNJFOC-20110405407",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "INFLIXIMAB"
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{
"abstract": "A 51-year-old woman with rheumatoid arthritis presented with mild hypertension 20 months after tacrolimus treatment and developing proteinuria 24 months after the treatment. Tacrolimus was discontinued 27 months after the treatment, followed by heavy proteinuria, accelerated hypertension, and deteriorating renal function without ocular fundus lesions as a clinical sign of malignant hypertension. Renal biopsy revealed malignant nephrosclerosis characterized by subacute and chronic thrombotic microangiopathy (TMA), involving small arteries, arterioles, and glomeruli. Focal segmental glomerulosclerosis, probably secondary to chronic TMA, was identified as a cause of heavy proteinuria. The zonal tubulointerstitial injury caused by subacute TMA may have mainly contributed to deteriorating renal function. The presence of nodular hyalinosis in arteriolar walls was indicative of tacrolimus-associated nephrotoxicity. Together with other antihypertensive drugs, administration of aliskiren stabilized renal function with reducing proteinuria. Owing to the preexisting proteinuria prior to severe hypertension and the complex renal histopathology, we postulated that chronic TMA, which was initially triggered by tacrolimus, was aggravated by severe hypertension, resulting in overt renal TMA.",
"affiliations": "Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Pathology, Teikyo University Hospital, Itabashi-ku, Tokyo, Japan.;Department of Diagnostic Pathology, Nippon Medical School Musashikosugi Hospital, Kawasaki, Kanagawa, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.;Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.",
"authors": "Honma|Fumika|F|;Fujigaki|Yoshihide|Y|0000-0003-2803-9161;Nemoto|Yoshikazu|Y|;Kikuchi|Hirotoshi|H|;Nagura|Michito|M|;Arai|Shigeyuki|S|;Ishizawa|Kenichi|K|;Yamazaki|Osamu|O|0000-0002-4251-403X;Tamura|Yoshifuru|Y|0000-0003-0486-3965;Kondo|Fukuo|F|;Ohashi|Ryuji|R|0000-0001-7053-038X;Uchida|Shunya|S|;Shibata|Shigeru|S|0000-0002-6868-0626",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2019/3923190",
"fulltext": "\n==== Front\nCase Rep NephrolCase Rep NephrolCRINCase Reports in Nephrology2090-66412090-665XHindawi 10.1155/2019/3923190Case ReportA Case of Rheumatoid Arthritis Presenting with Renal Thrombotic Microangiopathy Probably due to a Combination of Chronic Tacrolimus Arteriolopathy and Severe Hypertension Honma Fumika \n1\nhttp://orcid.org/0000-0003-2803-9161Fujigaki Yoshihide fujigaki@med.teikyo-u.ac.jp\n1\nNemoto Yoshikazu \n1\nKikuchi Hirotoshi \n1\nNagura Michito \n1\nArai Shigeyuki \n1\nIshizawa Kenichi \n1\nhttp://orcid.org/0000-0002-4251-403XYamazaki Osamu \n1\nhttp://orcid.org/0000-0003-0486-3965Tamura Yoshifuru \n1\nKondo Fukuo \n2\nhttp://orcid.org/0000-0001-7053-038XOhashi Ryuji \n3\nUchida Shunya \n1\nhttp://orcid.org/0000-0002-6868-0626Shibata Shigeru \n1\n\n1Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan\n2Department of Pathology, Teikyo University Hospital, Itabashi-ku, Tokyo, Japan\n3Department of Diagnostic Pathology, Nippon Medical School Musashikosugi Hospital, Kawasaki, Kanagawa, JapanAcademic Editor: Rumeyza Kazancioglu\n\n2019 6 3 2019 2019 392319022 12 2018 18 2 2019 Copyright © 2019 Fumika Honma 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.A 51-year-old woman with rheumatoid arthritis presented with mild hypertension 20 months after tacrolimus treatment and developing proteinuria 24 months after the treatment. Tacrolimus was discontinued 27 months after the treatment, followed by heavy proteinuria, accelerated hypertension, and deteriorating renal function without ocular fundus lesions as a clinical sign of malignant hypertension. Renal biopsy revealed malignant nephrosclerosis characterized by subacute and chronic thrombotic microangiopathy (TMA), involving small arteries, arterioles, and glomeruli. Focal segmental glomerulosclerosis, probably secondary to chronic TMA, was identified as a cause of heavy proteinuria. The zonal tubulointerstitial injury caused by subacute TMA may have mainly contributed to deteriorating renal function. The presence of nodular hyalinosis in arteriolar walls was indicative of tacrolimus-associated nephrotoxicity. Together with other antihypertensive drugs, administration of aliskiren stabilized renal function with reducing proteinuria. Owing to the preexisting proteinuria prior to severe hypertension and the complex renal histopathology, we postulated that chronic TMA, which was initially triggered by tacrolimus, was aggravated by severe hypertension, resulting in overt renal TMA.\n==== Body\n1. Introduction\nThrombotic microangiopathy (TMA) is a pathologic term where vascular and glomerular lesions due to endothelial damage and vascular occlusion can be observed and is characterized by a clinical presentation with thrombocytopenia, hemolytic anemia, and organ injuries, including acute kidney injury (AKI) [1]. However, localized renal TMA without systemic manifestation of TMA exists and can be diagnosed only by renal biopsy.\n\nSevere hypertension can induce TMA within the renal vasculature typically associated with fibrinoid necrosis of arterioles and the glomerular capillary tufts [2]. The exact mechanism remains to be established, but TMA may occur when vascular autoregulation cannot accommodate the severe hypertension-induced shear stress. Severe hypertension-induced TMA showed a low incidence of thrombocytopenia and hemolytic anemia [2]. Renal function may improve or stabilize in about 50 to 80% of patients of severe or malignant hypertension with or without biopsy-proven TMA upon adequate blood pressure (BP) control [2, 3].\n\nCalcineurin inhibitor (cyclosporine and tacrolimus)-associated TMA is a rare but well documented cause of AKI [4, 5]. Calcineurin inhibitor-associated TMA is attributed to the endothelial injury secondary to vasoconstriction, which induces ischemia, increases platelet aggregation, and activates prothrombotic factors [6]. Calcineurin inhibitor-associated TMA may often localize to the renal graft in posttransplant patients and show AKI or delayed graft function with few or no systemic manifestations of TMA [6]. Discontinuation or reduced dose of calcineurin inhibitor is the main treatment of calcineurin inhibitor-associated TMA [7].\n\nSevere hypertension may be either a cause of TMA or a manifestation of renal involvement from an underlying TMA. About 20-40% of patients with severe/malignant hypertension presented with TMA and/or microangiopathic hemolysis [3, 8]. Thus, concomitant renal TMA and severe hypertension could raise the differential diagnosis of TMA and lead to a vicious cycle.\n\nHere, we describe a patient of rheumatoid arthritis (RA) with a most recent history of long-term tacrolimus use, who presented with localized renal TMA in association with clinical feature of developing heavy proteinuria and severe hypertension, subsequently deteriorating renal function. We assumed that renal TMA in our case may be caused by a combination of chronic tacrolimus arteriolopathy and subsequent severe hypertension.\n\n2. Case Report\nA 51-year-old Japanese woman was admitted to our hospital for the evaluation of heavy proteinuria, deteriorating renal function, and severe hypertension. She had a medical history of RA at the age of 42 and left vitrectomy for retinal detachment and bilateral femoral head replacement following fracture at the age of 49. Since she had drug allergies to many drugs, various treatments for RA were tried to introduce including methotrexate, infliximab, etanercept, salazosulfapyridine, leflunomide, bucillamine, tacrolimus, abatacept, and/or tocilizumab in addition to prednisolone (PSL) and nonsteroidal anti-inflammatory drugs. She was treated with the dosage of 2 to 3 mg/day of tacrolimus, standard dose for RA in addition to PSL 8 mg/day from the age of 48 for 2 years and 3 months. Clinical course after introduction of tacrolimus is shown in Figure 1. BP was increased from 120/70 mmHg to 140/80 mmHg 20 months after tacrolimus treatment, trough levels of tacrolimus fell within acceptable ranges between 5 and 10 ng/dL during the course. Proteinuria began to increase from the baseline proteinuria of 0.3 to 0.5 g/g creatinine 24 months after tacrolimus treatment, but serum creatinine level was sustained around 0.8 mg/dL. Tacrolimus and tocilizumab were changed to tofacitinib citrate 27 months after tacrolimus treatment because of uncontrolled arthritis of RA. However, tofacitinib citrate was discontinued 2 months after the treatment because of allergic reaction. Proteinuria was further increased after discontinuation of tacrolimus and tocilizumab, and then severe hypertension 190/100 mmHg and progressive renal dysfunction developed. 40 mg telmisartan/5 mg amlodipine besilate combination tablet was introduced 2 months after tacrolimus discontinuation. Her renal function was further deteriorated to creatinine of 2.63 mg/dL; thus she was admitted to our hospital 3 months after tacrolimus discontinuation.\n\nOn admission, body temperature was 36.5°C, height 154.0 cm, weight 44.9 kg, BP 170/102 mmHg, and pulse rate 88/min. Physical examination showed numbness in hands, pain in the elbows, wrists, knees, and metacarpophalangeal (MP) joint of the right thumb finger, swelling of MP joint in the right second finger, and mild pitting edema in bilateral legs but no abdominal bruit. She had no focus of infection and sclerotic skin lesion and no experience of Raynaud's phenomenon. The laboratory data on admission are shown in Table 1. Urinary examination showed heavy proteinuria and microscopic hematuria. Urinary low-molecular-weight proteins and urinary N-acetyl-β-D-glucosaminidase were elevated. Blood examination showed anemia, hypoalbuminemia, renal dysfunction, and hypocalcemia. Immunological examination indicated normocomplementemia, normal tests for anti-DNA antibody, anticardiolipin antibody, and myeloperoxidase and proteinase 3-anti-neutrophil cytoplasmic antibodies, but positive tests for RA-associated factors including rheumatoid factor, matrix metalloproteinase-3, and anti-SS-A antibody. Repeated peripheral smears showed no evidence of hemolysis. Serum renin activity and aldosterone concentration were of high value. Her hypocalcemia could be explained by use of denosumab for the treatment of steroid-induced osteoporosis.\n\nThe electrocardiogram showed voltage criteria of left ventricular hypertrophy. Chest X-ray showed no apparent cardiomegaly and lung edema. Abdominal ultrasound detected normal shape and size in the kidneys and multiple hemangioma in the liver. Echocardiography revealed ejection fraction 56% Simpson method, ratio of E to e' 22.6, and left ventricular wall thickening. Fundoscopy did not show exudate hemorrhage and papilledema.\n\nWith a clinical suspicion of secondary amyloidosis, focal segmental glomerulosclerosis (FSGS), or malignant nephrosclerosis, renal biopsy was performed. A renal biopsy showed 5 glomeruli with adhesive lesions and segmental sclerosis or global sclerosis and 8 glomeruli with ischemic shrinkage of glomerular tufts out of 22 obtained glomeruli (Figures 2(a), 2(b), and 2(c)). Some of the remaining glomeruli showed collapse of capillary tufts (Figures 2(a) and 2(b)), FSGS (Figure 2(a)), and segmental thickening of capillary walls showing double contour (Figure 2(d)). There were extensive tubular atrophy and interstitial edema to fibrosis involving 70% of renal parenchyma, accompanied by chronic and acute inflammatory cell infiltration (Figures 2(a) and 2(b)). Distribution of the tubulointerstitial damage was zonal, indicative of ischemic injury following vascular compromise (Figure 2(b)). The afferent arteriole of the glomerulus was occluded by an organized thrombus, and the arterioles showed concentric intimal hyperplasia forming “onion skin” lesion (Figure 2(c)). Some of the small arterial and arteriolar lumina were markedly narrowed by thickened fibrous intima (Figure 2(e)). Of note, some arteriolar walls exhibited circumferential and transmural nodular hyalinosis (Figures 2(e) and 2(f)). An immunofluorescence study showed nonspecific segmental staining of IgM, C1q, and C3 in glomeruli, and IgA and IgM in tubular casts. Electron microscopy revealed swollen glomerular endothelial cells with loss of fenestrations, irregularly thickened lamina rara interna, and foot process effacement involving 30% of podocytes (Figure 3). No electron dense deposit was identified. Collectively, these histological findings are suggestive of malignant nephrosclerosis and tubulointerstitial damage, represented by subacute/chronic TMA.\n\nSevere hypertension and tacrolimus use were considered to be causes of TMA in our patient. Since tacrolimus had already been withdrawn, we tried to manage blood pressure on an appropriate level. It is reported that hypertension is highly prevalent among patients with RA, and use of anti-inflammatory analgesics and disease-modifying drugs with hypertensive potential, and yet to be determined inflammatory pathways, and genetic factors may synergistically lead to hypertension [9]. Nonsteroidal anti-inflammatory drugs and tofacitinib citrate [10] might have contributed to severe hypertension in our patient. However, it is more likely that her severe hypertension may have been caused by renal parenchymal damage with marked activation of renin-angiotensin-aldosterone system. To control severe hypertension, amlodipine besilate was changed to nifedipine. In addition, methyldopa and also aliskiren to inhibit renin-angiotensin system were introduced, then BP was gradually decreased. After aliskiren was administered, renin activity was reduced from 12 to 0.6 ng/mL/h and aldosterone concentration from 242 to 69.4 pg/mL in one week. Blood pressure and renal function eventually stabilized with gradual reduction of proteinuria. One year after renal biopsy, serum creatinine was 4.03 mg/dL and proteinuria was 1.0 g/g creatinine (Figure 1).\n\n3. Discussion\nCauses of TMA including hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and atypical hemolytic uremic syndrome, which were almost uniformly include thrombocytopenia and hemolytic anemia, were excluded in our patient. Thus, we did not examine ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-1-like domains) activity. As for secondary TMA, she had no clinical evidence of infection. She had no skin lesion, and anti-SCL-70 and anti-centromere antibodies were negative 2 and a half years ago. This may support the fact that scleroderma renal crisis is excluded. Our patient had conditions including RA, tacrolimus use, and severe hypertension which could raise TMA. However, we postulated that renal TMA in our patient was not caused by severe hypertension alone but by a combination of chronic tacrolimus arteriolopathy and severe hypertension. This could be explained as follows.\n\nFirst, our patient had severe hypertension, but the absence of fundus lesion, which did not fulfill the diagnosis of accelerated/malignant hypertension. Renal histology of accelerated/malignant hypertension shows TMA involving intrarenal fibrinoid necrosis of arterioles, containing the necrotic remnants of the smooth muscle cells as well as fibrin and platelet deposits [11]. Another type of lesion is a proliferative endarteritis of medium and small sized arteries and arterioles, containing proliferated smooth muscle cells and myofibroblasts. This lesion is called “onion skin” [11]. Though hyaline thrombus in one arteriole and onion skin in arterioles were observed in our patient, fibrinoid necrosis of renal arterioles, which is often observed in the acute phase of malignant hypertension-associated TMA, was not found. Signs of nephritis due to severe renal ischemia usually appear in parallel with severe hypertension in patients with malignant hypertension [11]. Unlike this clinical manifestation, our patient showed the development of proteinuria before severe hypertension occurred. These facts suggest that renal TMA was not merely caused by severe hypertension, but also by other exacerbating factors in the current case.\n\nSecond, the renal biopsy showed features of chronic TMA, characterized by double contours of glomerular capillary walls, and fibrous thickening of arterial walls with organized or recanalized thrombi, and nodular hyalinosis of arteriolar walls. Given the clinical course of the patient, the presence of these chronic changes cannot be explained by short-term severe hypertension alone. As these chronic lesions can reportedly be induced by calcineurin-associated nephrotoxicity [6, 12], it is probable that the chronic lesions of our case may have appeared as part of tacrolimus-associated TMA. It is reported that chronic calcineurin inhibitor nephrotoxicity is clinically characterized by hypertension, progressive renal insufficiency, and variable degree of proteinuria. Histologically, hyaline arteriolopathy, striped interstitial fibrosis with proportional tubular atrophy, and glomerulosclerosis are often found [12] like the present case. In calcineurin inhibitor-associated TMA among postrenal transplant patients, it is emphasized that TMA is confined to the kidney with little or no systemic evidence of the thromboangiopathic process, underscoring the importance of the graft biopsy in making the diagnosis [6]. Secondary FSGS in our patient could be caused by chronic calcineurin inhibitor nephrotoxicity and/or severe/malignant hypertension [13, 14]. It is noteworthy that normal donor kidneys of kidney-pancreas transplant recipients during tacrolimus based therapy with tacrolimus concentration averaged 7.9 ± 3.9 ng/dL showed chronic arteriolar toxicity in 4.3%, 33.6%, and 77.2% after 1-, 5-, and 10-year treatment, respectively [15]. The authors suggested that cumulative nephrotoxicity from prolonged tacrolimus exposure over years-to-decades remains the best explanation in their cohort. Earlier increasing proteinuria, raising BP, and subsequently deteriorating renal function may rather suspect that TMA lesions were made possibly by a contribution of chronic, smoldering tacrolimus arteriolopathy [16] and severe hypertension. Though nodular hyalinosis is not specific for calcineurin inhibitor nephrotoxicity, it is conceivable that nodular hyalinosis in our patient may indicate chronic tacrolimus nephrotoxicity [17].\n\nLastly, since our patient suffered from RA, secondary TMA associated with RA should be considered. Except for rheumatoid vasculitis only a few cases with RA were reported to be associated with systemic TMA not localized renal TMA [18, 19], all which were thought to be caused by severe deficiency of ADAMTS13 due to autoantibodies that alter its function [20]. Since there were no renal vasculitic lesions, RA-associated TMA was excluded in our patient.\n\nTaken together, since glomerular and tubulointerstitial lesions in our patient were too severe and chronic for her recorded BP to explain the lesions, we postulated that long-term tacrolimus arteriolopathy with smoldering renal TMA caused at least in part secondary FSGS with heavy proteinuria and hypertension [13]. Subsequently, even after discontinuation of tacrolimus, severe hypertension, not malignant hypertension level due to developing renal parenchymal damage further damaged arteriolar endothelium, resulting in overt renal TMA with deteriorating renal function. The zonal tubulointerstitial injury caused by subacute TMA may have mainly contributed to deteriorating renal function. Interestingly JAK3-STAT pathway has been claimed to be a responsible pathway in some forms of glomerulonephritis. Targeting of this pathway has been reported to be effective in the treatment of experimental lupus nephritis [21]. On the other hand disturbances of renal function have been reported with use of tofacitinib, a first-generation JAK inhibitor [22]. Therefore, increase in serum creatinine was also concerned in our patient with RA using tofacitinib; however, recent clinical trial reported that slightly decrease in measured glomerular filtration rate 6 weeks after tofacitinib treatment retuned towards baseline after tofacitinib discontinuation with no significant difference versus placebo [23]. Accordingly, it is conceivable that BP control with renin-angiotensin system inhibition could not ameliorate renal dysfunction due to the preexistence of chronic renal damage but stabilize renal function with reducing proteinuria in our patient.\n\nIn summary, some subsets of patients who receive tacrolimus for a long time may be suffered from heavy proteinuria, severe hypertension associated with progressive deterioration of renal function due to renal TMA even after withdrawal of tacrolimus. Severe hypertension must act as a subsequent aggressor to intensify damage of endothelial cells in small arteries, arterioles, and glomeruli, which had been already injured by tacrolimus arteriolopathy, leading to overt renal TMA. Physician should keep in mind that tacrolimus can insidiously evoke chronic smoldering renal TMA.\n\nAcknowledgments\nWe would like to thank Ms. Hiromi Yamaguchi for her technical assistance.\n\nConsent\nWritten informed consent was obtained from the patient.\n\nDisclosure\nThis article does not contain any studies with human participants performed by any of the authors.\n\nConflicts of Interest\nThe authors have declared that no conflicts of interest exist.\n\nFigure 1 Clinical course of the patient after introduction of tacrolimus treatment. ∗: surgical operation, Cr; creatinine, UP; proteinuria, and BP; blood pressure.\n\nFigure 2 Light micrographs of renal tissues. (a) A glomerulus (asterisk) is mildly enlarged, showing focal segmental glomerulosclerosis while another glomerulus exhibits collapsed capillary tuft (arrowhead). Dilated tubules with flattened epithelial cells containing proteinaceous casts are present (arrow) (periodic acid-Schiff stain; original magnification x200). (b) Several glomeruli have collapsed capillary tufts (arrows). There is an extensive striped pattern of interstitial fibrosis and tubular atrophy (Elastica–Masson staining; original magnification x200). (c) A glomerulus is globally sclerotic (asterisk). There is organized thrombus formation within an afferent arteriolar lumen (arrowhead). Concentric intimal hyperplasia of arterioles forming “onion skin” lesion is noted (arrow) (periodic acid-Schiff stain; original magnification x200). (d) Glomerular capillary wall is segmentally thickened showing double contour (arrow) (periodic acid-Schiff stain; original magnification x400). (e) Arteriolar lumina are occluded by fibrous intimal thickening with recanalization. Nodular hyalinosis of arterial walls is noted (arrow) (periodic acid-Schiff stain; original magnification x400). (f) An arteriolar wall shows circumferential and transmural hyalinosis forming peripheral nodules (periodic acid-Schiff stain; original magnification x400).\n\nFigure 3 Electron micrograph of a glomerulus. Swollen glomerular endothelial cells with loss of fenestrations, irregularity thickened lamina rara interna with small remnants in the subendothelial spaces (arrowheads), and partial foot process effacement are seen. Bar=5.0 μm.\n\nTable 1 Laboratory data on admission.\n\n\nUrinalysis \n\t\n Gravity 1.014\t\n pH 6.0\t\n Protein 3+\t\n Glucose (-)\t\n Occult blood trace\t\n\nSediments \n\t\n Red blood cell 1-4 /high power field\t\n Wight blood cell 10-19 /high power field\t\n\nUrine chemistry \n\t\n Protein 245 mg/dL\t\n Creatinine 60.2 mg/dL\t\n N-acetyl-β-D-glucosaminidase 12.5 U/L\t\n β2-microglobulin 40,066 μg/L\t\n\nComplete blood count \n\t\n WBC 15,000 /μL\t\n Hb 10.6 g/dL\t\n Platelet 36.8×104/μL\t\n\nBlood chemistry \n\t\n Albumin 2.7 g/dL\t\n Lactate dehydrogenase 385 IU/L\t\n Urea nitrogen 46.9 mg/dL\t\n Creatinine 2.86 mg/dL\t\n Uric acid 6.9 mg/dL\t\n Na 139 mEq/L\t\n K 3.4 mEq/L\t\n Cl 103 mEq/L\t\n Ca 6.8 mg/dL\t\n Pi 1.8 mg/dL\t\n Estimated GFR 14.7 ml/min/1.73m2\t\n\nSerology \n\t\n HBs antigen 0.1 C.O.I\t\n HCV antibody 0.1 C.O.I\t\n IgG 621 mg/dL\t\n IgA 251 mg/dL\t\n IgM 152 mg/dL\t\n CH50 60< U/mL\t\n C3 110 mg/dL\t\n C4 30 mg/dL\t\n C-reactive protein 2.87 mg/dL\t\n Rheumatoid factor 24.2 U/mL\t\n MMP-3 413.8 ng/mL\t\n Antinuclear antibody ×160 speckled\t\n Anti-DNA antibody 0.6 IU/mL (<9.0)\t\n Anti-SS-A antibody 89.7 U/ml (<6.0)\t\n MPO-ANCA 1.0 U/mL (<3.4)\t\n PR3-ANCA 1.0 U/mL (<3.4)\t\n Anti-cardiolipin antibody (IgM) <8 U/mL\t\nGFR; glomerular filtration rate, MMP-3; matrix metalloproteinase-3, MPO-ANCA; myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA; proteinase 3-anti-neutrophil cytoplasmic antibody. The values in the parentheses show the normal range.\n==== Refs\n1 Brocklebank V. Wood K. M. Kavanagh D. Thrombotic microangiopathy and the kidney Clinical Journal of the American Society of Nephrology 2018 13 2 300 317 2-s2.0-85041750196 10.2215/CJN.00620117 29042465 \n2 Zhang B. Xing C. Yu X. Sun B. Zhao X. Qian J. Renal thrombotic microangiopathies induced by severe hypertension Hypertension Research 2008 31 3 479 483 2-s2.0-42649105187 10.1291/hypres.31.479 18497467 \n3 Van Den Born B. J. H. Honnebier U. P. F. Koopmans R. P. Van Montfrans G. A. Microangiopathic hemolysis and renal failure in malignant hypertension Hypertension 2005 45 2 246 251 2-s2.0-13144265709 10.1161/01.HYP.0000151620.17905.ee 15596574 \n4 Pham P.-T. T. Peng A. Wilkinson A. H. Cyclosporine and tacrolimus-associated thrombotic microangiopathy American Journal of Kidney Diseases 2000 36 4 844 850 2-s2.0-0033820323 10.1053/ajkd.2000.17690 11007689 \n5 Herman M. T. Lugan D. T. Stephen B. Juan M. G. Wadi N. S. FK506-associated thrombotic microangiopathy Transplantation 1999 67 4 539 544 10071024 \n6 Zarifian A. Meleg-Smith S. O'Donovan R. Tesi R. J. Batuman V. Cyclosporine-associated thrombotic microangiopathy in renal allografts Kidney International 1999 55 6 2457 2466 2-s2.0-0032991739 10.1046/j.1523-1755.1999.00492.x 10354295 \n7 Thölking G. Gerth H. U. Schuette-Nuetgen K. Reuter S. Tacrolimus metabolism rate on renal function after solid organ transplantation World Journal of Transplantation 2017 7 26 33 10.5500/wjt.v7.i1.26 28280692 \n8 Akimoto T. Muto S. Ito C. Clinical features of malignant hypertension with thrombotic microangiopathy Clinical and Experimental Hypertension 2011 33 2 77 83 2-s2.0-79952934453 10.3109/10641963.2010.503303 21214403 \n9 Panoulas V. F. Metsios G. S. Pace A. V. Hypertension in rheumatoid arthritis Rheumatology 2008 47 9 1286 1298 2-s2.0-50949094884 10.1093/rheumatology/ken159 18467370 \n10 Gomez-Puerta J. A. Mócsai A. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis Current Topics in Medicinal Chemistry 2013 13 6 760 773 2-s2.0-84878789296 10.2174/15680266113139990094 23574525 \n11 Shantsila A. Lip G. Y. H. Malignant hypertension revisited - Does this still exist? American Journal of Hypertension 2017 30 6 543 549 2-s2.0-85020235833 10.1093/ajh/hpx008 28200072 \n12 Chapman J. R. Chronic calcineurin inhibitor nephrotoxicity-lest we forget American Journal of Transplantation 2011 11 4 693 697 2-s2.0-79953250784 10.1111/j.1600-6143.2011.03504.x 21446974 \n13 D'Agati V. D. Fogo A. B. Bruijn J. A. Jennette J. C. Pathologic classification of focal segmental glomerulosclerosis: a working proposal American Journal of Kidney Diseases 2004 43 2 368 382 10.1053/j.ajkd.2003.10.024 2-s2.0-0742323170 14750104 \n14 Fukuda K. Shimizu A. Kaneko T. A case of secondary focal segmental glomerulosclerosis associated with malignant hypertension CEN Case Reports 2013 2 1 68 75 10.1007/s13730-012-0041-2 28509227 \n15 Nankivell B. J. Ng C. H. P. O'Connell P. J. Chapman J. R. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: Comparison of cyclosporine and tacrolimus eras Transplantation 2016 100 8 1723 1731 2-s2.0-84974852000 10.1097/TP.0000000000001243 27306529 \n16 Sreedharanunni S. Joshi K. Duggal R. Nada R. Minz M. Sakhuja V. An analysis of transplant glomerulopathy and thrombotic microangiopathy in kidney transplant biopsies Transplant International 2014 27 8 784 792 2-s2.0-84905033220 10.1111/tri.12331 24684170 \n17 Lusco M. A. Fogo A. B. Najafian B. Alpers C. E. AJKD atlas of renal pathology: calcineurin inhibitor nephrotoxicity American Journal of Kidney Diseases 2017 69 5 e21 e22 10.1053/j.ajkd.2017.02.003 2-s2.0-85018858922 28434526 \n18 Kfoury Baz E. M. Mahfouz R. A. Masri A. F. Thrombotic thrombocytopenic purpura in a patient with rheumatoid arthritis treated by plasmapheresis Therapeutic Apheresis 1999 3 4 314 316 10.1046/j.1526-0968.1999.00166.x 2-s2.0-0032737353 10608725 \n19 Sakthirajan R. Dhanapriya J. Dineshkumar T. Gopalakrishnan N. Murugan S. Balasubramaniyan T. Thrombotic microangiopathy. An unusual cause of renal failure in rheumatoid arthritis Indian Journal of Nephrology 2017 27 1 81 83 10.4103/0971-4065.179207 2-s2.0-85009110712 28182045 \n20 Tateno S. Kobayashi Y. Renal thrombotic microangiopathy in a patient with rheumatoid arthritis and antiphospholipid syndrome: successful treatment with cyclophosphamide pulse therapy and anticoagulant Internal Medicine 1994 33 8 484 487 10.2169/internalmedicine.33.484 2-s2.0-0028136051 7803916 \n21 Ripoll È. de Ramon L. Draibe Bordignon J. JAK3-STAT pathway blocking benefits in experimental lupus nephritis Arthritis Research & Therapy 2016 18 1 p. 136 2-s2.0-84975744013 27287443 \n22 Isaacs J. D. 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"journal": "Case reports in nephrology",
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"pubdate": "2019",
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"title": "A Case of Rheumatoid Arthritis Presenting with Renal Thrombotic Microangiopathy Probably due to a Combination of Chronic Tacrolimus Arteriolopathy and Severe Hypertension.",
"title_normalized": "a case of rheumatoid arthritis presenting with renal thrombotic microangiopathy probably due to a combination of chronic tacrolimus arteriolopathy and severe hypertension"
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"abstract": "Objective: To reexamine previous findings that reported that blood cells' membrane potential ratios (MPRs™) differ between youth with ADHD and controls and to determine whether psychostimulants affect MPRs™. Method: Forty-four youth (ages 6-17) with ADHD (not currently taking psychostimulants; n = 24) and controls (n = 20) completed the Mini-International Neuropsychiatric Interview 7 (MINI 7) and a blood draw to determine MPR™. Youth with ADHD provided another blood draw 30 days after receiving psychostimulants. Results: MPR™ values of participants with ADHD who were not taking stimulants were not significantly different from those of the controls. MPR's™ sensitivity was 79.2% and specificity 25.0%. Among youth with ADHD, there was a trending association between lower MPRs™ and taking stimulants (compared with baseline). Conclusion: Results neither replicate prior findings nor support MPRs'™ utility in diagnosing ADHD in youth. We identified possible MPR™ changes after participants with ADHD began stimulants. Further studies are needed to establish the clinical significance of this finding.",
"affiliations": "Johns Hopkins Hospital and Health System, Baltimore, MD, USA.;Johns Hopkins University, Baltimore, MD, USA.;Johns Hopkins University, Baltimore, MD, USA.;Johns Hopkins University, Baltimore, MD, USA.;University of Pikeville, KY, USA.;Johns Hopkins University, Baltimore, MD, USA.",
"authors": "Stepanova|Ekaterina|E|;Findling|Robert L|RL|;Kaplin|Dana|D|;Frimpong|Bernice|B|;Pikalova|Sofia|S|;Young|Andrea S|AS|",
"chemical_list": "D000697:Central Nervous System Stimulants",
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"issue": "25(1)",
"journal": "Journal of attention disorders",
"keywords": "ADD/ADHD; children; diagnosis",
"medline_ta": "J Atten Disord",
"mesh_terms": "D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity; D001773:Blood Cells; D000697:Central Nervous System Stimulants; D002648:Child; D003955:Diagnostic Tests, Routine; D006801:Humans; D008564:Membrane Potentials",
"nlm_unique_id": "9615686",
"other_id": null,
"pages": "73-80",
"pmc": null,
"pmid": "29707999",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "An Examination of Blood Cell Membrane Potential as a Diagnostic Test of Attention Deficit Disorder in Children.",
"title_normalized": "an examination of blood cell membrane potential as a diagnostic test of attention deficit disorder in children"
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"companynumb": "US-OTSUKA-2021_021735",
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"abstract": "OBJECTIVE\nto evaluate the strategy for open heart surgery after renal transplantation performed in a single institution in Japan.\n\n\nMETHODS\nwe reviewed 6 open heart surgeries after renal transplantation in 5 patients, performed between January 1992 and December 2012. The patients were 3 men and 2 women with a mean age of 60 ± 11 years (range 46-68 years). They had old myocardial infarction and unstable angina, aortic and mitral stenosis, left arterial myxoma, aortic stenosis, and native valve endocarditis followed by prosthetic valve endocarditis. Operative procedures included coronary artery bypass grafting, double-valve replacement, resection of left arterial myxoma, 2 aortic valve replacements, and a double-valve replacement. Renal protection consisted of steroid cover (hydrocortisone 100-500 mg or methylprednisolone 1000 mg) and intravenous immunosuppressant infusion (cyclosporine 30-40 mg day(-1) or tacrolimus 1.0 mg day(-1)).\n\n\nRESULTS\n5 cases were uneventful and good renal graft function was maintained at discharge (serum creatinine 2.1 ± 0.5 mg dL(-1)). There was one operative death after emergency double-valve replacement for methicillin-resistant Staphylococcus aureus-associated prosthetic valve endocarditis. Although the endocarditis improved after valve replacement, the patient died of postoperative pneumonia on postoperative day 45.\n\n\nCONCLUSIONS\ncareful perioperative management can allow successful open heart surgery after renal transplantation. However, severe complications, especially methicillin-resistant Staphylococcus aureus infection, may cause renal graft loss.",
"affiliations": "Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan yamachan@hcm-mail.hyo-med.ac.jp.;Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan.;Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan.;Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan.;Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan.;Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan.;Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan.;Department of Cardiovascular Surgery, Hyogo College of Medicine, Japan.;Department of Urology & Kidney Transplant Center, Hyogo College of Medicine, Japan.",
"authors": "Yamamura|Mitsuhiro|M|;Miyamoto|Yuji|Y|;Mitsuno|Masataka|M|;Tanaka|Hiroe|H|;Ryomoto|Masaaki|M|;Fukui|Shinya|S|;Tsujiya|Noriko|N|;Kajiyama|Tetsuya|T|;Nojima|Michio|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1177/0218492313507784",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0218-4923",
"issue": "22(7)",
"journal": "Asian cardiovascular & thoracic annals",
"keywords": "Coronary artery bypass grafting; Coronary disease; Heart valve diseases; Japan; Kidney transplantation",
"medline_ta": "Asian Cardiovasc Thorac Ann",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001026:Coronary Artery Bypass; D004359:Drug Therapy, Combination; D005260:Female; D006085:Graft Survival; D006331:Heart Diseases; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D016030:Kidney Transplantation; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D012086:Reoperation; D012307:Risk Factors; D013530:Surgical Wound Infection; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9503417",
"other_id": null,
"pages": "775-80",
"pmc": null,
"pmid": "24887898",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Open heart surgery after renal transplantation.",
"title_normalized": "open heart surgery after renal transplantation"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201506335",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
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"drugadditional": null,
... |
{
"abstract": "Congenital anemias may be complicated by immune-mediated hemolytic crisis. Alloantibodies are usually seen in chronically transfused patients, and autoantibodies have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA), a serious and potentially life-threatening complication. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all clinically relevant AIHA cases occurring at a referral center for AIHA, hemoglobinopathies, and chronic hemolytic anemias, focusing on clinical management and outcome. In our cohort, AIHA had a prevalence of 1% (14/1410 patients). The majority were warm AIHA. Possible triggers were recent transfusion, infection, pregnancy, and surgery. All the patients received steroid therapy as the first line, and about 25% required further treatment, including rituximab, azathioprine, intravenous immunoglobulins, and cyclophosphamide. Transfusion support was required in 57% of the patients with non-transfusion-dependent anemia, and recombinant human erythropoietin was safely administered in one third of the patients. AIHA in congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. A proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the direct antiglobulin test is mandatory.",
"affiliations": "General Medicine Unit, Rare Diseases Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;General Medicine Unit, Rare Diseases Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Laboratorio di Immunoematologia di Riferimento, Dipartimento di Medicina Trasfusionale ed Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;General Medicine Unit, Rare Diseases Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.",
"authors": "Motta|Irene|I|0000-0001-5701-599X;Giannotta|Juri|J|0000-0001-9349-1627;Ferraresi|Marta|M|;Barbullushi|Kordelia|K|;Revelli|Nicoletta|N|;Graziadei|Giovanna|G|;Barcellini|Wilma|W|;Fattizzo|Bruno|B|0000-0003-0857-8379",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm10153439",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383\nMDPI\n\n10.3390/jcm10153439\njcm-10-03439\nArticle\nAutoimmune Hemolytic Anemia as a Complication of Congenital Anemias. A Case Series and Review of the Literature\nhttps://orcid.org/0000-0001-5701-599X\nMotta Irene 12*\nhttps://orcid.org/0000-0001-9349-1627\nGiannotta Juri 3\nFerraresi Marta 14\nBarbullushi Kordelia 34\nRevelli Nicoletta 5\nGraziadei Giovanna 1\nBarcellini Wilma 3\nhttps://orcid.org/0000-0003-0857-8379\nFattizzo Bruno 36\nAndrès Emmanuel Academic Editor\n1 General Medicine Unit, Rare Diseases Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; marta.ferraresi@unimi.it (M.F.); giovanna.GRAZIADEI@policlinico.mi.it (G.G.)\n2 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy\n3 Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; jurigiann@gmail.com (J.G.); kordelia.barbullushi@unimi.it (K.B.); wilma.barcellini@policlinico.mi.it (W.B.); bruno.fattizzo@unimi.it (B.F.)\n4 University of Milan, 20122 Milan, Italy\n5 Laboratorio di Immunoematologia di Riferimento, Dipartimento di Medicina Trasfusionale ed Ematologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; nicoletta.revelli@policlinico.mi.it\n6 Department of Oncology and Oncohematology, University of Milan, 20122 Milan, Italy\n* Correspondence: irene.motta@unimi.it; Tel.: +39-02-5503-3493\n02 8 2021\n8 2021\n10 15 343916 5 2021\n28 7 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nCongenital anemias may be complicated by immune-mediated hemolytic crisis. Alloantibodies are usually seen in chronically transfused patients, and autoantibodies have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA), a serious and potentially life-threatening complication. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all clinically relevant AIHA cases occurring at a referral center for AIHA, hemoglobinopathies, and chronic hemolytic anemias, focusing on clinical management and outcome. In our cohort, AIHA had a prevalence of 1% (14/1410 patients). The majority were warm AIHA. Possible triggers were recent transfusion, infection, pregnancy, and surgery. All the patients received steroid therapy as the first line, and about 25% required further treatment, including rituximab, azathioprine, intravenous immunoglobulins, and cyclophosphamide. Transfusion support was required in 57% of the patients with non-transfusion-dependent anemia, and recombinant human erythropoietin was safely administered in one third of the patients. AIHA in congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. A proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the direct antiglobulin test is mandatory.\n\nautoimmune hemolytic anemia\nalloimmunization\nthalassemia\nsickle cell disease\ncongenital hemolytic anemias\n==== Body\n1. Introduction\n\nCongenital anemias include a broad spectrum of rare red blood cell (RBC) disorders classified according to the affected RBC structure. They include hemoglobinopathies, namely sickle cell disease (SCD) and thalassemia syndromes, which are by far the most prevalent [1,2], and congenital hemolytic anemias (CHAs). In SCD, the abnormal hemoglobin (Hb), called hemoglobin S (HbS), tends to form polymers in erythrocytes that deform the structure of RBC [3]. Subsequent intravascular sickling results in hemolytic anemia and recurrent occlusion of small vessels leading to vaso-occlusive crisis. In β-thalassemia, the precipitation of α-chains aggregates in erythroid precursors leads to ineffective erythropoiesis in the bone marrow and peripheral hemolysis in the intravascular and extravascular compartments. Consequent anemia and hypoxia stimulate erythroid precursor proliferation in the medullary and extramedullary compartments [2]. CHAs are heterogeneous conditions, with either dominant, recessive, or X-linked inheritance, exhibiting a clinical course ranging from mild fully compensated anemia to chronic severe hemolysis. They include defects of erythrocyte membrane proteins, red cell enzymes, and disorders due to defective erythropoiesis.\n\nIn the most severe forms of all these disorders, transfusions and iron chelation are currently the main treatment strategy [4,5,6,7,8]. The chronic course of both hemoglobinopathies and CHAs may be complicated by the abrupt drop of Hb values due to several causes, including increased destruction/sequestration (i.e., hemolytic crisis) and reduced/inhibited erythropoiesis (i.e., aplastic crisis). The latter recognizes various triggers, particularly parvovirus B19 infection [9], while the former is mainly immune-mediated. In particular, alloantibodies (alloAbs) are usually seen in chronically transfused patients and may cause severe transfusion reactions. Autoantibodies (autoAbs) have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA). Autoimmunity may occur through several mechanisms, including modification of RBC membrane antigens, molecular mimicry, hidden epitopes spreading, and innocent bystander destruction [10]. Finally, both the increased destruction and impaired erythropoiesis may coexist when the autoimmune attack is directed against erythrocyte precursors [11,12]. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all the clinically relevant AIHA cases that occurred at our hospital, a referral center for AIHA, hemoglobinopathies, and CHAs, focusing on clinical management and outcome. A review of the available literature is also provided.\n\n2. Materials and Methods\n\nWe retrospectively collected clinical, laboratory, and treatment data from electronic medical records of the patients with congenital anemias followed at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico who developed AIHA over a period of 20 years, between January 1991 and December 2020. The patients belonged to a cohort of 1410 followed at the Hematology Unit and the Rare Diseases Center of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, including 410 non-transfusion-dependent thalassemia (NTDT), 260 transfusion-dependent thalassemia (TDT), 190 SCD and sickle thalassemia, and 550 CHA cases, namely hereditary spherocytosis (HS), stomatocytosis (HSt), elliptocytosis (HE), and enzymopathies (mainly including pyruvate kinase deficiency). Direct and indirect antiglobulin test (DAT and IAT) results were revised by an experienced immune hematologist, and the diagnosis of AIHA was made according to international guidelines [13]. Reticulocyte count was collected when available, and the bone marrow responsiveness index (BMRI) was calculated according to the formula “absolute reticulocyte count × patient’s Hb/normal Hb” using a cutoff of 121 to discriminate well-compensated hemolytic anemia from an ineffective response [14].\n\nResponse to AIHA therapy was defined as complete response (CR) (Hb > 12 g/dL and normalization of all hemolytic markers), partial response (PR) (Hb > 10 g/dL or at least 2 g/dL increase in Hb, and no transfusion requirement) [15,16], and no response (NR).\n\nThe study was approved by the ethical review committee of the coordinating center “Comitato Etico Milano Area 2” and was carried out according to the principles established by the Declaration of Helsinki. A literature review by searching for the terms “congenital anemia”, “thalassemia”, “sickle cell disease”, “hereditary spherocytosis”, “hereditary elliptocytosis”, “autoimmune hemolytic anemia”, “auto-antibodies” in indexed articles in MEDLINE via PubMed and the National Library of Medicine in the last 50 years was performed.\n\n3. Results\n\n3.1. AIHA in the Congenital Anemias Cohort\n\nAIHA complicated the clinical course of 14 (1%) patients regularly followed for congenital anemias, including nine β-thalassemia (mainly non-transfusion-dependent, n = 7), two SCD/β-thalassemia, one SCD, one HS, and one HE patients. Table 1 shows the main clinical laboratory findings collected during the AIHA episode. The median Hb values dropped from 9.5 g/dL to 5.9 g/dL during the AIHA crisis, with a significant increase in LDH. Reticulocyte response (i.e., BMRI > 121) was adequate to Hb levels in 7/11 (64%) of the evaluated subjects. AIHA cases were classified as warm (n = 11, of whom four were fixing complement), cold (n = 2), and DAT-negative (n = 1, patient #4, diagnosed after the exclusion of other causes of hemolysis and steroid response). Of note, eight patients exhibited anti-RBC alloAbs along with autoAbs. We were not able to identify a trigger in all the events; however, possible triggers were recent transfusion (n = 5), infection (n = 3), pregnancy (n = 2), and surgery (n = 1). All the patients received steroid therapy as the first-line, but the second- and third-line treatments were necessary in four (28.5%) and two (14%) patients, respectively, and included rituximab (n = 2), azathioprine (n = 2), intravenous immunoglobulins (n = 1), and cyclophosphamide (n = 1). Transfusion support was required in eight patients (57%) with non-transfusion-dependent congenital anemia, and recombinant human erythropoietin (rhEPO) was safely administered in five patients (36%). Hydroxycarbamide (HU) for the underlying condition was given to four patients during the acute event to obtain a reduction in transfusion requirements, while one was already on chronic treatment. On the whole, four CR, seven PR, and three NR were registered, with the median time to response of 2.5 months (range, 0.5–11). Notably, one HE (#2) and two TDT (patients ##3 and 5) subjects experienced more than one AIHA episode, and one patient (#14) died during acute AIHA because of underlying liver failure.\n\n3.2. Literature Review\n\nThe data available in the literature on RBC autoAb/AIHA occurrence in congenital anemias are summarized in Table 2 and Table 3 and mainly derive from retrospective studies, case series, or case reports on thalassemia and SCD. Most studies are focused on alloAbs in transfused patients and report the presence of autoAbs in this context. Notably, all the reports except for one in β-thalassemia [17] evaluated the frequency of autoAbs rather than that of AIHA. Finally, only one study from our group evaluated the presence of autoAbs in HS, by using the more sensitive mitogen-stimulated DAT [11,18].\n\nOverall, autoAb frequency ranges from 1% to 28.2% in β-thalassemia [17,19,20,21,22,23,24,25,26], from 0.8% to 42% in SCD [27,28,29,30], and reaches 61% in HS (likely due to more sensitive technique) [11]. Few data are available about the Ab type, with warm antibodies (IgG+) being reported in half of the DAT-positive cases, IgG+ complement (C)—in approximately one third of cases, and C+—in the remaining cases. Studies are consistent in identifying alloAbs, transfusion exposure, and splenectomy as risk factors for the development of autoAbs. Interestingly, only two observational studies and a few case reports evaluated clinically relevant AIHA, with the prevalence ranging from 1.8% to 6.4% [17,28]. The majority of autoAbs were warm, with or without complement fixation. A recent longitudinal study by Khaled et al. showed that 25 subjects developed AIHA among 385 β-thalassemia pediatric patients [17]. All the patients were transfusion-dependent, and the frequency of AIHA was inversely proportional to the number of blood transfusions received. AIHA was triggered by vaccination in two patients and by Mycoplasma pneumoniae infection in another. This study also showed that splenectomy in DAT-positive subjects was associated with an increased risk of AIHA in thalassemic patients. Finally, considering the autoAb type, thalassemic patients with IgG+ and C+ DAT were at higher risk for clinically overt AIHA. Overall, most AIHA patients presented with severe anemia and all required therapy. First-line steroids were the most frequent strategy, associated with IVIG in some cases. The use of various cytotoxic/immunosuppressive drugs is described for refractory cases, including azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, vincristine, anti-thymocyte globulin, and actinomycin D. Splenectomy was performed for AIHA in selected refractory cases [17,31,32]. The use of rhEPO has been reported only in one retrospective study [28], and only one case of thalassemia with AIHA was successfully treated with rituximab [33]. Responses to various therapies are difficult to establish given the heterogeneity of treatments and the small number of patients in each report. Finally, across the various reports, two pediatric patients had a fatal outcome. These were one SCD case with both autoAbs and alloAbs who developed an over-hemolytic transfusion reaction [29] and one β-thalassemia case who had received multiple lines of immunosuppressive therapies for AIHA (prednisone, cyclophosphamide, methotrexate, vincristine, anti-human lymphocyte globulin, and actinomycin D; splenectomy) and died due to infection [32].\n\n4. Discussion\n\nAlthough rare, AIHA is a serious and potentially life-threatening complication of congenital anemias. Our study represents the largest cohort of congenital anemias in which the prevalence and treatment of AIHA are evaluated. In our analysis, AIHA had a prevalence of 1%, which is lower than that reported in the paper by Khaled et al. [17], which, however, included pediatric thalassemic patients only. Regarding triggers, we also observed that previous splenectomy, recent transfusions, infections, and pregnancy may be associated with the development of anti-RBC autoimmunity. However, in more than half of the patients, the trigger was not identified. Different prevalence between studies can be related either to heterogeneous populations or frequency of potential triggers. Indeed, infections are more frequent in children and in certain regions, and transfusion strategies and blood product may differ. Additionally, more severe CHAs with early transfusion requirement during childhood may be at higher risk of allo- and autoimmunization. Finally, it is largely accepted that immune system maturation is a dynamic concept evolving along with age and that the type and severity of several autoimmune conditions consistently vary from infancy to adulthood and elderly age. More importantly, in our study, we evaluated the prevalence of clinically overt AIHA, whilst most reports deal with the presence of anti-RBC autoAbs only (DAT positivity). As a matter of fact, the diagnosis of AIHA may be challenging in chronic hemolytic patients and, even more, in those on transfusions. In the former, hemolytic features are already present, and AIHA should be suspected in case of sudden drop of Hb levels or significant worsening of hemolytic markers. In the latter, a further flag may be the decrease of pretransfusion hemoglobin or the increase in the transfusion need. In addition, most patients in our series also exhibited anti-RBC alloAbs, which is a known finding in congenital anemias, particularly in transfusion-dependent ones. One of the key points is the distinction of autoAbs from alloAbs either in transfusion-dependent or non-transfusion-dependent conditions. In fact, besides the importance of assigning the best-matched RBC units to the patient, recognition of the “true” AIHA is pivotal for proper therapy. In this study, all the patients received steroids, and mostly responded, whilst about 25% required further treatment. Of note, about 1/3 of the patients received rhEPO, which has been shown to be effective in primary AIHA [37] avoiding possible myelotoxicity of immunosuppressants. Generally, therapy of AIHA in the context of congenital anemias is not codified, and therefore the guidelines available for primary forms are applied. If steroids are given cautiously in patients with congenital anemias and several comorbidities, second-line therapies raise even more concerns. Hydroxyurea, which is extensively used in SCD and some NTDT patients to increase the total amount of hemoglobin and fetal hemoglobin, has been recently demonstrated to alleviate complement activation in sickle cell patients, thus acquiring a potential role in AIHA management [38]. Use of plasma exchange (PEX) has also been reported in very severe AIHA [39] in case of steroids/IVIG refractoriness. No cases of CHA-related AIHA receiving PEX have been reported; however, its use in CHA should be carefully evaluated, especially in SCD with the risk related to increased viscosity.\n\nIn this regard, a close collaboration with a transfusion medicine specialist is fundamental to perform DAT with more sensitive methods (microcolumn and solid phase tests, washings with low ionic strength solutions, or experimental methods) [10], as well as to characterize the alloAbs by studying the eluate and performing extended phenotyping and genotyping when required.\n\nThe pathophysiology underlying the development of anti-RBC autoAbs in congenital anemias is object of several hypotheses. Some mechanisms include the exposure to foreign antigens, as occurs in transfusion-dependent patients developing alloAbs, or during pregnancy, the molecular mimicry after infections, the spread of hidden epitopes during the hemolytic process through the deformation of erythrocyte membranes due to exposure to neoantigens, and the release of the free heme. The latter is involved in post-translational diversification of circulating Abs, may induce complement activation on SCD RBCs, thus increasing the risk of autoimmune reactions [40]. Additionally, the abnormal structure of SCD and thalassemic RBCs (prematurely expressing senescence antigens) may be more easily recognized by the immune system, as also shown by the increased amounts of RBC-bound IgG detected in these patients. Finally, the ineffective erythropoiesis typical of hemoglobinopathies, along with a proinflammatory bone marrow milieu, may also favor the development of anti-erythroblast autoAbs.\n\n5. Conclusions\n\nIn conclusion, AIHA in the context of congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. Clinical suspicion should be high and prompt a proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the DAT positivity for alloAbs and autoAbs.\n\nAuthor Contributions\n\nConceptualization, I.M., B.F. and W.B.; data curation, M.F., K.B., J.G., I.M., B.F. and N.R.; writing—original draft preparation, I.M., J.G., B.F. and W.B.; writing—review and editing, G.G. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was approved by the ethical review committee of the coordinating center Comitato Etico Milano Area 2 and was carried out according to the principles established by the Declaration of Helsinki.\n\nInformed Consent Statement\n\nInformed consent was obtained from all the subjects involved in the study.\n\nData Availability Statement\n\nThe data presented in this study are available in the article.\n\nConflicts of Interest\n\nJ.G., M.F., K.B., N.R., G.G. declare no conflict of interest. I.M. reports receiving consultancy honoraria from Sanofi-Genzyme and Amicus Therapeutics; W.B. provided consultancy services to Agios, Alexion, Apellis, Biocryst, Bioverativ, Incyte, Momenta, and Novartis, and received lecture fees/congress support from Alexion, Incyte, Novartis, and Sanofi; B.F. reports receiving consultancy honoraria from Novartis, Amgen, and Momenta.\n\njcm-10-03439-t001_Table 1 Table 1 Characteristics and clinical management of the patients with congenital hemolytic anemias (CHAs) experiencing autoimmune hemolytic anemia (AIHA) referred to our institution.\n\nID\tAge (Years)/\nSex Category\tUnderlying CHA, Spleen status\tUsual Hb Values (g/dL)\tYear of AIHA Occurrence\tTrigger\tHb Nadir during AIHA (g/dL)\tLDH (U/L) (xULN),\nUB (mg/dL)\tARC (×109/L), BMRI\tsEPO (U/L)\tDAT Positivity\tTreatments\tResponse at Last Crisis, Time to Restore Usual Hb Values\t\n1\t26/F\tHS\t9\t2018\t-\t6.3\t430 (2),\n4.3\t230;\n104\t50\tC\tIV mPDN 1 mg/kg/day, folic acid, vitamin B12, oral iron\tPR,\n15 days\t\n2\t81/M\tHE\t11\t2008, 2009, 2010\t-\t7.3\t530 (2),\n1.74\t310;\n141\t27.3\tIgG\tIV mPDN 500 mg for 2 days, then 2 mg/kg/day, rhEPO, folic acid\tPR,\n1.5 months\t\n3\t50/F\tTDT,\nsplenectomy\t8\t1991, 2003, 2008\t-\tNA\tNA\tNA\tNA\tIgG\tOral PDN, azathioprine, cyclophosphamide\tPR, NA\t\n4\t30/F\tNTDT\t10\t2007\tPregnancy\t4\tNA\tNA\tNA\tNA, alloAb+\tIV mPDN, rhEPO, transfusions (HU for NTDT)\tPR,\n>3 months\t\n5\t50/M\tTDT\t10\t2009, 2012\t-\tNA\tNA\tNA\tNA\tIgG\tOral PDN, azathioprine\tCR, NA\t\n6\t49/M\tNTDT\nsplenectomy\t9.5\t2013\t-\t7.6\t559 (2.5),\n2.46\t396;\n188\tNA\tIgG+C, AlloAb+\tOral PDN 5 mg/day, folic acid (HU for NTDT)\tCR,\n11 months\t\n7\t33/F\n\tNTDT\t9.5\t2018\tPregnancy and transfusion\t5.1\t599 (2),\n1.73\t439;\n160\t96.8\tIgG+C, alloAb+\tIV mPDN 1 mg/kg/day, folic acid, transfusions\tPR,\n2 months\t\n8\t43/F\tNTDT,\nsplenectomy\t12\t2018\tTransfusion, pielonephritis\t6.3\t510 (2),\n0.83\t392;\n174\tNA\tIgG+C,\nalloAb+\tIV mPDN 1.5 mg/kg/day, rituximab 375 mg/s.m., folic acid, vitamin B12 (HU for NTDT)\tPR,\n>3 months\t\n9\t67/M\tβ-thal trait\t9.5\t2019\t-\t6.9\t227 (1.06), 1.28\t7;\n3\t173\tIgG, alloAb+\tOral PDN 0.6 mg/kg/day, rhEPO, folic acid, vitamin B12, transfusions\tNR\t\n10\t24/F\tNTDT\t8.5\t2019\t-\t5.6\t601 (2.8),\n4.31\t246;\n98\tNA\tIgG, alloAb+\tOral PDN 0.5 mg/kg/day, folic acid, transfusions\tNR\t\n11\t54/M\tNTDT\t9.5\t2019\t-\t2.3\t1378 (6.4),\n4.06\t30;\n4\tNA\tC, alloAb+\tIV mPDN 1.5 mg/kg/day + high-dose boli 1 g/day for 3 days, IVIG, rituximab 375 mg/s.m., rhEPO, folic acid, vitamin B12, transfusions (HU for NTDT, imiglucerase for β-glucocerebrosidase deficiency)\tCR,\n4 months\t\n12\t34/F\tSCD\t10.5\t2020\tSurgery, infection, transfusion\t4.5\t4696 (21.9),\n3.33\t436;\n140\t3365\tIgG+C,\nalloAb+\tIV mPDN 1 mg/kg/day, folic acid, vitamin B12, transfusions\tCR,\n2.5 months\t\n13\t58/F\tSCD/β-thal, splenectomy\t8\t2020\tStart of chronic transfusion support\t6.3\t1235 (5.7),\n1.67\t668;\n301\tNA\tIgG\tIV mPDN 1.5 mg/kg/day, rhEPO, folic acid, transfusions (HU for SCD/thal)\tPR,\n20 days\t\n14\t55/M\tSCD/ β-thal\t8.5\t2020\tInfection, transfusion\t5\t791 (3.7),\n33\t557;\n174\t130\tIgG\tIV mPDN 1 mg/kg/day, folic acid, transfusions\tNR, dead\t\nSummary\nmedian, range\t49.5\n24–81\t-\t9.5\n8–12\t-\t-\t5.9\n2.3–7.6\t599,\n227–4696\n2.46\n0.83–33\t392\n7–668\t113.4\n27.3–3365\t-\t-\t-\t\nHS: hereditary spherocytosis, HE: hereditary elliptocytosis, TDT: transfusion-dependent thalassemia, NTDT: non-transfusion-dependent thalassemia, SCD: sickle cell disease, Hb: hemoglobin, LDH: lactate dehydrogenase, ULN: upper limit of normality, UB: unconjugated bilirubin, ARC: absolute reticulocyte count, sEPO: serum erythropoietin, DAT: direct antiglobulin test, C: complement, AlloAb: alloantibodies, IV: intravenous, mPDN: methylprednisolone, PR: partial response, rhEPO: recombinant human erythropoietin, NR: non-response, HU: hydroxycarbamide, PDN: prednisone, CR: complete response, IVIG: intravenous immunoglobulins.\n\njcm-10-03439-t002_Table 2 Table 2 Studies and case series/reports about RBC autoAbs/AIHA in thalassemia.\n\nType of Study;\nObjective of the Study\tNumber of pts; Pediatric/Adult;\nSex\tMain Findings\t\nLongitudinal study;\nto identify predictive factors of AIHA in patients with RBC autoAbs\n[17]\t385;\npediatric;\nF 57.5%, M 42.5%\t- Frequency of RBC autoAbs: 22.6%\n\n- AIHA: 6.4% of the entire population, 28.7% of the subjects with RBC autoAbs\n\n- DAT: IgG+ 65.5%, IgG+ C+ 32.1%, IgM+ 0.2%\n\n- AIHA risk factor: prior alloimmunization, β-TI, splenectomy, the first 72 transfusions, family history of AIHA, presence of polyspecific autoAbs, AB blood type\n\n- AIHA protective factor: transfusion with phenotypic and leukoreduced blood\n\n- First-line treatment: prednisone 2 mg/kg/d\n\n- Second-line treatments: IV methylprednisolone 1000 mg/m2/day for three days (n = 5), azathioprine (n = 7), mycophenolate mofetil (n = 4), splenectomy (n = 2)\n\n\t\nProspective observational study; incidence of RBC autoAbs [19]\t500;\npediatric and adult;\nF 57%, M 43%\t- Frequency of RBC autoAbs: 1%\n\n- No association with alloimmunization\n\n\t\nCross-sectional study\n[20]\t407;\npediatric and adult;\nF 55%, M 45%\t- Frequency of RBC autoAbs: 6.5%\n\n- Risk factor: alloAbs\n\n\t\nFrequency of RBC autoAbs\n[21]\t301;\nNA;\nNA\t- Frequency of RBC autoAbs: 15.9%\n\n- DAT: IgG+ 56.3%, IgG+ C+ 10.4%, C+ 33.3%\n\n- Risk factor: alloAbs\n\n\t\nFrequency of RBC autoAbs\n[22]\t319;\npediatric and adult;\nF 26.3%, M 73.7%\t- Frequency of RBC autoAbs: 28.2%\n\n- Risk factor: age, splenectomy, number of transfusions\n\n\t\nCase-control study;\nprevalance of autoAbs\n[23]\t280;\npediatric and adult;\nF 33.3%, M 66.7%\t- Frequency of RBC autoAbs: 1.8 %\n\n- DAT: IgG+ 100%\n\n- All (n = 5) developed clinically significant AIHA\n\n- Treatment: steroids\n\n\t\nFrequency of RBC autoAbs\n[24]\t200;\npediatric and adult;\nF 53%, M 47%\t- Frequency of RBC autoAbs: 16.5%\n\n- Risk factor: age, duration of transfusion support and the total number of transfusions, splenectomy\n\n\t\nRetrospective and prospective observational study; prevalence of RBC autoAbs; risk factor analysis [25]\t118;\npediatric and adult;\nF 50%, M 50%\t- Frequency of RBC autoAbs: 22.8%\n\n- 37% transient autoAbs without any treatment\n\n- DAT: IgG+ 48%, IgG+ C+ 52%\n\n- Risk factor: alloAbs, splenectomy\n\n\t\nFrequency of RBC autoAbs\n[26]\t49;\npediatric and adult;\nF 49%, M 51%\t- Frequency of RBC autoAbs: 2.14 %\n\n\t\nCase series of AIHA\n[31]\t4;\npediatric;\nF 25%; M 75%\t- DAT: IgG+\n\n- Treatment:\n\n- Case 1: High-dose IVIG (CR)\n\n- Case 2: prednisone therapy (ineffective); then azathioprine (PR); then High-dose IVIG (CR). Splenectomy for significant splenomegaly\n\n- Case 3: prednisone therapy (ineffective); then High-dose IVIG (PR).\n\n- Case 4: prednisone therapy (PR); then High-dose IVIG (CR). Recurrence after therapy interruption: treatment with IVIG repeated, with CR\n\n- The standard dose of 2 g/kg was used for IVIG treatment\n\n\t\nCase report of AIHA\n[34]\t2;\npediatric;\nF 50%, M 50%\t- Both cases of AIHA presented with severe anemia\n\n- DAT: C+ (case 1); negative at diagnosis, then strongly positive (case 2)\n\n- Treatment: transfusions, IVIG 2 g/kg + methylprednisolone 30 mg/kg/d for 3 days, followed by prednisolone 2 mg/kg/d in both cases\n\n- Response: PR weeks later\n\n\t\nCase report of AIHA\n[32]\t1;\npediatric;\nF\t- AIHA presenting with severe anemia\n\n- DAT: initially negative, IgG+ after splenectomy\n\n- Treatment: transfusion, oral prednisone 30 mg/day, cyclophosphamide 50 mg/day, and methotrexate 2.5 mg/day: no hemolysis reduction. Treatment with vincristine 1 mg/week, anti-human lymphocyte globulin 125 mg/day IV, and actinomycin D 15 mcg/kg/day for 5 days led to transient decrease in transfusion requirement. Splenectomy (for splenomegaly): no improvement in hemolysis\n\n- The patient died at the age of 45 months of bronchopneumonia, pericardial effusion, and congestive heart failure\n\n\t\nCase report of AIHA\n[33]\t1;\npediatric;\nM\t- AIHA presenting with severe anemia\n\n- DAT: IgG+ C+. IAT positive as well\n\n- First-line treatment: prednisolone 45 mg/day, then IVIG 20 mg in association (CR)\n\n- Second-line treatment at reactivation one year later: rituximab 375 mg/m2 (four doses) and regular transfusion of red cell antigen (major and minor)-matched blood (CR)\n\n\t\nRBC: red blood cells, autoAbs: autoantibodies; alloAbs: alloantibodies; AIHA: autoimmune hemolytic anemia; IV: intravenous; IVIG: intravenous immunoglobulin; F: female; M: male, CR: complete remission; PR: partial remission; DAT: direct antiglobulin test (with monospecific antisera unless otherwise specified).\n\njcm-10-03439-t003_Table 3 Table 3 Studies and case series/reports about RBC autoAbs/AIHA in SCD and CHAs.\n\nType of Study\nObjective of the Study\nDisease\tNumber of pts; Pediatric/Adult;\nSex\tMain Findings\t\nProspective study\nSCD, TDT\n[27]\t158\nPediatric and adult\nNA\t- Freque;ncy of RBC autoAbs: 12%\n\n- DAT: C+ (n = 12)\n\n- The antibody did not appear to be clinically important since it became thermally reactive at 4 °C and not at 37 °C\n\n- Risk factors: alloAbs\n\n\t\nRetrospective study\nSCD\n[28]\t167\nPediatric and adult\nNA\t- Frequency of RBC autoAbs: 3.6% of the total, 8–9.7% of the transfused\n\n- DAT: panagglutinin with no apparent specificity (83%)\n\n- Only 2/12 patients developed AIHA\n\n- Risk factors: alloAbs\n\n- Treatment and response of AIHA:\n\n- case 1 (IgG): steroids, IVIG, EPO, and RBC transfusions. CR after 2 months\n\n- case 2: unknown\n\n\t\nRetrospective study.\nFrequency, serological characteristics, and clinical significance of autoimmunization in pediatric patients\nSCD [29]\t184\nPediatric\nNA\t- Frequency of RBC autoAbs: 8%\n\n- DAT: IgG+ (n = 9), IgG+ C+ (n = 5)\n\n- AIHA 4/14 patients (all IgG+ C+)\n\n- Risk factors: alloAbs\n\n- Treatment: corticosteroids, RBC transfusion\n\n- Response: one fatal hemolytic reaction following transfusion\n\n\t\nSCD\n[30]\t12\nPediatric and adult\t- Frequency of RBC autoAbs: 42%\n\n- DAT: IgG+ (n = 1), C+ (n = 4)\n\n- Risk factors: alloAbs, chronic transfusion\n\n\t\nCase series\nSCD\n[35]\t5\nPediatric and adult\nF 2, M 3\t- DAT: IgG+ C+\n\n- Risk factors: alloAbs\n\n- Treatment: steroids; mercaptopurine in one patient\n\n- Response: CR/PR; autoAbs reverted to negative in all the patients after hospital discharge\n\n\t\nCase series and review of the literature\nSCD [36]\t2\nAdult\n1 M, 1 F\t- Case 1: severe anemia (Hb 2.8 g/dL). Treated with prednisone, IVIG, and RBC transfusion\n\n- Case 2: severe anemia (Hb 4 g/dL), LDH was 3175 IU, reticulocytes 28%. IgG+. Treated with prednisone with CR\n\n\t\nHS\n[11]\t91\nadult\n40 F, 51 M\t- Frequency of RBC autoAbs by mitogen-stimulated DAT: 61%—IgG fraction bound to α- and β-spectrin, Band 3, and Band 4.9\n\n- The positive cases displayed increased reticulocytosis and slightly reduced hemoglobin (Hb) values compared to the negative ones\n\n\t\nTDT: transfusion-dependent thalassemia, SCD: sickle cell disease; RBC: red blood cells, autoAbs: autoantibodies; alloAbs: alloantibodies; AIHA: autoimmune hemolytic anemia; IV: intravenous; IVIG: intravenous immunoglobulin; F: female; M: male, DAT: direct antiglobulin test (with monospecific antisera unless otherwise specified); EPO: erythropoietin; CR: complete remission; NA: not available.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Piel F.B. Steinberg M.H. Rees D.C. Sickle Cell Disease N. Engl. J. 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"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "10(15)",
"journal": "Journal of clinical medicine",
"keywords": "alloimmunization; autoimmune hemolytic anemia; congenital hemolytic anemias; sickle cell disease; thalassemia",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34362222",
"pubdate": "2021-08-02",
"publication_types": "D016428:Journal Article",
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"title": "Autoimmune Hemolytic Anemia as a Complication of Congenital Anemias. A Case Series and Review of the Literature.",
"title_normalized": "autoimmune hemolytic anemia as a complication of congenital anemias a case series and review of the literature"
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"abstract": "There have been no case reports of the risk of serious adverse events associated with the administration of irinotecan hydrochloride (CPT-11) in patients with gynecologic cancer who are compound heterozygous for UGT1A1*6 and UGT1A1*28. A 71-year-old patient presented with recurrent stage IIIb cervical cancer. Combined chemotherapy was initiated with CPT-11 (60 mg/m² on days 1 and 8) plus nedaplatin (NDP; 80 mg/m² on day 1), with each cycle lasting for 28 days. The patient was a compound heterozygote for UGT1A1*6 and UGT1A1*28. Hematotoxic adverse events observed during the chemotherapy were grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia, and the non-hematotoxic adverse events were grade 3 diarrhea and grade 3 fatigue. The findings in this patient indicate that CPT-11 should be administered with great care, even at a dose of 60 mg/m², in patients receiving combined therapy with CPT-11 and NDP who are compound heterozygous for UGT1A1*6 and UGT1A1*28.",
"affiliations": "Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Morioka, Japan.",
"authors": "Takatori|Eriko|E|;Shoji|Tadahiro|T|;Miura|Yuki|Y|;Takeuchi|Satoshi|S|;Yoshizaki|Akira|A|;Sugiyama|Toru|T|",
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"country": "Australia",
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"issue": "39(8)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "UGT1A1*28; UGT1A1*6; adverse events; cervical cancer; irinotecan hydrochloride",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D005260:Female; D014453:Glucuronosyltransferase; D006579:Heterozygote; D006801:Humans; D000077146:Irinotecan; D009364:Neoplasm Recurrence, Local; D009944:Organoplatinum Compounds; D011110:Polymorphism, Genetic; D002583:Uterine Cervical Neoplasms",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy.",
"title_normalized": "recurrent cervical cancer in a patient who was compound heterozygous for ugt1a1 6 and ugt1a1 28 presenting with serious adverse events during irinotecan hydrochloride nedaplatin therapy"
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"abstract": "Paroxysmal kinesigenic dyskinesia (PKD) is a rare condition characterized by abnormal involuntary movements that are precipitated by a sudden movement. PKD is often misdiagnosed with psychogenic movement disorders. Carbamazepine is usually the first choice of medication due to its well-established evidence but could induce Stevens-Johnson syndrome. We report a 21-year-old male patient with PKD referred to our movement disorders clinic after being misdiagnosed with conversion syndrome. PRRT2 gene testing using next-generation sequencing revealed a mutation in c.649dupC p. (Arg217fs). The patient responded well to carbamazepine but had to withdraw the treatment due to carbamazepine-induced Stevens-Johnson syndrome after 3 weeks of medication. Our patient did not respond to trials of levetiracetam and phenytoin but finally responded well to oxcarbazepine. The patient was followed up for 4 years, during which he had no attacks and no side effects. Here, we present a PKD case with carbamazepine-induced Stevens-Johnson syndrome successfully treated with oxcarbazepine despite the risk of cross-reactive skin eruption between these antiepileptics. Careful history taking and examining patient's attacks are crucial to accurate diagnosis and treatment in PKD patients.",
"affiliations": "Department of Neurology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.;Department of Neurology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.;Exploration Fonctionnelle du Système Nerveux, Pôle de Psychiatrie, Neurologie et Rééducation Neurologique, Centre Hospitalier Universitaire (CHU) Grenoble, Grenoble, France.",
"authors": "Tran|Hung T|HT|;Nguyen|Khang V|KV|;Vercueil|Laurent|L|",
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"country": "Switzerland",
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"doi": "10.1159/000518891",
"fulltext": "\n==== Front\nCase Rep Neurol\nCase Rep Neurol\nCRN\nCase Reports in Neurology\n1662-680X\nS. 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.com\n\n10.1159/000518891\ncrn-0013-0598\nSingle Case − General Neurology\nSuccessful Treatment of a Paroxysmal Kinesigenic Dyskinesia Patient with Carbamazepine-Induced Stevens-Johnson Syndrome Using Oxcarbazepine Monotherapy: A Case Report\nTran Hung T. a b *\nNguyen Khang V. a\nVercueil Laurent c d\naDepartment of Neurology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam\nbParkinson's disease and Movement disorders clinic, Nguyen Tri Phuong Hospital, Ho Chi Minh City, Vietnam\ncExploration Fonctionnelle du Système Nerveux, Pôle de Psychiatrie, Neurologie et Rééducation Neurologique, Centre Hospitalier Universitaire (CHU) Grenoble, Grenoble, France\ndINSERM U836, Grenoble Institut des Neurosciences, La Tronche, France\n*Hung T. Tran, tranthanhhungmd@ump.edu.vn\nSep-Dec 2021\n13 9 2021\n13 9 2021\n13 3 598604\n3 4 2021\n29 7 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nParoxysmal kinesigenic dyskinesia (PKD) is a rare condition characterized by abnormal involuntary movements that are precipitated by a sudden movement. PKD is often misdiagnosed with psychogenic movement disorders. Carbamazepine is usually the first choice of medication due to its well-established evidence but could induce Stevens-Johnson syndrome. We report a 21-year-old male patient with PKD referred to our movement disorders clinic after being misdiagnosed with conversion syndrome. PRRT2 gene testing using next-generation sequencing revealed a mutation in c.649dupC p. (Arg217fs). The patient responded well to carbamazepine but had to withdraw the treatment due to carbamazepine-induced Stevens-Johnson syndrome after 3 weeks of medication. Our patient did not respond to trials of levetiracetam and phenytoin but finally responded well to oxcarbazepine. The patient was followed up for 4 years, during which he had no attacks and no side effects. Here, we present a PKD case with carbamazepine-induced Stevens-Johnson syndrome successfully treated with oxcarbazepine despite the risk of cross-reactive skin eruption between these antiepileptics. Careful history taking and examining patient's attacks are crucial to accurate diagnosis and treatment in PKD patients.\n\nKeywords\n\nAntiepileptic drugs\nCase report\nParoxysmal kinesigenic dyskinesia\nStevens-Johnson syndrome\n==== Body\npmcIntroduction\n\nParoxysmal dyskinesia is a group of paroxysmal movement disorders consisting of paroxysmal kinesigenic, nonkinesigenic, and exercise-induced dyskinesia. Paroxysmal kinesigenic dyskinesia (PKD) is characterized by hyperkinetic movements that occur after sudden movement, acceleration, or intention to move. PKD manifestation consists of dystonia, choreoathetosis, ballismus, or a combination of those hyperkinetic movements [1]. Genetic testing often reveals mutations in proline-rich transmembrane protein (PRRT2), modulating the Na+ channel in neurons. Brain MRI and EEG often show no abnormalities in patients with PKD. Due to its uncommon symptoms and unrevealing routine diagnostic tests, PKD is often mistaken for psychiatric disorders [2]. Carbamazepine is the first line of treatment for PKD. Despite its efficacy, carbamazepine can cause Stevens-Johnson syndrome (SJS), which is a hypersensitivity reaction causing severe dermatitis and could be life threatening [3].\n\nOur patient was diagnosed with PKD and had an excellent response to carbamazepine. However, carbamazepine had to be withdrawn due to SJS 3 weeks later. His symptoms were not controlled by other medications except oxcarbazepine. Therefore, we present a case with a novel treatment of PKD with SJS due to carbamazepine.\n\nCase Report/Case Presentation\n\nA 21-year-old man presented to our movement disorders clinic with a 12-year history of attacks of involuntary movements of both upper limbs and upper trunk. These attacks are often triggered by sudden movements such as standing up quickly or running on the spot. The patient was conscious of experiencing a certain “feeling” before the onset of an attack. The patient was able to prevent these attacks by standing up slowly. He once had a febrile seizure when he was 2 months old and was treated in Children Hospital No. 1 in Ho Chi Minh City with an unclear diagnosis and treatment. He had no family history of similar conditions, epilepsy, seizure, or other movement disorders. These attacks were increased in frequency to >20 times a day, rendering him from continuing his education 3 years after symptom onset. His parents thought the symptoms were related to psychological disorders, so the patient did not receive proper medical care. When he was 21 years old, he was referred to a local psychiatric hospital in Ho Chi Minh City. A brain MRI and electroencephalogram were done, but no abnormal sign was found. He was diagnosed with “conversion disorder.” He was prescribed amisulpride 400 mg ½ tablet, BID; trihexyphenidyl 2 mg 1 tablet, BID; and valproate magnesium 200 mg 1 tablet, BID, for 2 months, but there was not any amelioration. He then withdrew medications for 6 months, and the symptoms unchanged.\n\nFinally, he came to our Parkinson's disease and Movement disorders clinic at Nguyen Tri Phuong Hospital. Careful history taking and clinical examination showed no signs of Parkinsonism, ataxia, and no focal neurologic deficits or psychiatric symptoms including delusions, hallucinations, disorientation, and emotional volatility. Therefore, PKD was suspected. However, we could not observe the attack at our clinic due to the transient and unpredictable nature of the attacks. We then instructed the patient to self-record the attack constantly at home. After observing and analyzing the patient's video, we witnessed the manifestations of the attack, including choreic movements and dystonic posture of the upper limbs, head, neck, and upper part of the trunk. The patient usually had to hold on to the nearest table to decrease the magnitude of movements. The duration of each attack was about 10–30 s. The patient's consciousness was preserved before, during, and after the attacks. There were no neurologic deficits after the attacks (see online suppl. Video 1; for all online suppl. material, see www.karger.com/doi/10.1159/000518891).\n\nNevertheless, PRRT2 gene testing was a relatively new test in Vietnam, so it took us a few months to get the test result. The next-generation sequencing test was done by using NextSeq 550 System Guide − Illumina Inc. at Medical Genetics Institute in Ho Chi Minh City, which later revealed a mutation in c.649dupC p. (Arg217fs). Therefore, PKD with PRRT2 mutation was our final diagnosis. After a few days of carbamazepine 200 mg ½ tablet, BID prescription, the patient no longer suffered from any attack. Twenty days later, he developed skin and mucous membrane eruptions. Following a dermatologist consultation, he was diagnosed with carbamazepine-induced SJS (shown in Fig. 1, 2, 3, 4). Therefore, carbamazepine was withdrawn, and the patient's SJS skin and mucous membrane lesions made a self-recovery without specific treatment. HLA-B gene testing was done using next-generation sequencing, but the HLA-B>*1502 allele was not found. After unsuccessful trials of levetiracetam 500 mg BID and phenytoin 100 mg TID monotherapy, the patient finally responded well to oxcarbazepine 300 mg tablet, BID, with no attack. He was followed up to 4 years at our movement disorders clinic, and oxcarbazepine dose was decreased to 300 mg 1 tablet a day in the morning. During the follow-up period, the patient had no attacks, no side effects, and no psychiatric symptoms and can continue his education. He now has a normal life and is pleased with the current treatment. However, when he forgets a dose, his symptoms re-emerge.\n\nDiscussion/Conclusion\n\nPKD is commonly misdiagnosed due to its unfamiliar clinical presentation and unrevealing signs in the routine workup, including EEG and brain MRI. Cases are also often sporadic, and no patient's relatives have similar symptoms [4]. Definite diagnosis is made by genetic testing, which often reveals mutations in PRRT2 in the long arm of chromosome 16 [5]. Our patient showed no sign of psychiatric symptoms but showed typical symptoms of PKD on history and patient's self-video-recording. Therefore, psychiatrists, general neurologists, and primary care clinicians need to recognize PKD's unusual symptoms to refer patients to movement disorders specialists. Our patient was on valproate magnesium 400 mg and amisulpride 400 mg for 2 months. Valproate could cause Parkinsonism, but this side effect would cease after drug withdrawal. Amisulpride could cause extrapyramidal symptoms, including akathisia, Parkinsonism, acute dystonia, or tardive dyskinesia [6]. Tardive dyskinesia is a hyperkinetic movement disorder with slow, persistent, involuntary, and repetitive body movements in the face, lips, tongue, trunk, and extremities that often occur in patients with prolonged use of antipsychotics [7]. However, to our knowledge, no case of amisulpride causing paroxysmal dyskinesia was reported.\n\nTreatment of PKD is only limited to symptomatic treatment, but patients usually experience complete relief of symptoms [4]. Carbamazepine is a well-established first-line treatment but can carry the risk of SJS, which is a severe delayed-type hypersensitivity reaction [3]. Many other antiepileptic drugs could also cause SJS, including phenytoin, lamotrigine, and oxcarbazepine [8]. Asian ethnicity has a higher risk of SJS because they often carry the HLA-B>*1502 allele [9]. Although our patient does not carry the HLA-B>*1502 allele, he had SJS during his treatment, making him stop using carbamazepine. Therefore, a patient without the HLA-B>*1502 allele is not without risk of SJS [10].\n\nThere also have been case reports on other effective anticonvulsants for PKD, including phenytoin, valproate, gabapentin, lamotrigine, levetiracetam, and phenobarbital [11]. However, our patient did not respond to phenytoin 100 mg TID or levetiracetam 500 mg BID monotherapy. He responded well to monotherapy of oxcarbazepine 300 mg per day. Other reported cases also responded to low doses, between 75 and 300 mg oxcarbazepine per day [12]. Despite the risk of cross-reactive skin eruption between carbamazepine and oxcarbazepine [13] and the report of many cases of oxcarbazepine-induced SJS [14], our patient did not experience any side effect during his oxcarbazepine monotherapy up until now.\n\nA particular strength of our study is that our PKD patient, in whom diagnosis was confirmed by next-generation sequence testing, was followed up continuously from 2017 to 2021. This long follow-up period allows us to monitor the patient's medication response and any side effects. Our study also has limitations. Because this is a case report, our treatment of PKD with SJS could not be generalized without more evidence from randomized controlled trials. However, our study has provided some background for the design of future study.\n\nIn this case report, we want to emphasize the importance of clinical suspicion of PKD not to be misdiagnosed with psychiatric disorders. To the authors' knowledge, no case of PKD confirmed by genetic testing with SJS due to carbamazepine successfully treated with oxcarbazepine was reported. We hope this case report would aid physicians in their treatment of PKD patients.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient to publish this case report and any accompanying images and video. The patient was followed up at our movement disorders clinic. The study is exempt from ethics committee approval because the study is observational. The conduct of this study did not affect the patient treatment course.\n\nConflict of Interest Statement\n\nThe authors declare that there are no conflicts of interest.\n\nFunding Sources\n\nThe authors received no financial support for the research, authorship, and publication of this article.\n\nAuthor Contributions\n\nT.T.H. is the chief investigator who examined, made the diagnosis, and treated the patient. He also wrote and edited the manuscript. N.V.K. and L.V. made substantial contributions to drafting and revising the manuscript. All authors read and approved the final manuscript.\n\nData Availability Statement\n\nAll data generated or analyzed during this study are included in this article and its online suppl. material files. Further enquiries can be directed to the corresponding author.\n\nSupplementary Material\n\nSupplementary data\n\nClick here for additional data file.\n\nSupplementary data\n\nClick here for additional data file.\n\nFig. 1 Front view of the patient's body.\n\nFig. 2 Back view of the patient's body.\n\nFig. 3 Palm view of the patient's hand.\n\nFig. 4 A closer image at the patient's trunk.\n==== Refs\nReferences\n\n1 Erro R Sheerin UM Bhatia KP Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification Mov Disord 2014 29 (9) 1108 16 24963779\n2 Pan F Li S Li H Xu Y Huang M Misdiagnosed atypical paroxysmal kinesigenic dyskinesia: a case report Neuropsychiatr Dis Treat 2018 14 1433 5 29892195\n3 Ferrell PB Jr Carbamazepine MLHL HLA-B>*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations Pharmacogenomics 2008 9 (10) 1543 6 18855540\n4 Unterberger I Trinka E Diagnosis and treatment of paroxysmal dyskinesias revisited Ther Adv Neurol Disord 2008 1 (2) 4 11 21180566\n5 Huang XJ Wang T Wang JL Liu XL Che XQ Li J Paroxysmal kinesigenic dyskinesia: clinical and genetic analyses of 110 patients Neurology 2015 85 (18) 1546 53 26446061\n6 Martino D Karnik V Osland S Barnes TRE Pringsheim TM Movement disorders associated with antipsychotic medication in people with schizophrenia: an overview of cochrane reviews and meta-analysis Can J Psychiatry 2018 63 (11)\n7 Cornett EM Novitch M Kaye AD Kata V Kaye AM Medication-induced tardive dyskinesia: a review and update Ochsner J 2017 17 (2) 162 74 28638290\n8 Sukasem C Katsila T Tempark T Patrinos GP Chantratita W Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis call for optimum patient stratification and theranostics via pharmacogenomics Annu Rev Genomics Hum Genet 2018 19 329 53 29652519\n9 Tangamornsuksan W Chaiyakunapruk N Somkrua R Lohitnavy M Tassaneeyakul W Relationship between the HLA-B>*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis JAMA Dermatol 2013 149 (9) 1025 32 23884208\n10 Shi YW Min FL Qin B Zou X Liu XR Gao MM Association between HLA and Stevens-Johnson syndrome induced by carbamazepine in Southern Han Chinese: genetic markers besides B>*1502? Basic Clin Pharmacol Toxicol 2012 111 (1) 58 64 22348435\n11 Strzelczyk A Bürk K Oertel WH Treatment of paroxysmal dyskinesias Expert Opin Pharmacother 2011 12 (1) 63 72 21108579\n12 Yang Y Su Y Guo Y Ding Y Xu S Jiang Y Oxcarbazepine versus carbamazepine in the treatment of paroxysmal kinesigenic dyskinesia Int J Neurosci 2012 122 (12) 719 22 22856516\n13 Beran RG Cross-reactive skin eruption with both carbamazepine and oxcarbazepine Epilepsia 1993 34 (1) 163 5 8422852\n14 Beken B Can C Örencik A Can N Yazıcıoğlu M Oxcarbazepine-induced Stevens-Johnson syndrome: a pediatric case report Oxf Med Case Rep 2017 2017 (6) omx028\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "13(3)",
"journal": "Case reports in neurology",
"keywords": "Antiepileptic drugs; Case report; Paroxysmal kinesigenic dyskinesia; Stevens-Johnson syndrome",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
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"pages": "598-604",
"pmc": null,
"pmid": "34703449",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29758999;22348435;21180566;18855540;28580160;8422852;22856516;23884208;28638290;24963779;21108579;26446061;29652519;29892195",
"title": "Successful Treatment of a Paroxysmal Kinesigenic Dyskinesia Patient with Carbamazepine-Induced Stevens-Johnson Syndrome Using Oxcarbazepine Monotherapy: A Case Report.",
"title_normalized": "successful treatment of a paroxysmal kinesigenic dyskinesia patient with carbamazepine induced stevens johnson syndrome using oxcarbazepine monotherapy a case report"
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"abstract": "OBJECTIVE\nThe tolerability and efficacy of simeprevir in combination with peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1 under actual clinical conditions were investigated.\n\n\nMETHODS\nA total of 176 patients with chronic HCV genotype 1 infection were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks. Overall, 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. Treatment discontinuation, sustained virological response 12 (SVR12), and viral relapse were evaluated and compared between younger patients and elderly patients.\n\n\nRESULTS\nThe rates of undetectable HCV RNA at the end of treatment were 95.8, 100 and 93.1 % in treatment-naïve, prior relapse, and prior non-responders, respectively. However, the rates of SVR12 were 82.4, 88.2 and 69.2 %, respectively. Especially in prior non-responders, viral relapse was relatively frequent. Treatment discontinuation and SVR12 were not different between patients aged <70 and ≥70 years, but viral relapse after completing treatment was significantly more frequent in patients aged ≥70 years (p = 0.012).\n\n\nCONCLUSIONS\nIn simeprevir with peginterferon and ribavirin therapy, viral relapse was relatively frequent. Especially in elderly patients, the relapse rate was high after completing treatment, instead of low frequency of discontinuation by the adverse events.",
"affiliations": "Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan.;Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime 790-8524 Japan.;Department of Gastroenterology, Uwajima City Hospital, 1-1 Gotenmachi, Uwajima, Ehime 798-0061 Japan.;Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasugamachi, Matsuyama, Ehime 790-0024 Japan.;Department of Gastroenterology, Saiseikai Imabari Hospital, 7-1-6 Kitamura, Imabari, Ehime 799-1502 Japan.;Department of Gastroenterology, Matsuyama Shimin Hospital, 2-6-5 Ootemachi, Matsuyama, Ehime 790-0067 Japan.;Department of Gastroenterology, Matsuyama Shimin Hospital, 2-6-5 Ootemachi, Matsuyama, Ehime 790-0067 Japan.;Department of Gastroenterology, Ehime Prefectural Imabari Hospital, 4-5-5 Ishiicho, Imabari, Ehime 794-0006 Japan.;Department of Internal Medicine, Shiritsu Oozu Hospital, 570 Kou Nishioozu, Oozu, Ehime 795-0013 Japan.;Department of Internal Medicine, Ehime Prefectural Niihama Hospital, 3-1-1 Hongo, Niihama, Ehime 792-0042 Japan.;Department of Gastroenterology, National Hospital Organization Ehime Medical Center, 366 Yokogawara, Toon, Ehime 791-0203 Japan.;Department of Gastroenterology, Saiseikai Imabari Hospital, 7-1-6 Kitamura, Imabari, Ehime 799-1502 Japan.;Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan.;Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan.;Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan.;Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan.;Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan.",
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"doi": "10.1186/s40064-016-2190-9",
"fulltext": "\n==== Front\nSpringerplusSpringerplusSpringerPlus2193-1801Springer International Publishing Cham 219010.1186/s40064-016-2190-9ResearchSimeprevir with peginterferon/ribavirin for patients with hepatitis C virus genotype 1: high frequency of viral relapse in elderly patients Watanabe Takao wtakao@m.ehime-u.ac.jp Joko Kouji koujijoko@matsuyama.jrc.or.jp Seike Hirotaka seikeshoukaki@ivy.ocn.ne.jp Michitaka Kojiro kojiromichitaka@gmail.com Horiike Norio horiike_n@yahoo.co.jp Kisaka Yoshiyasu kisaka1976@yahoo.co.jp Tanaka Yoshinori y.tanaka@matsuyama-shimin-hsp.or.jp Nakanishi Seiji i-snakani@epnh.pref.ehime.jp Nakanishi Kimio knozuhosp@gmail.com Nonaka Takashi pxp11277jp@yahoo.co.jp Yamauchi Kazuhiko kazu_yamauchi_1@yahoo.co.jp Onji Morikazu m-onji@imabari.saiseikai.or.jp Ohno Yoshinori ynori@m.ehime-u.ac.jp Tokumoto Yoshio yotoku@m.ehime-u.ac.jp Hirooka Masashi masashih@m.ehime-u.ac.jp Abe Masanori masaben@m.ehime-u.ac.jp Hiasa Yoichi +81-89-960-5308hiasa@m.ehime-u.ac.jp Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime 790-8524 Japan Department of Gastroenterology, Uwajima City Hospital, 1-1 Gotenmachi, Uwajima, Ehime 798-0061 Japan Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasugamachi, Matsuyama, Ehime 790-0024 Japan Department of Gastroenterology, Saiseikai Imabari Hospital, 7-1-6 Kitamura, Imabari, Ehime 799-1502 Japan Department of Gastroenterology, Matsuyama Shimin Hospital, 2-6-5 Ootemachi, Matsuyama, Ehime 790-0067 Japan Department of Gastroenterology, Ehime Prefectural Imabari Hospital, 4-5-5 Ishiicho, Imabari, Ehime 794-0006 Japan Department of Internal Medicine, Shiritsu Oozu Hospital, 570 Kou Nishioozu, Oozu, Ehime 795-0013 Japan Department of Internal Medicine, Ehime Prefectural Niihama Hospital, 3-1-1 Hongo, Niihama, Ehime 792-0042 Japan Department of Gastroenterology, National Hospital Organization Ehime Medical Center, 366 Yokogawara, Toon, Ehime 791-0203 Japan 26 4 2016 26 4 2016 2016 5 51817 9 2015 20 4 2016 © Watanabe et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nThe tolerability and efficacy of simeprevir in combination with peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1 under actual clinical conditions were investigated.\n\nMethods\nA total of 176 patients with chronic HCV genotype 1 infection were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks. Overall, 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. Treatment discontinuation, sustained virological response 12 (SVR12), and viral relapse were evaluated and compared between younger patients and elderly patients.\n\nResults\nThe rates of undetectable HCV RNA at the end of treatment were 95.8, 100 and 93.1 % in treatment-naïve, prior relapse, and prior non-responders, respectively. However, the rates of SVR12 were 82.4, 88.2 and 69.2 %, respectively. Especially in prior non-responders, viral relapse was relatively frequent. Treatment discontinuation and SVR12 were not different between patients aged <70 and ≥70 years, but viral relapse after completing treatment was significantly more frequent in patients aged ≥70 years (p = 0.012).\n\nConclusions\nIn simeprevir with peginterferon and ribavirin therapy, viral relapse was relatively frequent. Especially in elderly patients, the relapse rate was high after completing treatment, instead of low frequency of discontinuation by the adverse events.\n\nKeywords\nSimeprevir (TMC435)Elderly patientsViral relapseAdverse eventsGrant-in-Aid for Scientific Research (JSPS KAKENHI)15K09006Hiasa Yoichi issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nHepatitis C virus (HCV) infection is a major public health concern. About 150 million individuals are infected worldwide, and every year, 3–4 million individuals become infected with the virus (European Association for the Study of the Liver 2011; Manns and von Hahn 2013). Japan has one of the highest rates of HCV infection worldwide, and around 2 million people are estimated to be infected, with the majority being infected with HCV genotype 1b (Chung et al. 2010). Chronic infection and liver cirrhosis with HCV are major causes of liver disease (Lavanchy 2009), and hepatocellular carcinoma is a leading cause of cancer mortality in Japan, with more than 70 % of the cases related to HCV infection (Yuen et al. 2009).\n\nThe goal of chronic HCV infection treatment is virus eradication, to prevent progression to cirrhosis and hepatocellular carcinoma. Combination therapy with peginterferon (Peg-IFN) and ribavirin (RBV) for 48–72 weeks has been standard care for HCV genotype 1 infection for many years (Editors of the Drafting Committee for Hepatitis Management Guidelines: The Japan Society of Hepatology 2013; Ghany et al. 2011), resulting in sustained virologic response (SVR) in approximately 50 % of patients (Kuboki et al. 2007; Manns et al. 2001).\n\nThe development of direct-acting antiviral agents (DAAs), including protease inhibitors (PIs), represents a major breakthrough in the treatment of chronic HCV infection. The addition of PI to Peg-IFN and RBV has markedly improved treatment outcomes in both treatment-naïve and treatment-experienced patients (Bacon et al. 2011; Hayashi et al. 2012; Jacobson et al. 2011; Kumada et al. 2012). However, first-generation HCV PIs, such as telaprevir and boceprevir, are associated with multiple daily dosing and the potential for adverse events, including anemia, rash, and renal dysfunction (Poordad et al. 2011; Zeuzem et al. 2011), leading to high rates of treatment discontinuation (Hayashi et al. 2012; McHutchison et al. 2009).\n\nSimeprevir (TMC435) is a once-daily, oral HCV PI, with potent antiviral activity against HCV genotype 1, as well as against genotypes 2 and 4–6, although the efficacy against genotype 2 has been demonstrated only in vitro (Reesink et al. 2010; Moreno et al. 2012). In international phase 3 studies, simeprevir combined with Peg-IFN and RBV has shown good tolerability and high SVR rates in both treatment-naïve (Jacobson et al. 2014; Manns et al. 2014) and treatment-experienced patients (Forns et al. 2014; Reddy et al. 2015). In these studies, almost all treated patients were genotype 1 (1a: 41–56 %, 1b: 44–58 %), and 7.0–15.6 % of patients had liver cirrhosis. Japanese phase 3 studies of simeprevir combined with Peg-IFN and RBV have been reported in treatment-naïve patients (CONCERTO-1, 4) (Hayashi et al. 2014; Kumada et al. 2015), non-responders (CONCERTO-2), and relapsers (CONCERTO-3) to previous IFN-based therapy (Izumi et al. 2014). In these Japanese studies, almost all treated patients were genotype 1b, and no patients with liver cirrhosis were included.\n\nHowever, in Japan, after these clinical trials, the tolerability and efficacy in patients under real-world conditions have not been reported. Additionally, in the CONCERTO 1–4 study, the eligible patients were younger than 70 years, even though in Japan, the percentage of elderly patients with hepatitis C virus infection is high (Tanaka et al. 2004, 2011). In this study, efficacy and treatment discontinuation for adverse events of simeprevir/Peg-IFN/RBV therapy were evaluated in actual clinical practice, and these were compared between younger patients and elderly patients.\n\nPatients and methods\nStudy population\nA total of 176 patients with chronic HCV genotype 1 infection and plasma HCV RNA of 5.0 log10IU/mL or more at screening were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks at 10 hospitals belonging to the Ehime Kan-en Network (EKEN net; Ehime University Hospital, Matsuyama Red Cross Hospital, Ehime Prefectural Central Hospital, Uwajima City Hospital, Saiseikai Imabari Hospital, Matsuyama Shimin Hospital, Ehime Prefectural Imabari Hospital, Shiritsu Oozu Hospital, Ehime Prefectural Niihama Hospital, and National Hospital Organization Ehime Medical Center). The Ethics Committee of Ehime University Hospital approved the study protocol (approval ID 1411010), which conformed to the ethical guidelines of the Declaration of Helsinki amended in 2008. Written, informed consent was obtained from each patient.\n\nExclusion criteria included liver cirrhosis or hepatic failure, liver diseases of non-HCV etiology, co-infection with non-genotype 1 HCV, hepatitis B virus, HIV-1 or HIV-2, and any other clinically significant disease, organ transplant, or defined obvious laboratory abnormalities at screening, as well as a history of hepatocellular carcinoma within 5 years before study entry.\n\nTreatment administration\nSimeprevir (Janssen Pharmaceutical K.K., Tokyo, Japan) 100 mg was administered orally once daily as a single capsule. Simeprevir dose adjustments were not permitted. Two kinds of Peg-IFN/RBV were administered, namely Peg-IFN α-2a (Pegasys®, Chugai Pharmaceutical Co. Ltd, Tokyo, Japan) and RBV (Copegus®, Chugai Pharmaceutical Co. Ltd) or Peg-IFN α-2b (PegIntron®, Merck Sharp & Dohme, Whitehouse Station, NJ, USA) and RBV (Rebetol®, Merck Sharp & Dohme). Peg-IFN α-2a was administered by subcutaneous injection (180 μg once weekly), and Peg-IFN α-2b was administered by subcutaneous injection (1.5 μg/kg body weight). RBV was administered as oral tablets (600–1000 mg total daily dose, depending on body weight). Dose changes, temporary interruptions, or discontinuation of Peg-IFN and RBV had to be conducted in accordance with the manufacturer’s prescribing information.\n\nPatients stopped simeprevir if they experienced any of the following: grade 4 elevation of total bilirubin or aspartate transaminase; grade 3/4 skin events/allergic reactions; or worsening of hepatic disease. All study medications were stopped if patients experienced grade 4 adverse events or laboratory abnormalities that were not considered to be related to simeprevir specifically or were not expected toxicities of Peg-IFN/RBV or HCV infection or if patients experienced worsening of hepatic disease.\n\nAdditionally, all study medications were stopped if the following defined virologic stopping criteria were met: <2 log10IU/mL reduction in HCV RNA at week 12 relative to baseline, or HCV RNA levels of more than 2 log10IU/mL at week 12.\n\nStudy assessments\nPlasma HCV RNA was quantified at screening at baseline, and at 1, 2, 3, 4, 6, 8, 12, 24, 28 and 36 weeks using the Roche COBAS® TaqMan® HCV Auto assay system (Roche Molecular Diagnostics, Pleasanton, CA, USA) with a lower limit of quantification of 1.2 log10IU/mL.\n\nThe major efficacy end-point was the proportion of patients with undetectable HCV RNA at the end of treatment and 12 weeks after the last treatment (SVR12). Other efficacy end-points included the proportion of patients with: undetectable HCV RNA at the end of treatment (EOT); undetectable HCV-RNA at the end of treatment and 4 weeks after the last treatment (SVR4); increase of >1 log10IU/mL in plasma HCV RNA level from the lowest level reached or plasma HCV RNA level >2.0 log10IU/mL in patients whose plasma HCV RNA level had previously been <1.2 log10IU/mL detectable or undetectable (viral breakthrough); detectable or quantifiable plasma HCV RNA during the post-treatment follow-up period in patients who had undetectable plasma HCV RNA at the end of treatment (viral relapse); and the proportion of patients who discontinued treatment due to adverse events or virologic stopping criteria.\n\nStatistical analysis\nDifferences were evaluated using the χ2-test, Student’s t test, or Welch’s t test. Factors that were not normally distributed were evaluated by Welch’s t test. Predictors of SVR12 and viral relapse after treatment completion were evaluated using multivariate logistic regression analyses. Odds ratios (ORs) and 95 % confidence intervals were also calculated. All p values <0.05 on two-tailed testing were considered significant. Data were statistically analyzed using SPSS software ver. 18.\n\nResults\nPatients\nThis was a prospective, multicenter study. In total, 176 patients received treatment; 85 patients were treatment-naïve, and 90 patients were treatment-experienced. In treatment-experienced patients, 51 patients were prior relapsers (patients who had undetectable levels of HCV RNA at the last assessment while on IFN-based therapy and subsequent detectable levels of HCV RNA within 12 months from their last treatment), 26 patients were prior non-responders (patients who did not achieve undetectable HCV RNA on prior IFN-based therapy), and there was no prior treatment information for the remaining 12 patients. Demographic and disease characteristics at baseline are shown in Table 1. The patients’ median age was 62 years (range 28–78 years); 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. IL28B rs8099917 polymorphisms were determined in 91 patients; 69 patients were major allele TT, and 22 patients were minor allele TG/GG.Table 1 Clinical and virological characteristics of patients with HCV infection\n\nSex (male/female)\t95/81\t\nAge (years)\t62 (28–78)\t\nAST (IU/L)\t43.5 (18–217)\t\nALT (IU/L)\t48.0 (11–225)\t\nTotal bilirubin (mg/dL)\t0.8 (0.1–2.7)\t\nHemoglobin (g/dL)\t14.5 (10.1–18.3)\t\nWhite blood cells (/µL)\t4905 (2100–9610)\t\nPlatelet count (×104/µL)\t15.3 (5.9–28.0)\t\nHCV RNA (log copies/mL)\t6.5 (5.0–7.8)\t\nIL28B genotype (SNP8099917) (TT/non-TT)\t69/22\t\nHCV Core aa70 (wild/mutant)\t38/13\t\nHCV Core aa91 (wild/mutant)\t32/19\t\nTreatment-naïve/relapsers/non-responders/unknown\t85/51/26/14\t\nPrior therapy (IFN only/IFN + RBV/Peg-IFN/Peg IFN + RBV/teraprevir/Others)\t12/7/5/49/3/12\t\nHistological fibrosis (METAVIR score) (F0/F1/F2/F3/F4/ND)\t1/28/34/30/4/79\t\n\nALT alanine aminotransferase, AST aspartate aminotransferase, HCV hepatitis C virus, SNP single nucleotide polymorphism, Peg-IFN peginterferon, RBV ribavirin\n\n\n\nVirologic response\nThe rates of HCV RNA negative conversion during the treatment period in patients grouped according to past treatment experience are shown in Fig. 1 (ITT analysis); most patients in all groups had achieved levels below the lower limit of quantification. Non-responders had slightly lower rates of HCV RNA negative conversion at each time point, but significant differences were not seen.Fig. 1 The proportion of HCV RNA negative conversion at each time point after treatment start (ITT analysis). The black line shows the proportion of HCV RNA negative conversion in all patients. The gray line shows that in treatment-naïve patients, the black dotted line shows that in prior relapsers, and the gray dotted line shows that in prior non-responders. Non-responders have slightly lower rates of HCV RNA negative conversion at each time point, but no significant differences are seen\n\n\n\nThe EOT response, SVR4 response, and SVR12 response are shown in Fig. 2. In all patients, EOT, SVR4, and SVR12 responses were 96.0, 88.6 and 81.8 %, respectively. There was a relatively high frequency of viral relapse. The viral relapse rate was higher in non-responders than in treatment-naïve patients or relapsers.Fig. 2 The proportions of EOT, SVR4, and SVR12 achievement in all patients, treatment-naïve patients, relapsers, and non-responders are shown. EOT, undetectable HCV RNA at the end of treatment; SVR4, undetectable HCV-RNA at the end of treatment and 4 weeks after the last treatment; SVR12, undetectable HCV-RNA at the end of treatment and 12 weeks after the last treatment\n\n\n\nTreatment discontinuation\nTreatment discontinuation was seen in 20 patients (11.3 %). The reasons for discontinuation are shown in Table 2. Viral breakthrough was seen in three patients, and two patients stopped treatment according to the virologic stopping criteria. Three of these five patients had a mutation in the HCV NS3 Protease domain at position 168 (D168V, D168E, and D168A, respectively) at the end of treatment or at viral relapse.Table 2 Reasons for discontinuing treatment with simeprevir plus Peg-IFN/RBV\n\nReason for discontinuation\tNo. of patients\t\nViral breakthrough\t3\t\nVirological stopping criteria\t2\t\nDepression\t3\t\nRash\t1\t\nRetinopathy\t1\t\nAnemia\t3\t\nGeneral fatigue\t5\t\nOthers\t2\t\n\n\nTreatment discontinuation and efficacy in elderly patients\nIn Japan, the percentage of elderly patients with hepatitis C virus infection is high. In fact, 60.7 % of the present patients were aged 60 years or more, and 9 % of the patients were aged 70 years or more. The rates of treatment discontinuation and SVR12 achievement were compared between patients aged 60 years or more and patients aged <60 years. Similarly, the rates of treatment discontinuation and SVR12 achievement were compared between patients aged 70 years or more and patients aged <70 years. The rates of treatment discontinuation and SVR12 achievement were not significantly different between patients aged 60 years or more and patients aged <60 years (p = 0.225, p = 0.556, respectively) (Fig. 3a). Similarly, the rates of treatment discontinuation and SVR12 achievement were not significantly different between patients aged 70 years or more and patients aged <70 years (p = 0.090, p = 0.081, respectively) (Fig. 3b).Fig. 3 The proportions of treatment discontinuation and SVR12 achievement in patients aged 60 years or more and patients aged <60 years (a). The proportions of treatment discontinuation and SVR12 achievement in patients aged 70 years or more and patients aged <70 years (b). No significant differences are seen between younger and elderly patients\n\n\n\nAs mentioned above, there was a relatively high frequency of viral relapse after completion of 24 weeks therapy. Thus, the rates of viral relapse after completion of 24 weeks therapy were also compared between patients aged 60 years or more and patients aged <60 years, and between patients aged 70 years or more and patients aged <70 years. The rates of viral relapse after treatment completion were not significantly different between patients aged 60 years or more and patients aged <60 years (p = 0.49) (Fig. 4a). However, viral relapse after treatment completion was significantly more frequent in patients aged 70 years or more than in those aged <70 years (41.6 vs 12.5 %, p = 0.018) (Fig. 4b).Fig. 4 The proportions of viral relapse after 24-week therapy completion. There is no significant difference between patients aged 60 years or more and patients aged <60 years (a). However, viral relapse is more frequent in patients aged 70 years or more than in patients aged <70 years (b) (41.6 vs 12.5 %, p = 0.018)\n\n\n\nPredictors of SVR12 achievement\nFactors that might contribute to SVR achievement were evaluated (Table 3). Potential predictive factors associated with SVR12 included age (70 years or more/<70 years), sex, ALT, platelet count, AFP, HCV-RNA, IL28B rs8099917 polymorphisms (TT/non-TT), HCV Core aa70 (wild/mutant), HCV Core aa91 (wild/mutant), treatment-naïve/treatment-experienced, non-responders to past treatment/others, Peg-IFN adherence, and RBV adherence. HCV NS3 Q80 K status, which has been reported as a predictor of simeprevir failure, was tested in 38 patients, and only 1 (2.6 %) patient had Q80 K; thus, this was not evaluated as a predictive factor. It was found that the presence of IL28B rs8099917 polymorphisms was the only predictive factor (p = 0.02). Platelet count, HCV core aa70, and non-responders tended to be associated with SVR12 achievement, but they were not significant. Multivariate analysis was performed using the factors whose p values were <0.1 on univariate analyses (age 70 years or more/<70 years, platelet count, HCV-RNA, IL28B polymorphisms, HCV core aa 70, non-responders to past treatment/others). Only IL28B polymorphism (TT vs non-TT, odds ratio: 0.145, p = 0.029) was identified as a significant factor (Table 4).Table 3 Factors associated with SVR12 achievement\n\n\tSVR12\tNon-SVR12\tp value\t\nSex (male/female)\t82/62\t13/19\t0.11\t\nAge 70 years or more/<70 years\t134/10\t26/6\t0.08\t\nALT (U/L)\t62.5 ± 45.9\t64.9 ± 36.4\t0.81\t\nPlatelet count (×104/µL)\t15.8 ± 4.7\t14.1 ± 4.9\t0.08\t\nAFP (ng/mL)\t12.3 ± 34.4\t16.0 ± 19.4\t0.56\t\nHCV-RNA (log copies/mL)\t6.4 ± 0.68\t6.6 ± 0.58\t0.10\t\nIL28B (TT/non-TT)\t61/14\t8/8\t0.02\t\nHCV Core aa70 (wild/mutant)\t35/9\t3/4\t0.06\t\nHCV Core aa91 (wild/mutant)\t26/17\t6/2\t0.69\t\nTreatment naïve/re-treatment\t70/73\t15/17\t0.84\t\nNon-responders/others\t18/115\t8/21\t0.09\t\nPeg-IFN adherence (%)\t88.6 ± 22.4\t78.6 ± 39.1\t0.18\t\nRBV adherence (%)\t82.3 ± 22.4\t76.7 ± 45.1\t0.50\t\nHistological fibrosis (F0-2/F3-4)\t55/28\t8/6\t0.55\t\nData are expressed as mean ± standard deviation\n\n\nSVR sustained virological response, ALT alanine aminotransferase, AFP α-fetoprotein, HCV hepatitis C virus, Peg-IFN peginterferon, RBV ribavirin\n\nTable 4 Independent factors associated with SVR12 achievement on multiple logistic regression analysis\n\n\tOdds ratio\t95 % CI\tp value\t\nIL28B (TT/non-TT)\t0.145\t0.026-0.822\t0.029\t\n\nCI confidence interval\n\n\n\nPredictors of viral relapse after treatment completion\nIn simeprevir/Peg-IFN/RBV therapy, since viral relapse after completion of 24 weeks of therapy was frequent, an attempt was made to identify the predictors of viral relapse after treatment completion (Table 5). Potential predictive factors associated with SVR12 included age (age 70 years or more/<70 years), sex, ALT, platelet count, AFP, HCV-RNA, IL28B rs8099917 polymorphisms (TT/non-TT), HCV Core aa70 (wild/mutant), HCV Core aa91 (wild/mutant), treatment-naïve/treatment-experienced, non-responders to past treatment/others, Peg-IFN adherence, and RBV adherence. Age 70 years or more, IL28B rs8099917 polymorphisms, and platelet count were identified as predictive factors (p = 0.018, 0.012, 0.023, respectively). Multivariate analysis was conducted using the factors whose p values were <0.1 on univariate analyses (age 70 years or more/<70 years, platelet count, IL28B polymorphisms, non-responders to past treatment/others). Age (age 70 years or more vs <70 years, odds ratio: 15.1, p = 0.037) and IL 28B polymorphisms (TT vs non-TT, odds ratio: 6.29, p = 0.022) were identified as significant factors (Table 6). The factor age 70 years or more had the highest odds ratio for predicting viral relapse after treatment completion.Table 5 Factors associated with viral relapse after treatment completion\n\n\tViral relapse\tSVR12\tp value\t\nSex (male/female)\t9/14\t73/60\t0.18\t\nAge 70 years or more/<70 years\t5/18\t7/126\t0.018\t\nALT (U/L)\t62.6 ± 38.0\t63.6 ± 46.9\t0.92\t\nPlatelet count (×104/µL)\t13.5 ± 4.5\t15.9 ± 4.6\t0.023\t\nAFP (ng/mL)\t16.6 ± 21.8\t12.3 ± 35.4\t0.58\t\nHCV-RNA (log copies/mL)\t6.6 ± 0.57\t6.4 ± 0.69\t0.14\t\nIL28B (TT/non-TT)\t4/6\t57/14\t0.012\t\nHCV Core aa70 (wild/mutant)\t1/2\t33/9\t0.14\t\nHCV Core aa91 (wild/mutant)\t3/1\t24/17\t0.64\t\nTreatment naïve/re-treatment\t10/13\t66/66\t0.65\t\nNon-responders/others\t6/17\t16/106\t0.10\t\nPeg-IFN adherence (%)\t88.6 ± 19.5\t91.8 ± 18.6\t0.46\t\nRBV adherence (%)\t90.6 ± 43.9\t84.8 ± 20.7\t0.33\t\nHistological fibrosis (F0-2/F3-4)\t7/6\t52/25\t0.35\t\nData are expressed as mean ± standard deviation\n\n\nSVR sustained virological response, ALT alanine aminotransferase, AFP α-fetoprotein, HCV hepatitis C virus, Peg-IFN peginterferon, RBV ribavirin\n\nTable 6 Independent factors associated with viral relapse after treatment completion on multiple logistic regression analysis\n\n\tOdds ratio\t95 % CI\tp value\t\nAge 70 years or more/<70 years\t15.1\t1.18–194\t0.037\t\nIL28B (TT/non-TT)\t6.29\t1.29–30.5\t0.022\t\n\nCI confidence interval\n\n\n\nDiscussion\nIn patients treated with just Peg-IFN and ribavirin, IL28B genotype (non-TT) and advanced fibrosis are associated with a low rate of SVR (Tanaka et al. 2009; Manns et al. 2001; Fried et al. 2002). In an international study of simeprevir and Peg-IFN/Ribavirin, simeprevir treatment also resulted in higher SVR12 in patients with advanced fibrosis than just Peg-IFN and ribavirin (Jacobson et al. 2014; Manns et al. 2014; Forns et al. 2014). In the present study, platelet count and histological fibrosis did not affect the rate of SVR12. In these international studies, since the difference in SVR12 according to IL28B polymorphism was substantially smaller than in the placebo group, the correlation between IL28B genotype and efficacy of simeprevir was smaller than for just Peg-IFN/ribavirin therapy. In a Japanese study, the results of the subgroup analysis by IL28B polymorphism also showed that there were no significant differences in efficacy according to this genotype (Hayashi et al. 2014; Kumada et al. 2015; Izumi et al. 2014). On the other hand, in the present study, only IL28B genotype was a factor affecting SVR12. Though in the past clinical studies of simeprevir therapy the median age of patients was in the forties or fifties, that of the present patients was 62 years, and patients over 70 years were also included, which would be the reason for the difference in the effect on treatment efficacy between the present results and those of past studies. In Japanese actual clinical practice, the proportion of elderly patients is high, so the present results should be taken into account.\n\nThe present study showed that, especially in prior non-responders, there was a relatively high frequency of viral relapse (p = 0.060 compared with prior relapsers). This result agreed with past studies; for example, in CONCERT-2 (prior non-responders), viral relapse was seen in 38.6 % compared to 8.2 % in CONCERT-3 (prior relapsers). In the past reports, the factors involved in viral relapse after treatment completion were not analyzed; therefore, these factors were examined in the present study. It was found that low platelet count and IL28B SNP8099917 non-TT genotype were the significant risk factors for viral relapse. Moreover, patients aged over 70 years had a significantly higher frequency of viral relapse after treatment completion. In the present study, the number of patients aged over 70 years was small, so the result must be viewed in that light. However, multivariate analysis indicated that age over 70 years was an independent contributing factor to viral relapse after treatment completion. These data indicate that, for suppression of viral relapse, the treatment effect of Peg-IFN/ribavirin is important, because hepatic fibrosis, IL28B genotype, and age have previously been reported as factors affecting SVR in Peg-IFN/ribavirin therapy (Tanaka et al. 2009; Manns et al. 2001; Fried et al. 2002; Dienstag and McHutchison 2006).\n\nSome mutations, such as D168E/T/V, Q80R/K, and R155K, have been previously described in HCV genotype 1b after exposure to simeprevir in vitro and in clinical studies (Hayashi et al. 2014; Lenz et al. 2010; Fried et al. 2013). Additionally, the majority of patients with viral breakthrough or relapse had emerging mutations in the HCV NS3 protease domain. These mutations were mostly at position 168 (Lenz et al. 2010). In the present patients at treatment start, only one of 40 tested patients had a position 80 mutant, and all 40 tested patients were wild type at position 168 of the HCV NS3 protease domain. In the present study, viral breakthrough was seen in three patients, and two patients stopped treatment according to virologic stopping criteria. Three of these four patients had mutations in the HCV NS3 Protease domain at position 168 (D168V, D168E, D168A, respectively) at the end of treatment or viral relapse. Unfortunately, these mutations could not be examined in viral relapse patients.\n\nIn studies of first-generation protease inhibitors, rates of treatment discontinuation due to severe adverse events have been reported to be 10–20 % (Bacon et al. 2011; Hayashi et al. 2012; Jacobson et al. 2011; Kumada et al. 2012; Poordad et al. 2011). However, in simeprevir with Peg-IFN/ribavirin therapy, treatment discontinuations were much less frequent, at 3–5 % (Hayashi et al. 2014; Kumada et al. 2015; Izumi et al. 2014). Manns et al. (2015) reported a pooled safety analysis from international phase IIb and III studies. In this report, most adverse events were grade 1/2, and most grade 3/4 adverse events occurred in <5.0 % of patients. Moreover, tolerability did not vary with histological hepatic fibrosis. In the present study, the rate of treatment discontinuation was not different between patients aged <60 and ≥60 years, and even between those aged <70 and ≥70 years. These results mean that simeprevir therapy is well tolerated even in the actual clinical setting.\n\nThe combination of simeprevir and other direct-acting antivirals such as sofosbuvir as an HCV NS5B inhibitor is expected to be the treatment option for patients with chronic HCV genotype 1 infection by providing interferon-free treatment (Schinazi et al. 2014). Efficacy of the interferon-free combination of simeprevir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection was reported to be more than 90 % (SVR12 rate) (Lawitz et al. 2014). Moreover, although direct-acting antiviral combinations in an interferon-free regimen would be main stream in the future, Peg-IFN and ribavirin-based treatment could remain the standard of care in parts of the world in which the very high treatment costs of direct-acting antiviral interferon-free regimens would be prohibitive. Then, the present data of simeprevir with Peg-IFN and ribavirin in the actual clinical setting would be valuable.\n\nIn conclusion, in simeprevir with peginterferon and ribavirin therapy, both efficacy and tolerability are good, even in elderly patients, but viral relapse after completing treatment was high in patients aged over 70 years. Patients <70 years old and those discontinuing previous DAAs would be suitable for this treatment.\n\nAuthors’ contributions\nTW, YT, YH: Study design; TW, KJ, HS, KM, NH, YK, YT, SN, KN, TN, KY, MO, MA: Data acquisition; TW, YT, YH: Quality control of data and algorithms; TW, YT, YO, MH: Data analysis and interpretation; TW, YT: carried out the molecular genetic studies and participated in the sequence alignment; TW, YO, YT, MH: Statistical analysis; TW, YH: drafted the manuscript; TW, YH: Manuscript preparation; TW, YH: Manuscript editing; TW, YH: Manuscript review. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis study was supported by Grant-in-Aid for Scientific Research (JSPS KAKENHI number 15K09006) from Japanese Ministry of Education, Culture, Sports, Science and Technology (to Y.H.).\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nEthical standards\nAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent for being included in the study was obtained from all patients.\n==== Refs\nReferences\nBacon BR Gordon SC Lawitz E Boceprevir for previously treated chronic HCV genotype 1 infection N Engl J Med 2011 364 1207 1217 10.1056/NEJMoa1009482 21449784 \nChung H Ueda T Kudo M Changing trends in hepatitis C infection over the past 50 years in Japan Intervorology 2010 53 39 43 10.1159/000252782 \nDienstag JL McHutchison JG American Gastroenterological Association medical position statement on the management of hepatitis C Gastroenterology 2006 130 225 230 10.1053/j.gastro.2005.11.011 16401485 \nEditors of the Drafting Committee for Hepatitis Management Guidelines: The Japan Society of Hepatology Guideline for the Management of Hepatitis C Virus Infection: first edition, May 2012, The Japan Society of Hepatology Hepatol Res 2013 43 1 34 10.1111/hepr.12020 23332085 \nEuropean Association for the Study of the Liver EASL Clinical Practice Guidelines: management of hepatitis C virus infection J Hepatol 2011 55 245 264 10.1016/j.jhep.2011.02.023 21371579 \nForns X Lawitz E Zeuzem S Simeprevir with peginterferon and Ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial Gatroenterology 2014 146 1669 1679 10.1053/j.gastro.2014.02.051 \nFried MW Shiffman ML Reddy KR Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection N Engl J Med 2002 347 975 982 10.1056/NEJMoa020047 12324553 \nFried MW Buti M Dore GJ Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study Hepatology 2013 58 1918 1929 10.1002/hep.26641 23907700 \nGhany MG Nelson DR Strader DB An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases Hepatology 2011 54 1433 1444 10.1002/hep.24641 21898493 \nHayashi N Okanoue T Tsubouchi H Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C J Viral Hepat 2012 19 e134 e142 10.1111/j.1365-2893.2011.01528.x 22239511 \nHayashi N Izumi N Kumada H Simeprevir with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial J Hepatol 2014 61 219 227 10.1016/j.jhep.2014.04.004 24727123 \nIzumi N Hayashi N Kumada H Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies J Gastroenterol 2014 49 941 953 10.1007/s00535-014-0949-8 24626851 \nJacobson IM McHutchison JG Dusheiko G Telaprevir for previously untreated chronic hepatitis C virus infection N Engl J Med 2011 364 2405 2416 10.1056/NEJMoa1012912 21696307 \nJacobson IM Dore GJ Foster GR Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naïve patients with chronic hepatitis C virus henotype 1 infection (QUEST-1): a phase 3, randomized, double-blind, placebo-controlled trial Lancet 2014 384 403 413 10.1016/S0140-6736(14)60494-3 24907225 \nKuboki M Iino S Okuno T Peginterferon alpha-2a (40KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients J Gastroenterol Hepatol 2007 22 645 652 17444850 \nKumada H Toyota J Okanoue T Telaprevir with peginterferon and ribavirin for treatment-naïve patients chronically infected with HCV of genotype 1 in Japan J Hepatol 2012 56 78 84 10.1016/j.jhep.2011.07.016 21827730 \nKumada H Hayashi N Izumi N Simeprevir (TMC435) once daily with peginterferon-α-2b and ribavirin in patients with genotype 1 hepatitis C virus infection: the CONCERTO-4 study Hepatol Res 2015 45 501 513 10.1111/hepr.12375 24961662 \nLavanchy D The global burden of hepatitis C Liver Int 2009 29 Supp 1 74 81 10.1111/j.1478-3231.2008.01934.x 19207969 \nLawitz E Sulkowski MS Ghalib R Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naïve patients: the COSMOS randomized study Lancet 2014 384 1756 1765 10.1016/S0140-6736(14)61036-9 25078309 \nLenz O Verbinnen T Lin TI In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435 Anti-microb Agents Chemother 2010 54 1878 1887 10.1128/AAC.01452-09 \nManns MP von Hahn T Novel therapies for hepatitis C-one pill fits all? Nat Rev Drug Discov 2013 12 595 610 10.1038/nrd4050 23807378 \nManns MP McHutchison JG Gordon SC Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C: a randomized trial Lancet 2001 358 958 965 10.1016/S0140-6736(01)06102-5 11583749 \nManns M Marcellin P Poordad F Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomized, double-blind, placebo-controlled phase 3 trial Lancet 2014 384 414 426 10.1016/S0140-6736(14)60538-9 24907224 \nManns MP Fried MW Zeuzem S Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: pooled safety analysis from phase IIb and III studies J Viral Hepat 2015 22 366 375 10.1111/jvh.12346 25363449 \nMcHutchison JG Everson GT Gordon SC Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection N Engl J Med 2009 360 1827 1838 10.1056/NEJMoa0806104 19403902 \nMoreno C Berg T Tanwandee T Antiviral activity of TMC435 monotherapy in patients infected with HCV genotype 2–6: TMC435-C202, a phase II a, open-label study J Hepatol 2012 56 1247 1253 10.1016/j.jhep.2011.12.033 22326470 \nPoordad F McCone J Jr Bacon BR Boceprevir for untreated chronic HCV genotype 1 infection N Eng J Med 2011 364 1195 1206 10.1056/NEJMoa1010494 \nReddy KR Zeuzem S Zoulim F Simeprevir versus teraplevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomized, double-blind, non-inferiority phase 3 trial Lancet Infect Dis 2015 15 27 35 10.1016/S1473-3099(14)71002-3 25482330 \nReesink HW Fanning GC Farha KA Rapid HCV-RNA decline with once daily TMC435: a phase 1 study in healthy volunteers and hepatitis C patients Gastroenterology 2010 138 913 921 10.1053/j.gastro.2009.10.033 19852962 \nSchinazi R Halfon P Marcellin P HCV direct-acting antiviral agent: the best interferon-free combinations Liver Int 2014 34 suppl 1 69 78 10.1111/liv.12423 24373081 \nTanaka J Kumagai J Katayama K Sex- and age-specific carriers of hepatitis B and C viruses in Japan estimated by the prevalence in the 3,485,648 first-time blood donors during 1995–2000 Intervirology 2004 47 32 40 10.1159/000076640 15044834 \nTanaka Y Nishida N Sugiyama M Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C Nat Genet 2009 41 1105 1109 10.1038/ng.449 19749757 \nTanaka J Koyama T Mizui M Total numbers of undiagnosed carriers of hepatitis C and B viruses in Japan estimated by age- and area-specific prevalence on the national scale Intervirology 2011 54 185 195 10.1159/000324525 21454956 \nYuen MF Hou JL Chutaputti A Hepatocellular carcinoma in the Asia Pacific region J Gastroenterol Hepatol 2009 24 346 353 10.1111/j.1440-1746.2009.05784.x 19220670 \nZeuzem S Andreone P Pol S Telaprevir for retreatment of HCV infection N Eng J Med 2011 364 2417 2428 10.1056/NEJMoa1013086\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2193-1801",
"issue": "5()",
"journal": "SpringerPlus",
"keywords": "Adverse events; Elderly patients; Simeprevir (TMC435); Viral relapse",
"medline_ta": "Springerplus",
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"nlm_unique_id": "101597967",
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"pages": "518",
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"pmid": "27186482",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
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"title": "Simeprevir with peginterferon/ribavirin for patients with hepatitis C virus genotype 1: high frequency of viral relapse in elderly patients.",
"title_normalized": "simeprevir with peginterferon ribavirin for patients with hepatitis c virus genotype 1 high frequency of viral relapse in elderly patients"
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"abstract": "We recently treated a chronic myeloid leukemia (CML) patient with liver and renal dysfunction, who was undergoing hemodialysis (HD). He was treated with 50 mg dasatinib (DAS) once daily just before HD. The maximum plasma concentration of DAS was 227 ng/mL on a non-HD day and 46.9 ng/mL on a HD day. He was subsequently treated with 200 mg bosutinib (BOS) once daily. The plasma concentration of BOS changed from 74.5 ng/mL before HD to 58.8 ng/mL after HD. Our results indicate that close monitoring of the plasma tyrosine kinase inhibitor concentrations should be considered in CML patients with organ impairment.",
"affiliations": "Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Japan.;Department of Pharmacy, Akita University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Department of Hematology, PL General Hospital, Japan.;Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.;Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.",
"authors": "Taniguchi|Yasuhiro|Y|;Takahashi|Naoto|N|;Miura|Masatomo|M|;Hirase|Chikara|C|;Sueda|Sanae|S|;Espinoza|Jorge Luis|JL|;Rai|Shinya|S|;Nakayama|Shoko|S|;Serizawa|Kentaro|K|;Kumode|Takahiro|T|;Watatani|Yosaku|Y|;Morita|Yasuyoshi|Y|;Tanaka|Hirokazu|H|;Matsumura|Itaru|I|",
"chemical_list": "D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D000069439:Dasatinib",
"country": "Japan",
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"doi": "10.2169/internalmedicine.4871-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32641651\n10.2169/internalmedicine.4871-20\nCase Report\nThe Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia\nTaniguchi Yasuhiro 1 Takahashi Naoto 2 Miura Masatomo 3 Hirase Chikara 1 Sueda Sanae 4 Espinoza Jorge Luis 56 Rai Shinya 1 Nakayama Shoko 1 Serizawa Kentaro 1 Kumode Takahiro 1 Watatani Yosaku 1 Morita Yasuyoshi 1 Tanaka Hirokazu 1 Matsumura Itaru 1 \n1 Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan\n\n2 Departments of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Japan\n\n3 Department of Pharmacy, Akita University Hospital, Japan\n\n4 Department of Hematology, PL General Hospital, Japan\n\n5 Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan\n\n6 Faculty of Medicine, UNIDES University, Nicaragua\nCorrespondence to Dr. Yasuhiro Taniguchi, m11049@med.kindai.ac.jp\n\n\n7 7 2020 \n1 11 2020 \n59 21 2745 2749\n17 3 2020 28 4 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 recently treated a chronic myeloid leukemia (CML) patient with liver and renal dysfunction, who was undergoing hemodialysis (HD). He was treated with 50 mg dasatinib (DAS) once daily just before HD. The maximum plasma concentration of DAS was 227 ng/mL on a non-HD day and 46.9 ng/mL on a HD day. He was subsequently treated with 200 mg bosutinib (BOS) once daily. The plasma concentration of BOS changed from 74.5 ng/mL before HD to 58.8 ng/mL after HD. Our results indicate that close monitoring of the plasma tyrosine kinase inhibitor concentrations should be considered in CML patients with organ impairment. \n\ndasatinibbosutinibhemodialysisliver cirrhosisplasma concentrations\n==== Body\nIntroduction\nChronic myeloid leukemia (CML) is a cancer of the blood cells, which is characterized by the increased and unregulated proliferation of myeloid cells in the bone marrow. Proliferating myeloid cells, which include mature granulocytes (neutrophils, eosinophils, and basophils) and immature precursors, accumulate in the blood, and their excessive proliferation is largely responsible for the symptoms associated with CML.\n\nCML is a clonal disorder, originating from abnormal stem cells harboring a characteristic chromosomal abnormality called the Philadelphia chromosome, which is created via a translocation between the 9th and 22nd chromosomes. This chromosomal abnormality results in the formation of the BCR-ABL1 fusion gene, which generates the BCR-ABL protein. The BCR-ABL protein exhibits constitutive tyrosine kinase activity and affects the cell cycle and anti-apoptosis pathway, resulting in the unregulated proliferation that is characteristic of CML.\n\nMost CML patients are diagnosed in the chronic phase (CP) of the condition, which lasts for 4-6 years. If CML-CP patients are not treated or the treatment is ineffective, then CML progresses to the accelerated phase (AP) followed by the blastic phase (BP), in which CML exhibits severe resistance to all treatments. Therefore, the prevention of disease progression is the most important factor affecting the outcomes of CML-CP treatment.\n\nTyrosine kinase inhibitor (TKI) treatment has greatly improved the prognosis of CML-CP (1). At present, TKI-treated CML patients rarely experience disease progression to AP or BP, and the life expectancy of such patients was found to be almost the same as that of an age-matched control population (2).\n\nOn the other hand, the prognosis of CML patients with high Charlson comorbidity indices (CCI) was significantly worse than the prognosis of CML patients with low CCI (3). However, the efficacy of TKIs did not differ among these cohorts, suggesting that it is important to appropriately manage pre-existing complications and the toxicities of TKIs in CML patients. Therefore, appropriate dose adjustment of TKIs should be considered according to the patients' backgrounds (including their comorbidities).\n\nBoth the efficacy and toxicity of TKIs are dependent on the plasma concentrations of the drugs (4-7). However, the plasma concentrations of TKIs are affected by concomitantly administered drugs and the functions of the liver and kidneys, which are involved in drug absorption, metabolism, and excretion. Thus, special attention should be paid to patients who are taking multiple drugs or that have organ dysfunction when prescribing TKIs.\n\nWe recently experienced a case involving a CML-CP patient with liver cirrhosis, who was undergoing hemodialysis (HD).\n\nLittle is known about the influence of HD on the plasma concentrations of TKIs in CML patients with renal insufficiency. We herein report on the changes in the plasma concentrations of dasatinib (DAS) and bosutinib (BOS) that occurred in the abovementioned patient and review the effects of HD on the plasma concentrations of TKIs.\n\nCase Report\nA 64-year-old man was referred to Kindai University Hospital with leukocytosis. He had chronic kidney disease (CKD) due to chronic glomerulonephritis, and had been undergoing HD three times a week since 1985. In addition, he had liver cirrhosis (Child-Pugh classification: class A), and his indocyanine green retention rate at 15 minutes was 17%. He had a history of acute hepatitis B, and serological tests produced the following results: HBsAg (-), HBsAb (+), and HBV-DNA (-). At his first visit, he was free from splenomegaly, ascites, fever, night sweats, and general fatigue. His laboratory data are shown in Table 1. A bone marrow aspirate specimen revealed marked hypercellularity with myeloid hyperplasia, but no dysplasia or increase in the blast ratio was seen. Karyotyping of his bone marrow cells produced the following result: t(9;22)(q34;q11.2). No other cytogenetic abnormalities were detected. The patient was diagnosed with CML-CP, and DAS treatment was started at a dose of 50 mg once a day.\n\nTable 1. Laboratory Findings in This Case.\n\nCBC\t\tChemistry\t\tCoagulation\t\nRBC\t\t398\t×104/μL\t\tAST\t\t39\tU/L\t\tPT\t\t84.4\t%\t\nHb\t\t11.8\tg/dL\t\tALT\t\t16\tU/L\t\tAPTT\t\t35.8\ts\t\nHct\t\t37.1\t%\t\tALP\t\t441\tU/L\t\t\t\t\t\t\nPlt\t\t34.7\t×104/μL\t\tLDH\t\t364\tU/L\t\t\t\t\t\t\nWBC\t\t28,610\t/μL\t\tT-Bil\t\t0.5\tmg/dL\t\t\t\t\t\t\nMyeloblasts\t\t0.3\t%\t\tTP\t\t7.5\tg/dL\t\t\t\t\t\t\nMyelocytes\t\t4.3\t%\t\tAlb\t\t3.7\tg/dL\t\t\t\t\t\t\nMetamyelocytes\t\t3\t%\t\tBUN\t\t26\tmg/dL\t\tICG-R15\t\t17\t%\t\nStab neutrophils\t\t4.7\t%\t\tCre\t\t4.48\tmg/dL\t\t\t\t\t\t\nSeg. neutrophils\t\t59.4\t%\t\tUA\t\t4.2\tmg/dL\t\t\t\t\t\t\nEosinophils\t\t3.7\t%\t\tGlu\t\t91\tmg/dL\t\t\t\t\t\t\nBasophils\t\t10\t%\t\tCRP\t\t0.95\tmg/dL\t\t\t\t\t\t\nMonocytes\t\t6\t%\t\t\t\t\t\t\t\t\t\t\nLymphocytes\t\t8.3\t%\t\t\t\t\t\t\t\t\t\t\nNAP rate\t\t7\t%\t\t\t\t\t\t\t\t\t\t\t\nCBC: complete blood count, RBC: red blood cells, Hb: hemoglobin, Hct: hematocrit, Plt: platelets, WBC: white blood cells, Seg. neutrophils: segmented neutrophils, NAP: neutrophil alkaline phosphatase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, LDH: lactate dehydrogenase, T-Bil: total bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, Glu: glucose, CRP: C-reactive protein, PT: prothrombin time, APTT: activated partial thromboplastin time, ICG-R15: indocyanine green retention rate at 15 min\n\nOne week after the start of the DAS treatment, we had the drug's plasma concentration measured by MASIS (Food and Drug Nano Analysis, MASIS, Aomori, Japan) on two consecutive days (the patient was on HD on the 1st day and off HD on the 2nd day). DAS was given to the patient just before HD, and its maximum plasma concentration (Cmax) was 46.9 ng/mL at 2 hours. In contrast, its Cmax was elevated (227 ng/mL) on the non-HD day. The area under the time-concentration curve over the first 12 hours [AUC (0-12)] was 257 ng·h/mL on the HD day and 793 ng·h/mL on the non-HD day (Figure). However, 2 weeks after the start of the DAS treatment, mild bilateral pleural effusion and pulmonary hypertension (PH) (45 mmHg) were detected on an X-ray examination and cardiac ultrasonography. Although we considered that the PH had been caused by chronic heart failure, rather than the DAS treatment, because DAS had only been administered for a short period, we were worried about the possibility that DAS might further worsen the PH. Thus, we replaced the DAS with 200 mg BOS once a day.\n\nFigure. The plasma concentrations of dasatinib (DAS) before and after hemodialysis (HD) in our patient. The DAS concentration did not increase on the day of HD. The DAS concentration was markedly elevated on the non-HD day.\n\nAfter the start of the BOS treatment, we measured the plasma concentration of BOS at Akita University (Akita, Japan). BOS was administered just before HD, and its plasma concentration at 2 hours was 273 ng/mL, whereas its plasma concentration on the non-HD day was 180 ng/mL. The AUC (0-12) of BOS was 912 ng·h/mL on the HD day and 851 ng·h/mL on the non-HD day. However, the plasma concentration of BOS fluctuated markedly from 85.5 to 273 ng/mL during the HD. Therefore, we next examined whether HD removes BOS by examining its plasma concentrations before and after HD without administering BOS. As a result, it was found that the plasma concentration of BOS was 74.5 ng/mL before the HD and 58.8 ng/mL after the HD. Thus, we considered that BOS was only partially removed by HD and that the dosage of BOS was appropriate for this patient. He continued receiving BOS at the same dosage and achieved a BCR-ABL international scale value of <10% at 3 months [the optimal response according to the European LeukemiaNet (ELN) 2013 (8)] after the start of the BOS treatment.\n\nDiscussion\nThe liver plays a central role in the pharmacokinetics of most drugs by regulating not only their metabolism and elimination, but also their absorption and distribution. DAS is mainly metabolized by CYP3A4 in the liver. Most (85%) of its metabolites are excreted in feces, and only 4% are excreted in urine (9). Therefore, it is assumed that the plasma concentration of DAS is increased by hepatic dysfunction. However, according to the packaging data for DAS submitted to the US Food and Drug Administration (FDA), the mean Cmax and AUC values of DAS are lower in patients with hepatic dysfunction. As a result, dose adjustment, especially dose reduction, is not necessary to consider during DAS treatment, even for patients with hepatic dysfunction (9). In contrast, in Japan it is recommended that DAS should be prescribed with caution to patients with hepatic dysfunction due to the risk of overprescription (10). Our patient had mild liver cirrhosis (Child-Pugh class A). In addition, he was being treated with carvedilol for heart failure, which is also metabolized by CYP3A4, and it was assumed that it would increase the serum concentration of DAS through competitive metabolization. Therefore, we prescribed DAS at a daily dose of 50 mg. However, even though only a half-dose was administered, the Cmax of DAS was elevated (227 ng/mL), and its AUC was 793 ng·h/mL on the non-HD day. When DAS was given to Japanese patients with solid tumors at a daily dose of 100 mg, its Cmax was 140 ng/mL, and its AUC was 538 ng·h/mL (10). Although we have to consider the effects of carvedilol, these results suggest that dose reduction is required for CML patients with liver dysfunction who are treated with DAS.\n\nBOS is also primarily metabolized by CYP3A4 in the liver, and its plasma concentration is elevated by liver dysfunction (11). When BOS was taken at a daily dose of 200 mg, its mean Cmax in Western healthy controls was 34.0 ng/mL, whereas its mean Cmax in Child-Pugh A, B, and C patients was 86.7 ng/mL, 68.4 ng/mL, and 58.8 ng/mL, respectively (11). In our patient, the Cmax of BOS was 273 ng/mL on the HD day and 180 ng/mL on the non-HD day, which were much higher than the levels seen in the healthy controls and Child-Pugh A patients. Thus, we considered that the concomitant use of carvedilol was also responsible for the high Cmax of BOS observed in our patient.\n\nThe AUC of BOS increased by 35% in patients with mild renal dysfunction and by 60% in patients with severe dysfunction (12). As for the mechanism responsible for this, a previous study showed that the activity of cytochrome P450, including CYP3A4, in the liver (13) and intestines (14) was low in animals with CKD. Also, CYP3A4 activity was reported to be low in patients with renal dysfunction (15). These findings suggest that the reduced CYP3A4 activity seen in patients with renal dysfunction might result in excessive increases in the plasma concentration of BOS.\n\nIn addition to liver dysfunction, our patient was undergoing HD, which might have removed the administered TKIs from his plasma. At present, there are few reports about TKI treatment in HD patients. In previous cases, imatinib was given to 7 HD patients (16-20): in only one case, the plasma concentration of imatinib was measured, and there was no difference between before and after HD (16). Moreover, apparent toxicities of the imatinib for the HD patients have been rarely reported so far (Table 2), which suggests that it is not necessary to modify the dose of imatinib given to CML patients on HD. In addition, there have been 3 reports about the treatment of CML with nilotinib (NIL) in 3 HD patients (20). There were no significant differences between the plasma NIL concentrations observed before and after HD. This suggests that NIL is not eliminated by HD, and dose reduction of NIL is not necessary for patients on HD. As for DAS, we could only find three reports about its use in HD patients (21-23). In the first case, the patient exhibited a partial cytogenetic response without any marked toxicities (21). In the second case, although only 50 mg DAS was administered on the HD days, the DAS treatment was stopped immediately because it exacerbated the patient's pleural effusion (22). In these two cases, the effects of HD on the plasma DAS concentration were not evaluated. In the third case, the plasma concentration of DAS was not affected by HD (23). On the other hand, in the present case the Cmax of DAS was 46.9 ng/mL on the HD day, and it increased to 227 ng/mL on the following (non-HD) day, suggesting that DAS was markedly eliminated by HD. We administered DAS just before HD, and its Cmax was recorded during the HD. In contrast, the DAS concentration was recorded at its trough level in the previously reported case (23), which might have masked the impact of HD on the plasma concentration of DAS. In contrast, the Cmax of BOS was 273 ng/mL on the HD day and 180 ng/mL on the non-HD day. In addition, we confirmed that the plasma concentration of BOS only partially decreased from 74.5 ng/mL to 58.8 ng/mL after HD. These results imply that BOS was only partially removed by HD.\n\nTable 2. Case Reports of TKI Treatment in Patients on HD.\n\nReference\tAge\tSex\tDiagnosis\tTKI\tDosage\tConcentration change with HD\tResponse\t\n16\t44\tFemale\tGISTs\tIM\t400 mg QD\tNone\tPR\t\n17\t54\tFemale\tCML-CP\tIM\t400 mg QD\tN/A\tMR\t\n18\t69\tMale\tEGISTs\tIM\t400 mg QD\tN/A\tCR\t\n19\t75\tMale\tGISTs\tIM\t400 mg QD\tN/A\tN/A\t\n\t\t\t\t\t\t\t\t\n20\t46\tFemale\tCML-CP\tIM\t300 mg QD\tN/A\tMMR not achieved\t\n20\t46\tFemale\tCML-CP\tNIL\t200 mg BID\tNone\tMMR\t\n\t\t\t\t\t\t\t\t\n20\t61\tMale\tCML-CP\tIM\t200 mg QD\tN/A\tCCyR\t\n20\t61\tMale\tCML-CP\tNIL\t200 mg QD\tNone\tMMR\t\n\t\t\t\t\t\t\t\t\n20\t78\tFemale\tCML-CP\tIM\t400 mg QD\tN/A\tN/A\t\n20\t78\tFemale\tCML-CP\tNIL\t200 mg BID\tNone\tMMR\t\n\t\t\t\t\t\t\t\t\n21\t58\tFemale\tCML-BP\tDAS\t70 mg BID\tN/A\tPCyR\t\n22\t87\tMale\tCML-CP\tDAS\t50 mg QD/dialysis day\tN/A\tN/A\t\n23\t73\tMale\tCML-CP\tDAS\t100 mg QD\tNone\tDMR\t\nTKIs: tyrosine kinase inhibitors, HD: hemodialysis, GISTs: gastrointestinal stromal tumors, CML-CP: chronic myeloid leukemia in chronic phase, EGISTs: extra-gastrointestinal stromal tumors, CML-BP: chronic myeloid leukemia in blastic phase, IM: imatinib, NIL: nilotinib, DAS: dasatinib, QD: quaque die, BID: bis in die, N/A: not available, PR: partial response, MR: molecular response, CR: complete response, MMR: major molecular response, CCyR: complete cytogenetic response, PCyR: partial cytogenetic response, DMR: deep molecular response\n\nConclusion\nWe measured the plasma concentrations of DAS and BOS in a CML patient with renal failure requiring HD and liver cirrhosis. The concentrations of DAS and BOS are affected by liver function. In addition, we found that in our patient DAS was markedly eliminated by HD, while BOS was scarcely eliminated. Thus, in CML patients with renal and hepatic impairment it is necessary to measure TKI concentrations in order to optimize such drug treatment.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nNaoto Takahashi: Honoraria, Novartis, Otsuka and Pfizer; Research funding, Novartis, Otsuka, and Pfizer. Itaru Matsumura: Honoraria, Bristol-Myers Squibb, Novartis, Otsuka and Pfizer.\n==== Refs\n1. \nDruker BJ , Guihot F , O'Brien SG , et al \nFive-year follow-up of patients receiving imatinib for chronic myeloid leukemia\n. N Engl J Med \n355 : 2408 -2417\n, 2006 .17151364 \n2. \nLang K , McGarry LJ , Huang H , Dorer D , Kaufman E , Knopf K \nMortality and vascular events among elderly patients with chronic myeloid leukemia: a retrospective analysis of linked SEER-medicare data\n. Clin Lymphoma Myeloma Leuk \n16 : 275 -285.e1\n, 2016 .27013180 \n3. \nSaussele S , Krauss MP , Hehlmann R , et al \nImpact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV\n. Blood \n126 : 42 -49\n, 2015 .25918346 \n4. \nSohn SK , Oh SJ , Kim BS , et al \nTrough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia\n. Leuk Lymphoma \n52 : 1024 -1029\n, 2011 .21463107 \n5. \nGiles FJ , Yin OQ , Sallas WM , et al \nNilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia\n. Eur J Clin Pharmacol \n69 : 813 -823\n, 2013 .23052406 \n6. \nWang X , Roy A , Hochhaus A , Kantarjian HM , Chen TT , Shah NP \nDifferential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study\n. Clin Pharmacol \n10 : 85 -97\n, 2013 .\n7. \nDorer DJ , Knickerbocker RK , Baccarani M , et al \nImpact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients\n. Leuk Res \n48 : 84 -91\n, 2016 .27505637 \n8. \nBaccarani M , Deininger MW , Rosti G , et al \nEuropean LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013\n. Blood \n122 : 872 -884\n, 2013 .23803709 \n9. \nSprycelⓇ (dasatinib) [package insert]. Bristol-Myers Squibb Company\n [Internet]. [cited 2019 Nov 19]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021986s7s8lbl.pdf\n10. \nSprycelⓇ (dasatinib) [package insert]. Bristol-Myers Squibb Company\n [Internet]. [cited 2019 Nov 19]. Available from: https://www.info.pmda.go.jp/go/interview/1/670605_4291020F1027_1_013_1F.pdf (in Japanese).\n11. \nAbbas R , Chalson S , Leister C , El Gaaloul M , Sonnichsen D \nEvaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects\n. Cancer Chemother Pharmacol \n71 : 123 -132\n, 2013 .23053269 \n12. \nBosulif (bosutinib) [package insert]. Pfizer\n [Internet]. [cited 2019 Nov 19]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/20334s007s008lbl.pdf\n13. \nLeblond FA , Guevin C , Demers C , Pellerin I , Gascon-Barré M , Pichette V \nDownregulation of hepatic cytochrome P450 in chronic renal failure\n. J Am Soc Nephrol \n12 : 326 -332\n, 2001 .11158222 \n14. \nLeblond FA , Petrucci M , Dubé P , Bernier G , Bonnardeaux A , Pichette V \nDownregulation of intestinal cytochrome p450 in chronic renal failure\n. J Am Soc Nephrol \n13 : 1579 -1585\n, 2002 .12039987 \n15. \nDowling TC , Briglia AE , Fink JC , et al \nCharacterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease\n. Clin Pharmacol Ther \n73 : 427 -434\n, 2003 .12732843 \n16. \nPappas P , Karavasillis V , Briasoulis E , Pavlidis N , Marselos M \nPharmacokinetics of imatinib mesylate in end stage renal disease. A case study\n. Cancer Chemother Pharmacol \n56 : 358 -360\n, 2005 .15883819 \n17. \nOzdemir E , Koc Y , Kansu E \nSuccessful treatment of chronic myeloid leukemia with imatinib mesylate in a patient with chronic renal failure on hemodialysis\n. Am J Hematol \n81 : 474 , 2006 .16680756 \n18. \nWada Y , Ogata H , Misawa S , Shimada A , Kinugasa E \nA hemodialysis patient with primary extra-gastrointestinal stromal tumor: favorable outcome with imatinib mesylate\n. Intern Med \n51 : 1561 -1565\n, 2012 .22728491 \n19. \nNiikura R , Serizwa T , Yamada A , et al \nSafety of regular-dose imatinib therapy in patients with gastrointestinal stromal tumors undergoing dialysis\n. Case Rep Gastroenterol \n10 : 17 -23\n, 2016 .27403097 \n20. \nOnaka T , Takahashi N , Miura M , Yonezawa A , Imada K , Sawada K \nPharmacokinetics of nilotinib in imatinib-resistant/intolerant chronic myeloid leukemia patients on hemodialysis for chronic renal failure\n. Am J Hematol \n87 : 451 , 2012 .22407703 \n21. \nHolstein SA , Stokes JB , Hohl RJ \nRenal failure and recovery associated with second-generation Bcr-Abl kinase inhibitors in imatinib-resistant chronic myelogenous leukemia\n. Leuk Res \n33 : 344 -347\n, 2009 .18835038 \n22. \nShibazaki S , Tsuda K , Araki M , Yamasaki M , Miura K \nA case of long-term survival from chronic myeloid leukemia in a hemodialysis patient receiving imatinib and experiencing cardiotoxicity with dasatinib\n. Nihon Toseki Igakkai Zassi (J Jpn Soc Dalysis Therapy) \n48 : 713 -718\n, 2015 (in Japanese, Abstract in English).\n23. \nMori J , Oshima K , Tanimoto T , et al \nPharmacokinetics of dasatinib in a hemodialysis patient with chronic myeloid leukemia and chronic kidney disease\n. Int J Hematol \n112 : 115 -117\n, 2020 .32152879\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D000069439:Dasatinib; D005260:Female; D006801:Humans; D007564:Japan; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D006435:Renal Dialysis; D051437:Renal Insufficiency; D016896:Treatment Outcome",
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"title": "The Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia.",
"title_normalized": "the impact of hemodialysis and liver cirrhosis on the plasma concentrations of tyrosine kinase inhibitors in a patient with chronic myeloid leukemia"
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"abstract": "We currently have a wide range of antidepressants available. However, the mechanisms of action are different, giving a theoretical justification for their combination in the failure of monotherapy. However, the combination of drugs entails, in addition to benefits, an increase in the risk of, for example, drug interactions. Many drug interactions in psychiatry are due to the pharmacokinetic interactions between drugs, where their plasma concentrations are altered by inhibiting or inducing cytochrome P450 isoenzymes, especially CYP2D6 and CYP3A4 and P-glycoprotein. When treating depression, we should consider the risks and benefits of combination therapy in individual patients and take measures to minimize the side effects of medicines. The case report describes a case of a patient who reported significant depression after adding paroxetine and mirtazapine to psychiatric medication. As a theoretical cause, it discusses the possible clinically demonstrated interaction between paroxetine and mirtazapine, which has been clinically manifested by fatigue and pronounced daytime sleepiness.",
"affiliations": null,
"authors": "Červeňová|Jaroslava|J|",
"chemical_list": "D000928:Antidepressive Agents; D017374:Paroxetine; D003577:Cytochrome P-450 Enzyme System; D000078785:Mirtazapine",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combination of mirtazapine and paroxetine: possible clinically demonstrated interaction?",
"title_normalized": "combination of mirtazapine and paroxetine possible clinically demonstrated interaction"
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"abstract": "We report 2 cases of disseminated cryptococcosis with central nervous system involvement in patients with chronic lymphoid malignancies occurring within 1 month of starting on ibrutinib. Characteristically, in both cases, no inflammation was seen in the cerebrospinal fluid. Central nervous system mycoses should be considered as a potential complication of ibrutinib.",
"affiliations": "Department of Medicine, Duke University, Durham, North Carolina.;Department of Medicine, Duke University, Durham, North Carolina.;Division of Infectious Disease, Washington University, St. Louis, Missouri.;University of Texas MD Anderson Cancer Center, Houston.;Department of Medicine, Duke University, Durham, North Carolina.",
"authors": "Messina|Julia A|JA|;Maziarz|Eileen K|EK|;Spec|Andrej|A|;Kontoyiannis|Dimitrios P|DP|;Perfect|John R|JR|",
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"doi": "10.1093/ofid/ofw261",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n28480254\n10.1093/ofid/ofw261\nofw261\nBrief Report\nDisseminated Cryptococcosis With Brain Involvement in Patients With Chronic Lymphoid Malignancies on Ibrutinib\nMessina Julia A. 1 Maziarz Eileen K. 1 Spec Andrej 2 Kontoyiannis Dimitrios P. 3 Perfect John R. 1 1 \nDepartment of Medicine, Duke University, Durham, North Carolina\n2 \nDivision of Infectious Disease, Washington University, St. Louis, Missouri\n3 \nUniversity of Texas MD Anderson Cancer Center, Houston\nCorrespondence: John R. Perfect, MD, Box 102359, Room 163 Hanes House, Durham, NC 27710 (john.perfect@duke.edu).\n\n\nWinter 2017 \n09 2 2017 \n09 2 2017 \n4 1 ofw26124 10 2016 07 12 2016 © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nWe report 2 cases of disseminated cryptococcosis with central nervous system involvement in patients with chronic lymphoid malignancies occurring within 1 month of starting on ibrutinib. Characteristically, in both cases, no inflammation was seen in the cerebrospinal fluid. Central nervous system mycoses should be considered as a potential complication of ibrutinib.\n\nCARD9central nervous system mycosis; chronic lymphoid malignanciescryptococcosisibrutinibNational Institute of Allergy and Infectious Diseases10.13039/1000000605T32AI100851-03\n==== Body\nPatients with hematologic malignancies including indolent lymphoproliferative disorders have pleiotropic immune deficits due to their underlying disease, placing them at risk for opportunistic infections, such as invasive fungal infections (IFIs) [1]. Cryptococcosis is an IFI that has previously been described in this patient population, particularly associated with receipt of fludarabine or corticosteroids [2, 3]. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor used to treat lymphoproliferative disorders that has demonstrated significant improvement in progression-free survival in clinical trials [4, 5]. Two cases of cryptococcal infections were reported in the clinical trials for ibrutinib including one death from cryptococcal pneumonia [6, 7]. In this study, we report 2 cases of disseminated cryptococcosis due to Cryptococcus neoformans with central nervous system (CNS) involvement but no inflammation in patients with chronic lymphoid malignancies at our center, both occurring within 1 month of starting ibrutinib therapy.\n\nCASE 1\nAn 88-year-old white man with indolent lymphoma started therapy with ibrutinib 420 mg daily in 2015 due to progressive disease. Initial diagnosis of lymphoplasmacytic lymphoma was made in 1998, and previous therapies included rituximab in 2008 and R-Bendamustine in 2012. Approximately 3 weeks into starting ibrutinib therapy, the patient developed shortness of breath and pleuritic chest pain. He was lymphopenic (total T cells 400/liter) but not neutropenic at that time. A computerized tomography (CT) scan revealed a 1.3-cm, right paramediastinal spiculated lung lesion suspicious for primary lung cancer. The patient did not have any fevers or weight loss at this time, but ibrutinib therapy was withheld in the midst of further evaluation. One week later, he developed fevers up to 39°C and was treated with levofloxacin [8]. However, he then developed worsening fatigue, new nonproductive cough, and headache, which prompted hospital admission. Positron emission tomography-CT scan showed an 8-cm, right paramediastinal mass with increased fluorodeoxyglucose (FDG) activity, multiple enlarged, FDG-avid mediastinal lymph nodes thought to be consistent with progression of his underlying disease. Computerized tomography scan of the brain without contrast did not show an acute intracranial process. For further diagnostic work-up, the patient underwent mediastinoscopy with lymph node biopsy, and pathology showed necrotizing granulomatous lymphadenitis of level 3 and 4R lymph nodes with yeasts morphologically consistent with Cryptococcus. Fungal culture from one of the lymph nodes had no growth of organism. Serum cryptococcal antigen titer was positive at 1:40. The patient was started on liposomal amphotericin B (L-AMB) 3 mg/kg daily and flucytosine (5-FC) 25 mg/kg every 6 hours [9, 10]. With an ongoing headache, he underwent lumbar puncture (LP) that showed an opening pressure of 7 cm of cerebrospinal fluid (CSF). Cerebrospinal fluid analysis revealed 3 nucleated cells/mm3 (normal cell count 0–5/mm3), 29 red blood cells (RBCs)/mm3 (normal ≤0 cells/mm3), glucose 57 mg/dL, and protein 43 mg/dL (normal range 15–50 mg/dL). The patient’s serum glucose on this day was 158 mg/dL (normal range 70–140 mg/dL) with a resultant CSF to serum glucose ratio of 0.36. Cerebrospinal fluid cryptococcal antigen was negative, but CSF fungal culture grew Cryptococcus, and the species, C neoformas, was identified by matrix-assisted laser desorption/ionization time of flight. From follow-up LP results 2 weeks after starting L-AMB/5-FC induction therapy, CSF cryptococcal antigen remained negative, and fungal culture was negative for Cryptococcus, so the patient was transitioned to oral fluconazole 400 mg daily [11]. Follow-up CT chest imaging revealed a decrease in right paramediastinal mass size. The patient ultimately recovered from disseminated cryptococcosis and remains on lifelong fluconazole suppressive therapy (200 mg daily) as he has restarted chemotherapy.\n\nCASE 2\nA 54-year-old African American man with a history of chronic lymphocytic leukemia (CLL), bronchiolitis obliterans organizing pneumonia (BOOP), morbid obesity, diabetes mellitus, hypertension, and chronic kidney disease presented with nonproductive cough and fever approximately 1 month after starting ibrutinib therapy (dosed 420 mg daily) in 2016. He was not neutropenic or lymphopenic at this time. The patient was diagnosed with CLL in 2012 and had previously been treated with fludarabine, cyclophosphamide, and rituximab from 2014 to 2015. Upon hospital admission, he denied headache, nausea, vomiting, or visual changes but was febrile to 39.1°C and hypoxic requiring supplemental oxygen. Chest imaging revealed bilateral lower lobe ground-glass opacities consistent with either atypical infection or drug toxicity as well as bulky mediastinal and axillary lymphadenopathy consistent with his underlying CLL. The patient was started on broad-spectrum antibiotics, corticosteroids in view of his history of BOOP, and ibrutinib was withheld pending further work-up of possible drug-induced pneumonitis. He underwent bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL). Pathology from the biopsy demonstrated yeasts on Gomori methenamine silver stain, most consistent with Cryptococcus. Blood and BAL cultures grew C neoformans. The patient was started on L-AMB 5 mg/kg daily and 5-FC 25 mg/kg every 6 hours for disseminated cryptococcosis. However, he developed acute respiratory failure and septic shock and was transferred to the intensive care unit (ICU) necessitating mechanical ventilation and continuous veno-venous hemofiltration (CVVH). Computerized tomography scan of the brain without contrast performed before LP did not show an acute intracranial process. Lumbar puncture was performed without a report of an opening pressure, and CSF analysis revealed 4 nucleated cells, 6 RBCs, glucose 157 mg/dL, protein 30 mg/dL, negative CSF cryptococcal antigen, and a fungal culture grew C neoformans [12]. In total, the patient was treated with L-AMB for approximately 28 days, 5-FC for 14 days, and fluconazole (dosed 800 mg intravenous daily for CVVH) for approximately 14 days after discontinuation of 5-FC. The L-AMB duration of therapy was extended to 28 days because repeat LP attempts at bedside were unsuccessful, and the ICU team assessed the patient’s clinical status to be too tenuous to transport to interventional radiology for an image-guided attempt. Three weeks into his ICU stay, the patient once again developed profound systemic shock, progressive respiratory failure, and lactic acidosis of unclear etiology as blood cultures were negative at this time. His status declined further despite full support, the decision was made to withdraw care, and the patient died Characteristics from both cases are depicted in Table 1.\n\nTable 1. Demographics of the Invasive Fungal Infections\n\nClinical Feature\tCase 1\tCase 2\t\nUnderlying disease\tIndolent lymphoplasmacytic lymphoma\tChronic lymphocytic leukemia\t\nHIV-1/2 antibody testing\tNegative\tNegative\t\nAge (years)\t88\t54\t\nTime from starting ibrutinib to infection presentation\t3 weeks\t4 weeks\t\nWBC counta (×109/liter)b\nAbsolute neutrophil count (×109/liter)c\nAbsolute lymphocyte count (×109/liter)d\t6.7\n5.5\n0.4\t74.1\n11.5\n59.2\t\nSerum cryptococcal antigen titer\t1:40\tNot obtained\t\nSites of documented cryptococcal involvement\tLung, CSF\tBlood, lung, CSF\t\nCSF opening pressure (cm CSF)\t7\tNot recorded\t\nCSF nucleated cells\t1\t4\t\nCSF protein (mg/dL)\t43\t30\t\nCSF glucose (mg/dL)\t57\t157\t\nCSF India ink stain\tNegative\tNegative\t\nCSF fungal culture\t\nCryptococcus neoformans\n\t\nC neoformans\n\t\nAbbreviations: CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; WBC, white blood cell.\n\n\naAt the time of hospital admission.\n\n\nbNormal rage 3.2–9.8 × 109/liter.\n\n\ncNormal range 2.00–8.60 × 109/liter.\n\n\ndNormal range 0.60–4.20 × 109/liter.\n\nDISCUSSION\nThe association between ibrutinib and risk for IFI with a propensity for CNS invasion has previously been reported, and it is not limited to Cryptococcus. Specifically, Ruchlemer et al [13] reported 3 cases of invasive aspergillosis with CNS predilection in patients on ibrutinib within 2 months of drug initiation and concurrent glucocorticoids. The authors noted that 2 patients had documented Aspergillus brain abscesses, and 1 patient had documented sinusitis with suspected CNS involvement. Here, we described for the first time 2 cases of disseminated cryptococcosis with CNS involvement but a noninflammatory CSF analysis and negative CSF cryptococcal antigen titers, both presenting approximately 1 month after starting ibrutinib. The poor outcome of the second case reflects an overwhelming infection and cryptococcemia. Cryptococcemia has been long described as a marker of high fungal burden and a poor prognostic factor in cryptococcosis [14].\n\nOkamoto et al [15] have reported a case of disseminated cryptococcosis due to C neoformans in a patient with CLL approximately 1 month after starting ibrutinib with documented blood and suspected lung involvement. The early onset of disseminated cryptococcosis after the initiation of ibrutinib is similar to what occurred in our 2 cases and suggests that these patients had preceding pulmonary colonization with C neoformans. Of note, patients with chronic lymphoid malignancies are already at risk for disseminated infection due to immunosuppression from their underlying diseases and chemotherapy, but we propose that this risk may have been exacerbated by the initiation of ibrutinib. Whether the amplification of the risk is directly due to BTK inhibition or an off-target effect of ibrutinib requires further evaluation.\n\nOne potential mechanism is the role of caspase recruitment domain (CARD) homologs in facilitating entry and propagation of infection by fungal organisms in the CNS. The CARD homologs (CARD9, 10, and 11) form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1) to produce CARD-BCL10-MALT1 (CBM) complexes [16]. The CBM complexes activate nuclear factor κβ, which plays a critical role in regulation of the innate and adaptive immune systems and apoptosis [17]. CARD11, found in lymphocytes, is a key player in the CBM complex downstream of the B-cell receptor and BTK, the target for ibrutinib [18]. CARD9, found in myeloid cells, is a signaling adaptor used by C-lectin receptors, which are types of pattern recognition receptors and are involved in neutrophil recruitment and proinflammatory cytokine production in antifungal immunity [19]. Patients with CARD9 deficiency are uniquely susceptible to invasive fungal infections of the CNS due to diminished neutrophil accumulation in the brain [20]. Therefore, CARD9 could be essential for a complex similar to CBM in CNS macrophages and microglial cells, which is potentially affected by ibrutinib.\n\nAn unusual feature of the present cases is the noninflammatory CSF profile. In fact, the yeasts may have arrived quickly in the CNS after the start of ibrutinib because there was a negative CSF cryptococcal antigen despite positive CSF cultures for C neoformans. A similar finding of noninflammatory CSF with negative India ink stain and negative CSF cryptococcal antigen has been reported in a case of cryptococcal meningitis in a patient with Hodgkin’s lymphoma [21]. One possible explanation of the noninflammatory CSF profile was that the disseminated infection was detected relatively early in the course before a detectable level of antigen could be achieved in the CSF. In contrast, the noninflammatory CSF analysis may be due to an immune defect similar to that seen in acquired immunodeficiency syndrome, where 25%–30% of patients will have normal CSF profiles despite CNS infection documented by positive fungal cultures [22, 23].\n\nCONCLUSIONS\nIbrutinib shows promise for improving disease progression-free survival in otherwise difficult-to-treat chronic lymphoid malignancies, but cases of IFI with CNS involvement, specifically aspergillosis and cryptococcosis, seen shortly after drug initiation should raise caution to use of ibrutinib. The extent of immunosuppression and immunogenetic risks for this complication of ibrutinib therapy are unknown. Clinicians should be vigilant, and IFIs should be included in the differential diagnosis in patients with suspected infectious complications on ibrutinib therapy. Further study of the potential association between ibrutinib and IFI could offer insight into the immune implications of ibrutinib as well as host-pathogen interactions of disseminated cryptococcosis.\n\nAcknowledgments\n\nFinancial support. J. A. M. is supported by the National Institute of Allergy and Infectious Diseases Grant 5T32AI100851-03.\n\n\nPotential conflicts of interest. A. S. receives research funding from Astellas, Scynexis, MiraVista, and IMMY and consulting fees from Astellas and MiraVista. D. P. K. has received research support from Merck, Pfizer, and Astellas and has received honoraria from Merck, Astellas, Gilead, Pfizer, F2G, and Cidara, Inc. J. R. P. has served on advisory committees, honorariums, performed consulting, and has received research support from Astellas, Merck, Vical, Cidara, Viamet, F2G, Scynexis, Matinas, and TEVA.\n\nAll authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nPerfect JR \nThe impact of the host on fungal infections\n. Am J Med 2012 ; 125 :S39 –51\n.22196208 \n2. \nKontoyiannis DP Peitsch WK Reddy BT et al. \nCryptococcosis in patients with cancer\n. Clin Infect Dis 2001 ; 32 :E145 –50\n.\n3. \nMarchand T Revest M Tattevin P et al. \nEarly cryptococcal meningitis following treatment with rituximab, fludarabine and cyclophosphamide in a patient with chronic lymphocytic leukemia\n. Leuk Lymphoma 2013 ; 54 :643 –5\n.22924391 \n4. \nBurger JA Tedeschi A Barr PM et al. \nIbrutinib as initial therapy for patients with chronic lymphocytic leukemia\n. N Engl J Med 2015 ; 373 :2425 –37\n.26639149 \n5. \nIMBRUVICA® [package insert]. Pharmacyclics LLC, Sunnyvale, CA : Janssen Biotech, Inc., Horsham, PA ; 2016 Available at: https://www.imbruvicahcp.com/docs/librariesprovider2/pdf-downloads/prescribing_information.pdf Accessed 17 November 2016 .\n6. \nByrd JC Furman RR Coutre SE et al. \nTargeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia\n. N Engl J Med 2013 ; 369 :32 –42\n.23782158 \n7. \nWang ML Blum KA Martin P et al. \nLong-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results\n. Blood 2015 ; 126 :739 –45\n.26059948 \n8. \nLEVAQUIN® [package insert]. Titusville, NJ : Ortho-McNeil-Janssen Pharmaceuticals, Inc ; 2008 Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf Accessed 17 November 2016 .\n9. \nAmBisome® [package insert]. Northbrook, IL : Astellas Pharma US, Inc ; 2012 Available at: https://www.astellas.us/docs/ambisome.pdf Accessed 17 November 2016 .\n10. \nANCOBON® [package insert]. Bridgewater, NJ : Valeant Pharmaceuticals North America LLC ; 2013 Available at: http://www.valeant.com/Portals/25/Pdf/PI/FPO_LB0096-00-nov13.pdf.\n11. \nDIFLUCAN® [package insert]. New York, NY : Pfizer ; 2011 Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019949s051lbl.pdf Accessed 17 November 2016 .\n12. \nCryptococcal Antigen Lateral Flow Assay [package insert]. Norman, OK : IMMY ; 2016 Available at: http://www.immy.com/bluejuice/wp-content/uploads/2016/09/CR2003-CrAg-LFA-PI-US-1.pdf Accessed 17 November 2016 .\n13. \nRuchlemer R Ben Ami R Lachish T \nIbrutinib for chronic lymphocytic leukemia\n. N Engl J Med 2016 ; 374 :1593 –4\n.\n14. \nPerfect JR Durack DT Gallis HA \nCryptococcemia\n. Medicine (Baltimore) 1983 ; 62 :98 –109\n.6338344 \n15. \nOkamoto K Proia LA Demarais PL \nDisseminated cryptococcal disease in a patient with chronic lymphocytic leukemia on ibrutinib\n. Case Rep Infect Dis 2016 ; 2016 :4642831 .27703818 \n16. \nPerez de Diego R Sanchez-Ramon S Lopez-Collazo E et al. \nGenetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: molecular, immunologic, and clinical heterogeneity\n. J Allergy Clin Immunol 2015 ; 136 :1139 –49\n.26277595 \n17. \nKingeter LM Lin X \nC-type lectin receptor-induced NF-κB activation in innate immune and inflammatory responses\n. Cell Mol Immunol 2012 ; 9 :105 –12\n.22246129 \n18. \nTurvey SE Durandy A Fischer A et al. \nThe CARD11-BCL10-MALT1 (CBM) signalosome complex: stepping into the limelight of human primary immunodeficiency\n. J Allergy Clin Immunol 2014 ; 134 :276 –84\n.25087226 \n19. \nDrummond RA Collar AL Swamydas M et al. \nCARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system\n. PLoS Pathog 2015 ; 11 :e1005293 .26679537 \n20. \nDrewniak A Gazendam RP Tool AT et al. \nInvasive fungal infection and impaired neutrophil killing in human CARD9 deficiency\n. Blood 2013 ; 121 :2385 –92\n.23335372 \n21. \nShaunak S Schell WA Perfect JR \nCryptococcal meningitis with normal cerebrospinal fluid\n. J Infect Dis 1989 ; 160 :912 .2809269 \n22. \nDarras-Joly C Chevret S Wolff M et al. \nCryptococcus neoformans infection in France: epidemiologic features of and early prognostic parameters for 76 patients who were infected with human immunodeficiency virus\n. Clin Infect Dis 1996 ; 23 :369 –76\n.8842276 \n23. \nGarlipp CR Rossi CL Bottini PV \nCerebrospinal fluid profiles in acquired immunodeficiency syndrome with and without neurocryptococcosis\n. Rev Inst Med Trop Sao Paulo 1997 ; 39 :323 –5\n.9674282\n\n",
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"issn_linking": "2328-8957",
"issue": "4(1)",
"journal": "Open forum infectious diseases",
"keywords": "CARD9; central nervous system mycosis; chronic lymphoid malignancies; cryptococcosis; ibrutinib.",
"medline_ta": "Open Forum Infect Dis",
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"pages": "ofw261",
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"pmid": "28480254",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "9674282;26059948;23782158;2809269;26277595;22924391;22246129;26639149;27703818;8842276;25087226;22196208;11340547;27096597;6338344;26679537;23335372",
"title": "Disseminated Cryptococcosis With Brain Involvement in Patients With Chronic Lymphoid Malignancies on Ibrutinib.",
"title_normalized": "disseminated cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib"
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"abstract": "This single-center retrospective observational study aimed to identify risk factors for developing denosumab-related osteonecrosis of the jaw (DRONJ) in stage IV solid cancer patients with bone metastases. In total, 123 consecutive patients who had received 120 mg of denosumab every 4 weeks at least twice between July 2014 and October 2018 were included. We surveyed their demographics, medical history, blood test, underlying disease, and intraoral findings. Fourteen patients (11.4%) developed DRONJ within a mean denosumab administration period of 4 months (range: 2-52 months). Univariate analyses showed a statistically significant correlation between DRONJ and hormone therapy, chemotherapy/molecular target drug, apical periodontitis, periodontal disease, sex and body mass index. Multivariate analysis showed a statistically significant correlation between DRONJ and hormone therapy (odds ratio [OR], 22.07; 95% confidence interval [CI], 2.86-170.24), chemotherapy and/or molecular targeted therapy (OR, 18.61; 95% CI, 2.54-136.27), and apical periodontitis (OR, 22.75; 95% CI, 3.20-161.73). These findings imply that collaborative oral examinations by oral specialists may reduce the risk of development of DRONJ in patients treated with denosumab for bone metastases from solid cancers.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Shimane 693-8501, Japan.;Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Shimane 693-8501, Japan.;Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Shimane 693-8501, Japan.;Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Shimane 693-8501, Japan.;Department of Oncology/Hematology and Innovative Cancer Center, Shimane University Hospital, Shimane 693-8501, Japan.;Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Shimane 693-8501, Japan.",
"authors": "Okuma|Satoe|S|;Matsuda|Yuhei|Y|0000-0001-8922-3582;Nariai|Yoshiki|Y|;Karino|Masaaki|M|;Suzuki|Ritsuro|R|0000-0002-5974-7614;Kanno|Takahiro|T|",
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"doi": "10.3390/cancers12051209",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694 MDPI \n\n10.3390/cancers12051209\ncancers-12-01209\nArticle\nA Retrospective Observational Study of Risk Factors for Denosumab-Related Osteonecrosis of the Jaw in Patients with Bone Metastases from Solid Cancers\nOkuma Satoe 1 https://orcid.org/0000-0001-8922-3582Matsuda Yuhei 1 Nariai Yoshiki 12 Karino Masaaki 1 https://orcid.org/0000-0002-5974-7614Suzuki Ritsuro 3 Kanno Takahiro 1* 1 Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Shimane 693-8501, Japan; okuma125@med.shimane-u.ac.jp (S.O.); yuhei@med.shimane-u.ac.jp (Y.M.); y.nariai@matsue-cityhospital.jp (Y.N.); karino71@med.shimane-u.ac.jp (M.K.)\n2 Department of Oral and Maxillofacial Surgery, Matsue City Hospital, Shimane 690-8509, Japan\n3 Department of Oncology/Hematology and Innovative Cancer Center, Shimane University Hospital, Shimane 693-8501, Japan; rsuzuki@med.shimane-u.ac.jp\n* Correspondence: tkanno@med.shimane-u.ac.jp; Tel.: +81-853-20-2301\n12 5 2020 \n5 2020 \n12 5 120920 4 2020 10 5 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).This single-center retrospective observational study aimed to identify risk factors for developing denosumab-related osteonecrosis of the jaw (DRONJ) in stage IV solid cancer patients with bone metastases. In total, 123 consecutive patients who had received 120 mg of denosumab every 4 weeks at least twice between July 2014 and October 2018 were included. We surveyed their demographics, medical history, blood test, underlying disease, and intraoral findings. Fourteen patients (11.4%) developed DRONJ within a mean denosumab administration period of 4 months (range: 2–52 months). Univariate analyses showed a statistically significant correlation between DRONJ and hormone therapy, chemotherapy/molecular target drug, apical periodontitis, periodontal disease, sex and body mass index. Multivariate analysis showed a statistically significant correlation between DRONJ and hormone therapy (odds ratio [OR], 22.07; 95% confidence interval [CI], 2.86–170.24), chemotherapy and/or molecular targeted therapy (OR, 18.61; 95% CI, 2.54–136.27), and apical periodontitis (OR, 22.75; 95% CI, 3.20–161.73). These findings imply that collaborative oral examinations by oral specialists may reduce the risk of development of DRONJ in patients treated with denosumab for bone metastases from solid cancers.\n\ndenosumab-related osteonecrosis of the jawbone metastasisdenosumabretrospective cohort study\n==== Body\n1. Introduction\nBone metastasis is commonly found in patients with solid cancers [1]. The frequency of bone metastases is 65–75% in breast and prostate cancer, 40–60% in thyroid cancer, 30–40% in lung cancer, 40% in bladder cancer, 20–35% in renal cancer, 14–45% in malignant melanoma, and 5% in digestive organ cancer [2,3]. Bone metastasis, unlike the metastasis of other organs, is not life-threatening, but it does cause serious deterioration in the quality of life (QoL) because of symptoms such as pain, fractures, and paralysis [4].\n\nBone metastases are often treated with bisphosphonates (BPs), such as zoledronic acid, or the monoclonal antibody denosumab. Both treatments can prevent and alleviate the skeletal-related events (SREs) caused by bone metastasis from lung cancer, breast cancer, prostate cancer, and other cancers [5]. Moreover, these medicines improve the overall survival rate of patients with these cancers [6].\n\nDenosumab is a human monoclonal antibody that binds to, and interferes with, the activation of the receptor activator of nuclear factor kappa-β ligand (RANKL), a potent stimulator of osteoclastogenesis [7]. RANKL functions as an anti-resorptive agent by inhibiting osteoclast function and the subsequent resorption of bone [8]. Denosumab suppresses osteoclastic cell formation and survival via the RANKL pathway and decreases SREs caused by bone metastases [9]. Unlike BPs, denosumab is effective in patients with renal dysfunction and helps to reduce the monthly dosing frequency [10]. The bioavailability of denosumab is high, ranging between 60% and 80%; the highest blood concentration is observed at 1–4 weeks after administration [11]. Denosumab inhibits osteoclast formation, function, and survival [5]. Furthermore, denosumab does not become embedded within bone tissue, and has a short half-life of 12.5 days; by comparison, BPs have a half-life of 10–12 years [12]. A double-blind phase III trial comparing denosumab and BPs showed that the overall survival, disease progression, and percentage of adverse events were similar among the groups. However, patients treated with denosumab exhibited a more delayed onset of SREs [13,14]. Therefore, denosumab is widely used as a substitute for BPs in patients with bone metastases, osteoporosis, and other bone diseases [13,14].\n\nAnti-resorptive agents may cause osteonecrosis of the jaw (ONJ), called anti-resorptive agent-related osteonecrosis of the jaw (ARONJ,) and medication-related osteonecrosis of the jaw (MRONJ), which includes denosumab-related osteonecrosis of the jaw (DRONJ) and BP osteonecrosis of the jaw (BRONJ) [15]. The reported risk of developing denosumab-related ONJ (DRONJ) in patients with osteoporosis is 0.01–0.03%, while this risk is 1–3% for oncology patients, which was not significantly different from that in intravenous bisphosphonate users [15,16,17]. Initially, ONJ develops from exposed bone or bone probed by a periodontal probe through an intraoral or extraoral fistula. No surgical treatment is indicated for exposed or necrotic bone in patients who are asymptomatic and have no evidence of infection. However, surgical debridement/resection in combination with antibiotic therapy and local antimicrobial treatment is recommended for patients with exposed/necrotic bone, pain, infection, pathologic fractures, or extra-oral fistulae, together with conservative oral management and care [16,17]. Regardless of the disease stage, mobile segments of the sequestrum should be removed [18]. Moreover, a recent study indicated that segmental resection and immediate reconstruction with a reconstruction plate are recommended in severe cases to improve and maintain better oral and maxillofacial QoL [19].\n\nARONJ significantly affects QoL, and the decline in QoL is correlated with the ARONJ stage. The following factors found in ARONJ patients may contribute to decreased QoL: infected and painful necrotic jawbone; ulcerated, painful, and swollen oral mucosa; chronic sinus tract and facial disfigurement; impaired speech, swallowing, and eating; and frequent medical and dental collaborative evaluations and treatments [20,21,22].\n\nMoreover, the surgical treatment of ONJ leads to poor QoL in cancer patients [23]. A recent systematic analysis of clinical trials reported that the overall incidence of DRONJ in patients with cancer was 1.7% [24]. The dominant risk factors for ARONJ are the cumulative dose and the number of administrations of BPs or denosumab [24]. Typically, ARONJ develops following a local infection or trauma to the bone or soft tissue. Poor oral hygiene, invasive procedures, such as tooth extraction or dental implant placement, and mucosal trauma from ill-fitting prostheses have been identified as risk factors for ARONJ [25]. Several other factors are thought to be associated with an increased risk of ARONJ, including the use of other cancer therapies or corticosteroids, smoking, and comorbidities such as anemia, diabetes mellitus, and renal failure [26,27,28].\n\nHowever, the exact mechanisms underlying DRONJ remain unclear, and definitive treatment strategies have not yet been developed. Therefore, in this study, we retrospectively investigated the risk factors for DRONJ. The identification of such risk factors would facilitate the prediction and prevention of DRONJ onset, as well as improve the oral and maxillofacial QoL and treatment outcomes of patients with bone metastases from solid cancers.\n\n2. Results\n2.1. Patient Demographics and Characteristics\nIn total, 157 consecutive patients were enrolled in our study. Among them, 123 patients (57 males and 66 females) met the inclusion criteria, and their characteristics are shown in Table 1. The median age was 68.0 years, and the median BMI was 20.6. The performance status (PS) was 1 in 11 patients (8.9%), 2 in 51 patients (41.5%), 3 in 52 patients (42.3%), and 4 in 9 patients (7.3%). One hundred twenty-two patients (99.2%) received food orally. The median Brinkman index was 0. Ten patients (8.1%) consumed alcohol daily. In total, 16 patients (13.0%) had diabetes, 4 (3.3%) had rheumatoid arthritis, 60 (48.8%) had hypercalcemia, 4 (3.3%) had hypothyroidism, 7 (5.7%) had osteoporosis, 1 (0.8%) had vitamin deficiency, and 85 (69.1%) had anemia. Nineteen patients (15.4%) received antithrombotic therapy, while no patients were treated for osteomalacia, dialysis, or Paget’s disease. The median hemoglobin level was 11.4 g/dL, and those of total protein, albumin, cholesterol, calcium, and C-reactive protein were 6.7 g/dL, 3.4 g/dL, 180.0 mg/dL, 8.9 mg/dL, and 1.6 mg/dL, respectively.\n\nThe most common types of cancers in our cohort were breast (32 patients; 26.0%), lung (24 patients; 19.5%), prostate (16 patients; 13.0%), and colon cancer (13 patients; 10.6%). All patients had stage IV disease and bone metastases, and 67 patients (54.5%) had multiple metastases. Chemotherapy and/or molecular targeted therapy were given concurrently in 34 patients (27.6%), while 23 patients (18.7%) received hormone therapy. No patients received angiogenesis or tyrosine kinase inhibitors.\n\nIntraoral evaluations and checkups were performed in all patients before the start of denosumab treatment. The median number of teeth was 18.0 (range: 0.0–32.0), and 48 patients (39.0%) used partial or complete dentures. Forty-four patients (35.8%) were diagnosed with apical periodontitis, with the presence of a root apical lesion shown by panoramic or dental X-rays. Fifty-four patients had periodontal disease with marginal periodontitis (43.9%), which were diagnosed by panoramic or dental X-rays, or based on a pocket depth of at least 4 mm.\n\nThe median follow-up period was 4 months (range: 2–52 months). Denosumab treatment was continued in 40 patients (32.5%), while in 2 patients (1.6%) it was discontinued. Eighty-one patients (65.9%) died during the follow-up period. Fourteen patients (11.4%) developed DRONJ, which had a median onset of 10 months after the start of denosumab treatment (range: 7–45 months). DRONJ was diagnosed in 11 of 32 patients (34.4%) with breast cancer, 2 of 16 patients (12.5%) with prostate cancer, and 1 of 13 patients (7.7%) with colon cancer. At the time of DRONJ diagnosis, three patients were in stage 1 (21.4%), five were in stage 2 (35.7%), and the remaining six were in stage 3 (42.9%) according to the AAOMS guidelines [18]. DRONJ had progressed rapidly in these patients within 8 weeks of the initial manifestation of maxillary or mandibular bone exposure. Images from a representative DRONJ case are shown in Figure 1.\n\n2.2. Comparison of DRONJ and Non-DRONJ Patients\nThe demographics of DRONJ and non-DRONJ patients were compared (Table 2). Statistically significant differences were found in sex, height, Brinkman index, use of chemotherapy/targeted molecular therapy, use of hormone therapy, presence of apical periodontitis/root apical lesions and periodontal disease with marginal periodontitis, and the duration of denosumab treatment. No other variables differed significantly between the two groups.\n\n2.3. Risk Factors for DRONJ\nIn univariate analyses, statistically significant predictors of DRONJ onset included hormone therapy (odds ratio [OR], 5.81; 95% confidence interval [CI], 1.80–18.81), chemotherapy/molecular target drug (OR, 4.26; 95% CI, 1.35–13.40), apical periodontitis (OR, 5.52; 95% CI, 1.62–18.84), periodontal disease (OR, 9.57; 95% CI, 2.04–44.91), sex (OR, 6.11; 95% CI, 1.31–28.60), and body mass index (OR, 1.18; 95% CI, 1.02–1.37) (Table 3). Furthermore, in multivariate analysis, statistically significant predictors of DRONJ onset included hormone therapy (OR, 22.07; 95% CI, 2.86–170.24), chemotherapy/molecular targeted therapy (OR, 18.61; 95% CI, 2.54–136.27), and apical periodontitis (OR, 22.75; 95% CI, 3.20–161.73) (Table 3).\n\n3. Discussion\nBone metastases are a frequent complication of solid cancers, including breast cancer and prostate cancer, affecting 1.5 million patients worldwide [29]. Clinically important skeletal complications result from osteoclast-mediated bone destruction, often leading to severe pain, decreased QoL, instability, and neurological complications [30]. Bisphosphonates and denosumab have been used to alleviate SREs in cancer patients, and both reduce the risk of bone metastasis and SREs in colorectal, prostate, and breast cancers [30,31]. The overall survival rates of bone metastasis or lung cancer patients treated with denosumab are comparable or superior to that of patients treated with BPs [5,6,14,32].\n\nIn an integrated analysis of three major phase III head-to-head trials, denosumab was superior to BPs in preventing SREs [32]. However, in the clinic, irregular administration and discontinuation of denosumab therapy may affect its efficacy. The International Society for Pharmacoeconomics and Outcomes Research defines medication compliance as the act of conforming to the recommendations made by the provider with respect to the timing, dosage, and frequency of medication [33]. Medication persistence refers to the act of conforming to a recommendation that the patient continue treatment for the prescribed period of time [33]. \n\nLong-term use of denosumab could lead to several adverse effects, including ONJ, although a review study of the long-term treatment of osteoporosis found that denosumab treatment safely produced a continuous marked increase in bone mineral density at all body sites in women with postmenopausal osteoporosis [34]. However, based on concerns regarding adverse events related to putative RANKL inhibition or to bone turnover oversuppression, it is advised against longer-term administration [34]. Three major phase III trials reported that the incidence of DRONJ was low (cumulative incidence of only 1.8%; n = 52/2862) in patients receiving denosumab [35]. In the present study, DRONJ occurred 7–45 months after the start of therapy (median, 10 months). Similarly, a recent clinical study reported a mean onset time of 14 months (range: 8–25 months) after the administration of denosumab [15,36,37]. The median treatment duration for patients who did not develop DRONJ was 4 (range 2–52) months, primarily because of cancer deaths during the early part of the study. Therefore, prolonged continuous longer-term administration may have resulted in significantly more DRONJ cases in this study, because of the time-dependent nature of DRONJ development, considering its clinical impact on bone mineral density and bone turnover oversuppression [34,37].\n\nDRONJ causes severe functional and masticatory disorders, and thus has a major impact on patient QoL [22]. Therefore, it is essential to identify patients at risk, limit the number of such cases, and establish protocols for early treatment. Boquete-Castro et al. analyzed data from seven randomized controlled trials on denosumab (including the adverse effects thereof), and found that the overall incidence of ONJ in patients with cancer who received denosumab was 1.7% (95% CI, 0.9–3.1%) [24]. In the German X-TREME study, 15 patients had suspected ONJ (1.3%) [30]. In a randomized controlled study involving the use of denosumab, 2% of breast cancer patients, 2.3% of prostate cancer patients, and 1.1% of patients with either a solid tumor or multiple myeloma developed ONJ [38]. In the present study, 14 patients (11.4%) with bone metastases from solid tumors developed DRONJ (median onset, 10 months). However, this study included only Japanese advanced-stage solid cancer patients with bone metastasis. The patients were older than those included in previous studies [24,30,38], and the median duration of denosumab administration was 4 months; a higher rate of DRONJ might have been observed with longer denosumab administration. The “Position Paper 2017 of the Japanese Allied Committee” revealed that the possible incidence of DRONJ in cancer patients could be higher than that in patients with osteoporosis. However, the incidence was only about 1.8% in a 3-year prospective follow-up study of patients treated with denosumab with breast, prostate, and other solid cancers or multiple myeloma; this possible incidence rate is based only on a foreign study [39]. Prospective studies of the incidence of ONJ have been conducted in cancer patients treated with zoledronic acid or denosumab [6,11]. Of 5723 patients with breast, prostate, and other solid cancers and multiple myeloma, 52 patients (1.8%) treated with denosumab and 37 patients (1.3%) treated with zoledronic acid (i.e., 89 cancer patients in total) developed ONJ in a 3-year follow-up [6,11]. It is unclear whether demographic factors were associated with DRONJ in this study; however, no such associations were described in previous studies [38,40]. As the vast majority of patients in these studies were white and ~75% were from the United States or Europe, differences in DRONJ incidence by race and geographic region remain unknown [40]. Further, no Japanese prospective study has been conducted in cancer patients with bone metastasis treated with denosumab. In this regard, the administration of denosumab oncology doses of 120 mg every 4 weeks for bone metastasis from solid cancers in Japan might trigger a higher incidence of DRONJ in Japanese.\n\nInterestingly, the DRONJ rate and onset time after denosumab treatment in this study were consistent with those reported in a recent retrospective study investigating DRONJ in all cancer patients at any stage [37]. A single-center retrospective study performed in France reported DRONJ rates of 1% after 0–6 months of treatment and 8% after 30 months of treatment [37]. At 12 months of treatment, the rate reached 3%, but many patients were excluded because of missing or inaccurate data. Excluding patients previously treated with BPs also reduced the number of cases [37]. Therefore, we did not exclude patients who had previously received BPs. The current review study by the International Task Force on ONJ found that the incidence of ONJ in oncology patient populations is markedly higher than that in osteoporosis patient populations on denosumab [41].\n\nThe univariate analysis performed in this study showed that sex, BMI, use of chemotherapy and/or targeted therapy, use of hormone therapy, presence of apical periodontitis/root apical lesions and periodontal disease with marginal periodontitis, and the duration of denosumab treatment were significantly different between the non-DRONJ and DRONJ groups. Most DRONJ cases were female patients with breast cancer (11 of 14 DRONJ cases); this had a large effect on the sex distribution and might also affect BMI, as is often seen in studies where the majority of patients have breast cancer [37,40,41]. A recent review showed that tooth extraction was also associated with the development of DRONJ, and another retrospective study suggested tooth extraction, chemotherapy, poor oral hygiene, and ill-fitting dentures as possible risk factors for the development of DRONJ [42]. Other than the underlying advanced-stage solid cancers, systemic health conditions were not found to be risk factors for DRONJ [43]. Of note, while smoking and alcohol consumption were not risk factors for DRONJ, they were risk factors for oral diseases, including periodontal disease of marginal periodontitis and apical periodontitis [44]. Chemotherapy, targeted therapy, and hormone therapy modulate bone metabolism and might lead to immunosuppression. Further, the long-term use of systemic corticoids could also increase the risk as an immunosuppression factor, which may trigger the development of DRONJ [39,41]. In advanced-stage solid cancers, patients should be provided with evidence-based cancer care to improve QoL and life expectancy. However, in our study, no patients were treated with angiogenesis inhibitors or tyrosine kinase inhibitors, which might be significant risk factors for ONJ development. \n\nWe also found associations of DRONJ with existing apical/periapical periodontitis and periodontitis. Extraction of symptomatic infected teeth or progressively worsening teeth, removal of bone edges, and complete mucoperiosteal wound closure were performed in all patients before starting denosumab treatment. Asymptomatic or well-maintained teeth with periapical periodontitis or marginal periodontitis were statistically significant risk factors. No patients developed DRONJ at tooth extraction sites because denosumab was administered after complete mucoepithelial closure. Furthermore, oral and dental examinations were performed regularly at local dental clinics and Matsue City Hospital. Interestingly, the number of remaining teeth did not differ significantly between the non-DRONJ and DRONJ groups. Of the 14 patients with DRONJ, 3 (21.4%) were symptomatic but stable in stage 1 after conservative management. The condition of five patients (35.7%) progressed to stage 2, and in the remaining six patients (42.9%) aggressive progression to stage 3 occurred, indicating that DRONJ patients require regular professional care from oral and dental specialists during and after denosumab treatment.\n\nMultivariate regression analysis revealed statistically significant correlations between the onset of DRONJ and hormone therapy (OR, 22.07; 95% CI, 2.86–170.24), chemotherapy and/or molecular targeted therapy (OR, 18.61; 95% CI, 2.54–136.27) and apical periodontitis (OR, 22.75; 95% CI, 3.20–161.73). Thus, teeth with symptomatic, active apical periodontitis, as well as asymptomatic teeth with root apical lesions, should be carefully evaluated, treated, and potentially extracted before the start of denosumab treatment.\n\nFurther studies are required to elucidate the mechanisms underlying DRONJ development. Using an animal model of BRONJ and medication-related osteonecrosis of the jaw (MRONJ), Otto et al. showed that MRONJ developed in areas of gingival or periodontal infection [43]. Meanwhile, in a combined ligature-induced periodontitis/tooth extraction mouse model, a pre-existing inflammatory condition exacerbated MRONJ development after tooth extraction, performed following the administration of denosumab [42]. Several clinical studies have found that periodontal disease and apical periodontitis are risk factors for ONJ, similar to retrospective clinical studies on BRONJ [45]. Furthermore, Hallmer et al. reported a diverse range of bacteria (represented by 16 S rRNA sequences) in all MRONJ necrotic bone samples, and in 60% of visually healthy bone samples [46]. Eight dominant taxa were identified at the genus level, namely Porphyromonas, Lactobacillus, Tannerella, Prevotella, Actinomyces, Treponema, Streptococcus, and Fusobacterium. These anaerobic bacteria are commonly found under the gingival margin and root apical lesion in the oral cavity, and may be related to DRONJ [46]. According to recent studies, periodontal infection and immunosuppressive conditions in dentoalveolar regions might also cause DRONJ [27]. Denosumab inhibits RANKL by mimicking the effect of osteoprotegerin [47,48,49]. Given that RANKL is expressed in both T and B lymphocytes, denosumab may exert immunosuppressive effects. Nevertheless, as osteonecrosis does not occur in other areas of the body, the jaw is likely subject to higher bone turnover. Clinical trials are needed to determine why bone turnover is higher in the mandible, and why bone remodeling undergoes a change when RANKL inhibitors are administered [50]. \n\nDefinitive DRONJ treatment strategies have not yet been established [39,41]. Patient characteristics including age, sex, disease status, DRONJ stage, lesion size, medication exposure, and medical and pharmacological comorbidities may all inform the treatment choice. However, specific mechanisms through which these factors influence the course of DRONJ and the response to treatment are largely unknown, such that individual treatment strategies rely on clinical judgment. Other important factors to consider are prognosis, life expectancy, QoL, and the patient’s ability to cope with DRONJ lesions. Unlike BPs, stopping denosumab treatment may facilitate prevention of DRONJ [41]. In some patients, discontinuation of denosumab treatment profoundly improved the oral condition and induced the separation of highly necrotic sequestra of the mandible. Although no data exist regarding the effectiveness of discontinuing denosumab, we suggest that denosumab therapy should be stopped when a diagnosis of DRONJ is confirmed because of the rapid progression thereof. Re-initiation of denosumab may be considered when disease progression or new bone-related symptoms occur.\n\nWe recommend that oncologists highlight the importance of maintaining good oral hygiene and recognizing early signs of DRONJ in the context of denosumab treatment for stage IV advanced cancer bone metastases. Furthermore, we recommend the administration of denosumab as part of the management and care of cases with bone metastases from solid cancers, in combination with chemotherapy, targeted therapy, or hormonal therapy. All patients should undergo oral and dental examinations before the start of denosumab treatment, and should receive regular oral examinations while receiving denosumab. A previous report showed that the incidence and severity of ONJ could be minimized through proactive education [42,45]. Therefore, a lower incidence, and higher rate of resolution, of DRONJ may be achieved by educating health care providers. It may also be helpful to encourage the patient’s oral specialist, regular dentist, and oral and maxillofacial surgeons to ensure that the patient understands the risks of cancer treatment.\n\nThis study had several limitations. First, it used a retrospective observational design. Second, the risk factors associated with denosumab mortality require further clarification. Furthermore, the characteristics of solid cancers associated with bone metastases, including tumor site, histopathological type, and genetic factors, should be further examined to identify risk factors for DRONJ. Moreover, for greater clinical relevance, the number of patients in future investigations should be increased, and multicenter studies should be performed. Finally, the median duration of denosumab treatment and follow-up period were short in our study, because the majority of patients (65.9%) died early, especially in the non-DRONJ group.\n\n4. Patients and Methods\n4.1. Data Sources and Search Strategy\nThis was a retrospective single-center observational study to evaluate risk factors for developing DRONJ. All patients received denosumab for bone metastasis of solid cancers between July 2014 and October 2018 at Matsue City Hospital, Shimane, Japan. The observation began on the first day of denosumab treatment. All patients underwent an oral and dental examination before denosumab treatment by the same two oral surgeons (S.O. and Y.N.) throughout the study period. Furthermore, all symptomatic infected or problematic teeth were extracted using minimally invasive techniques with complete mucoperiosteal closure. Denosumab treatment was started four weeks after complete mucoepithelial closure was obtained. Patients were also advised to receive regular oral and dental care throughout the denosumab treatment and were followed by the same two hospital oral surgeons every month in the department of oral and maxillofacial surgery on the date of denosumab administration. This study was conducted with the approval of the Medical Ethics Committee of Shimane University (No. 20181225-1) and the Ethics Committee of Matsue City Hospital (No. 2019A-0004).\n\n4.2. Inclusion and Exclusion Criteria\nThe inclusion criteria were as follows: stage IV solid cancer with bone metastases, denosumab (RANMARK; Daiichi Sankyo Company, Ltd., Tokyo, Japan) administration by subcutaneous injection at a dose of 120 mg every 4 weeks at least twice, and denosumab dose adjustment based on the patient’s calcium level and renal function. The exclusion criteria were patients with missing or inaccurate data.\n\n4.3. Study Variables\nThe surveyed items were as follows: patient characteristics (age, sex, height, weight, body mass index [BMI], reason for treatment, duration of treatment, withdrawal of treatment, Brinkman index, and alcohol consumption), medical history (diabetes, rheumatism, hypercalcemia, hypercalcemia, hypocalcemia, osteoporosis, osteomalacia, vitamin B deficiency, anemia, dialysis, Paget’s disease, and antithrombotic therapy), blood examination (hemoglobin, total protein, albumin, cholesterol, calcium, and C-reactive protein), underlying characteristics of the solid cancer (type of cancer, cancer stage, bone metastasis, multiple metastasis, concurrent chemotherapy and/or molecular targeted therapy, angiogenesis inhibitor, tyrosine kinase inhibitor, and hormone therapy), and intraoral findings (number of teeth, denture use, and apical periodontitis such as root apical lesions or periodontal disease with marginal periodontitis).\n\n4.4. Study Outcomes\nThe DRONJ-affected site and staging were registered and included for DRONJ patients based on the guidelines of the American Association of Oral and Maxillofacial Surgeons (AAOMS) [18]. DRONJ was diagnosed if all of the following were present: current or previous treatment with antiresorptive or antiangiogenic agents, exposed bone or bone that could be probed through an intraoral or extraoral fistula in the maxillofacial region that had persisted for 8 weeks or more, and no history of radiation therapy to the jaw or obvious metastatic disease of the jaw.\n\n4.5. Statistical Analyses\nAll statistical analyses were performed using SPSS version 26.0 software (IBM Japan, Tokyo, Japan). Background factors in the two groups were analyzed using the chi-squared and Mann–Whitney U-tests. Univariate and multivariate analyses of the risk factors for the development of DRONJ were conducted using logistic regression analysis. All study variables were selected using the stepwise method.\n\n5. Conclusions\nIn conclusion, this retrospective observational study analysis revealed statistically significant correlations of DRONJ onset with hormone therapy, chemotherapy/molecular targeted therapy, and apical periodontitis. Close collaborative oral examination and regular maintenance of oral hygiene by oral specialists may reduce the incidence of DRONJ in cancer patients with bone metastases treated with denosumab.\n\nAcknowledgments\nThe authors thank all of the patients who took part in this study. We express our appreciation to all staff members of the Department of Oral and Maxillofacial Surgery of Shimane University for their kind assistance and support.\n\nAuthor Contributions\nConceptualization, S.O. and T.K.; methodology, T.K.; validation, Y.N., M.K. and T.K.; formal analysis, Y.M. and R.S.; investigation, S.O. and Y.N.; resources, Y.N. and T.K.; data curation, Y.M. and R.S.; writing—original draft preparation, S.O. and Y.N.; writing—review and editing, R.S. and T.K.; supervision, T.K.; project administration, Y.N. and T.K. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Representative case of a 61-year-old woman with bone metastases diagnosed as stage 3 denosumab-related osteonecrosis of the jaw (DRONJ) after surgical treatment and adjuvant hormone therapy for invasive ductal breast carcinoma. Denosumab was administered after chemotherapy and targeted therapy. After 16 months of denosumab administration, intraoral mandibular necrotic bone exposure, together with progressive spontaneous tooth loss was first observed during oral follow-up ((a) intraoral photo; (b) panoramic radiograph). Over the next 8 weeks, disease progression was aggressive, with surprisingly widespread necrotic bone exposure despite conservative management and care. After 18 months of denosumab administration, the patient was diagnosed with stage 3 DRONJ ((c) intraoral photo; (d) panoramic radiograph). The oncologist in charge recommended discontinuation of denosumab, while conservative treatment and regular care were continued. The patient was followed-up closely to check the progression of necrotic bone exposure, and complete separation of highly necrotic mandibular bone sequestra was confirmed after 10 months. The necrotic mandibular bone sequestra was surgically removed under local anesthesia at an outpatient clinic. Gradual mucoepithelial closure was observed, a newly fabricated denture was applied, and oral rehabilitation was achieved ((e) intraoral photo; (f) panoramic radiograph). Denosumab was not restarted after close consultation between the patient and oncologist. The patient remained systemically, locally, and intraorally stable, with gradual progression of multiple breast cancer metastases.\n\ncancers-12-01209-t001_Table 1Table 1 Patient characteristics.\n\nDescription\tn (%) or Median (Range)\t\nDemographic factors\tSex\tMale\t57 (46.3)\t\nFemale\t66 (53.7)\t\nAge (years)\t\n\t68.0 (25.0–95.0)\t\nPerformance status\t0\t0 (0.0)\t\n1\t11 (8.9)\t\n2\t51 (41.5)\t\n3\t52 (42.3)\t\n4\t9 (7.3)\t\nHeight (cm)\t\n\t158.0 (130.0–178.0)\t\nWeight (kg)\t\n\t51.4 (27.6–77.2)\t\nBMI 1\t\n\t20.6 (13.3–31.0)\t\nOral nutrition\tYes\t122 (99.2)\t\nBrinkman index\t\n\t0.0 (0.0–2460.0)\t\nAlcohol consumption\tYes\t10 (8.1)\t\nMedical history\tDiabetes mellitus\tYes\t16 (13.0)\t\nRheumatoid arthritis\tYes\t4 (3.3)\t\nHypocalcemia\tYes\t60 (48.8)\t\nHypercalcemia\tYes\t0 (0.0)\t\nHypothyroidism\tYes\t4 (3.3)\t\nOsteoporosis\tYes\t7 (5.7)\t\nVitamin B deficiency\tYes\t1 (0.8)\t\nAnemia\tYes\t85 (69.1)\t\nAntithrombotic therapy\tYes\t19 (15.4)\t\nBlood parameters\tHemoglobin (g/dL)\t\n\t11.4 (6.3–17.7)\t\nTotal protein (g/dL)\t\n\t6.7 (4.1–8.4)\t\nAlbumin (g/dL)\t\n\t3.4 (1.5–4.6)\t\nCholesterol (mg/dL)\t\n\t180.0 (53.0–337.0)\t\nCalcium (mg/dL)\t\n\t8.9 (6.2–10.2)\t\nC-reactive protein (mg/dL)\t\n\t1.6 (0.0–23.7)\t\nUnderlying disease\tCancer type\tBreast\t32 (26.0)\t\nLung\t24 (19.5)\t\nProstate\t16 (13.0)\t\nColon\t13 (10.6)\t\nPancreas\t6 (4.9)\t\nKidney\t7 (5.7)\t\nLiver\t8 (6.5)\t\nUterus\t2 (1.6)\t\nStomach\t6 (4.9)\t\nBladder\t3 (2.4)\t\nOther\t6 (4.9)\t\nBone metastasis\tYes\t123 (100)\t\nMultiple metastases\tYes\t67 (54.5)\t\nChemotherapy and/or molecular targeted drug\tYes\t34 (27.6)\t\nAngiogenesis inhibitor\tYes\t0 (0.0)\t\nTyrosine kinase inhibitor\tYes\t0 (0.0)\t\nHormonal therapy\tYes\t23 (18.7)\t\nIntraoral findings\tNumber of teeth\t\n\t18.0 (0.0–32.0)\t\nDenture use\tYes\t48 (39.0)\t\nApical periodontitis\tYes\t44 (35.8)\t\nPeriodontal disease\tYes\t54 (43.9)\t\nDenosumab\tAdministration period (months)\t\n\t4 (2–52)\t\nReason for dropout\tContinuing\t40 (32.5)\t\nCancelled\t2 (1.6)\t\nDeceased\t81 (65.9)\t\nFollow-up (months)\t\n\t\n\t4 (2–52)\t\nDRON J 2\tDRONJ 2 stage [18]\t0\t0 (0.0)\t\n1\t3 (2.4)\t\n2\t5 (4.1)\t\n3\t6 (4.9)\t\n1 body mass index, 2 denosumab-related osteonecrosis of jaw.\n\ncancers-12-01209-t002_Table 2Table 2 Comparison between the DRONJ and non-DRONJ groups after follow-up.\n\nVariables\tn (%) or Median (Range)\t\nControl (n = 109)\tDRONJ (n = 14)\tp-Value\t\nBackground factor\tSex\tMale\t55 (50.5)\t2 (14.3)\t0.011 *\t\nFemale\t54 (49.5)\t12 (85.7)\t\nAge (years)\t\n\t68.0 (25.0–95.0)\t64.0 (51.0–77.0)\t0.155\t\nPerformance status\t0\t0 (0.0)\t0 (0.0)\t0.422\t\n1\t10 (9.2)\t1 (7.1)\t\n2\t43 (39.4)\t8 (57.1)\t\n3\t48 (44.0)\t4 (28.6)\t\n4\t8 (7.3)\t1 (7.1)\t\nHeight (cm)\t\n\t160.0 (130.0–178.0)\t152.0 (145.0–164.0)\t0.010 *\t\nWeight (kg)\t\n\t51.4 (27.6–77.2)\t53.3 (31.0–72.5)\t0.469\t\nBMI 1\t\n\t20.4 (13.3–28.7)\t21.7 (13.4–31.0)\t0.055\t\nOral nutrition\tYes\t108 (99.1)\t14 (100)\t1.000\t\nBrinkman index\t\n\t0.0 (0.0–2460.0)\t0 (0.0–0.0)\t0.001 **\t\nAlcohol consumption\tYes\t10 (9.2)\t0 (0.0)\t0.602\t\nMedical history\tDiabetes mellitus\tYes\t15 (13.8)\t1 (7.1)\t0.692\t\nRheumatoid arthritis\tYes\t3 (2.8)\t1 (7.1)\t0.387\t\nHypocalcemia\tYes\t55 (50.5)\t5 (35.7)\t0.397\t\nHypercalcemia\tYes\t0 (0.0)\t0 (0.0)\t-\t\nHypothyroidism\tYes\t4 (3.7)\t0 (0.0)\t1.000\t\nOsteoporosis\tYes\t5 (4.6)\t2 (14.3)\t0.181\t\nVitamin B deficiency\tYes\t1 (0.9)\t0 (0.0)\t1.000\t\nAnemia\tYes\t76 (69.7)\t9 (64.3)\t0.761\t\nAntithrombotic therapy\tYes\t17 (15.6)\t2 (14.3)\t1.000\t\nBlood examination\tHemoglobin (g/dL)\t\n\t11.2 (6.3–17.7)\t11.9 (8.3–15.9)\t0.097\t\nTotal protein (g/dL)\t\n\t6.7 (4.1–8.4)\t7.0 (5.6–7.8)\t0.170\t\nAlbumin (g/dL)\t\n\t3.4 (1.5–4.6)\t3.3 (2.6–4.5)\t0.385\t\nCholesterol (mg/dL)\t\n\t179.0 (53.0–337.0)\t201.5 (146.0–334.0)\t0.232\t\nCalcium (mg/dL)\t\n\t8.9 (6.2–10.0)\t9.2 (6.4–10.2)\t0.187\t\nC-reactive protein (mg/dL)\t\n\t1.7 (0.0–23.7)\t1.0 (0.0–4.7)\t0.136\t\nUnderlying disease\tCancer type\tBreast\t21 (10.3)\t11 (78.6)\t-\t\nLung\t24 (22.0)\t0 (0.0)\t\nProstate\t14 (12.8)\t2 (14.3)\t\nColon\t12 (11.0)\t1 (7.1)\t\nPancreatic\t6 (5.5)\t0 (0.0)\t\nKidney\t7 (6.4)\t0 (0.0)\t\nLiver\t8 (7.3)\t0 (0.0)\t\nUterus\t2 (1.8)\t0 (0.0)\t\nStomach\t6 (5.5)\t0 (0.0)\t\nBladder\t3 (2.8)\t0 (0.0)\t\nOther\t6 (5.5)\t0 (0.0)\t\nBone metastasis\tYes\t109 (100)\t14 (100)\t-\t\nMultiple metastases\tYes\t56 (51.4)\t11 (78.6)\t0.085\t\nChemotherapy or molecular targeted drug\tYes\t26 (23.9)\t8 (57.1)\t0.021 *\t\nAngiogenesis inhibitor\tYes\t0 (0.0)\t0 (0.0)\t-\t\nTyrosine kinaseinhibitor\tYes\t0 (0.0)\t0 (0.0)\t-\t\nHormonal therapy\tYes\t16 (14.7)\t7 (50.0)\t0.005 **\t\nIntraoral findings\tNumber of teeth\t\n\t17.0 (0.0–32.0)\t21.5 (0.0–32.0)\t0.717\t\nDenture use\tYes\t41 (37.6)\t7 (50.0)\t0.395\t\nApical periodontitis\tYes\t34 (31.2)\t10 (71.4)\t0.006 **\t\nPeriodontal disease\tYes\t42 (38.5)\t12 (85.7)\t0.001 **\t\nDenosumab\tAdministration period (months)\t\n\t4 (2–52)\t10 (7–45)\t0.001 **\t\nDrop out reason\tContinuing\t32 (29.4)\t8 (57.1)\t-\t\nCancelled\t1 (0.9)\t1 (7.1)\t\nDeceased\t76 (69.7)\t5 (35.7)\t\nDRONJ 2\tDRONJ 2 stage [18]\t0\t0 (0.0)\t0 (0.0)\t-\t\n1\t0 (0.0)\t3 (21.4)\t\n2\t0 (0.0)\t5 (35.7)\t\n3\t0 (0.0)\t6 (42.9)\t\n1 body mass index, 2 denosumab-related osteonecrosis of jaw. **, p < 0.01; *, p < 0.05.\n\ncancers-12-01209-t003_Table 3Table 3 Risk factors for DRONJ in multivariate analysis.\n\nVariables\tUnivariate\tMultivariate\t\nOdds Ratio (CI)\tSignificance\tOdds Ratio (CI)\tSignificance\t\nHormonal therapy\t5.81 (1.80–18.81)\t0.003\t22.07 (2.86–170.24)\t0.003\t\nChemotherapy/molecular target drug\t4.26 (1.35–13.40)\t0.013\t18.61 (2.54–136.27)\t0.004\t\nApical periodontitis\t5.52 (1.62–18.84)\t0.006\t22.75 (3.20–161.73)\t0.002\t\nPeriodontal disease\t9.57 (2.04–44.91)\t0.004\t\n\t\n\t\nSex\t6.11 (1.31–28.60)\t0.022\t\n\t\n\t\nBody mass index\t1.18 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"issue": "12(5)",
"journal": "Cancers",
"keywords": "bone metastasis; denosumab; denosumab-related osteonecrosis of the jaw; retrospective cohort study",
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"title": "A Retrospective Observational Study of Risk Factors for Denosumab-Related Osteonecrosis of the Jaw in Patients with Bone Metastases from Solid Cancers.",
"title_normalized": "a retrospective observational study of risk factors for denosumab related osteonecrosis of the jaw in patients with bone metastases from solid cancers"
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"abstract": "The current prescription of clozapine in psychotic women of reproductive age makes it crucial to understand its pharmacokinetics during pregnancy and lactation as well as its risk profile for neonatal outcome. The aim of this case series was to provide new evidence on the pharmacokinetic features of clozapine that determine its passage through the placenta and amniotic fluid, as well as the neonatal clozapine elimination half-life (t1/2). This case series demonstrates for the first time that clozapine might show partial placental passage similar to other atypical antipsychotics. Clozapine levels decreased during the first few days in nursing infants. The half-life of clozapine in neonates was slightly higher than previously estimated. Clozapine use in pregnancy may be associated with diabetes mellitus, especially if there is a family history of this disease. Although no acute toxicological effects were observed in the intrauterine exposed newborn, close follow-up of pregnancy is recommended. However, these results must be taken with caution being a case series with small sample size.",
"affiliations": "Perinatal Psychiatry Program, Department of Psychiatry and Psychology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.;Department of Medicine, University of Barcelona, Barcelona, Spain.;Department of Medicine, University of Barcelona, Barcelona, Spain.;Division of Medicines, Pharmacy Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Perinatal Psychiatry Program, Department of Psychiatry and Psychology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.;Department of Medicine, University of Barcelona, Barcelona, Spain.",
"authors": "Imaz|M Luisa|ML|;Oriolo|Giovanni|G|;Torra|Mercè|M|;Soy|Dolors|D|;García-Esteve|Lluïsa|L|;Martin-Santos|Rocio|R|",
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"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2018.00264PharmacologyCase ReportClozapine Use During Pregnancy and Lactation: A Case-Series Report Imaz M. Luisa 12Oriolo Giovanni 23Torra Mercè 24Soy Dolors 5García-Esteve Lluïsa 12Martin-Santos Rocio 26*1Perinatal Psychiatry Program, Department of Psychiatry and Psychology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain2Department of Medicine, University of Barcelona, Barcelona, Spain3Department of Psychiatry and Psychology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain4Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Service, Biomedical Diagnostic Center (CBD), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain5Division of Medicines, Pharmacy Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain6Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigacions Biomèdiques Artur Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Barcelona, SpainEdited by: Maged Costantine, University of Texas Medical Branch, United States\n\nReviewed by: Shirley Seo, United States Food and Drug Administration, United States; Patrick John McNamara, University of Kentucky, United States\n\n*Correspondence: Rocio Martin-Santos rmsantos@clinic.catThis article was submitted to Obstetric and Pediatric Pharmacology, a section of the journal Frontiers in Pharmacology\n\n27 3 2018 2018 9 26411 1 2018 09 3 2018 Copyright © 2018 Imaz, Oriolo, Torra, Soy, García-Esteve and Martin-Santos.2018Imaz, Oriolo, Torra, Soy, García-Esteve and Martin-SantosThis 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 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.The current prescription of clozapine in psychotic women of reproductive age makes it crucial to understand its pharmacokinetics during pregnancy and lactation as well as its risk profile for neonatal outcome. The aim of this case series was to provide new evidence on the pharmacokinetic features of clozapine that determine its passage through the placenta and amniotic fluid, as well as the neonatal clozapine elimination half-life (t1/2). This case series demonstrates for the first time that clozapine might show partial placental passage similar to other atypical antipsychotics. Clozapine levels decreased during the first few days in nursing infants. The half-life of clozapine in neonates was slightly higher than previously estimated. Clozapine use in pregnancy may be associated with diabetes mellitus, especially if there is a family history of this disease. Although no acute toxicological effects were observed in the intrauterine exposed newborn, close follow-up of pregnancy is recommended. However, these results must be taken with caution being a case series with small sample size\n\nclozapinepregnancyplacentalpharmacokineticsamnioticlactationneonatalschizophrenia\n==== Body\nIntroduction\nClozapine is a second-generation antipsychotic agent, chemically a di-benzodiazepine, that is approved for treatment-resistant schizophrenia and risk reduction of recurrent suicidal behavior in schizophrenia or schizoaffective disorder. It is also used off-label to reduce craving in patients with substance use disorder (SUD) comorbidity (Hasan et al., 2015). Clozapine acts as an antagonist of serotonin 5HT2, dopamine D2, α1-adrenergic, muscarinic and H1 histaminic receptors and it induces relatively few extrapyramidal effects (Stahl, 2017). Unlike some first- and second-generation antipsychotics, it does not cause sustained increases in serum prolactin levels and does not affect other hormonal levels sufficiently to inhibit fertility (Haddad and Wieck, 2004).\n\nA recent systematic review of the safety of clozapine during pregnancy and lactation found very limited data on the topic (Mehta and Van Lieshout, 2017). In pregnant women, clozapine appears to be associated with an increased risk of gestational diabetes mellitus compared to mothers not taking any antipsychotic (Bodén et al., 2012), as also observed in several case reports (Waldman and Safferman, 1993; Dickson and Hogg, 1998; Nguyen and Lalonde, 2003; Karakula et al., 2004). Regarding the consequences for fetuses exposed to clozapine during pregnancy, a summary paper showed five cases of congenital malformations in 61 children (8.2%) (Dev and Krupp, 1995). A Novartis follow-up identified 22 fetal congenital malformations in 523 (4.2%) mothers treated with clozapine (McKenna et al., 2005). In a cohort study, women taking clozapine and/or olanzapine showed an increased risk for macrocephaly (Bodén et al., 2012). Moreover, a case series reported seven spontaneous abortions in 84 women exposed to clozapine (Bazire, 2005). Some case reports have described shoulder dystocia (Waldman and Safferman, 1993; Dickson and Hogg, 1998), atrial septum defect (Vavrusova and Konikova, 1998), and ectopic anus (Reis and Källén, 2008). Regarding the risk to infants, floppy infant syndrome (Di Michele et al., 1996) and a decrease in heart rate variability (Yogev et al., 2002; Coston et al., 2012; Guyon et al., 2015), seizure (Stoner et al., 1997), gastroesophageal problems, and delayed peristalsis (Karakula et al., 2004) have been observed. Concerning the clinical outcome associated with clozapine exposure during breastfeeding, data are even more scarce. One study reported delayed speech acquisition in an infant exposed to clozapine during 1 year of lactation (Mendhekar, 2007); an episode of agranulocytosis and a case of drowsiness were observed in another four cases (Dev and Krupp, 1995). Five cases of in-utero and lactation exposure to clozapine reported fewer sleep disturbances compared to those not exposed (Shao et al., 2015). Finally, there are few data on the long-term outcome of children exposed to clozapine during pregnancy. A case-control study showed a lower adaptive behavior (Bayley-III) score in children exposed to clozapine vs. other atypical antipsychotics (Shao et al., 2015). Lastly, a case report observed the retardation of psychomotor development in a child after 6 years of follow-up (Tenyi and Trixler, 1998).\n\nThe heterogeneity of studies and clinical outcomes based on distinct clozapine daily doses, different timing of exposures during pregnancy and lactation, and the usage of concomitant drugs in some cases leaves many questions unanswered (Mehta and Van Lieshout, 2017). It has been suggested that the accumulation of clozapine in fetal serum may be associated with an increased rate of neonatal complications (Dev and Krupp, 1995). There are currently two cases in the literature reporting neonatal clozapine blood concentrations. In the first, Barnas et al. (1994) suggested transplacental passage and relative accumulation of clozapine in the neonate. The same trend for clozapine accumulation was observed in breastmilk. The second case (Moreno-Bruna et al., 2012) described a newborn with delayed peristalsis on the second day of life, with an increase in half-life elimination of the drug suggesting a substantial newborn plasma clozapine concentration on the fifth and eighth day of life.\n\nGiven the current increase in the prescription of atypical antipsychotics, such as clozapine, in young psychotic women (Toh et al., 2013), it seems important to know better their pharmacokinetics and adverse effects during pregnancy and lactation as well as its risk profile for neonatal outcome.\n\nMethods\nWe report four cases of three Caucasian women who attended the outpatient Perinatal Psychiatry Program of a teaching hospital during pregnancy and postpartum with clozapine. Complementary to their obstetric and psychiatric care, clozapine and norclozapine plasma concentrations were determined in the mother–infant pair on the day of delivery [intrapartum maternal blood (IMB), fetal umbilical cord blood (UCB), and amniotic fluid (AF)] to calculate the infant–maternal plasma clozapine concentration ratio. The neonatal plasma concentration of clozapine was measured several times after delivery to observe half-life elimination in those neonates with artificial lactation (Food and Drug Administration, 2005). Only in one case it was possible to study the plasma concentrations of clozapine in both the mother and the neonate at 33 h postpartum to calculate the lactation transfer. Obstetric and pediatric outcomes were reviewed from medical records. Pharmacological treatment was administered with the consent of the patients. All patients gave written informed consent for the presentation of their data.\n\nThe drug was analyzed in venous blood samples drawn in the morning before a first daily dose of clozapine, and under steady-state conditions. The blood samples were allowed to clot at room temperature for 15–30 min, and then centrifuged at 1800 × g/10 min. Plasma was stored at −20°C until analysis. Plasma concentrations of clozapine/norclozapine, were measured using a validated high-performance liquid chromatography method, with UV diode array detection and solid- phase extraction (Gupta, 1995; Liu et al., 2001). For amniotic fluid, drugs were extracted using a double-step liquid–liquid procedure (Titier et al., 2003). The within- and between-day precision expressed as the coefficient of variation (CV) % were both <10%. The limit of quantification (LOQ) was 5 ng/mL. Assuming linear pharmacokinetic behavior, the elimination half-life (t1/2) was calculated by means of 0.693/ke. The elimination rate constant (ke) was determined from the neonate venous blood clozapine concentration data vs. time after birth by linear least squares regression analysis of the terminal portion of the log concentration-time curve. Drug urine screening and cotinine quantification were performed by immunoassay.\n\nThe aim of the present case-report series was to provide new information on the features of clozapine pharmacokinetics that determine its placental and lactation passage, as well as the neonatal clozapine elimination half-life (t1/2) and neonatal and infant/child outcomes.\n\nCase series\nThe first patient (M1) was a 37-year-old woman with paranoid schizophrenia since the age of 24. She was treated with risperidone 5 mg/day. Due to an episode of amenorrhea with galactorrhea, risperidone was replaced by quetiapine 300 mg/day. At 34 years of age, she required hospital admission for a new psychotic episode (Table 1). Clozapine was initiated and titrated up to 550 mg/day with partial remission. Thirty sessions of ECT were administered, and long-acting intramuscular (LAI) risperidone was added (50 mg/14 days). After 3 years in stable remission, she expressed the wish to have a child and her intrauterine device (IUD) was removed. She was a primipara, with a body mass index of 31.84, and no other medical problems. When pregnancy was confirmed she was taking clozapine 550 mg/day and LAI risperidone 50 mg/month and she was smoking 18 cigarettes/day. She subsequently reduced the number of cigarettes/day by 50%, and clozapine was progressively titrated down to 350 mg/day; the LAI risperidone dose was maintained. No agranulocytosis was detected. Four ultrasounds during gestation showed physiological fetal well-being parameters (Table 1). A spontaneous vaginal delivery was carried out in the 38th week of pregnancy, with no perinatal complications. No agranulocytosis, seizures, or other neonatal complications were observed (Table 2). The plasma concentrations of clozapine/ norclozapine in IMB, UCB, and AF ratios are displayed in Table 3. Figure 1 shows the half-life neonatal elimination of clozapine. Artificial lactation was carried out. No psychotic relapse was recorded. In the follow-up of the child at 6 years of age, symptoms of attention deficits and hyperactivity were present without any diagnostic criteria for ADHD.\n\nTable 1 Maternal characteristics and pregnancy-related outcomes in the case series and in the previous cases reported in the literature.\n\nVariables\tChronic clozapine exposure\tAcute clozapine exposure\t\n\tMother 1 (M1) 2007\tMother 2 (M2) 2014\tMother 3 (M3-1) 2015\tMother 3 (M3-2) 2016\tBarnas et al., 1994\tMoreno-Bruna et al., 2012\tKłys et al., 2007\tNovikova et al., 2009\t\nMATERNAL VARIABLES\t\nPsychiatric diagnosis\tCLZ- R Schizophrenia\tSchizoaffective\tSchizoaffective\t\tSchizophrenia\tSchizophrenia\tSchizophrenia\tSelf-intoxication\t\nConcurrent diagnosis\tNo\tNo\tSUD\t\tNo\tNo\tSelf-intoxication\tNo\t\nAge (years)*\t37\t34\t33\t34\t31\t27\t34\t16\t\nEthnicity\tCaucasian\tCaucasian\tCaucasian\t\tNA\tNA\tNA\tNA\t\nEducational level\tHigh School\tHigh School\tHigh School\t\tNA\tNA\tNA\tNA\t\nMarital status\tMarried\tMarried\tLiving together\t\tNA\tNA\tMarried\tNA\t\nEmployment status\tEmployed\tEmployed\tUnemployed\t\tNA\tNA\tNA\tNA\t\nPlanned pregnancy\tPlanned & happy\tPlanned & happy\tUnplanned & happy\t\tPlanned\tPlanned\tNA\tNA\t\nParity\tPrimiparous\tPrimiparous\tPrimiparous\tMultiparous\tNA\tMultiparous\tNA\tNA\t\nBMI (pre-pregnancy)—Kg/m2\t31.84\t27.78\t24.90\t28.09\tNA\tNA\t25.00\tNA\t\nPregestational diabetes\tNo\tNo\tNo\tNo\tNA\tNA\tNo\tNA\t\nFamily history of diabetes\tNo\tYes\tNo\tNo\tNA\tNA\tNA\tNA\t\nPREGNANCY VARIABLES\t\nWeight gain in pregnancy—Kg\t13\t16\t11.5\t11.7\t25\tNA\t16.00\tNA\t\nGestational diabetes\tNo\tYes at 14 gwk\tNo\tNo\tNA\tNo\tNo\tNo\t\nOther complications\tNo\tNo\tIUGR-1 at 28 g wk\tNo\tNA\tNo\tNo\tNo\t\nType of delivery\tVaginal\tCesarean†\tCesarean‡\tCesarean¶\tVaginal**\tVaginal\tVaginal\tCesarean†\t\nMaternal duration of gestation††\t38+6\t40+5\t38+6\t39\t41+0\t39+0\t40+0\t32+0\t\nBMI: body mass index; CLZ-R Schizophrenia: clozapine-resistant schizophrenia; GWK: gestational week; IUGR: intrauterine growth retardation; SUD: substance use disorder.\n\n* Age at the time of pregnancy;\n\n† Emergency cesarean section;\n\n‡ Elective cesarean section due to breech presentation;\n\n¶ Elective cesarean section for short interpregnancy period;\n\n** Instrumental vaginal;\n\n†† Maternal duration of gestation: weeks + days after last menstrual date.\n\nTable 2 Neonatal, infant, and child outcomes in the case series and in the previous cases reported in the literature.\n\nVariables\tChronic clozapine exposure\tAcute clozapine exposure\t\n\tNeonate 1 (M1) 2007\tNeonate 2 (M2) 2014\tNeonate 3 (M3-1) 2015\tNeonate 4 (M3-2) 2016\tBarnas et al., 1994\tMoreno-Bruna et al., 2012\tKłys et al., 2007\tNovikova et al., 2009\t\nNEONATAL OUTCOMES\t\nInfant sex\tMale\tFemale\tMale\tFemale\tFemale\tMale\tMale\tFemale\t\nEstimated gestational age\t38+6\t40+5\t38+6\t39\t41+0\t39+0\t40+0\t32+0\t\nApgar score (1/5/10 min)\t9/10/10\t9/10/10\t6/10/10\t9/10/10\t5/8/–\t1/–/–\t10/10/–\t–/5/–\t\nArterial cord pH\t7.09\t7.18\t7.21\tN/A\t7.34\tNA\tN/A\t7.19\t\nInfant weight (g) (%tile)\t3,850 (p75-80)\t3,660 (p85-90)\t2,498 (p < 3)\t3,650 (p85-9)\t3,600 (p80-85)\t4,050 (p > 95)\t4,060 (p90-95)\t1,700 (p23)\t\nLength (cm) (%tile)\t51.50 (p90-95)\t51.00 (p80-85)\t47.00 (p10)\t49.00 (p50)\tN/A\tNA\t55.50 (p > 95)\tNA\t\nCranial perimeter (cm) (%tile)\t36.00 (p85-90)\t36.00 (p > 95)\t34.00 (p25)\t35.50 (p90-95)\tN/A\tNA\t36.50 (p90-95)\tNA\t\nNICU admission\tNo\tNo\tYes\tNo\tNo\tNA\tNo\tNA\t\nHospital stay (days)\t4\t3\t4\t4\tN/A\t20 min\t17\tNA\t\nCongenital anomaly\tNo\tNo\tInguinal hernia and cryptorchi dism (left)\tNo\tNo\tNo\tNo\tNo\t\nCardiovascular\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tAbnormal fetal CTG\t\nRespiratory\tNo\tNo\tResuscitation procedures*\tNo\tNo\tResuscitation procedures*\tNo\t\t\nOthers†\tNo\tNo\tNo\tNo\tNo\tNo\tDelayed peristalsis\tDelayed peristalsis\t\nBlood leukocytes UCB (x 109/L)\t25.17\t22.23\t8.65‡\t12.49\tNA\tNA\tNormal\tNA\t\nUrine drug test¶ (1st day PP)\tNA\tNA\tBZD (+)\tNA\tNA\tEtanol (-)\tNA\tNA\t\nInfant feeding\tFormula\tMixed BF 5 days, then formula\tFormula\tFormula\tFormula\tNA\tFormula\tNA\t\nINFANT/CHILD OUTCOMES\t\nDevelopmental abnormalities\tTDH symptom at 6 years\tNo\tGeneral neurodeve-lopmental delay\tNo\tNo\tNA\tNo\tNo\t\nLast observation\t10 years\t32 months\t16 months\t5 months\t6 months\t20 min\t2 years\t6 days\t\nBZD, benzodiazepines; BF, breastfeeding; CGT, cardiotocography tracing; NICU, neonatal intensive care unit; PP, postpartum; UCB, umbilical cord blood; g, gram; cm, centimeter; %tile, percentile.\n\n* Positive pressure ventilation;\n\n† Others: renal, thyroid, gastrointestinal, central nervous system;\n\n‡ At 2nd day postpartum;\n\n¶ Urine drug test included alcohol, cannabis, heroin, methadone, cocaine, benzodiazepines.\n\nTable 3 Placental passage and neonatal half-life values of clozapine and metabolite in the case series and in the previous reported in the literature.\n\nVariable\tChronic clozapine exposure\tAcute clozapine exposure\t\n\tMother 1 (M1) 2007\tMother 2 (M2) 2014\tMother 3 (M3-1) 2015\tMother 3 (M3-2) 2016\tBarnas et al., 1994\tMoreno-Bruna et al., 2012\tKłys et al., 2007\tNovikova et al., 2009\t\nMATERNAL VARIABLES\t\nPsychiatric diagnosis\tCLZ-R Schizophrenia\tSchizoaffective\tSchizoaffective\t\tSchizophrenia\tSchizophrenia\tSchizophrenia\tNo\t\nCo-ocurrent diagnosis\tNo\tNo\tSUD*\t\tNo\tNo\tNo\tNo\t\nCLZ therapy duration\twk 0-delivery\twk 0-delivery\twk0-16, 21-delivery\twk 0-delivery\twk 0-delivery\twk 0-delivery\twk 0-12\n self-intox wk39\tSelf-intox wk 32\t\nOther medication during\n pregnancy\tLA-RIS 50 mg/month wk 0-34\tNo\tDZ 15 mg/day\n wk 30-37\tSER 100 mg/day\n wk 35-delivery\tNo\tNo\tVAL, PROM\n RIS, FX\tNo\t\nDrug use during pregnancy\tTobacco daily\tNo\tAlcohol, cocaine, cannabis†\n Tobacco daily\tTobacco daily\tNA\tNA\tNo\tNA\t\nUrine drug test during pregnancy‡\t(+) Cotinine\tNegative\t(+) Cotinine\t(+) Cotinine\tNA\tNA\tNo\tNA\t\nMaternal CLZ dose at delivery\n (mg/day)\t350\t100\t200\t200\t50\t100\t1000\t2000\t\n[CLZ] AT DELIVERY (ng/ml)\t¶\t**\t\nUmbilical cord blood (UCB)\t77\t68\t113\t67\t27\tNA\tNA\tNA\t\nAmniotic fluid (AF)\t61\tNA\t67\tNA\t11.60\tNA\tNA\tNA\t\nMaternal plasma (MP)\t198\t122\t194\t148\t14.10\tNA\tNA\tNA\t\nCLZ UCB/MP ratio (%)\t38.88\t55.70\t58.24\t45.27\t191.48\tNA\tNA\tNA\t\n[NORCLZ] AT DELIVERY (ng/ml)\t\nUmbilical cord blood (UCB)\t56\t26\t42\t32\tNA\tNA\tNA\tNA\t\nAmniotic fluid (AF)\t39\tNA\t52\tNA\tNA\tNA\tNA\tNA\t\nMaternal plasma (MP)\t200\t79\t114\t149\tNA\tNA\tNA\tNA\t\nNorCLZ UCB/MP ratio (%)\t28.00\t32.91\t36.84\t21.47\tNA\tNA\tNA\tNA\t\nNEONATAL HALF-LIFE (HOURS)\t\nCLZ\t99\tNA\t71.42\t106.61\tNA\tNA\tNA\tNA\t\nNorCLZ\t161.16\tNA\t187.30\t130.75\tNA\tNA\tNA\tNA\t\nCLZ, clozapine; CLZ-R, Schizophrenia, clozapine resistant schizophrenia; DZ, diazepam; FX, fluoxetine; LA-RIS, long acting risperidone; NA, not available; NorCLZ, norclozapine; PROM, prometazine; Self-intox, self intoxication; SER, sertraline: VAL, valproate; wk, week.\n\n* SUD, alcohol, nicotine, cannabis, or cocaine substance use disorder;\n\n† first 5 month of pregnancy;\n\n‡ Urine drug test included alcohol, cannabis, heroin, metadone, cocaine, benzodiazepines, and cotinine;\n\n¶ Postmortem (at 24 h), Blood (μg/ml): [CLZ] 7.3, [NorCLZ] 2.3, [CLZ-N-oxide] 0.5. Liver (μg/ml): [CLZ] 28.0, [NorCLZ] 17.1, [CLZ-N-oxide] 31.1. Kidney (μg/ml): [CLZ] 10.1, [NorCLZ] 6.1, [CLZ-N-oxide] 5.8;\n\n** Qualitative urine analysis of CLZ in the mother: (+)3 days after CLZ intake, and in urine of the neonate: (+) 6 days after maternal CLZ intake.\n\nFigure 1 Neonatal clozapine (A) and norclozapnie (B) plasma concentration time profile. M1, Mother case 1; M3-1, Mother case 3, first pregnancy; M3-2, Mother case 3, second pregnancy.\n\nThe second patient (M2), a 34-year-old woman, was diagnosed with schizoaffective disorder at the age of 18. She was treated initially with haloperidol 15 mg/day, and later on with sertindole 16 mg/day. Because of severe hypotension the treatment was changed to amisulpride 150 mg/day and risperidone 6 mg/day. She remained in remission for several years. At 30 years of age, she decided to plan a pregnancy. Due to an increase in prolactin level the risperidone dose was reduced to 4.5 mg/day. However, as the patient started being symptomatic, the 6 mg/day dose was reinstated and the patient became asymptomatic. After more than 3 years of follow-up without becoming pregnant, she switched treatment to 200 mg/day clozapine and after 6 months she became pregnant and she returned to our program (Table 1). In the 19th week of pregnancy, clozapine treatment was titrated down progressively to a dose of 100 mg/day to avoid fetal accumulation (Barnas et al., 1994). She developed diabetes during pregnancy that was successfully controlled with long-acting insulin at 6 U/day. Ultrasound examinations detected fetal macrosomia in the 29th week of gestation. No other physiological parameters were altered. She gave birth in the 40th week pregnancy by cesarean delivery. No perinatal complications were recorded and there was a good obstetric outcome (Table 2). No agranulocytosis, seizures or other neonatal complications were observed. Table 3 shows the plasma concentrations of clozapine/norclozapine in IMB and UCB. Mixed breastfeeding was conducted for 5 days. At 33 hours after delivery, the infant/mother clozapine ratio had decreased by 48.9%. However, 5 days after delivery, the mother was briefly hospitalized due to a relapse of manic psychotic symptoms, which responded rapidly to an increase in clozapine to 200 mg/day, and breastfeeding was stopped. No neurodevelopmental disorders were detected in the infant after 32 months follow-up.\n\nThe third case (M3-1), a 33-year-old woman, had a severe schizoaffective disorder comorbid with SUD for 8 years. She was treated with several antipsychotic treatments (risperidone 3 mg/day, LAI risperidone 50 mg/month, olanzapine 20 mg/day, paliperidone 9 mg/day, and aripiprazol 15 mg/day) without achieving clinical stability. Finally, treatment was switched to clozapine 200 mg daily. In 2014 she had one first trimester spontaneous abortion. In 2015, when she knew that she was pregnant again, she tried to stop antipsychotic medication at week 16, but the reappearance of auditory hallucinations forced her to reintroduce clozapine 200 mg daily at week 21. However, in week 26, due to psychotic decompensation, cocaine and alcohol abuse, as well as domestic abuse, she was hospitalized until the end of pregnancy and clozapine was increased up to 300 mg/day and diazepam 10 mg/day was added to achieve clinical remission. Ultrasound examinations showed type I intrauterine growth restriction in the 28th week of gestation. She gave birth to a boy in the 38th week of pregnancy by cesarean delivery due to breech presentation (Table 1). The Apgar-min 1 score was 6 and neonatal resuscitation was initiated in the delivery room. The Apgar-min 5 score was 10, and arterial cord PH was 7.21. It was also noted that the baby had a left inguinal hernia and left cryptorchidism. The urine drug test was positive for benzodiazepines. No agranulocytosis, seizures, or other neonatal complications were observed. Cerebral and cardiac ultrasounds were normal (Table 2). The plasma concentrations of clozapine/norclozapine in IMB, UCB, and AF were also measured (Table 3). Figure 1 shows the neonatal half-life elimination of clozapine. In this case, the infant was bottle fed, and was discharged from the hospital with his mother's family, awaiting surgery. Generalized neurodevelopmental delay was observed at the follow-up at 18 months. The mother was transferred to a mental institution 4 days after delivery to continue her treatment and clinical stabilization.\n\nThree months after discharge, the same patient arrived in the Psychiatry Emergency Unit after alterations in her behavior. There was no evidence of a relapse in schizoaffective disorder. However, she was 6-weeks pregnant. In this new pregnancy (M3-2) she was hospitalized. Treatment was maintained with clozapine 200 mg/day throughout pregnancy, and sertraline 100 mg/day was added in gestational week 35 until postpartum. She gave birth to a girl in the 39th week of pregnancy by elective cesarean section. The Apgar-min 1/5 score was 9/10. The serum concentrations of clozapine/norclozapine in IMB and UCB were measured (Table 3). Figure 1 shows the neonatal half-life elimination of clozapine. Again, the neonate was bottle fed and was discharged from the hospital with his mother's family. No agranulocytosis or neurodevelopmental disorders were detected in the infant at the 6-month follow-up. The mother continued asymptomatic with the same treatment and she now attends the Mental Health Community Center.\n\nDiscussion\nIn this report we present four cases of clozapine treatment during pregnancy focusing on the pharmacokinetics of clozapine and the maternal and neonatal outcomes. The placental passage of clozapine was partial in all four cases and the mean (SD) half-life value of clozapine in neonates who were exposed in utero was 92 (18) h. In the only case with maternal lactation we found no evidence of clozapine accumulation in the first 33 neonatal hours of life. One of the four pregnancies was complicated by diabetes mellitus. We did not observe any acute toxicological effects in three of the four neonates. The only neonate with respiratory problems was also exposed to maternal diazepam treatment. However, these results must be taken with caution being a case series with small sample size.\n\nThe current report indicates that placental passage of clozapine/norclozapine is partial during delivery (Table 2). These results contrast with those published previously by Barnas et al. (1994), who observed clear accumulation of clozapine in fetal serum. These differences in results could be explained by different maternal and fetal factors. The case by Barnas et al. (1994) was free of concomitant medication with no possible pharmacokinetic interaction. Our second case, treated also only with clozapine, showed a UCB/IMB ratio close to the mean ratio of the four cases. Another maternal factor to be taken into account is the fact that M1, M3-1, and M3-2 smoked during pregnancy. Pharmacokinetic studies have demonstrated lower clozapine /norclozapine concentrations in smokers compared to non-smokers (Lowe and Ackman, 2010). However, there was no information about smoking in Barnas' case report. Lastly, partial placental passage has been described in other atypical antipsychotics such as olanzapine, risperidone, and quetiapine as well as the first-generation antipsychotic haloperidol, suggesting a common pharmacokinetic behavior (Newport et al., 2007).\n\nThe elimination half-life of drugs has been related to adverse effects. Neonatal clozapine pharmacokinetics are thought to differ from those in adults (Jann et al., 1993) because cytochromes CYP450 3A4 and 1A2, which are responsible for demethylation of clozapine to norclozapine (desmethyl-clozapine) in adults, are present to a lesser extent in neonates (Myllynen et al., 2009). Furthermore, norclozapine is eliminated by glomerular filtration, which is known to be reduced in newborns (Smits et al., 2013). In our series the mean maternal, amniotic fluid and fetal concentrations of clozapine were higher than the concentrations of norclozapine. The clozapine/norclozapine concentrations were similar in amniotic fluid and fetal serum in our series. In contrast, in Barnas' case clozapine concentrations were similar in maternal serum and amniotic fluid, and there was a clear accumulation in fetal serum. In neonates we also observed higher concentrations of clozapine than norclozapine. The estimate of half-life elimination of clozapine by Moreno-Bruna et al. (2012) was 72 h. They found a delay in peristalsis that they hypothesized was related to the neonatal concentration of clozapine (200 ng/mL), which was indirectly estimated from the neonatal half-life elimination of clozapine. In our three neonates we found a mean half-life of clozapine of 92 h, with a mean plasma neonatal concentration of clozapine of 85(24) ng/mL in the first 24 h of life (Figure 1). This was not associated with any neonatal adverse effect. We must point out that our mean plasma neonatal concentration of clozapine was lower than that estimated by Moreno-Bruna et al. (2012). In the literature there are two cases of neonatal delayed peristalsis after maternal acute clozapine intoxication in late pregnancy in two women that were not receiving regular clozapine treatment (Kłys et al., 2007; Novikova et al., 2009). In the first case, the baby died after 3 h and the woman was saved. Post-mortem clozapine/norclozapine plasma levels were obtained. In the second, the baby developed abdominal distension on the first day of life, and the mother had a multisystemic failure and passed away after 3 days. Clozapine and its metabolites were detected in the urine of the mother at 3 days and the child at 6 days.\n\nWith regard to the lactation passage to clozapine, previous data (Barnas et al., 1994) suggested an accumulation in maternal milk. We were able to study lactation passage in only one mother (M2). The Food and Drug Administration (2005) suggests that the infant plasma concentration is probably the most direct measure of infant risk from a drug received from breast milk. In this sense, we observed that the infant/maternal plasma clozapine concentration ratio decreased close to 88% over time, from 0.557 (delivery day) to 0.065 (33 h post-delivery). In our case, the concentration of clozapine in the infant's plasma was ~6% of the corresponding maternal plasma drug concentration at 2nd day of life. Then, different to Barna's case our result did not suggest accumulation of clozapine and metabolite on the 2nd day of breastfeeding.\n\nFinally, clozapine had no acute toxicological effects such as agranulocytosis or seizures, in the exposed neonates, regardless of exposure to other medications. However, one of the newborns was diagnosed with intrauterine growth retardation in the 28th gestational week, as well as left inguinal hernia and cryptorchidism at birth. Moreover, he presented with generalized neurodevelopmental delay and the consequent need for continuous intensive care. His mother had a history of past and current drug abuse (M3-1) during pregnancy. Importantly, the second baby born to this mother (M3-2) showed normal neurodevelopment. In this case, the baby was not exposed to maternal substance use other than tobacco. Regarding the long-term clinical outcome, signs and symptoms of attention deficit and hyperactivity disorder were observed (M1) after 6 years of follow-up.\n\nEthics statement\nThis study was carried out in accordance with the recommendations of the Research and Ethical Committee (CEIC) of our Institution Hospital Clinic.\n\nAuthor contributions\nAll authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors: Case study concept and design. MI, GO, MT, DS, LG-E, and RM-S: Acquisition, analysis, or interpretation of data; MI, GO, and RM-S: Drafting of the manuscript; All authors: Critical revision of the manuscript for important intellectual content; MI, MT, and DS: Administrative, technical, or material support; All authors: Study supervision.\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\nThe study was supported by the Generalitat de Catalunya/Support a les activitats del Grups de Recerca: SGR2017/1798. The authors would like to thank to Full Professor Magi Farre, Unitat de Farmacologia Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), Badalona, Spain, for helpful comments on the manuscript.\n==== Refs\nReferences\nBarnas C. Bergant A. Hummer M. Saria A. Fleischhacker W. W. (1994 ). 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(2007 ). Possible delayed speech acquisition with clozapine therapy during pregnancy and lactation . J. Neuropsychiatry Clin. Neurosci. \n19 , 196 –197 . 10.1176/jnp.2007.19.2.196 17431071 \nMoreno-Bruna M. D. de Montgolfier I. Chabaud M. Dommergues M. (2012 ). Case report: neonatal delayed peristalsis after in-utero exposure to clozapine . Arch. Pediatr . 19 , 913 –916 . 10.1016/j.arcped.2012.06.019 22884999 \nMyllynen P. Immonen E. Kummu M. Vahakangas K. (2009 ). Developmental expression of drug metabolizing enzymes and transporter protein in human placenta and fetal tissues . Expert Opin. Drug Metab. Toxicol . 5 , 1483 –1499 . 10.1517/17425250903304049 19785513 \nNewport D. J. Calamaras M. R. DeVane C. L. Donovan J. Beach A. J. Winn S. . (2007 ). Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes . Am. J. Psychiatry . 164 , 1214 –1220 . 10.1176/appi.ajp.2007.06111886 17671284 \nNguyen H. N. Lalonde P. (2003 ). Clozapine and pregnancy . Encephale \n29 , 119 –124 . 14567163 \nNovikova N. Chitnis M. Linder V. Hofmeyr G. J. (2009 ). Atypical antipsychotic (clozapine) self-poisoning in late pregnancy presenting with absent fetal heart rate variability without acidosis and delayed peristalsis in the newborn baby: a case report . Aust. N. Z. Obstet. Gynaecol . 49 , 442 –444 . 10.1111/j.1479-828X.2009.01017.x 19694706 \nReis M. Källén B. (2008 ). Maternal use of antipsychotics in early pregnancy and delivery outcome . J. Clin. Psychopharmacol. \n28 , 279 –288 . 10.1097/JCP.0b013e318172b8d5 18480684 \nShao P. Ou J. Peng M. Zhao J. Chen J. Wu R. (2015 ). Effects of clozapine and other atypical antipsychotics on infants development who were exposed to as fetus: a post-hoc analysis . PLoS ONE \n10 :e0123373 . 10.1371/journal.pone.0123373 25909513 \nSmits A. Annaert P. Allegaert K. (2013 ). Drug disposition and clinical practice in neonates: cross talk between developmental physiology and pharmacology . Int. J. Pharm . 452 , 8 –13 . 10.1016/j.ijpharm.2012.03.035 22504091 \nStahl S. M. (ed.). (2017 ). Clozapine , in Stahl Essential Psychopharmacology: Prescriber's Guide, 6th Edn (New York, NY : Cambridge University Press ), 177 –186 .\nStoner S. C. Sommi R. W. Jr.Marken P. A. Anya I. Vaughn J. (1997 ). Clozapine use in two full term pregnancies . J. Clin. Psychiatry \n58 , 364 –365 . 10.4088/JCP.v58n0806f 9515978 \nTenyi T. Trixler M. (1998 ). Clozapine in the treatment of pregnant schizophrenic women . Psychiatr. Danub . 10 , 15 –18 .\nTitier K. Bouchet S. Péhourcq F. Moore N. Molimard M. (2003 ). High-performance liquid wiandhaloperidol in plasma after overdose . J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. \n788 , 179 –185 . 10.1016/S1570-0232(02)01003-6 12668083 \nToh S. Li Q. Cheetham T. C. Cooper W. O. Davis R. L. Dublin S. (2013 ). Prevalence and trends in the use of antipsychotic medication during pregnancy in the U.S. 2001-2007: a population-based study of 585,615 deliveries . Arch. Womens Ment. Health \n16 , 149 –157 . 10.1007/s00737-013-0330-6 23389622 \nVavrusova L. Konikova M. (1998 ). Clozapine administration during pregnancy . Ceska. Slov. Psychiatr . 94 , 282 –285 .\nWaldman M. D. Safferman A. Z. (1993 ). Pregnancy and clozapine . Am. J. Psychiatry \n150 , 168 –169 . 10.1176/ajp.150.1.168a 8018113 \nYogev Y. Bem-Haroush A. Kaplan B. (2002 ). Maternal clozapine treatment and decreased fetal hearth rate variability . Int. J. Gynaecol. Obstet . 79 , 259 –260 . 10.1016/S0020-7292(02)00276-X 12445996\n\n",
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"title": "Clozapine Use During Pregnancy and Lactation: A Case-Series Report.",
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"abstract": "In this paper we report 19 patients (14 males, 5 females; mean age 28.16 years +/- 7.68 SD) out of a series of 23 (17 males, 5 females) who developed a mood disturbance (moderate to severe depression) during treatment with finasteride, 1 mg/day orally, for androgenetic alopecia (Hamilton subtypes III-V; Ludwig subtypes I-II). Depression, which significatively impaired sociofamilial relations, sleep and eating behaviour, was associated to marked anxiety in some cases, developed after 9-19 weeks of treatment with finasteride, and promptly resolved after suspension of the drug. Two patients accepted reintroduction of the drug, and depression relapsed within 2 weeks. Depression as an adverse effect of finasteride has been reported only once. Further studies are needed to confirm our circumstantial observations, which are based on a retrospective series of patients.",
"affiliations": "Department of Dermatology, Ospedale Maggiore IRCCS, University of Milan, Italy.",
"authors": "Altomare|Gianfranco|G|;Capella|Giovanni Luigi|GL|",
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"title": "Depression circumstantially related to the administration of finasteride for androgenetic alopecia.",
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"abstract": "Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of solid organ transplantation. The current report presents the case of a 42-year-old male who developed PTLD within the first year following renal transplantation. The disorder manifested as a tumor adjacent to the lower pole of the renal allograft and resulted in urinary obstruction. Durable complete remission was achieved as a result of surgical resection followed by a reduction in immunosuppression and low-dose rituximab-based chemotherapy, indicating that this therapeutic strategy may be safe and effective for the treatment of specific cases of localized and resectable PTLD.",
"affiliations": "Department of Urological Organ Transplantation, Second Xiangya Hospital, Central South University, Changsha, Hunan 41011, P.R. China.;Department of Urological Organ Transplantation, Second Xiangya Hospital, Central South University, Changsha, Hunan 41011, P.R. China.;Department of Urological Organ Transplantation, Second Xiangya Hospital, Central South University, Changsha, Hunan 41011, P.R. China.;Department of Urological Organ Transplantation, Second Xiangya Hospital, Central South University, Changsha, Hunan 41011, P.R. China.;Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, Hunan 41011, P.R. China.",
"authors": "Gao|Chen|C|;Peng|Longkai|L|;Peng|Fenghua|F|;Tuo|Ting|T|;Li|Daiqiang|D|",
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"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2014.2586ol-08-06-2607ArticlesPost-transplant lymphoproliferative disorder presenting as a tumor adjacent to the renal allograft: A case report and review of the literature GAO CHEN 1PENG LONGKAI 1PENG FENGHUA 1TUO TING 1LI DAIQIANG 21 Department of Urological Organ Transplantation, Second Xiangya Hospital, Central South University, Changsha, Hunan 41011, P.R. China2 Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, Hunan 41011, P.R. ChinaCorrespondence to: Dr Longkai Peng, Department of Urological Organ Transplantation, Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 41011, P.R. China, E-mail: gylchygc@126.com12 2014 02 10 2014 02 10 2014 8 6 2607 2610 16 2 2014 19 9 2014 Copyright © 2014, Spandidos Publications2014This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of solid organ transplantation. The current report presents the case of a 42-year-old male who developed PTLD within the first year following renal transplantation. The disorder manifested as a tumor adjacent to the lower pole of the renal allograft and resulted in urinary obstruction. Durable complete remission was achieved as a result of surgical resection followed by a reduction in immunosuppression and low-dose rituximab-based chemotherapy, indicating that this therapeutic strategy may be safe and effective for the treatment of specific cases of localized and resectable PTLD.\n\npost-transplant lymphoproliferative disorderEpstein-Barr virusearly-onsetkidney transplantation\n==== Body\nIntroduction\nPost-transplant lymphoproliferative disorder (PTLD) is a rare, but critical complication that occurs following solid organ and hematopoietic stem cell transplantation (1). PTLD encompasses a heterogeneous group of disorders, ranging from benign self-limited lesions to aggressive widely disseminated disease. Generally, PTLD is considered to be an iatrogenic complication due to the intensive immunosuppressive treatment administered following transplantation (2). The overall incidence of PTLD in adult kidney transplantation surgery was between 1 and 3% worldwide (3). However, early-onset PTLD (<1 year from transplantation to presentation of PTLD) is closely associated with the Epstein-Barr virus (EBV) infection and exhibits a predilection for allograft localization (4), occasionally occuring at sites adjacent to the allograft. The current study describes a rare case of PTLD that presented as a tumor adjacent to the allograft within the first year following renal transplantation. The treatment strategy included surgical resection that was followed by a reduction in immunosuppression and low-dose rituximab-based chemotherapy. This study may lead to future improvements for the treatment of post-transplant lymphoproliferative disorder. Written informed consent was obtained from the patient.\n\nCase report\nIn March 2012, a 42-year-old male exhibiting end-stage renal disease secondary to hypertension received a kidney transplant at the Second Xiangya Hospital of Central South University (Changsha, China). The donor was a 27-year-old male who had succumbed to cardiac failure caused by craniocerebral trauma. The human leukocyte antigen (HLA) type of the donor and the recipient were A11/A2-B58/B13-DR4/DR53, DR9/DR53 and A2/A2-B13/B61-DR15/DR51, DR9/DR53, respectively. The recipient was EBV seronegative, however, the donor’s EBV serologic status was unknown, as EBV serologic status was not tested routinely at the time of donation. Furthermore, the donor and recipient were seronegative for cytomegalovirus, and the Hepatitis B and C viruses. There were no complications during surgical follow-up. The patient’s post-transplant immunosuppressive regimen included: Intravenous methylprednisolone (dose during surgery, 0.5 g; dose for the first three days following surgery, 0.5 g/day); followed by cyclosporine (CsA; initial dose, 6 mg/kg/day; trough concentration was adjusted to 220–250 ng/ml 0–6 months following transplantation and 180–220 ng/ml over the next 6–12 months); oral mycophenolate mofetil (MMF; dose, 0.75 g per 12 h; gradually reduced to 0.5 g per 12 h for long-term maintenance immunosuppression); and prednisolone (initial dose, 80 mg/day; gradually reduced to 10 mg/day over the next 6 months for long-term maintenance immunosuppression). Good renal allograft function was observed immediately following surgery. On the twelfth postoperative day, the patient exhibited a serum creatinine level of 133 μmol/l (normal range, 44–133 μmol/l) and was discharged. The allograft function remained normal during the out-patient follow-up, however, seven months post-transplantation, the patient developed a fever, oliguria and an elevated serum creatinine level (410.7 μmol/l). Sonography and computed tomography revealed a solid mass adjacent to the renal allograft (Fig. 1A) and computed tomography with coronal multiplanar reformation revealed a solid mass (size, 6×4×8 cm) in the lower pole of the allograft and hydronephrosis (Fig. 1B). Percutaneous nephrostomy tubes were inserted, resulting in a decline in the serum creatinine level. Subsequently, surgical resection was performed and a tumor with a poorly defined margin, located adjacent and in close proximity to the lower pole of the allograft, was removed. Postoperatively, serum creatinine returned to within the normal range following treatment of the urinary obstruction. Intra- and postoperative histopathological assessments determined a diagnosis of polymorphic PTLD with positive stains for cluster of differentiation (CD)20, CD79a, CD3 and EBV-encoded RNA (Fig. 2). The proliferation index of Ki-67 was 40%. Upon diagnosis, the blood EBV DNA level was 1.3×104 copies/ml, and the lactate dehydrogenase level (normal range, 135–215 U/l) and bone marrow biopsy were normal. Therefore, MMF therapy was discontinued and CsA was replaced with Rapamune (Wyeth Pharmaceuticals, Dallas, TX, USA) (trough concentration adjusted to 6–8 ng/ml) to reduce the level of immunosuppression. Furthermore, four cycles of adjuvant low-dose chemotherapy were administered, including rituximab (300 mg/m2), cyclophosphamide (500 mg/m2), vincristine (1.2 mg/m2) and prednisolone (50 mg/m2). The patient’s blood was negative for EBV DNA following the first cycle of chemotherapy. During the 16-month follow-up after resection, the patient remained in remission, neither EBV viremia nor PTLD recurred and renal allograft function was preserved. Outpatient follow-up is ongoing to determine the long-term outcome of the treatment strategy.\n\nDiscussion\nPTLD is the second most commonly occurring malignancy in solid organ transplant recipients, worldwide. Approximately 20% of kidney transplant patients developed PTLD within the first year following surgery (5). Early-onset PTLD occurs more commonly in EBV seronegative recipients compared with EBV seropositive recipients and is characterized by an EBV in situ hybridization-positive, CD20-positive phenotype and allograft involvement (6). An immunosuppressed state and EBV infection are considered to be the two most important risk factors in PTLD development (2). In the majority of EBV-associated cases of PTLD, immunosuppression depresses the EBV-specific cellular immune response, which may promote uncontrolled EBV-infected lymphocyte proliferation, resulting in PTLD (7). The rare case described in the current report presented as a tumor adjacent to the lower pole of the renal allograft and developed into a urinary obstruction. To the best of our knowledge, few similar cases have been reported to date (8–12). In the present case, the risk factors for the development of PTLD included EBV seronegativity prior to transplantation, EBV infection post-transplantation, mismatching at the HLA-B locus and a high dose of CsA (13,14).\n\nNo consensus on the optimal management of PTLD has been determined, however, a reduction in immunosuppression (RI) has been demonstrated to be an effective initial treatment modality for PTLD. In a recent analysis of 148 solid organ transplant-associated PTLD cases, Reshef et al (15) reported that the overall response rate for a RI alone was 45% and the three year overall survival rate was 55%. Recent guidelines recommend commencing the reduction of immunosuppression therapy as soon as possible in all PTLD patients (16) and in specific cases of localized PTLD, surgical excision of isolated lesions or debulking of the tumor may be an effective component of first-line treatment. Reshef et al (15) identified that patients who underwent surgery and adjuvant RI exhibited a favorable outcome, with 27% patients relapsing at a median of five months. Rituximab is a monoclonal antibody against the B lymphocyte-specific CD20 antigen (17). Recent data indicates that immediate commencement of rituximab-based therapy followed by anthracycline-based chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) may result in durable progressive-free survival in PTLD patients (18) and may reduce the risk of renal graft impairment following the reduction of immunosuppression (19). In the present case, surgical excision was performed for the diagnosis and resolution of the urinary obstruction. RI, followed by rituximab-based therapy combined with low-dose chemotherapy, for four months, the standard dose is as follows: rituximab (375 mg/m2, day 1), cyclophosphamide (400 mg/m2, days 1–5), vincristine (1.4 mg/m2, day 1) and prednisolone (100 mg/m2, days 1–5) and was prescribed due to the aggressive nature of the disease. The therapeutic strategy administered to the patient in the present study resulted in complete remission with few manageable side-effects, including nausea/vomiting and leukopenia. Consistent with the present case, two previous studies reported that surgical intervention in combination with other therapies achieved durable remission in specific patients exhibiting localized PTLD (20,21). The maintenance of immunosuppression remains a challenge in renal recipients who develop PTLD. The use of calcineurin inhibitors has been associated with an increased incidence of PTLD (22), however, treatment with rapamycin and its analogs has demonstrated immunosuppression and antiproliferative action. Previous studies demonstrated that rapamycin immunosuppressant therapy produced favorable effects in kidney transplant patients exhibiting PTLD (23,24). Therefore, serolimus was introduced in the present case for maintenance immunosuppression. However, the use of rapamycin in PTLD patients remains controversial (25), thus, further studies are required to reach a consensus for the optimal management of PTLD.\n\nIn conclusion, the current report presents a rare case of PTLD that manifested as an obstructive uropathy within the first year following kidney transplantation. Surgical excision followed by a reduction in immunosuppression and low-dose rituximab-based chemotherapy may present as an effective and safe strategy for specific cases of localized and resectable PTLD.\n\nFigure 1 (A) Abdominal computed tomography showing a solid mass adjacent to the renal allograft. (B) Abdominal computed tomography with coronal multiplanar reformation showing a solid mass adjacent to the lower pole of the renal allograft and hydronephrosis. The arrow indicates the solid mass.\n\nFigure 2 Histopathological images of the tumor. (A and B) Diffuse infiltration of lymphocytes, immunoblasts and plasma cells (stain, hematoxylin and eosin). Abundant lymphoid cells were positive for (C) cluster of differentiation 20 (staining, brown) and (D) Epstein-Barr virus-encoded RNA in situ hybridization (staining, brown). Magnification, (A, C and D) ×100; (B) ×400.\n==== Refs\nReferences\n1 Everly MJ Bloom RD Tsai DE Trofe J Posttransplant lymphoproliferative disorder Ann Pharmacother 41 1850 1858 2007 17940127 \n2 Dierickx D Tousseyn T De Wolf-Peeters C Pirenne J Verhoef G Management of posttransplant lymphoproliferative disorders following solid organ transplant: an update Leuk Lymphoma 52 950 961 2011 21338285 \n3 Caillard S Lelong C Pessione F Moulin B French PTLD Working Group Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry Am J Transplant 6 2735 2742 2006 17049061 \n4 Khedmat H Taheri S Early onset post transplantation lymphoproliferative disorders: analysis of international data from 5 studies Ann Transplant 14 74 77 2009 19644164 \n5 Morton M Coupes B Roberts SA Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients Transplantation 95 470 478 2013 23222821 \n6 Ghobrial IM Habermann TM Macon WR Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases? Transplantation 79 244 247 2005 15665775 \n7 Tsao L Hsi ED The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders Arch Pathol Lab Med 131 1209 1218 2007 17683183 \n8 Kew CE II Lopez-Ben R Smith JK Posttransplant lymphoproliferative disorder localized near the allograft in renal transplantation Transplantation 69 809 814 2000 10755531 \n9 Palmer BF Sagalowsky AI McQuitty DA Dawidson I Vazquez MA Lu CY Lymphoproliferative disease presenting as obstructive uropathy after renal transplantation J Urol 153 392 394 1995 7815594 \n10 Khedmat H Taheri S Characteristics and prognosis of post-transplant lymphoproliferative disorders within renal allograft: Report from the PTLD Int Survey Ann Transplant 15 80 86 2010 \n11 Cosio FG Nuovo M Delgado L EBV kidney allograft infection: possible relationship with a peri-graft localization of PTLD Am J Transplant 4 116 123 2004 14678042 \n12 Caillard S Porcher R Provot F Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score J Clin Oncol 31 1302 1309 2013 23423742 \n13 Quinlan SC Pfeiffer RM Morton LM Engels EA Risk factors for early-onset and late-onset post-transplant lymphoproliferative disorder in kidney recipients in the United States Am J Hematol 86 206 209 2011 21264909 \n14 Bakker NA van Imhoff GW Verschuuren EA HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical Transplantation 80 595 599 2005 16177631 \n15 Reshef R Vardhanabhuti S Luskin MR Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder Am J Transplant 11 336 347 2011 21219573 \n16 Parker A Bowles K Bradley JA Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society: Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines Br J Haematol 149 693 705 2010 20408848 \n17 Svoboda J Kotloff R Tsai DE Management of patients with post-transplant lymphoproliferative disorder: the role of rituximab Transpl Int 19 259 269 2006 16573540 \n18 Trappe R Oertel S Leblond V German PTLD Study Group; European PTLD Network Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial Lancet Oncol 13 196 206 2012 22173060 \n19 Trappe R Hinrichs C Appel U Treatment of PTLD with rituximab and CHOP reduces the risk of renal graft impairment after reduction of immunosuppression Am J Transplant 9 2331 2337 2009 19663889 \n20 Foroncewicz B Mucha K Usiekniewicz J Posttransplant lymphoproliferative disorder of the lung in a renal transplant recipient treated successfully with surgery Transplant Proc 38 173 176 2006 16504695 \n21 Moudouni SM Tligui M Doublet JD Haab F Gattegno B Thibault P Lymphoproliferative disorder presenting as a tumor of the renal allograft Int Urol Nephrol 38 779 782 2006 17160544 \n22 André N Roquelaure B Conrath J Molecular effects of cyclosporine and oncogenesis: a new model Med Hypotheses 63 647 652 2004 15325009 \n23 Pascual J Post-transplant lymphoproliferative disorder - the potential of proliferation signal inhibitors Nephrol Dial Transplant 22 Suppl 1 i27 i35 2007 17456616 \n24 Alexandru S Gonzalez E Grande C Monotherapy rapamycin in renal transplant recipients with lymphoma successfully treated with rituximab Transplant Proc 41 2435 2437 2009 19715944 \n25 DiNardo CD Tsai DE Treatment advances in posttransplant lymphoproliferative disease Curr Opin Hematol 17 368 374 2010 20473161\n\n",
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"issue": "8(6)",
"journal": "Oncology letters",
"keywords": "Epstein-Barr virus; early-onset; kidney transplantation; post-transplant lymphoproliferative disorder",
"medline_ta": "Oncol Lett",
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"title": "Post-transplant lymphoproliferative disorder presenting as a tumor adjacent to the renal allograft: A case report and review of the literature.",
"title_normalized": "post transplant lymphoproliferative disorder presenting as a tumor adjacent to the renal allograft a case report and review of the literature"
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"abstract": "SARS-CoV-2 (COVID-19) infections have been recently shown to be associated with a high rate of thromboembolic events due to pro-coagulative mechanisms that have not yet been fully understood. This paper reports on a 55-year-old female COVID-19 patient with severe ARDS and pulmonary embolism (PE) complicated by cardiogenic shock after 12 days of hospitalization under initial prophylactic anticoagulation with low molecular weight heparin (LMWH). An ultima-ratio va (veno-arterial) ECMO implantation and subsequent rapid upgrade to vvaECMO due to insufficient oxygenation was performed. The patient developed severe coagulopathy with intrapulmonary bleeding. The present report aims to highlight and discuss the pros and cons of various anticoagulation strategies in COVID-19 patients focusing on current scientific debates to address this frequently observed complication in the current situation worldwide.",
"affiliations": "Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Oncology, Internal Medicine, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.;Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany.",
"authors": "Gaisendrees|Christopher|C|0000-0002-7232-3330;Walter|Sebastian G|SG|;Elderia|Ahmed|A|;Vollmer|Mattias|M|;Kaya|Süreyya|S|;Djordjevic|Ilija|I|0000-0002-5810-8626;Eghbalzadeh|Kaveh|K|;Sabashnikov|Anton|A|;Kahlert|Heike Anelie|HA|;Deppe|Antje-Christin|AC|;Böll|Boris|B|;Madershahian|Navid|N|;Wahlers|Thorsten|T|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight",
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"doi": "10.1177/0267659120979887",
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"issn_linking": "0267-6591",
"issue": "36(6)",
"journal": "Perfusion",
"keywords": "COVID-19; ECMO; anticoagulation; cardiogenic shock; cytokine storm; mechanical circulatory support; pulmonary embolism",
"medline_ta": "Perfusion",
"mesh_terms": "D000925:Anticoagulants; D000086382:COVID-19; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008875:Middle Aged; D011655:Pulmonary Embolism; D000086402:SARS-CoV-2",
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"pages": "575-581",
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"pmid": "33280533",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adequate anticoagulation and ECMO therapy in COVID-19 patients with severe pulmonary embolism.",
"title_normalized": "adequate anticoagulation and ecmo therapy in covid 19 patients with severe pulmonary embolism"
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"abstract": "BACKGROUND\nWarfarin related nephropathy is one of the potential complications of warfarin therapy. Despite the well described histological entity, the clinical course and approach to warfarin related nephropathy in patients requiring life-long anticoagulation is however not well described in the literature.\n\n\nMETHODS\nWe report the clinical course of a 56 years old Chinese lady who presented with over anti-coagulation and acute kidney injury while on warfarin therapy for permanent atrial fibrillation and mechanical valve replacement. Renal biopsy was performed as the acute kidney injury was persistent despite normalization of the International Normalized Ratio and the diagnosis of warfarin related nephropathy was made. Temporary interruption of anti-coagulation, in combination with oral N-acetylcysteine resulted in subsequent stabilization of renal function.\n\n\nCONCLUSIONS\nThe diagnosis of warfarin induced nephropathy should be considered in patients presenting with unexplained acute kidney injury and over anti-coagulation. Awareness of this clinical entity is important for clinician managing anti-coagulation therapy and renal function should be monitored regularly in patients who are on warfarin therapy.",
"affiliations": "Department of Renal Medicine, Singapore General Hospital, 20 College Road, Academia, Level 3, Singapore, 169856, Singapore.;Department of Renal Medicine, Singapore General Hospital, 20 College Road, Academia, Level 3, Singapore, 169856, Singapore. tan.chieh.suai@sgh.com.sg.;National Heart Centre Singapore, Singapore, Singapore.;National Heart Centre Singapore, Singapore, Singapore.;National Heart Centre Singapore, Singapore, Singapore.;Department of Renal Medicine, Singapore General Hospital, 20 College Road, Academia, Level 3, Singapore, 169856, Singapore.;Department of Pathology, Singapore General Hospital, Singapore, Singapore.",
"authors": "Ng|Chee Yong|CY|;Tan|Chieh Suai|CS|;Chin|Chee Tang|CT|;Lim|See Lim|SL|;Zhu|Ling|L|;Woo|Keng Thye|KT|;Tan|Puay Hoon|PH|",
"chemical_list": "D000925:Anticoagulants; D016166:Free Radical Scavengers; D014859:Warfarin; D000111:Acetylcysteine",
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"doi": "10.1186/s12882-016-0228-4",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 22810.1186/s12882-016-0228-4Case ReportWarfarin related nephropathy: a case report and review of the literature Ng Chee Yong cheeyong.ng@mohh.com.sg Tan Chieh Suai +65-6326 6149tan.chieh.suai@sgh.com.sg Chin Chee Tang chin.chee.tang@nhcs.com.sg Lim See Lim lim.see.lim@nhcs.com.sg Zhu Ling ling.zhu2@mohh.com.sg Woo Keng Thye woo.keng.thye@sgh.com.sg Tan Puay Hoon tan.puay.hoon@sgh.com.sg Department of Renal Medicine, Singapore General Hospital, 20 College Road, Academia, Level 3, Singapore, 169856 Singapore Department of Pathology, Singapore General Hospital, Singapore, Singapore National Heart Centre Singapore, Singapore, Singapore 1 2 2016 1 2 2016 2016 17 1531 3 2015 20 12 2015 © Ng et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWarfarin related nephropathy is one of the potential complications of warfarin therapy. Despite the well described histological entity, the clinical course and approach to warfarin related nephropathy in patients requiring life-long anticoagulation is however not well described in the literature.\n\nCase presentation\nWe report the clinical course of a 56 years old Chinese lady who presented with over anti-coagulation and acute kidney injury while on warfarin therapy for permanent atrial fibrillation and mechanical valve replacement. Renal biopsy was performed as the acute kidney injury was persistent despite normalization of the International Normalized Ratio and the diagnosis of warfarin related nephropathy was made. Temporary interruption of anti-coagulation, in combination with oral N-acetylcysteine resulted in subsequent stabilization of renal function.\n\nConclusion\nThe diagnosis of warfarin induced nephropathy should be considered in patients presenting with unexplained acute kidney injury and over anti-coagulation. Awareness of this clinical entity is important for clinician managing anti-coagulation therapy and renal function should be monitored regularly in patients who are on warfarin therapy.\n\nKeywords\nWarfarin related nephropathyMechanical valveAnticoagulationissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe potential deleterious effect of warfarin in patients with chronic kidney disease (CKD) was first observed in the 1970s. Warfarin, when given in anticoagulant dose as part of the “Melbourne cocktail” for the treatment of IgA nephropathy, was noted to result in an increase in urinary red blood cell counts [1]. Subsequently in 2009, Brodsky et al. reported a case series of 9 CKD patients with biopsy proven acute kidney injury during warfarin therapy [2]. The documented histological finding of acute tubular injury in the presence of glomerular hemorrhage became the hallmark feature of warfarin related nephropathy (WRN). An animal model validating WRN was subsequently reported [3] and retrospective analysis of databases of patients receiving warfarin therapy revealed that WRN could occur in patients without CKD and was associated with accelerated progression of CKD when above therapeutic range [4–6].\n\nDespite the well described clinical entity, the clinical course of WRN remains unclear. In the original case series reported by Brodsky, four patients remained dialysis dependent and many did not recover despite normalization of the international normalized ratio (INR). Moreover, the outcome of WRN in patients where anti-coagulation should not be stopped permanently, such as in patients with mechanical heart valve, is unclear. We report the clinical course of a patient with WRN where anti-coagulation could not be stopped permanently.\n\nCase presentation\nA 56 years old diabetic chinese lady with atrial fibrillation and mechanical mitral valve replacement (Bileaflet tilting disc valve, St Jude) was found to be over anti-coagulated [international normalized ratio (INR) of 4.95] during a routine follow up. She had been on warfarin therapy since 2001 for permanent atrial fibrillation and remained on anticoagulation after her valve replacement surgery for severe mitral stenosis secondary to rheumatic heart disease in 2008. Her medications included warfarin 3 mg OD, digoxin 250 mcg OD, bisoprolol 1.25 mg OD, fenofibrate 300 mg OD, furosemide 20 mg OD, potassium chloride 600 mg OD, glipizide 2.5 mg BiD and metformin 850 mg BiD. There were no recent changes in her medication and diet. On physical examination, she was well with no overt signs of bleeding. Her blood pressure was 130/70 mm Hg with a heart rate of 60 beats per minute. Fundoscopy did not reveal the presence of any hemorrhages or diabetic retinopathy.\n\nThe serum creatinine was noted to be elevated at 317 μmol/L, a five-fold increase from her last measured serum creatinine of 72 μmol/L 6 months ago. The provisional diagnosis was acute kidney injury (AKI) in the background of over anti-coagulation and diabetes mellitus. Further investigations were performed to elucidate the cause of her acute kidney injury. Urine microscopy revealed microscopic hematuria (Red blood cell 675/UL). Ultrasonography and computed tomography showed normal size kidneys with no evidence of urinary calculi or obstruction respectively. Autoimmune markers including anti-neutrophil cytoplasmic antibody, antinuclear antibody, anti-double stranded DNA and anti-glomerular basement membrane antibody were negative and there was no hypocomplementemia. Her urine culture was negative and 24-hour urine protein was 0.35 g/day.\n\nWarfarin was initially suspended to restore a therapeutic INR level. Decision was subsequently made for a renal biopsy 12 days after admission due to persistent AKI. Histology showed focal segmental and global glomerulosclerosis with mesangial hypercellularity but no crescents. The interstitium was edematous with presence of acute tubular necrosis. Specifically, a number of tubules demonstrated red cell casts, which were consistent with warfarin related nephropathy (Fig. 1). Immunofluorescence was not performed due to inadequate tissue sample. Electron microscopy, carried out on appropriately reprocessed material derived from the paraffin block, showed several electron dense deposits in the mesangial and paramesangial zones, suggestive of underlying IgA nephropathy. All anticoagulation therapy was interrupted for 5 days post renal biopsy due to the development of perinephric hematoma. Oral acetylcysteine 1.2 g BiD, followed by oral prednisolone 30 mg OD was started when the serum creatinine increased to 428 μmol/L. The serum creatinine improved to 274 μmol/L with the above interventions. The patient was bridged with low molecular weight heparin before being restarted back on warfarin, with a target INR of 2–2.5. The serum creatinine and INR 3 months post discharge were 274 μmol/L and 2.1 respectively. The INR and creatinine trends are as summarized in Fig. 2.Fig. 1 \na. Masson trichrome-silver stain shows a glomerulus with a small segment of sclerosis (arrow) that is adherent to the Bowman’s capsule. A few tubules around the glomerulus show luminal red cell casts. b. Low magnification of several tubules containing luminal red cell casts. c. High magnification of a glomerulus demonstrating segmental mesangial matrix expansion and increased mesangial cells. d. Electron micrograph shows paramesangial electron dense deposits\n\nFig. 2 INR and serum creatinine trend of the patient\n\n\n\nDiscussion\nAs illustrated in our patient, WRN is an important differential diagnosis in the evaluation of unexplained AKI in patients on warfarin therapy, especially in the presence of over anti-coagulation and microscopic hematuria. Although the renal biopsy showed background Ig A nephropathy, the patient had normal renal function prior to admission. The AKI was probably precipitated by over anti-coagulation, which was consistent with what was reported in the literature.\n\nThe management of WRN in patients where anti-coagulation should not be stopped permanently poses a management dilemma. The lifetime risk of mechanical valve thrombosis following permanent cessation of warfarin is exceedingly high and potentially life-threating [7]. As of now, the only novel oral anticoagulant (NOAC) drug that has been studied in patients with mechanical valves is dabigatran. In the RE-ALIGN study, dabigatran, as compared with warfarin, was associated with excess thromboembolic and bleeding events and as such is currently not indicated for use in patients with mechanical valve replacements [8]. Moreover, WRN has also been reported with dabigatran in animal models [9]. Intuitively, temporary interruption of anti-coagulation may ameliorate glomerular bleeding and result in stabilization of the renal function; however, the risks of thromboembolic events need to be taken into consideration. Extrapolating experience from management of intracranial hemorrhage in patients with mechanical heart valve, the incidence of thromboembolic events without anticoagulation in patients with mechanical heart valve was estimated to be 0.06 % per day [10]. Indeed, the European Stroke Initiative recommended that patients with very high risk for thromboembolic events should be restarted on warfarin after 10 to 14 days after intra-cranial hemorrhage [11]. In our patient, anticoagulation was interrupted for 5 days in view of post biopsy hematoma and this might have limited the extent of glomerular bleeding and renal dysfunction.\n\nWhile glomerular hematuria is the inciting event in WRN, the dominant mechanism of AKI was secondary to tubular obstruction by red blood cell casts and the increased oxidative stress in the kidney. N-acetylcysteine is a well-characterized antioxidant, which has been used for many years in experimental research. Specifically, it has been shown to prevent increases in creatinine in a dose-dependent manner in animal models of warfarin induced AKI [12] and was used without any adverse reaction in our patient. We postulated that temporary interruption of anti-coagulation in conjunction with N-acetylcystine might have resulted in the stabilization of renal function that was observed in our patient.\n\nThe anti-inflammatory effect of steroids may also be useful in mitigating the onset of interstitial fibrosis as a consequence of WRN. Specifically in our patient, the beneficial effect may be secondary to its impact on the concurrent IgA nephropathy and interstitial edema. While early steroid administration was reported to accelerate recovery of AKI after gross haematuria in IgA nephropathy [13], the use of prednisolone in WRN is not strongly supported in experimental models and is limited to a single prior case report [14]. Nevertheless, based on our anecdotal evidence, the use of steroids in WRN requires further validation.\n\nConclusion\nIn conclusion, renal function should be monitored in patients on anticoagulation therapy and the diagnosis of WRN, especially in the presence of over anticoagulation, should be considered in patient with unexplained AKI. Temporary interruption of anticoagulation in combination with N-acetylcystine may result in stabilization of the renal function. Low dose corticosteroids may be added as it can potentially suppress the inflammatory response following glomerular hemorrhage and tubular obstruction in the kidney.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nAbbreviations\nCKDchronic kidney disease\n\nWRNwarfarin related nephropathy\n\nINRinternational normalized ratio\n\nAKIacute kidney injury\n\nCompeting interests\n\nThe author(s) declare that they have no competing interests.\n\nAuthors’ contributions\n\nCY N participated in the care of patient and drafted the manuscript. CS T participated in the care of patient and preparation of the manuscript. CT C, LS L, L Z participated in the management of patient. KT W conceptualized the management plan of the patient. PH T reported the histological findings and reviewed the manuscript. All authors read and approved the final manuscript\n\nAcknowledgements\nWe will like to acknowledge Madam Chin Yok Mooi, our senior medical technologist who assisted with the renal biopsy and processing of biopsy tissue for histological reading.\n==== Refs\nReferences\n1. Woo KT Lee GS Foo MW Chan CM Warfarin-related nephropathy in patients with chronic kidney disease Kidney Int 2012 82 1 113 10.1038/ki.2012.91 22699379 \n2. Brodsky SV Satoskar A Chen J Nadasdy G Eagen JW Hamirani M Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases Am. J. Kidney Dis. 2009 54 6 1121 1126 10.1053/j.ajkd.2009.04.024 19577348 \n3. Ozcan A Ware K Calomeni E Nadasdy T Forbes R Satoskar AA 5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy Am J Nephrol 2012 35 4 356 364 10.1159/000337918 22473220 \n4. Brodsky SV Nadasdy T Rovin BH Satoskar AA Nadasdy GM Wu HM Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate Kidney Int 2011 80 2 181 189 10.1038/ki.2011.44 21389969 \n5. Brodsky SV Collins M Park E Rovin BH Satoskar AA Nadasdy G Warfarin therapy that results in an International Normalization Ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease Nephron Clin. Pract. 2010 115 2 c142 c146 10.1159/000312877 20413993 \n6. An JN Ahn SY Yoon CH Youn TJ Han MK Kim S The occurrence of warfarin-related nephropathy and effects on renal and patient outcomes in korean patients PLoS One 2013 8 4 e57661 10.1371/journal.pone.0057661 23560034 \n7. Cannegieter SC Rosendaal FR Briet E Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses Circulation 1994 89 2 635 641 10.1161/01.CIR.89.2.635 8313552 \n8. Eikelboom JW Connolly SJ Brueckmann M Granger CB Kappetein AP Mack MJ Dabigatran versus warfarin in patients with mechanical heart valves N Engl J Med 2013 369 13 1206 1214 10.1056/NEJMoa1300615 23991661 \n9. Ryan M Ware K Qamri Z Satoskar A Wu H Nadasdy G Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats Nephrol. Dial. Transplant. 2013 29 2228 2234 10.1093/ndt/gft380 24009280 \n10. Romualdi E Micieli E Ageno W Squizzato A Oral anticoagulant therapy in patients with mechanical heart valve and intracranial haemorrhage. A systematic review Thromb Haemost 2009 101 2 290 297 19190812 \n11. European Stroke Initiative Writing C Writing Committee for the EEC Steiner T Kaste M Forsting M Mendelow D Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee Cerebrovasc. Dis. 2006 22 4 294 316 10.1159/000094831 16926557 \n12. Ware K Qamri Z Ozcan A Satoskar AA Nadasdy G Rovin BH N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy Am. J. Physiol. Renal Physiol. 2013 304 12 F1421 F1427 10.1152/ajprenal.00689.2012 23576637 \n13. Moreno JA Martin-Cleary C Gutierrez E Toldos O Blanco-Colio LM Praga M AKI associated with macroscopic glomerular hematuria: clinical and pathophysiologic consequences Clin. J. Am. Soc. Nephrol. 2012 7 1 175 184 10.2215/CJN.01970211 22096039 \n14. Di Maso V Carraro M Bevilacqua E Bucconi S Artero ML Boscutti G Warfarin-related nephropathy: possible role for the warfarin pharmacogenetic profile Clin Kidney J 2014 7 6 605 608 10.1093/ckj/sfu112 25859382\n\n",
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"mesh_terms": "D000111:Acetylcysteine; D058186:Acute Kidney Injury; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D016166:Free Radical Scavengers; D006350:Heart Valve Prosthesis; D006801:Humans; D008875:Middle Aged; D014859:Warfarin; D028761:Withholding Treatment",
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"title": "Warfarin related nephropathy: a case report and review of the literature.",
"title_normalized": "warfarin related nephropathy a case report and review of the literature"
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"abstract": "Cefepime is a fourth-generation cephalosporin that has multitude of uses in various conditions. Cefepime associated neurotoxicity was first described in 1999. Here, we describe a case in which we appreciated the neuropsychiatric effects of cefepime on a patient who had underlying chronic kidney disease.",
"affiliations": "Internal Medicine, Harlem Hospital Center, New York, USA.;Internal Medicine, Harlem Hospital Center, New York, USA.;Internal Medicine, Harlem Hospital Center, New York, USA.",
"authors": "Achi|Sai S|SS|;White-Gittens|Ian C|IC|;Weerasinghe|Anya|A|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.11395\nInternal Medicine\nNephrology\nCefepime-Induced Neuropsychiatric Manifestations in a Patient With Chronic Kidney Disease: A Case Report\nMuacevic Alexander Adler John R Achi Sai S 1 White-Gittens Ian C 1 Weerasinghe Anya 1 \n1 \nInternal Medicine, Harlem Hospital Center, New York, USA \n\nSai S. Achi achis@nychhc.org\n9 11 2020 \n11 2020 \n12 11 e113959 11 2020 Copyright © 2020, Achi et al.2020Achi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/42750-cefepime-induced-neuropsychiatric-manifestations-in-a-patient-with-chronic-kidney-disease-a-case-reportCefepime is a fourth-generation cephalosporin that has multitude of uses in various conditions. Cefepime associated neurotoxicity was first described in 1999. Here, we describe a case in which we appreciated the neuropsychiatric effects of cefepime on a patient who had underlying chronic kidney disease.\n\ncefepimeneuropsychiatry symptomschronic kidney diseaseThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nCefepime is a fourth-generation cephalosporin antibiotic that provides coverage against Pseudomonas aeruginosa, other AmC beta-lactamase producing bacteria, and infections with both gram-negative and gram-positive aerobes. Given the majority of excretion is via the kidneys-the medication is renally dosed. Some adverse effects have been noted to be nausea, rash, delirium, and seizures [1]. Many of the noted side effects of cefepime do not include some of the neuropsychiatric manifestations that may occur especially in patients with kidney disease. The pathophysiology of how cefepime causes neurotoxicity has been attributed to inhibiting the gamma-aminobutyric acid-A (GABA-A) receptors potentially inhibiting the release of GABA which would explain the manifestations of seizures, myoclonus, or even global encephalopathy that is seen [2]. We present a case of an elderly immunocompromised gentleman who had been started on Cefepime during the hospital course and developed neuropsychiatric symptoms that resolved after the medication was discontinued. \n\nCase presentation\nA 70-year-old man with a past medical history significant for hypertension, diabetes mellitus, chronic kidney disease stage 4, and prostate cancer stage 4 on outpatient chemotherapy at another facility presented to our emergency department with complaints of vomiting and nausea a day prior to admission. He had three episodes of nonbloody, non-bilious, and nonbloody diarrhea as well. The patient had one-day history of productive cough with whitish sputum and subjective fevers. Patient, though adherent with chemotherapy, had admitted that he was not able to take his other home medications. In the ED, patient had a temperature of 103.1degrees F, heart rate of 98 beats per minute, blood pressure of 102/55 mmHg, respiratory rate of 18 breaths per minute, glucose of 121 mg/dl. Physical exam was significant for conscious, alert and oriented to person, place, and time; pink and moist mucosa, right surgical scar at the right hypochondriac, soft, nontender, bowel sounds were present. Pertinent abnormal labs include: white blood cell count (WBC), 14.5 units/mcl (reference range: 4.80-10.80 units/mcl) with neutrophils of 82.1% (reference range: 44%-70%), blood urea nitrogen (BUN) 39 mg/dl (reference range: 7-18 mg/dl), creatinine (Cr) 3.8 mg/dl (reference range: 0.7-1.2 mg/dl), calcium (Ca) 7.7 mg/dl (reference range: 8.5-10.1 mg/dl). Chest x-ray showed a focal area of consolidation involving the left midlung. Patient was admitted and managed on the medical floor for sepsis likely secondary hospital acquired pneumonia especially given his immunocompromised state. Patient was started on IV vancomycin and piperacillin-tazobactam in the emergency department.\n\nDuring the course of the hospitalization, infectious disease was consulted and they recommended to start the patient on IV cefepime 1 g Q24 hours, oral linezolid 600 mg Q12H, and oral clindamycin 450 mg Q8H. In addition, patient was started on calcium acetate for his hypocalcemia and was continued on sodium bicarbonate 1300 mg Q8H for his AKI on CKD. After two days the cefepime dose was increased to 2 mg. Two days after increasing the dose of cefepime, patient started developing altered mental status. Patient was alert and oriented only to person, incoherent and expressed thoughts like “I would kill myself if I had the chance” so the cefepime was discontinued and within one day the patient was more conversant, denied any suicidal ideations and was alert and oriented to person and place. In addition, the BUN and creatinine (Cr) levels trended up to 41 mg/dl and 5.4 mg/dl. So the calcium acetate was switched to calcium carbonate and calcitriol. After making these changes the Cr level trended down to 3.4 mg/dl. In addition, the corrected Calcium level was at normal levels based on the albumin level of the patient. The mental status improved and patient was subsequently discharged. Table 1 provides the electrolyte levels.\n\nTable 1 Lab values showing the electrolytes\nOn August 2nd, the cefepime was increased to 2 gm; on August 10th, the cefepime was discontinued. Albumin values are also provided for corrected calcium levels.\n\n \tReference Range and Units\t2-Aug\t10-Aug\t12-Aug\t13-Aug\t14-Aug\t17-Aug\t\nSodium (mmol/L)\t136-145 mmol/L\t144\t151\t151\t147\t146\t140\t\nPotassium (mmol/L)\t3.5-5.1 mmol/L\t4.09\t4.28\t4.82\t4.7\t4.4\t4.6\t\nChloride (mmol/L)\t98-107 mmol/L\t116\t115\t117\t109\t109\t105\t\nBicarbonate (mmol/L)\t22-29 mmol/L\t12\t20\t20\t24\t22\t21\t\nGlucose (mg/dL)\t74-109 mg/dL\t123\t149\t119\t133\t109\t96\t\nBlood Urea Nitrogen (mg/dL)\t7-18 mg/dL\t35\t32\t31\t28\t27\t28\t\nCreatinine (mg/dL)\t0.7-1.2 mg/dL\t3.9\t4.9\t4.5\t4\t3.7\t3.5\t\nCalcium (mg/dL)\t8.5-10.1 mg/dL\t7.1\t6.4\t6.5\t6.6\t6.7\t6.5\t\nAnion Gap (mEq/L)\t6-18 mEq/L\t16\t16\t15\t14\t15\t14\t\nTotal protein (g/dl)\t6.4-8.3 g/dL\t7\t \t8\t \t \t8\t\nTotal bilirubin (mg/dl)\t<=1.2 mg/dL\t0.7\t \t0.8\t \t \t0.6\t\nAlanine Aminotransferase (U/L)\t<=33 U/L\t20\t \t21\t \t \t20\t\nAlkaline Phosphate (U/L)\t35-104 U/L\t70\t \t68\t \t \t72\t\nAspartate Aminotransferase (U/L)\t<=32 U/L\t16\t \t18\t \t \t16\t\nAlbumin (g/dl)\t3.97-4.94 g/dL\t3.3\t \t3.4\t \t \t3.5\t\nDirect bilirubin (mg/dl)\t0.0-0.3 mg/dL\t0.3\t \t0.5\t \t \t0.4\t\nDiscussion\nCefepime is a fourth-generation cephalosporin. Cefepime associated neurotoxicity was first described in 1999. Studies have indicated that up to 15% of patients in the intensive care unit (ICU) will experience the neurotoxicities [3]. Cefepime neurotoxicity is relatively common and often underdiagnosed and has been seen mainly in the Intensive Care Unit setting with symptoms occurring four days after initiation of treatment and most common symptoms include decreased consciousness levels, myoclonus, and confusion [4]. In addition, as cefepime is renally excreted, studies have shown that a reduced renal function will reduce the clearance of cefepime from the body [5]. In 2012, the Food and Drug Administration (FDA) had recommended that the cefepime dose should be adjusted for patients with renal disease as there is an association with status epilepticus. This recommendation had resulted from the FDA reviewing the database from the years 1996 to 2012 with 59 reported cases of nonconvulsive epilepticus cases during the administration of cefepime; of those patients who received cefepime, 58 patients had renal impairment of which 56 patients didn’t have renally dosed cefepime. Symptomology of the patients mainly were decreased level of consciousness, myoclonus, confusion, aphasia, seizure, and agitation. The treatments that were adopted were discontinuing the antibiotic, trial of benzodiazepines which opposed the cefepime’s antiGABA mechanism, or hemodialysis session which cleared cefepime’s levels up to 70% [6,7]. A study was conducted and indicated that eight patients with renal failure given cefepime developed neurotoxicity that ranged from decreased level of consciousness to seizures; of the eight patients, three indicated clinical improvement after cefepime was discontinued [8]. Another study shows that the neurological effects and the notion of hallucinations are reversible once the offending agent is taken out which was seen in our patient as well [9].\n\nHowever, in our patient, his symptoms were atypical. As previously mentioned Cefepime’s neurotoxicity was associated with anti-GABA receptor activity, while our patient’s symptoms appeared to be more Dopaminergic in nature given his psychotic features. Previously psychotic features have only been described in patients using Quinolones and Trimethoprim-Sulphamethoxazole. \n\nSome limitations that exist in our case report does include confounders do exist that could also have contributed to the neuropsychiatric changes in our patient such as delirium/confusion in hospitalized elderly patients. A study expresses that manifestations of delirium can range from incoherence to poor cognition or even hallucinations [10]. Other limitations do include as well electrolyte abnormalities such as the hypernatremia that was seen for a couple of days during the time that the cefepime was also discontinued; studies mention some of the side effects of dysnatremia include drowsiness/confusion or lethargy [11]. Thus the resolution of symptoms could also be accounted for correcting the electrolyte disorders as well.\n\nThis case report urges the clinician to consider that in patient who is on cefepime with sudden progressive deterioration in mentation that there is a possibility of the antibiotic contributing to the neurotoxicity especially in patients with kidney disease as well in the differential diagnoses. It is also imperative that patients on cefepime in an ICU setting that are Confusion Assessment Method (CAM) positive should have the dose adjusted or medication discontinued with observation for improvement as we believe it may be a frequently underdiagnosed condition [12].\n\nConclusions\nGiven this interesting case and the literature about cefepime and neurotoxicity, the neuropsychiatric side effects should be considered as potential side effects whenever administering the medications in patient who had kidney disease. In addition, a focused neurological exam and mental status exam as well in patients who are on cefepime in order to identify possible side effects of the medication and make appropriate changes to the antibiotic regiment if a patient is to develop side effects from cefepime.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 The Washington Manual of Medical Therapeutics Bhat P Philadelphia Lippincott Williams & Wilkins 2016 \n2 Characterizing cefepime neurotoxicity: a systematic review Open Forum Infectious Dis Appa AA Jain R Rakita RM 0 4 2017 \n3 Cefepime-induced neurotoxicity: a systematic review Crit Care Payne LE Gagnon DJ Riker RR 276 21 2017 29137682 \n4 Cefepime-induced neurotoxicity The HMS CME Online Team: Trends in Medicine McGrath M 2018 https://trends.hms.harvard.edu/2018/02/20/cefepime-induced-neurotoxicity/ \n5 Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy Crit Care Fugate JE Kalimullah EA Hocker SE 0 17 2013 \n6 Center for Drug Evaluation and Research. “Cefepime and Risk of Seizure in Patients Not Receiving Dosage Adjust” U.S. Food and Drug Administration FDA, 26 June 2012 http://www.fda.gov/Drugs/DrugSafety/ucm309661.htm \n7 Cephalosporin-induced nonconvulsive status epilepticus: clinical and electroencephalographic features Epilepsia Fernández-Torre JL Martínez-Martínez M González-Rato J 1550 1552 46 2005 16146453 \n8 The neurotoxicity and safety of treatment with cefepime in patients with renal failure Nephrol Dialysis Transplant Sonck J Laureys G Verbeelen D 966 970 23 2008 \n9 Neuropsychiatric symptoms during cefepime treatment Pharm World Sci Diemont W MacKenzie M Schaap N Goverde G van Heereveld H Hekster Y van Grootheest K 36 23 2001 11344590 \n10 Hospital-induced delirium hits hard Can Med Assoc J Collier R 23 24 184 2012 22158403 \n11 Disturbances of sodium in critically ill adult neurologic patients: a clinical review J Neurosurg Anesthesiol Tisdall M Crocker M Watkiss J 2006 https://www.researchgate.net/publication/299486503_Disturbances_of_sodium_in_critically_ill_adult_neurologic_patients_A_clinical_review \n12 Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration Pediatrics Saidinejad M Ewald MB Shannon MW 0 115 2005\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(11)",
"journal": "Cureus",
"keywords": "cefepime; chronic kidney disease; neuropsychiatry symptoms",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pages": "e11395",
"pmc": null,
"pmid": "33312793",
"pubdate": "2020-11-09",
"publication_types": "D002363:Case Reports",
"references": "15867013;24200036;11344590;18175786;16146453;29137682;29071284;22158403;16369141",
"title": "Cefepime-Induced Neuropsychiatric Manifestations in a Patient With Chronic Kidney Disease: A Case Report.",
"title_normalized": "cefepime induced neuropsychiatric manifestations in a patient with chronic kidney disease a case report"
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"abstract": "Solid organ transplantation has evolved along with dramatic advancements in definitive treatment for irreversible and uncompensated organ failure. Transplanted organ survival has improved as a result of reduced allograft rejection. However, negative long-term outcomes which were largely due to the adverse effects of rapidly evolving immunosuppressive regimens are still evident. The emergence of malignancies following prolonged exposure to immunosuppression treatment has affected the quality of life in transplant recipients. They are approximately one hundred times more likely to develop squamous cell carcinoma (SCC) compared to the general population and the incidence of malignant melanomas, basal cell carcinomas, and Kaposi's sarcomas are also on the rise. The incidence of de novo malignancies ranges from 9 to 21% and is commonly seen in the skin and the lymphoreticular system in these patients.\n\n\nMETHODS\nA 78-year-old male presented with a lump in the right axilla, which had grown in size over a 4-week period. Patient had received a cardiac transplant 9 years prior and was on a regimen of Tacrolimus and Mycophenolate Mofetil since then.\nFollowing 4 years of immunosuppression therapy, the patient developed a non-healing ulcer on his right forearm and the biopsy confirmed SCC. The recent biopsy performed on the new axillary lump also confirmed SCC. Iatrogenic immune suppressive treatment is associated with the occurrence of de novo, non-melanoma skin cancers in the solid organ transplant recipients and this necessitates early and comprehensive cancer surveillance models to be included in the pre and post-transplant assessment.\n\n\nCONCLUSIONS\nAdvances in immunology suggest that peripheral blood mononuclear cell sequencing and immune profiling to identify immune phenotypes associated with keratinocyte cancers allow us to recognize patients who are more susceptible for SCC following organ transplantation and immunosuppression.",
"affiliations": "Ohio State University, Columbus, OH, United States.;University of North Carolina, Wilmington, NC, United States.;Knox College, Galesburg, IL, United States.;Carolina Physicians Group, Charlotte, NC, United States.;Division of Vascular and Endovascular Surgery, Department of Surgery, University of Washington and Puget Sound VA Health Care System, Seattle, WA, United States.;Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA, United States. Electronic address: spremaratne@vuu.edu.",
"authors": "Ruwanpathirana|Anushka S|AS|;Fernando|Samantha J|SJ|;Vinati Molligoda|M|M|;Fernando|Jay G|JG|;Zhang|Wayne W|WW|;Premaratne|Shyamal|S|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.ijscr.2021.01.031",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(21)00033-X\n10.1016/j.ijscr.2021.01.031\nCase Report\nRecurrent squamous cell carcinoma in a post cardiac transplant patient\nRuwanpathirana Anushka S. a Fernando Samantha J. b Vinati Molligoda M. c Fernando Jay G. d Zhang Wayne W. e Premaratne Shyamal spremaratne@vuu.eduf⁎ a Ohio State University, Columbus, OH, United States\nb University of North Carolina, Wilmington, NC, United States\nc Knox College, Galesburg, IL, United States\nd Carolina Physicians Group, Charlotte, NC, United States\ne Division of Vascular and Endovascular Surgery, Department of Surgery, University of Washington and Puget Sound VA Health Care System, Seattle, WA, United States\nf Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA, United States\n⁎ Corresponding author at: Hunter Holmes McGuire Veterans Administration Medical Center, 1201 Broad Rock Boulevard, Richmond, VA 23249, United States. spremaratne@vuu.edu\n15 1 2021 \n2 2021 \n15 1 2021 \n79 275 280\n15 12 2020 3 1 2021 9 1 2021 © 2021 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Patient having recurrent carcinomas following heart transplant due to possible immunosuppression.\n\n• Early Cancer surveillance in transplant patients is necessary to detect and treat malignancies early.\n\n• Unique in having two recurrences post-transplant.\n\n\n\nIntroduction and importance\nSolid organ transplantation has evolved along with dramatic advancements in definitive treatment for irreversible and uncompensated organ failure. Transplanted organ survival has improved as a result of reduced allograft rejection. However, negative long-term outcomes which were largely due to the adverse effects of rapidly evolving immunosuppressive regimens are still evident. The emergence of malignancies following prolonged exposure to immunosuppression treatment has affected the quality of life in transplant recipients. They are approximately one hundred times more likely to develop squamous cell carcinoma (SCC) compared to the general population and the incidence of malignant melanomas, basal cell carcinomas, and Kaposi’s sarcomas are also on the rise. The incidence of de novo malignancies ranges from 9 to 21% and is commonly seen in the skin and the lymphoreticular system in these patients.\n\nCase presentation\nA 78-year-old male presented with a lump in the right axilla, which had grown in size over a 4-week period. Patient had received a cardiac transplant 9 years prior and was on a regimen of Tacrolimus and Mycophenolate Mofetil since then.\n\nClinical discussion\nFollowing 4 years of immunosuppression therapy, the patient developed a non-healing ulcer on his right forearm and the biopsy confirmed SCC. The recent biopsy performed on the new axillary lump also confirmed SCC. Iatrogenic immune suppressive treatment is associated with the occurrence of de novo, non-melanoma skin cancers in the solid organ transplant recipients and this necessitates early and comprehensive cancer surveillance models to be included in the pre and post-transplant assessment.\n\nConclusion\nAdvances in immunology suggest that peripheral blood mononuclear cell sequencing and immune profiling to identify immune phenotypes associated with keratinocyte cancers allow us to recognize patients who are more susceptible for SCC following organ transplantation and immunosuppression.\n\nKeywords\nImmunosuppressionHeart transplantationCancerSquamous cell carcinoma\n==== Body\n1 Introduction\nCardiac transplantation is the definitive mode of treatment for advanced heart failure in patients who would otherwise succumb to their heart disease. According to statistics from the International Thoracic Organ Transplant (TTX) Registry of the International Society for Heart and Lung Transplantation, total heart transplants performed through June 30th, 2018 was 146,975 which included 131,249 adult heart transplants and 15,264 pediatric heart transplants. Patient survival has steadily improved since the first cardiac transplantation which took place at the Groote Schuur Hospital in Cape Town, South Africa in December of 1967 by a team lead by Christiaan Barnard [1]. Current survival data following cardiac transplant shows a one-year survival of 84.5% and 5-year survival of 72.5% compared to 76.9% and 62.7% respectively from data in 1980 [2]. A cardiovascular surgical clinic attached to a University Hospital in Zurich, Switzerland has shown survival rates at 1, 10, and 20 years to be 82.7%, 63.9%, and 55.6% respectively [3]. The two long-term complications accounting for a reduced 10-year survival are chronic allograft vasculopathy and malignancies which account for 35% of cumulative deaths after 10–15 years post-transplant [1]. Looking at the demographic registry (1988 - present) among cardiac transplant recipients in the United States, the 50–64-year age group represents the highest number of recipients (https://optn.transplant.hrsa.gov/data/citing-data/).\n\nWhen considering all solid organ transplantations, older populations are the most vulnerable for its negative long-term and short-term outcomes due to their elevated morbidity and mortality risk associated with advanced age. Widely available immunosuppressive treatments play a significant role in the management of transplant related morbidity and mortality allowing an optimum graft versus host relationship resulting in prolonged graft survival which play a significant role in transplant related morbidity and mortality. Most commonly used immune suppressants following solid organ transplantation are calcineurin inhibitors (CNI) such as Ciclosporin and Tacrolimus, mTOR inhibitors (mTORi) such as Everolimus and Sirolimus and Mycophenolic Acid (MPA). An improved understanding and introduction of Ciclosporin immunosuppression regimens have led to a growing community of solid organ transplant recipients (SOTRs) due to minimal graft rejection. However, cumulative occurrences of malignancies in transplant recipients has increased, with those who received 10 years of uninterrupted immunosuppression accounting for 20% de novo malignancies while the general population reports numbers ranging from 4 to 16% [4]. The increased incidence of malignancies following organ transplantation compared to the general population has been attributed to decreased immune-surveillance, infection with oncogenic viruses such as Epstein-Barr virus (EBV), human papillomavirus (HPV), human herpesvirus 8 (HHV-8), chronic stimulation of the immune system, and immunosuppression [4].\n\nThere are 3 major categories of malignancies which occur in solid organ transplant recipients listed as de novo, recurrence of existing malignancy and those acquired through an allograft. Within the category of de novo malignancies, cutaneous and lympho-reticular varieties are the most common. Although cutaneous malignancies could be either melanoma or non-melanoma cancers, the highest incidence was reported with non-melanoma skin cancers (NMSC), which have a higher morbidity and mortality in the transplant population compared to the general population. There was a study among 835 cardiac transplant recipients who survived a month or more after the solid organ transplant between 1979 and 2002, that evaluated occurrences of cutaneous carcinomas, solid organ cancers and lymphomas. In this study, 139 malignancies were observed in 126 patients (15.1%), consisting of skin cancers (49%), solid organ tumors (27%), and lymphomas (24%) [5].\n\nIn an Australian cohort of renal transplant recipients, 82.1% had at least one confirmed NMSC within 20 years following immunosuppressive treatment and approximately a third (29.1%) showed an emergence of NMSC within 5 years of immunosuppression [6]. The background of iatrogenic host immune suppression is the major reason behind increased predilection to NMSC in SOTRs, compared to individuals with inherited immunodeficiency or even Acquired Immune Deficiency Syndrome (AIDS). In particular, the risk for the development of NMSC is substantially higher in SOTRs. This finding suggests there is a direct correlation between immunosuppressive medications that stand for iatrogenic immune suppression and incidence of NMSC. Cardiac transplant recipients appear to have the highest risk of developing skin malignancies among all solid organ transplantations due to the fact that high doses and strengths of immunosuppressive medications needed during the post-transplant phase to minimize allograft rejection. This results in the possibility of developing a cancer being about 2–3 times greater than in renal transplant recipients. The cumulative incidence of NMSC following cardiac transplantation was 31% and 43% at 5 and 10 years, respectively, in an Australian cohort [7,8].\n\nEach immunosuppressive medication regimen carries its own adverse effects. A retrospective cohort study was designed to determine skin cancer risk associated with immunosuppressants and 182 SOTRs were tracked for 1000 person-years. The results demonstrated that patients who developed skin cancer had been exposed to significantly higher cumulative doses of Cyclosporine, Azathioprine, Prednisone and Mycophenolate Mofetil (MMF) than those who did not [9].\n\nThis patient’s post-transplant journey was complicated by the de novo occurrence of a SCC in the 4th year and a recurrence in the 9th year following the cardiac transplant. Keratinocyte cancers (SCC and BCC) are associated with an increased risk of subsequent malignancies in the general population. This suggests a possibly enhanced genetic etiology for recurrent SCC in the setting of iatrogenic immunosuppression. The occurrence of cutaneous SCC following transplantation could serve as a marker for elevated risk of malignancy [10].\n\n2 Case presentation\nThis work is been reported in line with the Surgical CAse REport (SCARE) guidelines [11]. Written informed consent was obtained from the patient’s next of kin for publication of this case report and accompanying images. A 78-year-old Caucasian male presented with a painless swelling of the right hand developed over a three-week period (Fig. 1). There was no history of trauma and he did not have any other symptoms such as weakness, sensory loss in the hand, neck pain, shortness of breath, fever, weight loss, or a loss of appetite. He had noticed a painless lump in his right axilla four weeks prior to the development of swelling in the right hand. The axillary nodule enlarged rapidly to a size of 2″ X 2″ over a 4-week period (Fig. 2). His past medical history was unremarkable until 10 years ago when he was diagnosed with fulminant viral myocarditis that subsequently progressed to a dilated cardiomyopathy. A year later, he underwent a cardiac transplant. He was kept on a regimen of Tacrolimus 0.5 mg every 12 h, in addition to 500 mg of MMF twice daily. Four years later, the patient consulted a dermatologist for a non-healing ulcer on his right forearm. The lesion was removed with a wide excision, and the biopsy confirmed squamous cell carcinoma. Excision of skin was free of tumor margins. There was no evidence of metastatic disease, and he was followed up by the dermatologist every 3–6 months.Fig. 1 Swollen right hand compared with the left hand.\n\nFig. 1Fig. 2 Lump in the right axilla measuring 2″ X 2″.\n\nFig. 2\n\nAt presentation, this patient had been treated with Tacrolimus and MMF since his cardiac transplantation ten years ago. Upon examination, non-pitting swelling of the right hand and forearm were noted. A firm, non-tender lump measuring 2″ X 2″ was noticed in the right axilla with mild induration around the lesion. A CT scan of the chest showed a lung nodule 1 cm in diameter, but the biopsy was negative for malignancy. The patient’s MRI and PET scans did not show any evidence of metastatic disease. The axillary lump was surgically removed, and the biopsy confirmed squamous cell carcinoma.\n\n3 Discussion\nLong-term maintenance immunosuppressive therapy is the mainstay of post-transplant management in order to increase host tolerance to the transplanted organs. The goal of immune suppression is to adapt a T cell tolerance in the host immune cell environment to overcome the immune mechanism in transplant rejection which is driven by specific T cell immunity, directed against major and minor histocompatibility antigens in the allograft. Simply put, T cell tolerance implies creating an inadequate response to allo-antigens. Common mechanisms associated with T cell tolerance are anergy, immune-regulation, clonal exhaustion and ignorance. Currently, clinically used immune-suppressants target immune-depletion or blockage of one of the three steps of T-cell activation (antigen recognition, co-stimulation and proliferation/differentiation). A combination of induction and maintenance treatment augments the therapeutic potential to prevent transplant rejection. Most of the induction therapies concentrate on profound immune cell depletion at the time of transplantation when immune activation is most intense. Thus, the predominant side effect seen is severe life-threatening infections during this acute phase. Anti-thymocyte globulin (ATG), Anti CD52 mAb (Alemtuzumab), Anti CD3 mAb, Anti-α, β TCR antibodies, Cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA-4), and Anti-IL-2R mAb (Basiliximab and Daclizumab) are among some of the currently used induction agents. However, the occurrence of malignancy is not an identified risk factor of treatment with these induction agents [12].\n\nMaintenance immunosuppressant therapy contributes to an increased risk for malignancy in SOTRs. Combinations of two or more of Azathioprine, Cyclosporine, Methotrexate, Mycophenolate Mofetil, Sirolimus, Steroids, Tacrolimus, and Fingolimod are frequently used in maintenance regimens. Skin is the most common site for the development of such malignancies, particularly cutaneous squamous cell carcinomas (CSCC) and basal cell carcinomas (BCC), both composing Non-Melanoma Skin cancers. A variety of factors, such as the intensity and duration of immunosuppression, ethnic background of the patient, exposure to the sun, and geographic location can all influence the likelihood for the development of skin cancers in these patients. However, along with improved survival following solid organ transplants, the risk of skin cancer is proportionately elevated as it prolongs the exposure to immune suppressants causing defective host immune surveillance.\n\nCalcineurin inhibitors, Cyclosporine, Tacrolimus and purine synthesis inhibitors like Azathioprine and MMF are among the drugs used in the maintenance pace of the immune suppression. These drugs suppress the immune system so that it will accept the transplanted organ and not attack it. The incidence of skin cancer in SOTRs is common, and this risk is further exacerbated by advanced age, Caucasian race, male sex, and thoracic organ transplantation. Understanding the risk factors and trends in post-transplant skin cancer is fundamental to targeted screening and prevention in such a population [13]. Squamous cell carcinoma, which is the most common skin malignancy after basal cell carcinoma in the general population, is frequently found in transplant patients, accounting for 65–250 times more in this population [14]. Melanoma occurs 6–8 times more frequently. Basal cell carcinoma, Kaposi’s Sarcoma, and Merkel cell carcinoma (a virulent but normally rare skin malignancy) are also commonly seen in SOTRs.\n\nManagement of a post-cardiac transplant patient is different from other solid organ transplant recipients because they require a higher level of immunosuppression to counteract the high risk of death associated with organ rejection. The relationship between an increased level of immunosuppression and the likelihood of malignancy is well-demonstrated [15]. In 1970, Burnet proposed that the immune system was responsible for the recognition of specific antigens present on the cancer cell surface and for the destruction of the emerging cancer clone, which is the concept of immunological surveillance of cancer. According to this theory, immune deficient populations should experience, higher incidence in all types of cancers [16]. If immune deficiency is associated with such a broad range of cancers, it will raise a major concern that cancer is likely to become an increasingly important cause of morbidity and mortality in patients with HIV/AIDS [17]. This is not always the case. Instead, this shows that lifestyle-related risk factors for cancers may differ quite substantially between these populations. If patterns of the incidence of cancers are similar, then it would be more likely that immune deficiency is primarily responsible [17]. However, the risk of skin cancer among individuals with AIDS or naturally occurring immunodeficiency conditions, does not approach the levels seen in organ transplant recipients, suggesting that individuals in this population carry another risk in common to factoring more incidences. Focusing on the tumor characteristics also revealed a significant aggressive behavior among skin cancers which demonstrate the development of tumor metastases, 1.4 years following the diagnosis of the primary skin cancer in transplant recipients compared to the general immunocompetent population [14,22].\n\nThere is evidence suggesting that Calcineurin inhibitors interfere with p53 signaling and nucleotide excision repair (NER). These two pathways are associated with non-melanoma skin cancers in general and squamous cell carcinomas in particular. This finding may help explain the predominance of squamous cell carcinomas compared to basal cell carcinomas in this population. Mammalian targets of Rapamycin inhibitors (mTORi) do not appear to impact these pathways. Immunosuppression, viral infection, impaired DNA repair, and p53 signaling all interact in organ transplant recipients to create a phenotype of extreme risk for non-melanoma skin cancers [18]. In clinical trials switching from Calcineurin inhibitors to Rapamycin inhibitors consistently led to a significant reduction in the risk for developing new skin cancers. Hence researchers are guided to find the contribution of each class of immune suppressants in the generation of malignant clones. The cumulative incidence of skin cancers and other non-lymphoma cancers increased with age at cardiac transplantation (CT) and with time post-cardiac transplantation (from 5.2 and 8.9 per 1000 person-years in the first year to 14.8 and 12.6 in the 10th year, respectively). Incidence was also greater in men compared to women, the age at transplant >45 years, use of induction therapy, and a high level of exposure to the sun, Caucasian race, lighter skin, type of immunosuppressant used, duration of use, dosage levels, low Fitzpatrick skin types, subsequent solid organ re-transplantation, heart or lung transplantation (with a lower risk seen in liver or kidney transplantation), Calcineurin inhibition (via Cyclosporine or Tacrolimus), Azathioprine for SCC risk, mTOR inhibitors (Everolimus, Sirolimus), Mycophenolate Mofetil, and Voriconazole use were noted as risk factors for both SCC and BCC following transplantation [[18], [19], [20], [21]].\n\nNER is the exclusive repair mechanism for the two most common UV-mediated types of DNA damage leading to photo-carcinogenesis - Cyclobutane Pyrimidine dimers (CPD) and pyrimidine-6,4-pyrimidone photoproducts (6-4PP) [22,23]. Further, the increased potential for malignancy was demonstrated through an increased production of transforming growth factor-beta (TGF-ß), potentiation of the oncogene ATF3, decreased apoptosis following UVB and interruption of nuclear factor of activated T-cells (NFAT) [22,24]. Cyclosporine which represents the prototype of CNI was in use as the first-line immunosuppressant for most SOTRs and it was strongly proven through many data sets to increase the occurrence of skin cancers [25,26]. SCC, which is the most common among NMSCs in SOTRs on Cyclosporine, has shown a dose dependent relationship with cyclosporine [27]. The combination treatment of Cyclosporine A, Azathioprine and Prednisolone demonstrated close to a 3-fold higher skin cancer risk compared with a regimen of azathioprine and prednisolone only [27].\n\nTacrolimus is next in the CNI group and it has largely replaced the use of Cyclosporine. But it is less evident whether skin cancer is more or less frequent in SOTRs treated with Tacrolimus compared to Cyclosporine. Many studies have found both supporting and contradicting evidence for the hypothesis that tacrolimus causes a lower incidence of skin cancers compared to cyclosporine [[28], [29], [30], [31]]. This drug has a dose-dependent effect on the progression of tumors related to TGF-beta 1 expression. Tacrolimus-induced over expression of TGF-beta 1 may be a pathogenic mechanism in the progression of tumors [32]. MMF impairs lymphocyte function by blocking purine biosynthesis via inhibition of the enzyme Inosine Monophosphate Dehydrogenase. MMF modulates adhesion receptors of the beta-1 integrin family on tumor cells, reducing the recurrence of tumors and malignancy. A recent study suggests that the increased risk of CSCC historically associated with Azathioprine is not seen in organ transplant recipients prescribed newer regimens, including MMF and Tacrolimus [33].\n\nTacrolimus and MMF impair the repair of UVB induced DNA and apoptosis in human epidermal keratinocytes. Further, Tacrolimus inhibits UVB induced check point signaling. However, MMF had no effect. This finding demonstrates that Tacrolimus compromises a proper UVB response in keratinocytes, suggesting an immunosuppression-independent mechanism in the tumor-promoting action of these immunosuppressants [34]. Everolimus and Sirolimus are from the mTOR inhibitor group and mostly used when tacrolimus is not tolerated or contraindicated. These medications demonstrated no inhibition of NER, retained residual T cell memory function and a lower potential for angiogenesis [35,36]. Antitumor activity of mTOR inhibitors was also demonstrated in already developed cancers [37]. It’s use is limited by a profile of side effects, it is still used in the early conversion to mTORi therapy from CNIs to reduce the CNI dose by early simultaneous administration of mTORi [38].\n\nA minimum of four different viruses may be co-carcinogenic in transplanted patients. They are the Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), human papillomavirus (HPV), and Merkel cell polyomavirus (MCV). Even though a clear mechanism is not explained, data shows that the beta genus HPV is associated with risks for SCC [39]. Azathioprine is directly related to UVA mediated DNA mutagenesis [40]. Mechanism of photocarcinogens is a cumulative effect of UV induced direct DNA damage, UV effect on host immunity and synergism with other drug affected molecular pathways [41]. Isolation of the high-risk population with biological and environmental factors, molecular cytogenetics and immune profiling will also aid in realizing their predisposition to post transplant carcinoma types and in terms of effective and rational use of immunosuppression medication regimes to suit the individual risk. Based on the specific patient and tumor-related data, adjusted tumor suppression regimens should be individualized [36,42]. To identify high-risk populations by a multifactorial association model, a clinically derived predictive index was developed to calculate the risk of developing SCC in transplant recipients [43].\n\nIt was recognized that the presence of high numbers of regulatory T cells (CD4+CD25highFOXP3+and CD8+CD28−cells) in the tumor or in the peripheral blood is linked with a poor prognosis of a cancer in the general population. Recent advancements in deep immune profiling and understanding of different immune phenotypes with immune cell subsets explain immune signatures of the tumor micro-environment which will provide a lead to early identification of individuals at risk of developing SCC following solid organ transplantation. In two studies where lymphocyte subsets were measured to map with the risk of SCC, reduced CD4 + T cells were found in individuals at risk of developing any cancer including SCC following transplantation [44]. Very important findings from a large study on immune phenotyping of peripheral blood mono nuclear cells (PBMC) showed kidney transplant recipients (KTR) with previous SCC have a higher number of FOXP3+CD4+CD127lowand CD8+CD28−T cells present in the peripheral blood than KTRs without SCC. Hence, new tumor development is associated with a low CD8/FOXP3 ratio [45].\n\nA better understanding of the above aspects can improve the post-transplant surveillance by adjusting immunosuppressant regimens considering risk factors known to enhance the occurrence of solid organ tumors in transplant recipients. Reappraisal of pre- and post-transplant cancer surveillance tools or models will play an important role for early identification of a growing number of carcinomas associated with solid organ transplantation. We are in an era where acute rejection is no longer a burden following organ transplantation. That said, the long-term outcome from carcinomas affect the quality of life since it absolutely increases transplant-associated morbidity and mortality.\n\n4 Conclusion\nWhile the growing community of solid organ transplant recipients overcome the problem of allograft rejection through advanced T cell tolerance mechanisms applied through immunosuppressive regimens, it is evident that immunosuppression is increasing the incidence of malignancy. The emergence of NMSC can occur as a direct result of immune suppressive agents, activation of carcinogenic viruses or by the disruption of immunosurveillance mechanisms, resulting in carcinogenesis. These are among the well-recognized pathways for the majority of NMSC, identified following solid organ transplantation. Deep immune profiling has recognized immune cell phenotypes which are associated with skin cancers following exposure to immune suppressive regimens. Cardiac transplant recipients are particularly at risk of such malignancies and should be monitored more closely focusing on risk assessment strategies/indexes, and pre and post-transplant vigilant cancer screening tools.\n\nDeclaration of competing interest\nNone.\n\nFunding\nNone.\n\nEthical approval\nPatient deceased.\n\nConsent\nNot applicable.\n\nAuthor contribution\nAnushka Ruawanpathrina – literature search and data analysis\n\nSaman Fernando – first draft of article and data analysis\n\nVinati Molligoda – data analysis\n\nJay G. Fernando – data analysis and critical review\n\nWei Zhang – critical review\n\nShyamal Premaratne – final article submission and critical review\n\nRegistration of research studies\nNot applicable.\n\nGuarantor\nN/A.\n\nProvenance and pee review\nNot commissioned, externally per-reviewed.\n==== Refs\nReferences\n1 Khush K.K. Cherikh W.S. Chambers D.C. 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Non-melanoma skin cancer risk in the Queensland renal transplant population Br. J. Dermatol. 147 5 2002 950 956 12410706 \n7 Krynitz B. Edgren G. Lindelof B. Baecklund E. Brattstrom C. Wilczek H. Smedby K.E. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008: a Swedish population-based study Int. J. Cancer 132 6 2013 1429 1438 22886725 \n8 Ong C.S. Keogh A.M. Kossard S. Macdonald P.S. Spratt P.M. Skin cancer in Australian heart transplant recipients J. Am. Acad. Dermatol. 40 1 1999 27 34 9922009 \n9 Colegio O.R. Billingsley E.M. Skin cancer in transplant recipients, out of the woods. Scientific retreat of the ITSCC and SCOPE Am. J. Transplant. 11 8 2011 1584 1591 21797972 \n10 Zamoiski R.D. Yanik E. Gibson T.M. Risk of second malignancies in solid organ transplant recipients who develop keratinocyte cancers Cancer Res. 77 15 2017 4196 4203 28615224 \n11 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. SCARE Group The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358 \n12 Getts D.R. Shankar S. Chastain E.M.L. Martin A. Getts M.T. Current landscape for T-cell targeting in autoimmunity and transplantation Immunotherapy 3 7 2011 853 870 21751954 \n13 Garrett G.L. Blanc P.D. Boscardin J. Incidence of and risk factors for skin cancer in the organ transplant recipients in the United States JAMA Dermatol. 153 3 2017 296 303 28097368 \n14 Euvard S. Kanitakis J. Claudy A. Skin cancers after organ transplantation N. Engl. J. Med. 348 17 2003 1681 1691 12711744 \n15 McCarty J.M. Massey cancer center, Virginia commonwealth university school of medicine, Richmond, Virginia Pers. Commun. 2019 \n16 Burnet F.M. The concept of immunological surveillance Prog. Exp. Tumor Res. 13 1970 1 27 4921480 \n17 Grulich A.E. van Leeuwen M.T. Falster M.O. Vajdic C.M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis Lancet 370 9581 2007 59 67 17617273 \n18 Wheless L. Jacks S. Mooneyham Potter K.A. Leach B.C. Cook J. Skin cancer in organ transplant recipients: more than the immune system J. Am. Acad. Dermatol. 71 2 2014 359 365 24725477 \n19 Crespo-Leiro M.G. Alonso-Pulpon L. Vázquez de Prada J.A. Malignancy after heart transplantation: incidence, prognosis and risk factors Am. J. Transplant. 8 5 2008 1031 1039 18416739 \n20 Molina B.D. Leiro M.G. Pulpón L.A. Incidence and risk factors for nonmelanoma skin cancer after heart transplantation Transpl. Proc. 42 8 2010 3001 3005 \n21 Jensen P. Hansen S. Moller B. Leivested T. Pfeffer P. Geiran O. Fauchald P. Simonsen S. Skin Cancer in kidney and heart transplant recipients and different long-tern immunosuppressive therapy regimens J. Am. Acad. Dermatol. 40 2 Pt 1 1999 177 186 10025742 \n22 Yarosh D.B. Pena A.V. Nay S.L. Canning M.T. Brown D.A. Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultra violet B irradiation J. Invest. Dermatol. 125 5 2005 1020 1025 16297204 \n23 Howard M.D. Su J.C. Chong A.H. Skin cancer following solid organ transplantation: a review of risk factors and models of care Am. J. Clin. Dermatol. 19 4 2018 585 597 29691768 \n24 Dziunycz P. Lefort K. Wu X. Freiberger S. Neu J. Djerbi N. The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light a J. Invest. Dermatol. 134 7 2014 1998 2004 24509533 \n25 Jensen P. Hansen S. Møller B. Leivestad T. Pfeffer P. Geiran O. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens J. Am. Acad. Dermatol. 40 2 1999 177 186 10025742 \n26 Kaufmann R. Oberholzer P. Cazzaniga S. Hunger R. Epithelial skin cancers after kidney transplantation: a retrospective single center study of 376 recipients Eur. J. 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Perrett C.M. Zhang X. Montaner B. Xu Y.-Z. Harwood C.A. Azathioprine and UVA light generate mutagenic oxidative DNA damage Science 309 5742 2005 1871 1874 16166520 \n41 Ng J.C. Cumming S. Leung V. Chong A.H. Accrual of nonmelanoma skin cancer in renal-transplant recipients: experience of a Victorian tertiary referral institution Australas. J. Dermatol. 55 1 2014 43 48 23808627 \n42 Otley C.C. Berg D. Ulrich C. Stasko T. Murphy G.M. Salasche S.J. Christenson L.J. Sengelmann R. Loss G.E. Jr. Garces J. Reduction of immunosuppression for transplant associated skin cancer: expert consensus survey Br. J. Dermatol. 154 3 2006 395 400 16445766 \n43 Carroll R.P. Ramsay H.M. Fryer A.A. Hawley C.M. Nicol D.L. Harden P.N. Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in Queensland, Australia Am. J. Kidney Dis. 41 3 2003 676 683 12612993 \n44 Thibaudin D. Alamartine E. Mariat C. Absi L. Berthoux F. Long-term kinetic of T-Lymphocyte subsets in kidney-transplant recipients: influence of anti-T-cell antibodies and association with post-transplant malgnancies Transplantation 80 10 2005 1514 1517 16340799 \n45 Carroll R.P. Segundo D.S. Hollowood K. Marafioti T. Clark T.G. Harden P.N. Wood K.J. Immune phenotype predicts risk for post-transplantation squamous cell carcinoma J. Am. Soc. Nephrol. 21 4 2010 713 722 20110382\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "79()",
"journal": "International journal of surgery case reports",
"keywords": "Cancer; Heart transplantation; Immunosuppression; Squamous cell carcinoma",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "275-280",
"pmc": null,
"pmid": "33757259",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "17617273;15147424;26824445;29691768;24725477;19389529;26985913;33181358;25612559;12612993;20970593;19486222;12410706;17913661;4921480;24140213;16340799;16445766;29232446;25088685;9922009;25039758;18416739;23808627;28097368;29024374;10025742;16166520;16249734;24509533;20485437;30293612;21751954;22886725;21797972;10083500;12923450;20110382;12711744;16297204;28615224",
"title": "Recurrent squamous cell carcinoma in a post cardiac transplant patient.",
"title_normalized": "recurrent squamous cell carcinoma in a post cardiac transplant patient"
} | [
{
"companynumb": "US-TEVA-2021-US-1908373",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
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